There continues to be an overarching problem of high mortality and poor outcome for victims of severe traumatic brain injury (TBI). Preclinical and clinical investigations indicate that hyperbaric oxygen (HBO2) has a positive impact on reducing brain injury and improving outcomes in severe TBI. By markedly increasing oxygen (O2) delivery to the traumatized brain, HBO2 can reverse the lack of O2 that precipitates cellular energy failure and subsequent brain cell death. In past clinical investigations, HBO2 in comparison to standard care has significantly improved energy production in the brain and improved clinical outcome. However, prior to a formal phase III definitive efficacy study, important information is required regarding optimizing the HBO2 treatment schedule to be instituted in terms of pressure and frequency and other parameters. The lungs in severe TBI patients have frequently been compromised by direct lung injury and/or acquired ventilator pneumonia and are susceptible to O2 toxicity. It is essential to determine the most effective HBO2 dose schedule without producing O2 toxicity and clinical complications. This proposed adaptive clinical trial is designed to answer these questions and to provide important data to plan a definitive phase III efficacy trial. Primary aims of this trial are to select, in patients with severe TBI, the combination of HBO2 treatment parameters that is most likely to demonstrate improvement in the outcome of severe TBI patients in a subsequent phase III trial. Also the trial will determine, in patients with severe TBI, whether there is a > 50% probability of HBO2 treatment demonstrating improvement in the outcome of severe TBI in a subsequent confirmatory phase III trial. This trial is supported and sponsored by the SIREN-NETT Network which is funded by the National Institutes of Neurologic Disease and Stroke to conduct clinical trials such as the one described. SIREN-NETT helps ensure a well-planned and well-conducted clinical trial.