title: Association of CSF biomarkers and secondary insults following severe traumatic brain injury.
abstract: BACKGROUND
  Management of severe traumatic brain injury (TBI) focuses on mitigating secondary insults. There are a number of biomarkers that are thought to play a part in secondary injury following severe TBI. Two of these, S100β and neuron-specific enolase (NSE), have been extensively studied in the setting of neurological injury. This pilot study was undertaken to investigate the relationship of S100β and NSE to clinical markers of severity and poor outcome: intracranial hypertension (ICH), and cerebral hypoperfusion (CH).
  
  
  METHODS
  Patients at the R Adams Cowley Shock Trauma Center were prospectively enrolled over an 18-month period. Inclusion criteria were: age > 18, admission within the first 6 h after injury, Glasgow Coma Scale (GCS) < 9 on admission, isolated TBI, and placement of an intraventricular catheter (IVC). Patients were managed according to an institutional protocol based on the Brain Trauma Foundation Guidelines. CSF was collected from the IVC on admission and twice daily for 7 days. S100β and NSE levels were analyzed by ELISA. CSF levels drawn before (PRE) and after (POST) 12-h time periods were compared to percentage time intracranial pressure (ICP) > 20 mmHg (% ICP(20)) and cerebral perfusion pressure (CPP) < 60 mmHg (% CPP(60)), and cumulative "Pressure times Time Dose" (PTD) for episodes of ICP > 20 mmHg (PTD ICP(20)) and CPP < 60 mmHg (PTD CPP(60)). Statistical analysis was performed using the Student's t test to compare means and non-parametric Wilcoxon statistic to compare ranked data. Linear regression methods were applied to compare levels of S100β and NSE with ICP and CPP(.)
  
  
  RESULTS
  Twenty-three patients were enrolled. The cohort of patients was severely injured and neurologically compromised on admission (admission GCS = 5.6 ± 3.1, Injury Severity Score (ISS) = 31.9 ± 10.6, head Abbreviated Injury Scale (AIS) = 4.4 ± 0.7, Marshall score = 2.6 ± 0.9). Elevated levels of S100β and NSE were found in all 223 CSF samples analyzed. ICH was found to be associated with PRE and POST S100β levels when measured as % ICP(20) (r = 0.20 and r = 0.23, P < 0.01) and PTD ICP(20) (r = 0.35 and r = 0.26, P < 0.001). POST increasing NSE levels were weakly correlated with increasing PTD ICP(20) (r = 0.17, P = 0.01). PRE S100β levels were associated with episodes of CH as measured by % CPP(60) (r = 0.20, P = 0.002) and both PRE and POST S100β levels were associated with PTD CPP(60) (r = 0.24 and r = 0.23, P < 0.001). PRE and POST NSE levels were also associated with episodes of CH as measured by % CPP(60) (r = 0.22 and r = 0.18, P < 0.01) and PTD CPP(60) (r = 0.20 and r = 0.21, P < 0.01).
  
  
  CONCLUSIONS
  In this preliminary analysis, S100β levels were associated with ICH and CH over a full week of ICP monitoring. We also found associations between CH and NSE levels in CSF of patients with severe TBI. Our results suggest that there is an association between levels of ICH and CH and these biomarkers when measured before episodes of clinically significant secondary insults. These markers of neuronal cell death demonstrate promise as both indicators of impending clinical deterioration and targets of future therapeutic interventions.
authors.affiliation: Division of Critical Care/Program in Trauma, R Adams Cowley Shock Trauma Center, University of Maryland School of Medicine, 22 South Greene Street, Baltimore, MD 21201, USA. dstein@umm.edu
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Stein
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Kufera
authors.forename: Allison
authors.initials: A
authors.lastname: Lindell
authors.forename: Karen R
authors.initials: KR
authors.lastname: Murdock
authors.forename: Jay
authors.initials: J
authors.lastname: Menaker
authors.forename: Grant V
authors.initials: GV
authors.lastname: Bochicchio
authors.forename: Bizhan
authors.initials: B
authors.lastname: Aarabi
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Scalea
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D001930:Brain Injuries / Q000134:cerebrospinal fluid* / Q000175:diagnosis* / Q000401:mortality; D002560:Cerebrovascular Circulation / Q000502:physiology; D005260:Female; D006801:Humans; D007427:Intracranial Pressure / Q000502:physiology; D016014:Linear Models; D008297:Male; D009414:Nerve Growth Factors / Q000134:cerebrospinal fluid*; D010751:Phosphopyruvate Hydratase / Q000134:cerebrospinal fluid*; D010865:Pilot Projects; D011446:Prospective Studies; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000134:cerebrospinal fluid*; D015599:Trauma Severity Indices; D055815:Young Adult
chemical_list: D015415:Biomarkers; D009414:Nerve Growth Factors; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; D010751:Phosphopyruvate Hydratase