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Predictive value of S-100β protein for prognosis in patients with moderate and severe traumatic brain injury: systematic review and meta-analysis

BMJ 2013; 346 doi: (Published 04 April 2013) Cite this as: BMJ 2013;346:f1757
  1. Eric Mercier, MSc candidate1,
  2. Amélie Boutin, PhD candidate1,
  3. François Lauzier, assistant professor123,
  4. Dean A Fergusson, associate professor4,
  5. Jean-François Simard, research assistant1,
  6. Ryan Zarychanski, assistant professor5,
  7. Lynne Moore, assistant professor16,
  8. Lauralyn A McIntyre, assistant professor47,
  9. Patrick Archambault, assistant professor8,
  10. François Lamontagne, assistant professor9,
  11. France Légaré, professor810,
  12. Edward Randell, associate professor11,
  13. Linda Nadeau, assistant professor12,
  14. François Rousseau, professor1012,
  15. Alexis F Turgeon, assistant professor12
  1. 1Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec (Hôpital de l’Enfant-Jésus), Traumatologie - Urgence - Soins Intensifs (Trauma - Emergency - Critical Care Medicine), Université Laval, Québec City, QC, Canada
  2. 2Department of Anesthesiology, Division of Critical Care, Université Laval, Québec City, QC, Canada
  3. 3Department of Medicine, Université Laval, Québec City, QC, Canada
  4. 4Clinical Epidemiology Unit, Ottawa Hospital Research Institute, Ottawa, ON, Canada
  5. 5Department of Internal Medicine, Section of Critical Care Medicine, University of Manitoba, Winnipeg, MB, Canada
  6. 6Department of Social and Preventive Medicine, Université Laval, Québec, QC, Canada
  7. 7Department of Medicine, Division of Critical Care, University of Ottawa, Ottawa, ON Canada
  8. 8Department of Family and Emergency Medicine, Université Laval, Québec, QC, Canada
  9. 9Centre de Recherche Clinique Étienne-Le Bel du CHUS, Université de Sherbrooke, Sherbrooke, QC, Canada
  10. 10Centre de Recherche du CHU de Québec, Knowledge Transfer and Health Technology Assessment, Université Laval, Québec City, QC, Canada
  11. 11Department of Laboratory Medicine, Memorial University, St John’s, NF, Canada
  12. 12Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Québec City, QC, Canada
  1. Correspondence to: A F Turgeon, Centre de Recherche du CHU de Québec (Hôpital de l’Enfant-Jésus), Traumatologie - Urgence - Soins Intensifs (Trauma - Emergency - Critical Care Medicine), 1401, 18e rue, local H-012a, QC, Canada G1J 1Z4 alexis.turgeon{at}
  • Accepted 12 February 2013


Objectives To determine the ability and accuracy of the S-100β protein in predicting prognosis after a moderate or severe traumatic brain injury.

Design Systematic review and meta-analysis of randomised controlled trials and observational studies.

Data sources Medline, Embase, Cochrane Central Register of Controlled Trials, BIOSIS (from their inception to April 2012), conference abstracts, bibliographies of eligible articles, and relevant narrative reviews.

Study selection Two reviewers independently reviewed citations and selected eligible studies, defined as cohort studies or randomised control trials including patients with moderate or severe traumatic brain injury and evaluating the prognostic value of S-100β protein. Outcomes evaluated were mortality, score on the Glasgow outcome scale, or brain death.

Data extraction Two independent reviewers extracted data using a standardised form and evaluated the methodological quality of included studies. Pooled results were presented with geometric means ratios and analysed with random effect models. Prespecified sensitivity analyses were performed to explain heterogeneity.

Results The search strategy yielded 9228 citations. Two randomised controlled trials and 39 cohort studies were considered eligible (1862 patients). Most studies (n=23) considered Glasgow outcome score ≤3 as an unfavourable outcome. All studies reported at least one measurement of S-100β within 24 hours after traumatic brain injury. There was a significant positive association between S-100β protein concentrations and mortality (12 studies: geometric mean ratio 2.55, 95% confidence interval 2.02 to 3.21, I2=56%) and score ≤3 (18 studies: 2.62, 2.01 to 3.42, I2=79%). Sensitivity analysis based on sampling time, sampling type, blinding of outcome assessors, and timing of outcome assessment yielded similar results. Thresholds for serum S-100β protein values with 100% specificity ranged from 1.38 to 10.50 µg/L for mortality (six studies) and from 2.16 to 14.00 µg/L for unfavourable neurological prognosis as defined by the Glasgow outcome score.

Conclusions After moderate or severe traumatic brain injury, serum S-100β protein concentrations are significantly associated with unfavourable prognosis in the short, mid, or long term. Optimal thresholds for discrimination remain unclear. Measuring the S-100β protein could be useful in evaluating the severity of traumatic brain injury and in the determination of long term prognosis in patients with moderate and severe injury.


  • We thank Lucie Côté from the Library of the CHU de Québec, Hôpital de l’Enfant-Jésus, for her help with the retrieval of study publications and Marie-Joëlle Poitras-Pariseau, Information Specialist at the Library of the Université Laval, for her help in the design of the search strategy.

  • Contributors: E Mercier, F Lauzier, R Zarychanski, L Moore, PA Archambault, F Lamontagne, F Légaré, E Randell, F Rousseau, DA Fergusson and AF Turgeon contributed to the conception and design of the study. EM, J-FS, AB, and AFT determined eligibility of search results and extracted data from included studies. EM, J-FS, AB, and AFT performed and reviewed the analyses. EM, AB, and AFT drafted the manuscript. All authors participated to the interpretation of the data, the critical review of the manuscript for important intellectual content and approved the final version. EM and AFT are guarantors.

  • Funding: This work was funded by the Fonds de la Recherche du Québec - Santé (FRQ-S) (Traumatology Research Consortium, grant No 23698), the Canadian Anesthesia Research Foundation (CARF), the Foundation of the Association des Anesthésiologistes du Québec (AAQ Foundation) and the Regroupement en Soins Critiques of the FRQ-S Respiratory Health Network. EM was supported by a research training grant (MSc) from the FRQ-S during the conduction of the study (No 23819). AFT, FL, and PL are recipients of a research career award from the FRQ-S. AFT and FL are supported by the Traumatology Research Consortium of the FRQ-S. LM, LAM, and DAF are recipients of new investigator awards from the Canadian Institutes of Health Research (CIHR). RZ is a recipient of an RCT mentorship award from the CIHR. Funding agencies had no role in any part of conduct of the study or preparation of the manuscript.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: Not required.

  • Data sharing: No additional data available.

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