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Ann Thorac Surg 1999;67:1911-1914
© 1999 The Society of Thoracic Surgeons

S-100ß release in hypothermic circulatory arrest and coronary artery surgery

^a Cardiothoracic Surgical Unit, University Hospital Birmingham, Queen Elizabeth Medical Centre, Edgbaston, Birmingham, United Kingdom

Address reprint requests to Mr Bonser, Cardiothoracic Surgical Unit, University Hospital Birmingham, Queen Elizabeth Medical Centre, Edgbaston, Birmingham B15 2TH, UK
e-mail: r.s.bonser{at}bham.ac.uk

Presented at the Aortic Surgery Symposium VI, April 30–May 1, 1998, New York, NY.

	Abstract

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Background. Aortic surgery utilizing profound hypothermic circulatory arrest (HCA) has a higher incidence of neurological injury than coronary artery bypass grafting (CABG). S-100ß is a potential marker of cerebral ischemic injury. The aim of this study is to assess its use in investigating cerebral injury during HCA.

Methods. We studied 40 patients (10 CABG, 30 HCA). The mean cardiopulmonary bypass (CPB) times were 72 and 158 minutes, respectively. Mean HCA duration was 27.6 min, with retrograde cerebral perfusion (RCP) used in 18 patients (mean 28.5 minutes, 95% CI 16–25). Perioperative venous blood samples were subjected to S100ß assay.

Results. S100ß levels with HCA (peak: 2.68 µg/L, 95% CI 1.99–3.38 µg/L; calculated area under the curve [AUC]: 1596 µg/L/min, 95% CI 825–2368 µg/L/min) were significantly higher (peak, p = 0.028 and AUC, p = 0.007) than with CABG (peak: 1.16 µg/L, 95% CI 0.25–2.1 µg/L and AUC: 53.4 µg/L/min 95% CI 3.0–103.8). Peak S100ß correlated with CPB time in CABG cases (r = 0.76, p < 0.05), and with both CPB and HCA time in HCA cases: without RCP (r = 0.46 and 0.21, respectively, p > 0.05) and with RCP (r = 0.88 and 0.33, respectively, p < 0.05). There was no significant difference in the S100ß levels between HCA groups with and without RCP, but HCA time was longer in the RCP group (p = 0.05).

Conclusions. S100ß release correlates with duration of CPB and HCA. Elevated serum S100 indicates astrocyte death or activation, and suggests blood-brain barrier dysfunction. The continuing release of S100 after the end of operation suggests that HCA may be associated with greater injury than CABG. RCP did not influence S-100ß release in this study.

	Introduction

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Thoracic aortic surgery utilizing profound hypothermic circulatory arrest has an incidence of permanent neurological deficit of 7%–15%, and a 19%–25% incidence of transient neurological injury [1–3], despite evidence that at 15°C–18°C, periods of circulatory arrest of <40 min are clinically "safe." In comparison, coronary artery bypass grafting (CABG) has a much lower incidence of stroke (3.1%) [4].

S100ß is a 22,000-Dalton astrocyte protein that is released under conditions of cerebral ischemia, trauma, and metabolic stress. The sensitivity and specificity of the S100ß assay as a measure of cerebral injury occurring during cardiopulmonary bypass procedures have not been defined, however. The aim of this study was to investigate the release of serum S100ß during and after coronary artery surgery, and its profile in aortic surgery using hypothermic circulatory arrest (HCA) with and without retrograde cerebral perfusion (RCP).

	Material and methods

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The study was approved by the Local Research Ethics Committee, and all patients gave informed consent. Ten CABG and 30 HCA cases were recruited.

Patients undergoing CABG and HCA received the same anaesthetic induction and maintenance regime using intravenous propofol and alfentanil with standard monitoring protocols. In patients undergoing HCA, a retrograde jugular bulb line was also inserted via the right internal jugular vein. Placement was later checked with a plain skull roentgenogram. Cardiopulmonary bypass was instituted using a nonpulsatile roller pump, membrane oxygenator, and -stat acid-base protocol. Before circulatory arrest, intravenous dexamethasone (100 mg) and mannitol (1 g/kg) were given. Electrocerebral silence was confirmed at 15°C just before circulatory arrest. The head was topically cooled with ice-packs during HCA, and patients were placed in the Trendelenburg position. Coronary artery surgery was performed using an intermittent ischemic arrest technique and systemic temperature drift (temperature nadir 32°C–34°C). RCP was initiated using a method previously described [5].

Mean patient age was 62.1 years in the CABG group and 61.3 in the HCA groups. The mean cardiopulmonary bypass (CPB) time was 72 minutes for CABG (range 33–129) and 158 minutes for HCA (range 106–204). An average of three (range 1–4) aortocoronary grafts were performed in the CABG group. The mean HCA duration was 27.6 minutes (range 11–49). RCP was used in 18 of 30 HCA cases (60%), for a mean duration of 28.5 minutes (range 8–39).

Blood sampling and S100ß assay
Samples were drawn from central venous cannulae and centrifuged for 5 minutes at 6000 rpm. The serum was separated and stored at -20°C. A commercial assay (Sangtec; Cambridge Life Science, Bury St. Edmunds, UK) was used. For CABG cases, samples were taken at the start and the end of CPB, and at 24 hours. For HCA cases, samples were obtained pre-CPB, 5 minutes on CPB immediately before HCA, at the end of CPB, and 24 hours after the operation.

Data handling and statistical analysis
Peak and area under the curve (AUC) for S100 were calculated for each patient. Group comparisons were performed using Student’s t-test. Correlational analysis were performed using bivariate nonparametric methods.

	Results

Top Abstract Introduction Material and methods Results Comment References

 
Patient age weakly correlated with peak S100 in the CABG group (Pearson r = 0.369, p = 0.147, Spearman rho = 0.515, p = 0.064). In the CABG group, a significant correlation was found for S100 AUC and CPB time (Pearson r = 0.732, p = 0.008, Spearman rho = 0.685, p = 0.014). In the HCA group, CPB time was correlated with peak S100 (Pearson r = 0.686, p < 0.001, Spearman rho = 0.375, p = 0.025), and AUC (Pearson r = 0.593, p = 0.001, Spearman rho = 0.542, p = 0.002) (Fig 1).

View larger version (19K): [in this window] [in a new window]   Fig 1. Correlation of cardiopulmonary bypass (CPB) duration and peak S100ß release in HCA cases (r = 0.685, p < 0.001, Rho = 0.375, p = 0.025).

View larger version (15K): [in this window] [in a new window]   Fig 2. Comparison of peak and area under curve (AUC) S100ß levels between coronary artery bypass grafting (CABG) and hypothermic circulatory arrest (HCA) groups.

View larger version (8K): [in this window] [in a new window]   Fig 3. Mean serum S100ß levels plotted at different time points in patients undergoing surgery utilizing cardiopulmonary bypass (CPB) and hypothermic circulatory arrest (HCA). Data expressed as mean ± SEM; *p < 0.05, **p < 0.01, compared with reference levels.

	Comment

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S100ß has received considerable attention as a potential marker of cerebral injury [6]. S100 proteins mediate a diverse range of functions, including cellular communication, growth, structure, energy metabolism, contraction, and transduction of intracellular signals [7]. S100ß is released not only after astrocyte death but after astrocytic activation [8].

Serum S100ß levels rise during and after CABG, and this rise has been correlated with the duration of CPB [9]. In intracardiac operations, there is a weak age correlation, but no correlation with CPB time [10]. Serum levels studied after intracardiac operations have been reported to be higher than those in patients undergoing CABG alone, and surgery not involving CPB, such as thoracotomy, does not cause an elevation in serum S100ß [11].

We found immediate and sustained release of S100ß during CPB, implying not only cellular release, but also increased permeability of the blood-brain barrier, since S100B is a charged, large molecular weight protein. There is normally a large S100 gradient after cerebral injury between cerebral spinal fluid (CSF) and blood: CSF S100ß levels are typically 10 times serum levels [11]. This CSF-blood gradient may be reduced by CPB.

The higher peak levels of S100 in HCA cases compared with CABG could be partially explained by the longer periods of CPB involved, and the possibly increased micro-embolic load. Previous work has demonstrated that arterial line filtration does not affect intraoperative S100ß release, however [12]. Our data suggest that either hypothermic CPB or circulatory arrest increases S100ß release independent of the effect of CPB duration.

The pronounced elevation of S100 levels with HCA is potentially alarming, particularly since the HCA periods (mean 27.6 min, range 10–50) were relatively short and predominantly within the range considered clinically safe [1]. However, no HCA patient suffered neurological deficit, and further studies are required to ascertain if the enhanced release of S100ß in HCA cases translates into greater subclinical neuronal injury. In the CABG group, S100 levels returned to normal after 24 hours, suggesting that no lasting injury occurred, and that S100 release was mainly a response to CPB. In the HCA group, however, mean S100 levels were still 1.0 µg/L (12 half-lives) [6] after the end of the operation, suggesting that significantly greater cerebral injury may have occurred.

S-100 induces nitric oxide synthase in vitro [13]. This enzyme has been demonstrated to play a role in the development of brain injury in experimental models of profound hypothermic circulatory arrest in which release of intracranial nitric oxide has been linked to apoptotic neuronal death [14]. This hypothesis requires further investigation, but suggests that S100 release may be both a mechanism and consequence of injury.

In proven middle cerebral artery territory strokes, the S100ß level is elevated for 1–2 weeks and peaks 2–3 days after the injury event [15]. The increase of S100ß associated with CPB will mask the occurrence of a focal thromboembolic event for at least 24 hours, making perioperative S100 measurement not a useful marker of stroke in cardiac surgery. After 24 hours, S100 analysis may be a more specific index of cerebral injury, although it may not supplant simple clinical examination.

RCP has been advocated as an adjunct to cerebral protection during hypothermic circulatory arrest. Although its efficacy is unproven, it has been suggested that RCP may aid cerebral protection by substrate delivery, catabolite removal, sustained cooling, and prevention of particulate and gaseous embolism. In this limited study, RCP did not affect S100 release, but the interval of HCA in the RCP group was significantly longer than in the group with HCA alone, and this may have masked what otherwise would have been a measurable difference. Several retrospective studies have suggested improved outcome when RCP is used, but no randomized trials have been reported to date.

The results of this study may indicate that HCA is more injurious to the brain than CPB alone, but although S100ß levels rose significantly, they were not accompanied by clinically detectable neurological injury. Whether S100ß release reflects and correlates with neuropsychological deficits after CABG and HCA requires further study. Such a study will define the utility of S100ß as an index of brain injury, and help ascertain whether a biochemical assay can supplant conventional neuropsychological assessment techniques.

	References

Top Abstract Introduction Material and methods Results Comment References

 

1. Svensson L.G., Crawford E.S., Hess K.R., et al. Deep hypothermia with circulatory arrest. Determinants of stroke and early mortality in 656 patients. J Thorac Cardiovasc Surg 1993;106:19-28.[Abstract]
2. Okita Y., Takamoto S., Ando M., et al. Mortality and cerebral outcome in patients who underwent aortic arch operations using deep hypothermic circulatory arrest with retrograde cerebral perfusion: no relation of early death, stroke and delirium to the duration of circulatory arrest. J Thorac Cardiovasc Surg 1998;115:129-138.[Abstract/Free Full Text]
3. Ergin M.A., Galla J.D., Lansman S.L., et al. Hypothermic circulatory arrest in operations on the thoracic aorta. Determinants of operative mortality and neurologic outcome. J Thorac Cardiovasc Surg 1994;107:788-797.[Abstract/Free Full Text]
4. Roach G.W., Kanchuger M., Mangano C.M., et al. Adverse cerebral outcomes after coronary bypass surgery. Multicenter study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation Investigators. N Engl J Med 1996;335:1857-1863.[Abstract/Free Full Text]
5. Pagano D., Boivin C.M., Faroqui M.H., Bonser R.S. Surgery of the thoracic aorta with hypothermic circulatory arrest: experience with retrograde perfusion via the SVC. Eur J Cardio-Thorac Surg 1996;10:833-838.[Abstract]
6. Aberg T. Signs of brain cell injury during open heart operations: past and present. Ann Thorac Surg 1995;59:1312-1315.[Abstract/Free Full Text]
7. Zimmer D.B., Cornwall E.B., Landar A., Song W. The S100 protein family: history, function, and expression. Brain Res Bull 1995;37:417-429.[Medline]
8. Kretzschmar H.A., Ironside J.W., DeArmond S.J., Tateishi J. Diagnostic criteria for sporadic Creutzfeldt-Jakob disease. Arch Neurol 1996;53:913-920.[Abstract]
9. Westaby S., Johnsson P., Parry A.J., et al. Serum S100 protein: a potential marker for cerebral events during cardiopulmonary bypass. Ann Thorac Surg 1996;61:88-92.[Abstract/Free Full Text]
10. Taggart D., Mazel J., Bhattacharya K., et al. Comparison of serum S-100ß levels during CABG and intra-cardiac operations. Ann Thorac Surg 1997;63:492-496.[Abstract/Free Full Text]
11. Kumar P., Dhital K., Hossein-Nia M., Patel S., Holt D., Treasure T. S-100 protein release in a range of cardiothoracic surgical procedures. J Thorac Cardiovasc Surg 1997;113:953-954.[Free Full Text]
12. Taggart D.P., Bhattacharya K., Meston N., et al. Serum S-100 protein concentration after cardiac surgery: a randomized trial of arterial line filtration. Eur J Cardio-Thorac Surg 1997;11:645-649.[Abstract]
13. Hu J., Castets F., Guevara J.L., Van Eldik L.J. S100ß stimulates inducible nitric oxide synthase activity and mRNA levels in rat cortical astrocytes. J Biological Chem 1996;271:2543-2547.[Abstract/Free Full Text]
14. Tseng E.E., Brock M.V., Lange M.S., et al. Neuronal nitric oxide synthase inhibition reduces neuronal apoptosis after hypothermic circulatory arrest. Ann Thorac Surg 1997;64:1639-1647.[Abstract/Free Full Text]
15. Buttner T., Weyers S., Postert T., et al. S-100 protein: serum marker of focal brain damage after ischaemic territorial MCA infarction. Stroke 1997;28:1961-1965.[Abstract/Free Full Text]

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Carl H. Wong Stephen J. Rooney Robert S. Bonser Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wong, C. H. Articles by Bonser, R. S. Search for Related Content PubMed PubMed Citation Articles by Wong, C. H. Articles by Bonser, R. S.