A Randomized Placebo-Controlled Trial of Mild Hyperbaric Oxygen on Serum Biomarkers in Persistent Post-Concussive Symptoms: Analysis at 13-Week Follow-Up

Background: The management of persistent post-concussive symptoms (PPCS) is limited by the absence of objective biomarkers to guide treatment. We examined the early effects of a mild hyperbaric oxygen protocol on serum biomarkers of neuronal injury (neurofilament light chain, NfL), astrogliosis (glial fibrillary acidic protein, GFAP), acute neuronal injury (ubiquitin C-terminal hydrolase L1, UCH-L1), and axonal stability (total tau) in patients with PPCS. Methods: In this single-center, randomized, placebo-controlled trial, we enrolled adults with PPCS lasting from 3 months to 5 years after mild traumatic brain injury. Participants received 40 sessions of either active treatment (≥99% O2 at 1.5 atmospheres absolute, ATA) or a true chamber placebo (21% O2 with simulated pressure changes). Serum samples were collected at baseline and 13 weeks after treatment. The primary outcome was the difference between groups in serum NfL levels. Analysis was performed on an intention-to-treat basis using a two-way ANOVA with Šídák’s multiple comparison test. Findings: Of 84 individuals assessed, 20 were randomized (Placebo, n = 9; Intervention, n = 11). Eight from each group received their respective interventions. At 13 weeks, one participant from each group was lost to follow-up, leaving seven per group for analysis. We found no significant differences in serum levels of GFAP, NfL, total tau, or UCH-L1 between the intervention and placebo groups from baseline to 13 weeks. Conclusions: A 40-session mild hyperbaric oxygen protocol at 1.5 ATA did not significantly change serum biomarkers of neuronal injury, astrogliosis, or acute neuronal damage at 13 weeks post-treatment in individuals with PPCS. This early-phase analysis, at the highest point of participant retention, provides no evidence of a treatment effect on these pathophysiological markers.