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Discussion: An Update on the Appropriate Role for Hyperbaric Oxygen Indications and Evidence

www.PRSJournal.com 117S F et al review the use of hyperbaric oxygen therapy (HBOT) in which an individual breathes near 100% oxygen intermittently, whereas the entire body is pressurized inside a hyperbaric chamber to at least 141.86 kPa (1.4 ATA).1 The authors highlight the use of HBOT for diabetic foot ulcers (DFUs) to explore current challenges in the field, including the way the physics of the hyperbaric environment hinders the design of controlled trials. Most intriguing is the novel proposal to use mathematical modeling as a method to facilitate the acquisition of real-world HBOT data for comparative effectiveness studies and improve the cost-effective use of HBOT, by first identifying the patients who will not heal spontaneously and then from that group, the patients who are most likely to benefit with HBOT. HBOT fundamentally delivers high amounts of oxygen to the body by increasing the driving pressure of O2 from the lungs through the blood to the tissues. It also induces oxidative stress with controlled production of reactive oxygen and nitrogen species, causing activation of various cellular processes and pathways. Consequently, it results in numerous clinical benefits related to wound healing. Three of the most relevant biochemical mechanisms are increment in the production of growth factors (e.g., hypoxia-inducible factor 1-α [HIF-1α], vascular endothelial growth factor, and stromal-derived factor 1), mobilization of bone marrow–derived stem/progenitor cells (CD34), and the reduction of neutrophil adhesion (modification of integrin β-2).2 Despite a clear scientific rationale for its use, randomized clinical trial evidence of efficacy, and a low incidence of side effects, its value remains debated. Fife et al mention on-going concerns regarding its cost-effectiveness. Other concerns are the common use of off-label indications in free-standing clinics3 and the time required for the treatment. A patient with a DFU needs a minimum of 20 days of HBOT of 90 minutes per session. These factors have resulted in limited acceptance of HBOT by the medical community, severe limitations established by the Centers for Medicare and Medicaid Services (CMS) National Coverage Indications,4 and third-party payers restricting reimbursement even for recognized indications cleared by the Food and Drug Administration. A major barrier to clinical HBOT research is the shortage of adequate funding for sufficiently powered trials. Although oxygen breathed under hyperbaric conditions behaves like a drug, it is not patentable; thus, there is minimal interest in research investment by pharmaceutical companies. The authors discuss several possible techniques for conducting controlled trials. However, the vast majority of controlled trials have been unable to avoid exposing control subjects to increases in ambient pressure and thus increases in the partial pressure of inspired oxygen and/or inspired nitrogen. There are challenges associated with all of these methods, the obvious one being the risk of decompression illness with sufficient absorption of nitrogen. However, recent publications report that small changes in oxygen levels (from normobaric hyperoxia to normoxia), rather than steady-state hypoxic or hyperoxic conditions, play an important role in the transcriptional effects of HIF-1α (the relative hypoxia obtained after a period of normobaric hyperoxia can act as a hypoxic trigger).5 The HIF-1α is responsible for the regulation of expression of several different genes, including erythropoietin and vascular endothelial growth factor. This phenomenon has been called the “normobaric oxygen paradox”