Prognostic Value of a Combination of Circulating Biomarkers in Critically Ill Patients with Traumatic Brain Injury: Results from the European CREACTIVE Study

Primoz Gradisek, Greta Carrara, Luca Antiga, Barbara Bottazzi, Arturo Chieregato, Akos Csomos, Enrico Fainardi, Suada Filekovic, Joanne Fleming, Andreas Hadjisavvas, Rafael Kaps, Theodoros Kyprianou, Roberto Latini, Isaac Lazar, Serge Masson, Malgorzata Mikaszewska-Sokolewicz, Deborah Novelli, Giulia Paci, Nektaria Xirouchaki, Elisa ZanierGiovanni Nattino, Guido Bertolini

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Individualized patient care is essential to reduce the global burden of traumatic brain injury (TBI). This pilot study focused on TBI patients admitted to intensive care units (ICUs) and aimed at identifying patterns of circulating biomarkers associated with the disability level at 6 months from injury, measured by the extended Glasgow Outcome Scale (GOS-E). The concentration of 107 biomarkers, including proteins related to inflammation, innate immunity, TBI, and central nervous system, were quantified in blood samples collected on ICU admission from 80 patients. Patients were randomly selected among those prospectively enrolled in the Collaborative Research on Acute Traumatic Brain Injury in Intensive Care Medicine in Europe (CREACTIVE) observational study. Six biomarkers were selected to be associated with indicators of primary or secondary brain injury: three glial proteins (glial cell-derived neurotrophic factor, glial fibrillary acidic protein, and S100 calcium-binding protein B) and three cytokines (stem cell factor, fibroblast growth factor [FGF] 23 and FGF19). The subjects were grouped into three clusters according to the expression of these proteins. The distribution of the 6-month GOS-E was significantly different across clusters (p < 0.001). In two clusters, the number of 6-month deaths or vegetative states was significantly lower than expected, as calculated according to a customization of the corticosteroid randomization after significant head injury (CRASH) scores (observed/expected [O/E] events = 0.00, 95% confidence interval [CI]: 0.00-0.90 and 0.00, 95% CI: 0.00-0.94). In one cluster, less-than-expected unfavorable outcomes (O/E = 0.50, 95% CI: 0.05-0.95) and more-than-expected good recoveries (O/E = 1.55, 95% CI: 1.05-2.06) were observed. The improved prognostic accuracy of the pattern of these six circulating biomarkers at ICU admission upon established clinical parameters and computed tomography results needs validation in larger, independent cohorts. Nonetheless, the results of this pilot study are promising and will prompt further research in personalized medicine for TBI patients.

Original languageEnglish
Pages (from-to)2667-2676
Number of pages10
JournalJournal of Neurotrauma
Issue number19
StatePublished - 1 Oct 2021


  • Glasgow outcome scale
  • circulating biomarkers
  • cluster analysis
  • traumatic brain injury

ASJC Scopus subject areas

  • Clinical Neurology


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