title: Serum biomarkers as predictors of long-term outcome in severe traumatic brain injury: analysis from a randomized placebo-controlled Phase II clinical trial.
abstract: OBJECTIVE There has been increased interest in the potential importance of biochemical parameters as predictors of outcome in severe traumatic brain injury (sTBI). METHODS Of 107 patients with sTBI (age 18-65 years with a Glasgow Coma Scale score of 4-8 presenting within 8 hours after injury) who were randomized for a placebo-controlled Phase II trial of progesterone with or without hypothermia, the authors serially analyzed serum biomarkers (S100-B, glial fibrillary acidic protein [GFAP], neuron-specific enolase [NSE], tumor necrosis factor-α, interleukin-6 [IL-6], estrogen [Eg], and progesterone [Pg]). This analysis was performed using the sandwich enzyme-linked immunosorbent assay technique at admission and 7 days later for 86 patients, irrespective of assigned group. The long-term predictive values of serum biomarkers for dichotomized Glasgow Outcome Scale (GOS) score, functional independence measure, and survival status at 6 and 12 months were analyzed using an adjusted binary logistic regression model and receiver operating characteristic curve. RESULTS A favorable GOS score (4-5) at 1 year was predicted by higher admission IL-6 (above 108.36 pg/ml; area under the curve [AUC] 0.69, sensitivity 52%, and specificity 78.6%) and Day 7 Pg levels (above 3.15 ng/ml; AUC 0.79, sensitivity 70%, and specificity 92.9%). An unfavorable GOS score (1-3) at 1 year was predicted by higher Day 7 GFAP levels (above 9.50 ng/ml; AUC 0.82, sensitivity 78.6%, and specificity 82.4%). Survivors at 1 year had significantly higher Day 7 Pg levels (above 3.15 ng/ml; AUC 0.78, sensitivity 66.7%, and specificity 90.9%). Nonsurvivors at 1 year had significantly higher Day 7 GFAP serum levels (above 11.14 ng/ml; AUC 0.81, sensitivity 81.8%, and specificity 88.9%) and Day 7 IL-6 serum levels (above 71.26 pg/ml; AUC 0.87, sensitivity 81.8%, and specificity 87%). In multivariate logistic regression analysis, independent predictors of outcome at 1 year were serum levels of Day 7 Pg (favorable GOS-OR 3.24, CI 1.5-7, p = 0.003; and favorable survival-OR 2, CI 1.2-3.5, p = 0.01); admission IL-6 (favorable GOS-OR 1.04, CI 1.00-1.08, p = 0.04); and Day 7 GFAP (unfavorable GOS-OR 0.79, CI 0.65-0.95, p = 0.01; and unfavorable survival-OR 0.80, CI 0.66-0.96, p = 0.01). CONCLUSIONS Serial Pg, GFAP, and IL-6 monitoring could aid in prognosticating outcomes in patients with acute sTBI. A cause and effect relationship or a mere association of these biomarkers to outcome needs to be further studied for better understanding of the pathophysiology of sTBI and for choosing potential therapeutic targets. Clinical trial registration no.: CTRI/2009/091/000893 ( http://www.ctri.nic.in ).
authors.affiliation: Departments of 1 Neurosurgery.
authors.forename: Amol
authors.initials: A
authors.lastname: Raheja
authors.affiliation: Departments of 1 Neurosurgery.
authors.forename: Sumit
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Departments of 1 Neurosurgery.
authors.forename: Neha
authors.initials: N
authors.lastname: Samson
authors.affiliation: Emergency Medicine, and.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Bhoi
authors.affiliation: Laboratory Medicine, All India Institute of Medical Sciences, New Delhi, India; and.
authors.forename: Arulselvi
authors.initials: A
authors.lastname: Subramanian
authors.affiliation: Department of Anaesthesiology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
authors.forename: Pushpa
authors.initials: P
authors.lastname: Sharma
authors.affiliation: Departments of 1 Neurosurgery.
authors.forename: Bhawani Shankar
authors.initials: BS
authors.lastname: Sharma
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D000070642:Brain Injuries, Traumatic / Q000097:blood*; D005260:Female; D023261:Glasgow Outcome Scale; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011446:Prospective Studies; D016037:Single-Blind Method; D013997:Time Factors; D055815:Young Adult
chemical_list: D015415:Biomarkers
keywords: AUC = area under the curve; BBB = blood-brain barrier; DAI = diffuse axonal injury; Eg = estrogen; FIM = functional independence measure; GCS = Glasgow Coma Scale; GFAP = glial fibrillary acidic protein; GOS = Glasgow Outcome Scale; ICP = intracranial pressure; IL = interleukin; IQR = interquartile range; NGF = nerve growth factor; NSE = neuron-specific enolase; Pg = progesterone; ROC = receiver operating characteristic; TNF-α = tumor necrosis factor–α; glial fibrillary acidic protein; interleukin-6; predictors of outcome; progesterone; sTBI = severe traumatic brain injury; serum biomarkers; severe traumatic brain injury; trauma