TBI can be classified as mild, moderate, or severe based on specific criteria, such as the length of time an individual is unconscious following their injury. For example, an individual would meet the criteria for mild TBI if they suffered a loss of consciousness for 30 minutes or less. Similarly, an individual would meet the criteria for moderate TBI if they lost consciousness for more than 30 minutes and for severe TBI if they lost consciousness for more than 24 hours. (See table 1.) Early detection of injury is critical in the management of TBI patients. The diagnosis of moderate and severe TBI usually occurs in a timely manner due to the visible nature of the head injury, as well as the duration of symptoms, such as memory loss. Identification of mild TBI, also known as a concussion, can be challenging because there may be no visible head injury, and symptoms may be minimal and brief. In addition, in the combat theater, a mild TBI may not be identified if it occurs at the same time as other combat injuries that are more visible or life-threatening, such as orthopedic injuries or open wounds. Furthermore, some of the symptoms of mild TBI, which account for the majority of these injuries in the military, are similar to those associated with other conditions, such as PTSD. Individuals sustaining mild TBIs often report physical, cognitive, and emotional or behavioral symptoms referred to collectively as postconcussion symptoms. The most commonly reported postconcussion symptoms are headache, dizziness, decreased concentration, memory problems, irritability, fatigue, visual disturbances, sensitivity to noise, judgment problems, depression, and anxiety. Although the majority of individuals with mild TBI have symptoms that resolve within 1 month, some symptoms may persist for months to years following injury, potentially becoming permanent and causing disability. When these symptoms are persistent, they are often referred to as postconcussion syndrome or persistent postconcussion symptoms. PTSD can develop following exposure to life-threatening events, natural disasters, terrorist incidents, serious accidents, or violent personal assaults and may have a delayed onset, which is described as a clinically significant presentation of symptoms at least 6 months after exposure to trauma. Individuals diagnosed with PTSD may experience problems sleeping, maintaining relationships, and returning to their previous civilian lives. They may also suffer from other ailments, such as depression and substance abuse. PTSD is one of the most prevalent mental disorders arising from combat. for clinical purposes was “100 percent oxygen” instead of “near 100 percent oxygen” Hyperbaric Oxygen Therapy Indications, 12th Edition, 2008. However, the latest edition remained consistent that pressurization for clinical purposes should be 1.4 ATA or higher. FDA approves drugs and approves/clears devices for specific indications (diseases or medical conditions). However, it does not generally prevent healthcare practitioners’ use or prescribing of approved or cleared drugs/devices for indications for which the drugs/devices have not been approved or cleared. FDA has approved/cleared both the drug (oxygen) and the device (hyperbaric chamber) used in HBO therapy for certain medical uses, such as treating decompression sickness suffered by divers. As described by FDA officials, in order for HBOTBI or PTSD, sponsors would be required to submit a new marketing application or applications to support the new indications. Such submissions could be made in one of two ways: 1) the sponsor could submit one marketing application to FDA’s Center for Drug Evaluation and Research for both the drug and the device; or 2) the sponsor could submit a new drug application to FDA’s Center for Drug Evaluation and Research to add the new oxygen indication for the drug and a device premarket submission to FDA’s Center for Devices and Radiological Health to add the new indication for existing hyperbaric oxygen chambers. Typically before a marketing application submission, the sponsor meets with FDA to discuss the most appropriate investigational studies and the details of the regulatory process. If existing literature and data are available to address the scientific and technical questions, it might be possible to submit this information only, and new investigational studies might not be needed. If new investigational studies are needed, an investigational new drug (IND) application would be used. The IND would include information on both the drug and the device. The IND must also include a “proposed indication(s) for use” section that explains what the drug (or drug-device combination product) does and the clinical condition and population for which it is intended. The IND sponsor has overall responsibility for the conduct of clinical studies that would support use for the proposed indication. Typically, the investigational process is iterative and begins with early studies that focus on safety and dosing. Later studies generally focus on safety and effectiveness of the product. When the applicant completes the investigational studies and submits the necessary marketing application for review, FDA first determines whether the submission is complete and provides the information necessary for review. For example, the submission would provide information regarding the product description, proposed indications and potential clinical benefits, as well as the data needed to support approval or clearance, labeling, dose of the drug, and device instructions for use. FDA reviews the marketing application to determine such things as whether 1) the drug-device combination is safe and effective for its proposed use, which is answered, at least in part, by whether the benefits of the treatment outweigh its risks; 2) the proposed labeling meets the applicable regulatory requirements; 3) the methods used to manufacture the drug are adequate to preserve the drug’s identity, strength, quality, and purity; and 4) the methods used to maintain device functionality and performance are acceptable. If two marketing applications are used as in the second option noted above, FDA would generally issue the marketing authorizations concurrently when they are approved. Most of the 32 peer-reviewed, published articles that we identified examined the use of HBO therapy for treating TBI: 29 focused solely on TBI, 2 focused on both TBI and PTSD, and 1 focused solely on PTSD. The 32 articles we identified included 7 case reports, 10 literature reviews, and 15 articles on interventional studies or clinical trials. Case reports are collections of reports on the treatment of individual patients. Six of the seven case reports we reviewed found that the patients with TBI (mild, moderate, severe, or not specified) or PTSD improved after treatment. The remaining case report noted safety issues to consider when treating TBI patients with cranial fractures. Literature reviews use a search to identify studies on a specific clinical topic. Of the 10 literature reviews we identified, 1 concluded based on the articles it had identified that HBO therapy for treating TBI (severe and not specified), and all 3 concluded that the therapy is safe. The remaining 12 articles evaluated the effectiveness of HBO The 8 articles on mild TBI had differing conclusions on the effectiveness of HBO therapy, while the other 4 articles (two on severe TBI and two that did not specify severity) reported that this therapy was an effective treatment for these conditions. (For more detailed information about the articles and their conclusions, see appendix III for case reports, appendix IV for literature reviews, and appendix V for interventional studies or clinical trials.) The eight articles on interventional studies or clinical trials that were focused on treating mild TBI had different conclusions—six articles concluded that it was not effective and two concluded that it was. The six articles that concluded HBO Each of the three studies was affiliated with a branch of military service—Army, Navy, or Air Force. The remaining two articles were based on two studies conducted by researchers in Israel and the United States. The differences in the articles’ conclusions about the effectiveness of HBO therapy for treating mild TBI are based, in part, on methodological differences, as well as differences in researchers’ interpretations of the studies’ results. All of the DOD-funded studies were randomized, double- blinded, and included a sham control group in which participants received a procedure that is similar to the HBO For a sham control group in HBO therapy studies, some atmospheric pressure within the hyperbaric chamber is required for participants to perceive they are receiving treatment. However, there is no standard sham control group design for HBO therapy was not effective in treating mild TBI and related symptoms because participants in the sham control and treatment groups had similar outcomes. Although both groups of participants showed improvement, the authors concluded that the improvement was likely attributable to other factors, such as a placebo effect, and not to HBO DOD officials and researchers involved with the studies told us that they believe some improvements were due to factors, such as being away from home and everyday stress. therapy from this study. other researchers not affiliated with the DOD-funded studies have reported that hyperbaric treatments at 1.2 ATA (without increased oxygen levels), which was used as the sham treatment in one DOD-funded study, substantially increase the amount of dissolved oxygen in the blood and simultaneously induces other physiological changes. As a result, these other researchers stated that the sham control group’s treatment does not represent a true sham or placebo, and participants’ improvement shows that even a small increase in pressure is an effective treatment. In a published editorial, the researchers who conducted the DOD-funded study that used a sham control group with hyperbaric treatments at 1.2 ATA responded to these concerns by reporting that they recognize that the sham treatment may have caused physiologic effects from slight increases in oxygen, nitrogen, and direct pressure, as well as a variety of other effects. They added that the study was not designed to separate these effects, but rather to show a benefit of HBO therapy, and found it was not effective because the initial improvements identified after the treatments were not sustained. Nonetheless, DOD officials told us that there have been no studies completed on the long-term effects of the treatment, and such studies would help confirm whether the sham control groups’ improvements should be attributed to placebo effects or other factors. The remaining two (of eight) articles on mild TBI, which concluded that HBO The study conducted in the United States was not blinded and did not use a control group. DOD and VA researchers and other subject matter experts told us that these studies were not designed with the same methodological rigor as the DOD-funded studies on mild TBI because they were not blinded, randomized clinical trials, and they did not use sham control groups— qualities that help ensure the validity of a study’s findings. The group of researchers in Israel noted in their article that they did not use a sham control group because it was difficult to design a treatment for the control group that would not be considered therapeutic. The researchers for the other study that was conducted in the United States noted in their article that a sham control group was not used because this was preliminary work, and further work would be needed to confirm the study’s findings. In addition to the 10 published literature review articles we identified, both VA and DOD conducted their own literature reviews on the effectiveness of HBO therapy to treat TBI (all severities); VA’s literature review also included PTSD. In developing the department’s policy on the use of HBO VA’s report concluded that high quality, well-designed research is needed to determine the efficacy and effectiveness of HBO therapy for both of these conditions. In 2014, VA updated its report to include articles published between January 1, 2010 and January 17, 2014. In its updated report, VA concluded that none of the well-designed studies it reviewed, including the DOD-funded studies, demonstrated that HBO Further, the report noted that the 2013 Israeli study—which found the treatment to be effective for improving cognitive performance and self-perceived quality of life—did not have adequate controls, such as a sham control group. therapy to treat stroke. The review concluded that there was no new scientific evidence indicating that HBOtherapy, and 3) the outcome measures were susceptible to improving based upon the participants’ expectations as to whether they should improve or not. The paper noted that the last criticism could explain many of the reported improvements in cognitive performance. severities of TBI. With respect to mild TBI, it noted that the improvements in outcomes shown within the groups receiving HBO therapy. Specifically, the report stated that a true sham treatment may have to be done with normal atmospheric pressure and that more research is needed to be confident that a sham is not a therapeutic treatment. The report concluded that further research, such as conducting studies comparing other types of interventions to HBO therapy to treat PTSD. As noted in our report, PTSD was only included in three articles that we reviewed, and as a result, our description of research on HBOof Congressional Relations and Public Affairs may be found on the last page of this report. Major contributors to this report are listed in appendix VIII. To identify and describe published research on the use of hyperbaric oxygen (HBO) therapy in the treatment of traumatic brain injury (TBI) or post-traumatic stress disorder (PTSD), we conducted a literature search for relevant articles published during the most recent 10-year period, from January 1, 2005 through April 6, 2015. Our librarian searched more than 30 databases for research published in relevant peer-reviewed and industry journals including Academic One File, ArticleFirst, BIOSIS Previews, CINAHL, Embase, MEDLINE, NTIS: National Technical Information Service , PILOTS: Published International Literature on Traumatic Stress, PsycINFO, and WorldCat. Key search terms included various combinations of “hyperbaric oxygen,” “hyperbaric oxygen therapy,” “hyperbaric oxygen treatment,” “traumatic brain injury,” and “post-traumatic stress disorder.” From all database sources, 230 abstracts were identified. therapy was not at least one treatment used in the research, the abstract was from a conference and not available in a full article, or the abstract was from a book. severity of TBI and then by study location). As part of our work, we examined the methodologies of each of these studies and determined that they were sufficiently reliable for the purposes of our report. Case Reports vs (7 Articles) Hardy, P.G., K.M. Johnston, L. DeBeaumont, D.L. Montgomery, J. M., Lecomete, J.P. Soucy, D. Bourbonnais, and M. Lassonde. “Pilot Case Study of the Therapeutic Potential of Hyperbaric Oxygen Therapy on Chronic Brain Injury.” Journal of Neurological Sciences, vol. 253 (2007). Harch, P., E.F. Fogarty, P.K. Staab, and K. Van Meter. “Low Pressure Hyperbaric Oxygen Therapy and SPECT Brain Imaging in the Treatment of Blast-Induced Chronic Traumatic Brain Injury (Post-Concussion Syndrome) and Post Traumatic Stress Disorder: A Case Report.” Cases Journal, vol. 2 (2009). Wright, Col. J,K., E. Zant, K. Groom, R.E. Schlegel, and K. Gilliland. “Case Report Treatment of Mild Traumatic Brain Injury with Hyperbaric Oxygen.” Undersea & Hyperbaric Medicine, vol. 36, no. 6 (2009). Eovaldi, B., and C. Zanetti. “Hyperbaric Oxygen Ameliorates Worsening Signs and Symptoms of Post-Traumatic Stress Disorder.” Neuropsychiatric Disease and Treatment, vol. 6 (2010). Lv, L.Q., L.J. Hou, M.K. Yu, X.H. Ding, X.Q. Qi, and Y.C. Lu. “Hyperbaric Oxygen Therapy in the Management of Paroxysmal Sympathetic Hyperactivity after Severe Traumatic Brain Injury: A Report of 6 Cases.” Arch. Phys. Med. Rehabil., vol. 92 (2011). Stoller, K. “Hyperbaric Oxygen Therapy (1.5 ATA) in Treating Sports Related TBI/CTE: Two Case Reports.” Medical Gas Research, vol. 1 (2011). Lee, L.C., F.K. Lieu, Y.H. Chen, T.H. Hung, and S.F. Chen. “Tension Pneumocephalus as a Complication of Hyperbaric Oxygen Therapy in a Patient with Chronic Traumatic Brain Injury.” American Journal of Physical Medicine & Rehabilitation, vol. 91, no. 6 (2012). Literature Reviews (10 Articles) Adamides, A.A., C.D. Winter, P.M. Lewis, D.J. Cooper, T. Kossmann, and J.V. Rosenfeld. “Current Controversies in the Management of Patients with Severe Traumatic Brain Injury.” ANZ. J. Surg., vol. 76 (2006). Bennett, M.H., B.E. Trytko, and B. Jonker. “A Systematic Review of the Use of Hyperbaric Oxygen Therapy in the Treatment of Acute Traumatic Brain Injury.” Diving and Hyperbaric Medicine, vol. 36, no. 1 (2006). Rockswold, S.B., G. L. Rockswold, and A. Defillo. “Hyperbaric Oxygen in Traumatic Brain Injury.” Neurological Research, vol. 29 (2007). Kumaria, A., and C.M. Tolias. “Normobaric Hyperoxia Therapy for Traumatic Brain Injury and Stroke: a Review.” British Journal of Neurosurgery, vol. 23, no. 6 (2009). Huang, L., and A. Obenaus. “Hyperbaric Oxygen Therapy for Traumatic Brain Injury.” Medical Gas Research, vol. 1, no. 21 (2011). Bennett, M.H., B. Trytko, and B. Jonker. “Hyperbaric Oxygen Therapy for the Adjunctive Treatment of Traumatic Brain Injury (Review).” Cochrane Database of Systematic Reviews, vol. 12 (2012). Beyon, C., K.L. Kiening, B. Orakcioglu, A.W. Unterberg, and O.W. Sakowitz. “Brain Tissue Oxygen Monitoring and Hyperoxic Treatment in Patients with Traumatic Brain Injury.” Journal of Neurotrauma, vol. 29 (2012). McCrary, Col. B.F., L. Weaver, LCDR K. Marrs, Col. R. S. Miller, C. Dicks, K. Deru, N. Close, and Col. M. DeJong. “Hyperbaric Oxygen (HBO2) for Post-Concussive Syndrome/Chronic TBI Product Summary.” Undersea & Hyperbaric Medicine: Journal of Undersea and Hyperbaric Medical Society, vol. 40, no. 5 (2013). Cossu, G. “Therapeutic Options to Enhance Coma Arousal after Traumatic Brain Injury: State of the Art of Current Treatments to Improve Coma Recovery.” British Journal of Neurosurgery, vol. 28, no. 2 (2014). Wang, Y., D. Chen, and G. Chen. “Hyperbaric Oxygen Therapy Applied Research in Traumatic Brain Injury: From Mechanisms to Clinical Investigation.” Medical Gas Research, vol. 4, no. 18 (2014). Interventional Studies or Clinical Trials (15 Articles) Studies on Mild TBI (8 Articles) DOD Funded Study (Air Force): Wolf, G., D. Cifu, L. Baugh, W. Carne, and L. Profenna. “The Effect of Hyperbaric Oxygen on Symptoms after Mild Traumatic Brain Injury.” Journal of Neurotrauma, vol. 29 (2012). DOD Funded Study (Navy): Cifu, D.X., B.B. Hart, S.L. West, W. Walker, and W. Carne. “The Effect of Hyperbaric Oxygen on Persistent Postconcussion Symptoms.” Journal of Head Trauma Rehabilitation, vol. 29, no. 1 (2014). Cifu, D.X., K.W. Hoke, P.A. Wetzel, J. R. Wares, G. Gitchel, and W. Carne. “Effects of Hyperbaric Oxygen on Eye Tracking Abnormalities in Males after Mild Traumatic Brain Injury.” Journal of Rehabilitation Research and Development, vol. 51, no. 7 (2014). Cifu, D.X., W.C. Walker, S.L. West, B.B. Hart, L.M. Franke, A. Sima, C.W. Graham, and W. Carne. “Hyperbaric Oxygen for Blast-Related Postconcussion Syndrome: Three-Month Outcomes.” Annals of Neurology, vol. 75 (2014). Walker, W.C., L.M. Franke, D.X. Cifu, and B.B. Hart. “Randomized, Sham-Controlled, Feasibility Trail of Hyperbaric Oxygen for Service Members with Postconcussion Syndrome: Cognitive and Psychomotor Outcomes 1 Week Postintervention.” Neurorehabilitation and Neural Repair, vol. 28, no. 5 (2014). DOD Funded Study (Army): Miller, R.S., L. K. Weaver, N. Bahraini, S. Churchill, R.C. Price, V. Skiba, J. Caviness, S. Mooney, B. Hetzell, J. Liu, K. Deru, R. Ricciardi, S. Fracisco, N.C. Close, G.W. Surrett, C. Bartos, M. Ryan, and L.A. Brenner. “Effects of Hyperbaric Oxygen on Symptoms and Quality of Life among Service Members with Persistent Postconcussion Symptoms: A Randomized Clinical Trial.” JAMA Internal Medicine, vol. 175, no. 1 (2015). Boussi-Gross, R., H. Golan, G. Fishlev, Y. Bechor, O. Volkov, J. Bergan, M. Friedman, D. Hoofien, N. Shlamkovitch, E. Ben-Jacob, and S. Efrati. “Hyperbaric Oxygen Therapy Can Improve Post Concussion Syndrome Years after Mild Traumatic Brain Injury-Randomized Prospective Trial.” PLOS ONE, vol. 8, no. 11 (2013). Harch, P.G., S.R. Andrews, E.F. Fogarty, D. Amen, J.C. Pezzullo, J. Lucarini, C. Aubrey, D.V. Taylor, P.K. Staab, and K.W. Van Meter. “A Phase I Study of Low-Pressure Hyperbaric Oxygen Therapy for Blast- Induced Post-Concussion Syndrome and Post-Traumatic Stress Disorder.” Journal of Neurotrauma, vol. 29 (2012). Studies on Severe TBI (2 articles) Rockswold, S.B., G.L. Rockswold, D.A. Zaun, X. Zhang, C.E. Cerra, T.A. Bergman, and J. Liu. “A Prospective, Randomized Clinical Trial to Compare the Effect of Hyperbaric to Normobaric Hyperoxia on Cerebral Metabolism, Intracranial Pressure, and Oxygen Toxicity in Severe Traumatic Brain Injury.” Journal of Neurosurgery, vol. 112 (2010). Rockswold, S.B., G.L. Rockswold, D.A. Zaun, and J. Liu. “A Prospective, Randomized Phase II Clinical Trial to Evaluate the Effect of Combined Hyperbaric and Normobaric Hyperoxia on Cerebral Metabolism, Intracranial Pressure, Oxygen Toxicity, and Clinical Outcome in Severe Traumatic Brain.” Journal of Neurosurgery, vol. 118 (2013). Studies on Non-Specified TBI (2 Articles) Xia-yan, S., T. Zhong-quan, S. Da, and H. Xiao-ju. “Evaluation of Hyperbaric Oxygen Treatment of Neuropsychiatric Disorders Following Traumatic Brain Injury.” Chinese Medical Journal, vol. 119, no. 23 (2006). Sahni, T., M. Jain, R. Prasad, S.K. Sogani, and V.P. Singh. “Use of Hyperbaric Oxygen in Traumatic Brain Injury: Retrospective Analysis of Data of 20 Patients Treated at a Tertiary Care Centre.” British Journal of Neurosurgery, vol. 26, no. 2 (2012). Studies on Safety of Treating TBI with Hyperbaric Oxygen Therapy (3 articles) Gossett, W.A., G.L. Rockswold, S.B. Rockswold, C.D. Adkinson, T.A. Bergman, and R.R. Quickel. “The Safe Treatment, Monitoring and Management of Severe Traumatic Brain Injury Patients in a Monoplace Chamber.” Undersea & Hyperbaric Medicine, vol. 37, no. 1 (2010). Wolf, E.G., J. Prye, R. Michaelson, G. Brower, L. Profenna, and O. Boneta. “Hyperbaric Side Effects in a Traumatic Brain Injury Randomized Clinical Trial.” Undersea & Hyperbaric Medicine, vol. 39, no. 6 (2012). Churchill, S., L.K. Weaver, K. Deru, A.A. Russo, D. Handrahan, W.W. Orrison, J.F. Foley, H.A. Elwell. “A Prospective Trial of Hyperbaric Oxygen for Chronic Sequelae after Brain Injury.” Undersea & Hyperbaric Medicine, vol. 40, no. 2 (2013). Appendix II: Ongoing Interventional and Observational Studies on Hyperbaric Oxygen Therapy to Treat Traumatic Brain Injury (TBI) We obtained information about eight ongoing clinical trials on the use of hyperbaric oxygen therapy to treat TBI. Information on these trials was obtained through ClinicalTrials.gov, an international registry and results database of publicly and privately supported clinical studies of human participants, which is maintained by the National Institutes of Health. We identified six interventional clinical trials on hyperbaric oxygen therapy (see table 4). The remaining two ongoing studies are observational (see table 5). Interventional studies are studies in which participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. The assignments are determined by the study protocol. Participants may receive diagnostic, therapeutic, or other types of interventions. An observational study is a clinical study in which participants identified as belonging to study groups are assessed for biomedical or health outcomes. Participants may receive diagnostic, therapeutic, or other types of interventions, but the researcher does not assign participants to specific interventions (as in an interventional study). Hyperbaric Oxygen Therapy and SPECT Brain Imaging in Traumatic Brain Injury (https://clinicaltrials.gov/show/NCT00594503 ) Paul G. Harch, M.D. (Louisiana State University Health Sciences Center in New Orleans) Brain Injury and Mechanisms of Action of HBO2 for Persistent Post-Concussive Symptoms after Mild Traumatic Brain Injury (BIMA) Protocol (https://clinicaltrials.gov/show/NCT01611194) Phase 1-2 Study of Hyperbaric Treatment of Traumatic Brain Injury (https://clinicaltrials.gov/show/NCT01847755) Barry Miskin, M.D. (Jupiter Medical Center, Florida) Hyperbaric Oxygen Therapy Treatment of Chronic Mild Traumatic Brain Injury/Persistent Post-Concussion Syndrome (https://clinicaltrials.gov/show/NCT02089594) A Double-Blind Randomized Trial of Hyperbaric Oxygen Versus Sham in Civilian Post- Concussive Syndrome (https://clinicaltrials.gov/show/NCT01986205) Lindell Weaver (Intermountain Health Care, Inc., Utah) Hyperbaric Oxygen Brain Injury Treatment (HBOIT) Trial (https://clinicaltrials.gov/show/NCT02407028) Gaylan Rockswold (Minneapolis Research Foundation) December 2015 to December 2017 to determine the optimal hyperbaric oxygen treatment paradigm to be instituted in terms of atmospheric pressure, frequency of treatment and whether normobaric hyperoxia following hyperbaric oxygen treatments enhances the treatment effect Development of Normative Datasets for Assessments Planned for Use in Patients with Mild Traumatic Brain Injury (NORMAL) (https://clinicaltrials.gov/show/NCT01925963) Lindell Weaver (Intermountain Health Care, Inc., Utah) Brain Angiogenesis (formation of new blood vessels) Induced by Hyperbaric Oxygen Therapy Can be Visualized by Perfusion MRI in Brain Injury Patients (https://clinicaltrials.gov/show/NCT02452619) We identified and reviewed seven articles on case reports. Six of the seven articles focused on the effectiveness of hyperbaric oxygen therapy in treating traumatic brain injury (TBI) or post-traumatic stress disorder (PTSD). The remaining article focused on safety issues. We identified and reviewed 10 articles based on literature reviews about the use of hyperbaric oxygen therapy in treating traumatic brain injuries. Eight of these articles noted that further research in the area was needed to determine if this treatment was effective. One article reported that hyperbaric oxygen therapy had positive effects when used to treat severe traumatic brain injury (TBI), another reported that the therapy can be delivered with relative safety for severe TBI. We identified and reviewed 15 articles on interventional studies or clinical trials. Of these, 12 articles were focused on the effectiveness of hyperbaric oxygen therapy in treating traumatic brain injury (TBI), including 8 articles on mild TBI (see table 8) and 4 articles on severe or non-specified TBI (see table 9). The remaining 3 articles are related to the safety of this treatment (see table 10). Debra A. Draper, Director, (202) 512-7114 or draperd@gao.gov. In addition to the contact name above, Bonnie Anderson, Assistant Director; Jennie Apter; Danielle Bernstein; Leia Dickerson; Natalie Herzog; Sylvia Diaz Jones; and Emily Wilson made key contributions to this report.

Summary: TBI and PTSD are signature wounds for servicemembers returning from the conflicts in Iraq and Afghanistan. Within the military, the majority of TBI cases have been classified as mild. Studies have found that one-third or more of servicemembers with mild TBI also have PTSD. As an alternative to traditional treatments, some researchers have studied the use of HBO2 therapy, which delivers higher levels of oxygen to the body inside of pressurized hyperbaric chambers to promote healing. The Joint Explanatory Statement accompanying the Consolidated and Further Continuing Appropriations Act, 2015, included a provision for GAO to review the use of HBO2 therapy to treat TBI and PTSD. This report identifies and describes published research on the use of HBO2 therapy for these conditions. GAO conducted a literature review for relevant articles published in peer-reviewed journals during the most recent 10-year period, from January 1, 2005 through April 6, 2015. GAO interviewed DOD, VA, and researchers affiliated with published articles, as well as other stakeholders, including officials with the Undersea and Hyperbaric Medical Society. GAO also interviewed officials from the Food and Drug Administration about the process to approve HBO2 therapy for the treatment of TBI and PTSD. GAO provided a draft of this report to DOD, VA, and the Department of Health and Human Services. Each of the departments provided technical comments, which GAO incorporated, as appropriate. GAO identified 32 peer-reviewed, published articles on research about the use of hyperbaric oxygen (HBO2) therapy to treat traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD), most of which were focused solely on TBI (29 articles). The 32 articles consisted of 7 case reports (reports on the treatment of individuals), 10 literature reviews (reviews of studies), and 15 articles on interventional studies or clinical trials, which provide the strongest clinical evidence about a treatment. Three of the 15 articles on interventional studies or clinical trials focused on the safety of HBO2 therapy for treating TBI and concluded that it is safe. The other 12 articles described the effectiveness of HBO2 therapy in treating TBI. Four of these articles (two on severe TBI and two that did not specify severity) reported that HBO2 therapy was effective. The remaining eight articles focused on mild TBI—six concluded that it was not effective and two concluded that it was. The six articles that concluded HBO2 therapy was not effective in treating mild TBI were based on three studies funded by the Department of Defense (DOD) with collaboration from the Department of Veterans Affairs (VA) and others. Each of the DOD-funded studies 1) was randomized—participants were randomly assigned to clinical trial groups, 2) was double-blinded—neither researchers nor participants knew who was assigned to which group, and 3) included a sham control group—participants received a procedure that was similar to HBO2 therapy but lacked certain components of the intervention. However, there is no standard design for sham control groups in HBO2 therapy, and in each of the DOD-funded studies the approach varied. The authors of the six articles based on these studies concluded that HBO2 therapy was not effective in treating mild TBI because participants in the sham control and treatment groups had similar outcomes. Although both groups showed improvement, the researchers concluded that this was likely due to other factors, such as a placebo effect. Researchers not affiliated with the DOD-funded studies have raised concerns about whether the sham control groups received a placebo or a therapeutic treatment. In a published editorial, researchers affiliated with one of the DOD-funded studies acknowledged the challenges associated with designing a sham control group and stated that additional research would be needed to determine whether these participants actually received a therapeutic benefit. DOD officials told us that studying the long-term effects of the treatment also would help confirm whether the sham control groups' improvements should be attributed to a placebo effect. The two articles that concluded that HBO2 therapy was effective in treating mild TBI were based on studies that were designed differently than the DOD-funded studies. DOD and VA researchers told GAO that the studies related to these articles did not have the same methodological rigor as the DOD-funded studies because they did not have design features such as sham control groups, which help ensure the validity of a study's findings. The researchers for one of these two studies noted in their article that they did not use a sham control group because it was difficult to ensure that participants would receive a non-therapeutic treatment. Researchers for the other study noted in their article that a sham control group was not used because this was preliminary work, and further work would be needed to confirm the findings.