Defense Health Care: Research on Hyperbaric Oxygen Therapy to Treat Traumatic Brain Injury and Post-Traumatic Stress Disorder
Published: 2015-12-18T00:00:00

Fast Facts:

Highlights:
section_title: Why GAO Did This Study
paragraphs: 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.
section_title: What GAO Found
paragraphs: 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.

section_title: Letter
paragraphs: Traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD)  are signature wounds for servicemembers returning from the conflicts in  Iraq and Afghanistan. TBI is a traumatically induced structural injury or  physiological disruption of brain function resulting from an external force  that is indicated by clinical signs, such as confusion, disorientation, or  memory loss. PTSD is a trauma- and stressor-related disorder that can  develop after an extremely stressful event, such as the threat of death or  serious injury. The nature of the current conflicts—particularly the  widespread use of improvised explosive devices—increases the  likelihood that active duty servicemembers will be exposed to incidents,  such as blasts, that can result in these conditions.
TBIs vary greatly in terms of severity. Mild TBIs are commonly referred to  as concussions and may be difficult to detect because of the absence of a  visible injury, while severe cases may involve an extended period of  unconsciousness or amnesia after the injury. The health implications of  TBI, which can be dependent on the severity of the injury, may include a  wide range of physical, mental, social, and emotional symptoms. The  majority of TBIs overall, in the military and the general population, have  been classified as mild. Most individuals with mild TBI recover quickly,  within a matter of hours to days.
Symptoms of PTSD include insomnia, intense anxiety, nightmares, and  difficulties coping with work, family, and social relationships, among  others. PTSD can also be associated with substance abuse, severe  depression, and suicide. Experts believe that early identification and  treatment of PTSD-related symptoms may lessen the severity of the  condition and improve the overall quality of life for servicemembers.  Studies have found that one-third or more of servicemembers with mild  TBI also have PTSD.
Treatment for mild TBIs may consist of therapies, such as physical and  cognitive rest, while treatment for moderate and severe TBIs is usually  focused on managing the initial injury to the brain followed by other  therapies. To treat PTSD, patients are often prescribed various  psychotropic drugs to ease their symptoms, although these drugs may  have negative side effects. As an alternative to these treatments, some  researchers have studied the use of hyperbaric oxygen (HBO) therapy to  treat TBI or PTSD, which delivers higher-than-normal levels of oxygen to  the body inside of a hyperbaric chamber and is hypothesized to promote  healing, reduce brain damage, and improve long-term outcomes. Some of  these researchers have reported positive results with this therapy. In  contrast, research conducted by the Department of Defense (DOD) and  the Department of Veterans Affairs (VA) has found that it does not appear  to be effective in treating mild TBI based on their research to date.  Additionally, to date, the Food and Drug Administration (FDA) has not  approved this therapy as a treatment for TBI or PTSD. therapy for patients with TBI, and to  develop conclusions based on the current state of the evidence for its application as well  as next steps for researching its effectiveness.
We conducted this performance audit from May 2015 to December 2015  in accordance with generally accepted government auditing standards.  Those standards require that we plan and perform the audit to obtain  sufficient, appropriate evidence to provide a reasonable basis for our  findings and conclusions based on our audit objectives. We believe that  the evidence obtained provides a reasonable basis for our findings and  conclusions based on our audit objectives.
subsections: section_title: Background
paragraphs: 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.
subsections: section_title: HBO2 Therapy
paragraphs: 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.
section_title: FDA Drug Approval and Device Approval/ Clearance Process
paragraphs: 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.
section_title: Published Research on the Use of HBO2 Therapy to Treat TBI and PTSD is Primarily Focused on TBI; Conclusions on Effectiveness for Mild TBI Differ
subsections: section_title: Most Published HBO2 Therapy Research Is Focused on the Safety and Effectiveness of Treating TBI with Few Studies on PTSD
paragraphs: 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.)
section_title: Articles about the Effectiveness of HBO2 Therapy for Treating Mild TBI Report Different Conclusions
paragraphs: 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.
section_title: VA and DOD Also Conducted Literature Reviews That Incorporated Recent Published Research on the Effectiveness of HBO2 Therapy to Treat TBI
paragraphs: 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.
section_title: Appendix I: Literature Review Methodology and Bibliography
paragraphs: 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).
section_title: Appendix II: Ongoing Interventional and Observational Studies on Hyperbaric Oxygen Therapy to Treat Traumatic Brain Injury (TBI)
paragraphs: 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)
subsections: section_title: Title
paragraphs: 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)
section_title: Sponsor (sponsor affiliation) Severity of TBI addressed in study Study start date and estimated study completion date Purpose
section_title: Title
paragraphs: Phase 1-2 Study of Hyperbaric Treatment of Traumatic Brain Injury  (https://clinicaltrials.gov/show/NCT01847755)
section_title: Sponsor (sponsor affiliation) Severity of TBI addressed in study Study start date and estimated study completion date Purpose
paragraphs: Barry Miskin, M.D. (Jupiter Medical Center, Florida)
section_title: Title
paragraphs: Hyperbaric Oxygen Therapy Treatment of Chronic Mild Traumatic Brain Injury/Persistent  Post-Concussion Syndrome (https://clinicaltrials.gov/show/NCT02089594)
section_title: Sponsor (sponsor affiliation) Severity of TBI addressed in study Study start date and estimated study completion date Purpose
section_title: Title
paragraphs: A Double-Blind Randomized Trial of Hyperbaric Oxygen Versus Sham in Civilian Post- Concussive Syndrome (https://clinicaltrials.gov/show/NCT01986205)
section_title: Sponsor (sponsor affiliation) Severity of TBI addressed in study
paragraphs: Lindell Weaver (Intermountain Health Care, Inc., Utah)
section_title: Study start date and estimated study completion date Purpose
section_title: Title
paragraphs: Hyperbaric Oxygen Brain Injury Treatment (HBOIT) Trial  (https://clinicaltrials.gov/show/NCT02407028)
section_title: Sponsor (sponsor affiliation) Severity of TBI addressed in study Study start date and estimated study completion date Purpose
paragraphs: 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)
section_title: Sponsor (sponsor affiliation) Severity of TBI addressed in study Study start date and estimated study completion date Purpose
paragraphs: Lindell Weaver (Intermountain Health Care, Inc., Utah)
section_title: Title
paragraphs: 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)
section_title: Appendix III: Relevant Case Report Articles on Hyperbaric Oxygen Therapy
paragraphs: 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.
section_title: Appendix IV: Relevant Literature Review Articles on Hyperbaric Oxygen Therapy
paragraphs: 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.
section_title: Appendix V: Relevant Interventional Study or Clinical Trial Articles on Hyperbaric Oxygen Therapy
paragraphs: 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).
section_title: Appendix VI: Comments from the Department of Defense
section_title: Appendix VII: Comments from the Department of Veterans Affairs
section_title: Appendix VIII: GAO Contact and Staff Acknowledgments
paragraphs: Debra A. Draper, Director, (202) 512-7114 or draperd@gao.gov.
subsections: section_title: Staff Acknowledgments
paragraphs: 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.