Serum biomarkers as predictors of long-term outcome in severe traumatic brain injury: analysis from a randomized placebo-controlled Phase II clinical trial

Abstract

abbreviatioNs 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; sTBI = severe traumatic brain injury; TNF-a = tumor necrosis factor-a. 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 p = 0.01; 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

Serial Sampling of Serum Protein Biomarkers for Monitoring Human Traumatic Brain Injury Dynamics: A Systematic Review

“…Commercial or custom made enzyme-linked immunosorbent assays (ELISAs) were used in some studies (21, 34, 35, 40, 42, 44, 49, 52, 57, 61, 67, 68, 77, 81, 85, 86, 91), as well as other techniques (or not mentioned in the text) (36, 51, 55, 66, 69, 71), even if a majority used clinically available assays such as the (C)LIA-mat system from Sangtec/DiaSorin (7, 11, 18, 37–39, 41, 43, 45–48, 50, 53, 54, 56, 58–60, 62–65, 70, 72–76, 78–80, 82–84, 87–90, 92–95). In general, ELISA samples showed less volatility over time (42, 49, 68, 81, 91).…”

Evaluating the neurotherapeutic potential of a water-soluble progesterone analog after traumatic brain injury in rats

“…Three small, single-center clinical studies have now shown positive outcomes with low-dose i.m. PROG (Xiao et al, 2008;Mofid et al, 2016;Raheja et al, 2016), but large phase III clinical trials using i.v. administration at much higher doses of the hormone had negative results (Wright et al, 2007(Wright et al, , 2014Skolnick et al, 2014).…”

“…Further, three small, single-center clinical studies using lowdose intramuscular (i.m.) PROG have shown positive outcomes (Xiao et al, 2008;Mofid et al, 2016;Raheja et al, 2016). HBC has been used clinically (Preskorn, 2005;Mermelstein et al, 2013) as a vehicle for i.m.…”

The Serum Changes of Neuron-Specific Enolase and Intercellular Adhesion Molecule-1 in Patients With Diffuse Axonal Injury Following Progesterone Administration: A Randomized Clinical Trial

“…The relation of the NSE level in serum with outcome has been shown in 72 h postinjury, probably because of its short half-life (29). The increase in the serum level of NSE was associated to favorable outcome in other study (30). However, previous (19) and present studies indicate that the serum level of NSE is not different between patients with favorable outcome and those with unfavorable outcome.…”