Background:Among advanced therapeutic interventions for wounds, hyperbaric oxygen therapy (HBOT) has the unique ability to ameliorate tissue hypoxia, reduce pathologic inflammation, and mitigate ischemia reperfusion injury. Most of the conditions for which it is utilized have few successful alternative treatments, and the morbidity and mortality associated with treatment failure are significant. Data on the efficacy and effectiveness of HBOT were reviewed, comparative effectiveness research of HBOT was explained, and a new paradigm for the appropriate use of HBOT was described.Methods:Systematic reviews and randomized controlled trials that have evaluated HBOT were reviewed.Results:Although numerous small randomized controlled trials provide compelling support for HBOT, the physics of the hyperbaric environment create significant barriers to trial design. The electronic health record infrastructure created to satisfy mandatory quality and registry reporting requirements as part of healthcare reform can be harnessed to facilitate the acquisition of real world data for HBOT comparative effectiveness studies and clinical decision support.Conclusions:Predictive models can identify patients unlikely to heal spontaneously and most likely to benefit from HBOT. Although electronic health records can automate the calculation of predictive models making them available at the point of care, using them in clinical decision making is complicated. It is not clear whether stakeholders will support the allocation of healthcare resources using mathematical models, but the current patient selection process mandates a 30-day delay for all patients who might benefit and allows treatment for at least some patients who cannot benefit.