DEFENSE HEALTH 

CARE

Research on 

Hyperbaric Oxygen 

Therapy to Treat 

Traumatic Brain Injury 

and Post-Traumatic 

Stress Disorder

Report to Congressional Committees

December 2015

GAO-16-154

United States Government Accountability Office
United States Government Accountability Office

Highlights of GAO-16-154, a report to 

congressional committees

December 2015

DEFENSE HEALTH CARE

Research on Hyperbaric Oxygen Therapy to Treat 

Traumatic Brain Injury and Post-Traumatic Stress 

Disorder

Why GAO Did This Study

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 peerreviewed 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.

What GAO Found

GAO identified 32 peer-reviewed, published articles on research about the use of 

hyperbaric oxygen (HBO2) therapy to treat traumatic brain injury (TBI) and posttraumatic 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 DODfunded 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 nontherapeutic 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.

View GAO-16-154. For more information, 

contact Debra A. Draper at (202) 512-7114 or 

draperd@gao.gov.
Page i GAO-16-154 Hyperbaric Oxygen Therapy

Letter 1

Background 4

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 9

Agency Comments 16

Appendix I Literature Review Methodology and Bibliography 19

Appendix II Ongoing Interventional and Observational Studies on Hyperbaric 

Oxygen Therapy to Treat Traumatic Brain Injury (TBI) 25

Appendix III Relevant Case Report Articles on Hyperbaric Oxygen Therapy 29

Appendix IV Relevant Literature Review Articles on Hyperbaric Oxygen Therapy 31

Appendix V Relevant Interventional Study or Clinical Trial Articles on Hyperbaric 

Oxygen Therapy 34

Appendix VI Comments from the Department of Defense 38

Appendix VII Comments from the Department of Veterans Affairs 39

Appendix VIII GAO Contact and Staff Acknowledgments 41

Contents
Page ii GAO-16-154 Hyperbaric Oxygen Therapy

Tables

Table 1: Classification of Traumatic Brain Injury (TBI) Severity 4

Table 2: Medical Indications for Hyperbaric Oxygen (HBO2) 

Therapy in the United States Approved by the Food and 

Drug Administration (FDA) or Adopted or Endorsed by 

Others 7

Table 3: Design of the Sham Control and Treatment Groups for 

DOD-Funded Studies by Service Branch 12

Table 4: Ongoing Interventional Studies on Hyperbaric Oxygen 

Therapy to Treat Traumatic Brain Injury (TBI), Enrolling 

Participants from Jan. 1, 2005 to July 22, 2015 26

Table 5: Ongoing Observational Studies on Hyperbaric Oxygen 

Therapy to Treat Traumatic Brain Injury (TBI), Enrolling 

Participants from Jan. 1, 2005 to July 22, 2015 27

Table 6: Case Report Articles on Hyperbaric Oxygen Therapy to 

Treat Traumatic Brain Injury (TBI) or Post-Traumatic 

Stress Disorder (PTSD), Published from Jan. 1, 2005 to 

Apr. 6, 2015 29

Table 7: Literature Review Articles on Hyperbaric Oxygen Therapy 

to Treat Traumatic Brain Injury (TBI), Published from Jan. 

1, 2005 to Apr. 6, 2015 31

Table 8: Eight Articles on Interventional Studies or Clinical Trials 

on Hyperbaric Oxygen Therapy to Treat Mild Traumatic 

Brain Injury (TBI) or Post-Traumatic Stress Disorder 

(PTSD), Published from Jan. 1, 2005 to Apr. 6, 2015 34

Table 9: Four Articles on Interventional Studies or Clinical Trials 

on Hyperbaric Oxygen Therapy to Treat Severe Traumatic 

Brain Injury (TBI) or Non-Specified TBI, Published from 

Jan. 1, 2005 to Apr. 6, 2015 36

Table 10: Three Articles on Interventional Studies or Clinical Trials 

on the Safety of Hyperbaric Oxygen Therapy to Treat 

Traumatic Brain Injury (TBI), Published from Jan. 1, 2005 

to Apr. 6, 2015 37
Page iii GAO-16-154 Hyperbaric Oxygen Therapy

Abbreviations

ATA atmosphere absolute

DOD Department of Defense

FDA Food and Drug Administration

HBO2 hyperbaric oxygen

IND investigational new drug 

NIH National Institutes of Health

PTSD post-traumatic stress disorder

TBI traumatic brain injury

VA Department of Veterans Affairs

This is a work of the U.S. government and is not subject to copyright protection in the 

United States. The published product may be reproduced and distributed in its entirety 

without further permission from GAO. However, because this work may contain 

copyrighted images or other material, permission from the copyright holder may be 

necessary if you wish to reproduce this material separately.
Page 1 GAO-16-154 Hyperbaric Oxygen Therapy

441 G St. N.W.

Washington, DC 20548

December 18, 2015

Congressional Committees

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.1 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.2

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 

 1

TBI is indicated by new onset or worsening of at least one of the following clinical signs 

immediately following the event: any alteration in mental status (e.g. confusion, 

disorientation, slowed thinking, etc.); any loss of memory for events immediately before or 

after the injury; and any period of loss of or a decreased level of consciousness, observed 

or self-reported. External forces may include any of the following events: the head being 

struck by an object, the head striking the object, the brain undergoing a movement without 

direct external trauma to the head, or forces generated from events such as a blast or 

explosion, including penetrating injuries.

2

According to Department of Defense (DOD) officials, the majority of TBIs for 

servicemembers occur in the United States from injuries that are not combat related. 

Letter
Page 2 GAO-16-154 Hyperbaric Oxygen Therapy

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.3

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 (HBO2) 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.4

The Joint Explanatory Statement accompanying the Consolidated and 

Further Continuing Appropriations Act, 2015, included a provision for us 

to review the use of HBO2 therapy to treat TBI and PTSD. In this report, 

we identify and describe published research on the use of this therapy in 

the treatment of these conditions.

To identify and describe published research on the use of HBO2 therapy 

in the treatment of TBI or PTSD, we conducted a literature review and 

interviewed relevant federal officials, researchers, and other stakeholders 

about their work related to this therapy for these conditions. For the 

literature review, we searched for relevant articles published in peerreviewed journals during the most recent 10-year period, from January 1, 

 3

According to DOD officials, some studies have reported that up to 60 to 70 percent of 

veterans with mild TBI also have PTSD.

4

FDA is the agency responsible for protecting the public health by assuring, among other 

things, the safety and efficacy of drugs, biological products, and medical devices. 
Page 3 GAO-16-154 Hyperbaric Oxygen Therapy

2005 through April 6, 2015, and we identified and reviewed 32 articles 

that met our inclusion criteria.5 We examined the methodologies for each 

of these articles and determined that they were sufficiently reliable for the 

purposes of our report. (For more details about the methodology of our 

literature review and a list of the articles we reviewed, see appendix I.) 

We interviewed DOD and VA officials and researchers about their 

completed and ongoing research on the effectiveness of HBO2 therapy for 

the treatment of TBI or PTSD, including their viewpoints on research 

completed by others. We also reviewed VA’s literature review on this 

topic, as well as a literature review that was prepared for DOD by a 

contractor.6 In addition, we interviewed DOD’s literature-review contractor 

and other researchers, including researchers affiliated with published 

articles we identified; and other stakeholders, including officials with the 

Undersea and Hyperbaric Medical Society and the American Association 

of Hyperbaric Awareness.7 We also interviewed FDA officials about the 

process to approve HBO2 therapy for the treatment of TBI or PTSD. 

Finally, we obtained information from the National Institutes of Health 

(NIH) about ongoing clinical studies on the use of HBO2 therapy for the 

treatment of TBI or PTSD included in the database it maintains, 

ClinicalTrials.gov, the world’s largest registry of publicly and privately 

supported clinical studies. Specifically, we obtained information about 

clinical studies with start dates between January 1, 2005 and July 22, 

2015 that had not completed data collection. We determined that the data 

in the ClinicalTrials.gov registry was sufficiently reliable for the purposes 

of this report based on information from NIH officials about the 

procedures in place to ensure the quality and completeness of these 

data. Information about ongoing research is contained in appendix II.

 5

We chose this period because federal officials became aware of increased rates of TBI 

among active duty servicemembers in the mid-2000s. 

6

In July 2014, DOD hired the Samueli Institute, a non-profit research institute, to conduct a 

systematic literature review of the efficacy of HBO2 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.

7

The Undersea and Hyperbaric Medical Society is an international scientific organization 

that was founded in 1967 to foster exchange of data on the physiology and medicine of 

commercial and military diving. Over the years, its focus has expanded to include HBO2 

therapy, and it has become an important source for scientific information for hyperbaric 

medicine. 
Page 4 GAO-16-154 Hyperbaric Oxygen Therapy

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.

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.)

Table 1: Classification of Traumatic Brain Injury (TBI) Severity

Criteria Mild Moderate Severe 

Structural imaginga Normalb Normal or abnormal Normal or abnormal 

Loss of consciousness 0—30 minutes >30 minutes and <24 hours >24 hours

Alteration of consciousness or

mental statec a moment up to 24 hours >24 hours, severity based on other criteria 

>24 hours, severity based on 

other criteria 

Post-traumatic amnesia 0—1 day >1 and <7 days >7 days

Glasgow Coma Scale (best 

available score in first 24 hours)d 13—15 9—12 <9

Source: Departments of Veterans Affairs and Defense. | GAO-16-154

a

Structural imaging refers to the structure of the brain as viewed through magnetic resonance 

imaging, computed tomography scanning, or other technologies.

b

Structural imaging is not always indicated for patients with mild TBIs.

c

Alteration of mental state must be immediately related to the head trauma. Typical symptoms would 

be looking and feeling dazed and uncertain of what is happening, confusion, difficulty thinking clearly 

or responding appropriately to mental status questions, and being unable to describe events

immediately before or after the trauma event.

d

The Glasgow Coma Scale was designed to and is used to assess the depth and duration of the 

coma and impaired consciousness. This scale helps to gauge the impact of a wide variety of 

conditions, such as acute brain damage due to traumatic injuries, vascular injuries or both. As of April 

2015, DOD’s definition of TBI did not include the Glasgow Coma Scale.

Background

TBI and PTSD
Page 5 GAO-16-154 Hyperbaric Oxygen Therapy

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.

HBO2 therapy is a medical procedure which results in higher-than-normal 

levels of oxygen in the body’s blood and tissues. It is a first-line therapy 

for medical emergencies related to decompression sickness, air or gas 

embolism, and carbon monoxide poisoning. It can also be used as an 

adjunctive (additional) therapy to surgical or pharmacologic interventions. 

As defined by the Undersea and Hyperbaric Medical Society, hyperbaric 

oxygen is an intervention that involves breathing near 100 percent oxygen 

intermittently while inside a sealed chamber that is pressurized to greater 

HBO2 Therapy
Page 6 GAO-16-154 Hyperbaric Oxygen Therapy

than sea level pressure (1 atmosphere absolute [ATA]). For clinical 

purposes, the Undersea and Hyperbaric Medical Society has said that the 

pressure must equal or exceed 1.4 ATA while breathing near 100 percent 

oxygen.8 In contrast to the oxygen levels used in HBO2 therapy, the 

ambient air that we breathe contains 20.9 percent oxygen.

Currently, FDA has not approved HBO2 therapy as a treatment for TBI 

and PTSD, although it has approved it for treating other conditions. 

Similarly, DOD and VA have adopted, and the Undersea and Hyperbaric 

Medical Society has endorsed, the use of HBO2 therapy for a variety of 

indications (diseases or medical conditions), but not as a treatment for

TBI and PTSD. (See table 2.)

 8

See the Undersea and Hyperbaric Medical Society, Hyperbaric Oxygen Therapy 

Indications, 13th Edition, 2014, as well as its website accessed on August 19, 2015 at 

https://www.uhms.org/resources/hbo-indications.html. Prior to the 13th edition, the 

definition of HBO2 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. 
Page 7 GAO-16-154 Hyperbaric Oxygen Therapy

Table 2: Medical Indications for Hyperbaric Oxygen (HBO2) Therapy in the United States Approved by the Food and Drug 

Administration (FDA) or Adopted or Endorsed by Others

Medical indications FDA

Department of 

Defense (DOD)a

Department of 

Veterans 

Affairs(VA) 

Undersea and 

Hyperbaric 

Medical Society

Acute thermal burn injury √ √ √

Air or gas embolism √ √ √ √

Arterial insufficiencies (central retinal artery 

occlusion or enhancement of healing in 

selected problem wounds)

√ √ √ √

Carbon monoxide poisoning or carbon 

monoxide poisoning complicated by cyanide 

poisoning

√ √ √ √

Clostridial myositis and myonecrosis (gas 

gangrene) √ √ √ √

Crush injury, compartment syndrome and other 

acute traumatic ischemias √ √ √ √

Compromised skin graphs and flaps √ √ √ √

Decompression sickness √ √ √ √

Delayed radiation injury (soft tissue and bony 

necrosis) √ √ √ √

Exceptional blood loss (anemia) √ √ √ √

Idiopathic sudden sensorineural hearing loss √

Intracranial abscess √ √ √

Necrotizing soft tissue infections √ √ √

Osteomyelitis (refractory) √ √ √ √

Source: FDA, DOD, VA, and the Undersea and Hyperbaric Medical Society. | GAO-16-154

Notes: There are some small variations in the names of the approved, adopted, or endorsed

indications by organizations.

a

According to TRICARE (DOD’s health care program) policy, DOD may cover HBO2 for other 

indications when documented by other reliable evidence as safe, effective, and comparable or 

superior to standard care.

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 HBO2 therapy for certain 

medical uses, such as treating decompression sickness suffered by 

divers. As described by FDA officials, in order for HBO2 therapy and the 

hyperbaric oxygen chamber to be marketed for new indications, such as 

FDA Drug Approval and 

Device Approval/ 

Clearance Process
Page 8 GAO-16-154 Hyperbaric Oxygen Therapy

TBI or PTSD, sponsors would be required to submit a new marketing 

application or applications to support the new indications.9 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.10

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.

 9

A sponsor is typically the drug or device manufacturer that submits the application. 

10FDA’s Center for Drug Evaluation and Research regulates over-the-counter and 

prescription drugs, including biological therapeutics and generic drugs. FDA’s Center for 

Devices and Radiological Health is responsible for the premarket approval of all medical 

devices, as well as overseeing the manufacturing, performance and safety of these 

devices. FDA’s clearance of a device for a specific use under the “510(k) process (a 

premarket review process set forth in section 510(k) of the Federal Food, Drug, and 

Cosmetic Act) means FDA determined that 1) the device has the same intended use as a 

predicate (a device already on the market) and (2) has the same technological 

characteristics as the predicate or has different technological characteristics but the 

device is at least as safe and effective as a predicate and does not raise different 

questions of safety and effectiveness than the predicate. Devices that do not qualify for 

premarket review under the 510(k) process (e.g. when there is no qualifying predicate 

device) would need to submit the application under a different Center for Devices and 

Radiological Health regulatory pathway.
Page 9 GAO-16-154 Hyperbaric Oxygen Therapy

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.11 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 HBO2 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.

 11Sponsors may submit more than one application as noted above. 

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

Most Published HBO2

Therapy Research Is 

Focused on the Safety 

and Effectiveness of 

Treating TBI with Few 

Studies on PTSD
Page 10 GAO-16-154 Hyperbaric Oxygen Therapy

• 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 HBO2 therapy had positive effects 

when used to treat severe TBI, 1 concluded that the therapy can be 

delivered with relative safety for severe TBI, and 8 noted that further 

research was needed to determine if this treatment was effective.

• Interventional studies or clinical trials assign participants to receive 

one or more interventions (or no intervention) so that researchers can 

evaluate the effects of the interventions on health-related outcomes. 

This type of research provides the strongest clinical evidence on 

whether the intervention has an effect on the disease because these 

studies are designed to isolate the effect of the intervention in 

question. Of the 15 articles we reviewed on interventional studies or 

clinical trials, 3 focused on the safety of HBO2 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 HBO2

therapy in treating TBI: 8 focused on mild TBI, 2 focused on severe 

TBI, and the remaining 2 articles did not specify severity.12 The 8 

articles on mild TBI had differing conclusions on the effectiveness of 

HBO2 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.)

 12Based on our review of the articles, we determined that 4 of the 12 articles related to the 

same study. Researchers used the data to produce more than one published article, each 

of which focused on different aspects of the study.
Page 11 GAO-16-154 Hyperbaric Oxygen Therapy

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 HBO2 therapy was not effective were based on 

three studies funded by DOD with collaboration from VA and others 

(referred to in this report as DOD-funded studies).13 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 

HBO2 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, doubleblinded, and included a sham control group in which participants received 

a procedure that is similar to the HBO2 therapy being studied.

14 For a 

sham control group in HBO2 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 HBO2 therapy, and in each of the DOD-funded studies

the approach varied. (See table 3.) The authors of the six articles based 

on these studies concluded that HBO2 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 HBO2 therapy.15 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.

 13These studies were funded by DOD and conducted by researchers affiliated with DOD, 

VA, universities, and other organizations.

14Randomization is a strategy in which participants are assigned to groups of a clinical 

trial by chance. Blinding of a study is a design strategy in which one or more parties 

involved with the trial, such as the researcher, participant or both, do not know which 

participants have been assigned which interventions. Types of blinding include: none, 

single blinded, or double blinded. A sham control group receives a treatment or procedure 

under investigation, but is lacking the component(s) of the intervention being studied.

15The placebo effect is a change in symptoms for patients who unknowingly receive a 

treatment that does not contain the therapy or therapies being studied. 

Articles about the 

Effectiveness of HBO2

Therapy for Treating Mild 

TBI Report Different 

Conclusions
Page 12 GAO-16-154 Hyperbaric Oxygen Therapy

Table 3: Design of the Sham Control and Treatment Groups for DOD-Funded Studies by Service Branch

Service branch Design of sham control group Design of treatment group(s)

Air Force Room air (about 21% oxygen) at 1.3 ATAa 100% oxygen at 2.4 ATA

Army Room air (about 21% oxygen) at 1.2 ATA 100% oxygen at 1.5 ATAb

Navy 10.5% oxygen at 2.0 ATAc

75% oxygen at 2.0 ATAd

100% oxygen at 2.0 ATA

Source: GAO review of published articles. | GAO-16-154

a

ATA refers to atmosphere absolute.1.0 ATA is equal to pressure at sea level.

b

Some of the participants in this study were also placed in a third group that received standard care 

for mild TBI, but did not receive supplemental hyperbaric oxygen therapy.

c

This is the oxygen breathing equivalent of room air at sea level.

d

This is the oxygen breathing equivalent of 100 percent oxygen at 1.5 ATA.

However, other researchers (who did not participate in the DOD-funded 

studies) have stated that these studies demonstrate that HBO2 therapy is 

effective in treating mild TBI since both the sham control and treatment 

groups showed improvement. These other researchers have raised 

concerns about the methodology of the DOD-funded studies, which are 

related to whether the sham control groups received a true sham 

treatment (a placebo) rather than HBO2 therapy.16 The researchers who 

conducted the DOD-funded studies considered the Undersea and 

Hyperbaric Medical Society’s clinical definition of HBO2 therapy (near 100 

percent oxygen at a pressure greater than or equal to 1.4 ATA) when 

designing the sham control groups for their studies to ensure that 

participants in these groups received a lower pressure or a much lower 

concentration of oxygen than would be considered therapeutic. A 

researcher not associated with the DOD-funded studies stated that the 

Undersea and Hyperbaric Medical Society definition is arbitrary because 

it implies that there is no therapeutic effect for a patient who receives 

pressure less than 1.4 ATA and less than 100 percent oxygen.17 Further, 

 16A researcher who did not participate in the DOD-funded studies also expressed 

concerns about the statistical analyses used in the DOD-funded research. For example, 

the researcher told us that in one of articles based on a DOD-funded study (Navy), the 

authors did not compare patients’ test scores for cognitive, balance, or fine motor deficits 

prior to receiving HBO2 therapy to test scores obtained after receiving this therapy. This 

researcher stated that without this comparison, it is impossible to draw conclusions on the 

effects of HBO2 therapy from this study. 

17Harch, P. G., “Hyperbaric Oxygen in Chronic Traumatic Brain: Oxygen, Pressure, and 

Gene Therapy” Medical Gas Research (2015) 5-9. 
Page 13 GAO-16-154 Hyperbaric Oxygen Therapy

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.18 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.19 They added that the study was not designed to separate 

these effects, but rather to show a benefit of HBO2 therapy beyond these 

effects, which it failed to do. Their article also acknowledged the 

challenges associated with designing a sham control group as 

participants must feel some pressure to mask the intervention. They 

reported that the DOD-funded studies varied the design of the sham 

control groups so that the results could be examined collectively and that 

the oxygen dose used in the sham control groups would never be 

considered therapeutic. Furthermore, their article stated that additional 

research would be needed to determine if there was an actual therapeutic 

benefit of higher pressure without an increased oxygen concentration. 

They also reported that what may be more important than whether the 

observed benefits are due to factors, such as placebo effects, is whether 

these benefits are durable. One of the researchers involved in the DODfunded studies also told us that they studied the results for participants in 

the sham control and treatment groups 3 months after they received 

HBO2 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 

 18Marios, P., A. Mukherjee, L. Ballaz, “Hyperbaric Oxygen Treatment for Persistent 

Postconcussion Symptoms-A Placebo Effect?” JAMA Internal Medicine, vol. 175, no. 7 

(2015) 1239-1240.

19Miller, R.S., L.K. Weaver, L.A. Brenner, “Hyperbaric Oxygen Treatment for Persistent 

Postconcussion Symptoms-A Placebo Effect?” JAMA Internal Medicine, vol. 175, no. 7 

(2015) 1240-1241. 
Page 14 GAO-16-154 Hyperbaric Oxygen Therapy

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 

HBO2 therapy is effective, used different methodologies than the DODfunded studies. The research conducted in Israel was a prospective study 

that was single-blinded and used a crossover control group.20 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.

 20A crossover design describes a clinical trial in which groups of participants receive 

interventions in a particular order. For example, in the Israeli study, the crossover design 

involved two groups of participants receiving either HBO2 therapy or no treatment for TBI. 

One group received the therapy during the initial phase of the trial, followed by no 

treatment during a later phase. The other group received no treatment during the initial 

phase, followed by the therapy during a later phase. During the study, participants 

“crossed over” to the other intervention. All participants received HBO2 therapy and no 

treatment at some point during the study, but in a different order, depending on the group 

to which they are assigned. Further, the practitioners evaluating the results of this study 

did not know, or were blinded, to the participants’ group assignments.
Page 15 GAO-16-154 Hyperbaric Oxygen Therapy

In addition to the 10 published literature review articles we identified, both 

VA and DOD conducted their own literature reviews on the effectiveness 

of HBO2 therapy to treat TBI (all severities); VA’s literature review also 

included PTSD. In developing the department’s policy on the use of HBO2

therapy for TBI and PTSD, VA produced a report in 2010 that 

summarized information from published, peer-reviewed research on the 

appropriate clinical use of this therapy for TBI and PTSD.21 VA’s report 

concluded that high quality, well-designed research is needed to 

determine the efficacy and effectiveness of HBO2 therapy for both of 

these conditions.22 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 HBO2 therapy was 

effective for the treatment of TBI.23 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.24

In July 2014, DOD hired a contractor, the Samueli Institute, to conduct a 

systematic literature review on the efficacy of HBO2 therapy for patients 

with TBI and to develop conclusions based on the current state of the 

evidence for its application, as well as determine next steps for 

researching its effectiveness. The report prepared by the contractor 

reviewed all available literature through the end of 2014 and covered all 

 21In 2009, VA officials requested that VA’s Technology Assessment Advisory Group 

examine the use of HBO2 therapy to treat TBI and PTSD. To conduct this assessment, the 

advisory group examined published, peer-reviewed evidence, input from VA’s Technology 

Assessment Program and Clinical Expert Panels, and a utilization and cost analysis.

22For both VA white papers, see 

http://www.indianapolis.va.gov/VERC/White_Papers/Hyperbaric%20oxygen%20therapy%

20for%20TBI%20and%20PTSD..pdf [Accessed on October 13, 2015].

23The updated review of literature in 2014 also reviewed literature on the use of HBO2 

therapy to treat stroke. The review concluded that there was no new scientific evidence 

indicating that HBO2 therapy is an effective treatment for either TBI or stroke. 

24While the paper did not explicitly define well-designed, the following limitations were 

noted: 1) the study did not incorporate a valid sham control group, 2) the participants and 

researchers were not effectively blinded about HBO2 therapy, 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. 

VA and DOD Also 

Conducted Literature 

Reviews That Incorporated 

Recent Published 

Research on the 

Effectiveness of HBO2

Therapy to Treat TBI
Page 16 GAO-16-154 Hyperbaric Oxygen Therapy

severities of TBI.25 With respect to mild TBI, it noted that the 

improvements in outcomes shown within the groups receiving HBO2

therapy, as well as the sham treatment, in the DOD-funded studies 

cannot be ignored. It also discussed the debate on what constitutes a true 

sham for HBO2 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 HBO2

therapy for TBI, should be considered in order to resolve the controversy 

surrounding this field, but only if these studies can be designed without 

methodological flaws.

We provided a draft of this report to DOD, the Department of Health and 

Human Services, and VA for comment. Each of the departments provided 

technical comments, which we incorporated as appropriate. VA also 

provided general comments about the extent to which we cover research

on HBO2 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 HBO2 therapy to treat PTSD was limited.

DOD’s comments are reprinted in appendix VI, and VA’s comments are 

reprinted in appendix VII. The Department of Health and Human Services 

did not provide a formal response letter. 

We are sending copies of this report to the Secretaries of Defense, Health 

and Human Services, Veterans Affairs, and appropriate congressional 

committees. In addition, the report will be available at no charge on the 

GAO website at http://www.gao.gov. 

If you or your staff have any questions about this report, please contact 

me at (202) 512-7114 or draperd@gao.gov. Contact points for our Offices 

25DOD officials told us that the report would be publicly available in 2016.

Agency Comments
Page 17 GAO-16-154 Hyperbaric Oxygen Therapy

of 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.

Debra A. Draper

Director, Health Care
Page 18 GAO-16-154 Hyperbaric Oxygen Therapy

List of Committees

The Honorable John McCain

Chairman

The Honorable Jack Reed

Ranking Member

Committee on Armed Services

United States Senate

The Honorable Thad Cochran

Chairman

The Honorable Richard J. Durbin

Ranking Member

Subcommittee on Defense

Committee on Appropriations

United States Senate

The Honorable Mac Thornberry

Chairman

The Honorable Adam Smith

Ranking Member

Committee on Armed Services

House of Representatives

The Honorable Rodney Frelinghuysen

Chairman

The Honorable Peter J. Visclosky

Ranking Member

Subcommittee on Defense

Committee on Appropriations

House of Representatives
Appendix I: Literature Review Methodology 

and Bibliography

Page 19 GAO-16-154 Hyperbaric Oxygen Therapy

To identify and describe published research on the use of hyperbaric 

oxygen (HBO2) 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, 2015.1 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. 

We first reviewed the abstracts for each of these articles for relevancy in 

determining the effectiveness of HBO2 therapy in treating TBI or PTSD.2

For those abstracts we found relevant, we obtained and reviewed the full 

article and excluded those for which the research (1) was an editorial 

submission; (2) studied animals; or (3) included children. After excluding 

these articles, duplicates, and those only available in a foreign language, 

32 articles remained. Articles were then categorized as a case report, 

literature review, or interventional study or clinical trial.3 We identified 7 

case reports, 10 literature reviews, and 15 interventional studies or 

clinical trials, which are listed below (chronologically, then alphabetically 

by first author, and for the interventional studies or clinical trials, by 

 1

We chose this period because federal officials became aware of increased rates of TBI 

among active duty servicemembers in the mid-2000s. 

2

We reviewed the abstracts and did not obtain full articles if TBI or PTSD was not included 

in the research, HBO2 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.

3

Case reports consist of collections of reports on the treatment of individual patients or a 

report on a single patient. For the purposes of our work, if a case report examined more 

than one patient it would describe each of the cases individually. Literature reviews focus 

on a clinical topic and answer a specific question. An interventional study or clinical trial is 

a clinical study 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 receiving an intervention may receive diagnostic, therapeutic, or 

other types of interventions.

Appendix I: Literature Review Methodology 

and Bibliography
Appendix I: Literature Review Methodology 

and Bibliography

Page 20 GAO-16-154 Hyperbaric Oxygen Therapy

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).
Appendix I: Literature Review Methodology 

and Bibliography

Page 21 GAO-16-154 Hyperbaric Oxygen Therapy

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).
Appendix I: Literature Review Methodology 

and Bibliography

Page 22 GAO-16-154 Hyperbaric Oxygen Therapy

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).
Appendix I: Literature Review Methodology 

and Bibliography

Page 23 GAO-16-154 Hyperbaric Oxygen Therapy

Israeli Study:

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).

United States Study:

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 BlastInduced 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)
Appendix I: Literature Review Methodology 

and Bibliography

Page 24 GAO-16-154 Hyperbaric Oxygen Therapy

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)

Page 25 GAO-16-154 Hyperbaric Oxygen Therapy

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.1

We identified six interventional clinical trials on hyperbaric oxygen therapy 

(see table 4). The remaining two ongoing studies are observational (see 

table 5).2 ClinicalTrials.gov information, such as the study start date—the 

date that enrollment of participants for a clinical study begins—is provided 

and updated by the sponsor or principal researcher of the clinical study. 

In addition to these ongoing studies, DOD officials told us that they are 

conducting additional analyses to follow up with participants from a 

recently funded study more than one year after their intervention to 

determine if any of the initial improvements observed in both the 

treatment and sham groups has been sustained over time.3

 1

ClinicalTrials.gov was created in response to the Food and Drug Administration 

Modernization Act of 1997, which required the Department of Health and Human Services, 

through NIH, to establish a registry of clinical trials information for both federally and 

privately funded trials of experimental drugs for serious or life-threatening diseases or 

conditions. Pub. L. No. 105-115, § 113, 111 Stat. 2296, 2310-12 (codified as amended at 

42 U.S.C. § 282(i)). The Food and Drug Administration Amendments Act of 2007 

expanded the scope of trials required to be registered and added a requirement for 

summary results to be submitted for some registered trials. Pub. L. No 110-85, § 801, 121 

Stat. 823, 904-22 (codified as amended at 42 U.S.C. § 282(j)). The site, which was made 

available to the public in February 2000, included registration information for more than 

198,000 clinical studies as of September 10, 2015. 

2

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).

3

As of September 2015, DOD officials told us that data collection was complete on this 

survey, and they were analyzing the results. However, officials did not have a date for 

completion of this analysis.

Appendix II: Ongoing Interventional and 

Observational Studies on Hyperbaric Oxygen 

Therapy to Treat Traumatic Brain Injury (TBI)
Appendix II: Ongoing Interventional and 

Observational Studies on Hyperbaric Oxygen 

Therapy to Treat Traumatic Brain Injury (TBI)

Page 26 GAO-16-154 Hyperbaric Oxygen Therapy

Table 4: Ongoing Interventional Studies on Hyperbaric Oxygen Therapy to Treat Traumatic Brain Injury (TBI), Enrolling 

Participants from Jan. 1, 2005 to July 22, 2015 

Title 

Hyperbaric Oxygen Therapy and SPECT Brain Imaging in Traumatic Brain Injury 

(https://clinicaltrials.gov/show/NCT00594503 )

Sponsor (sponsor affiliation) Paul G. Harch, M.D. (Louisiana State University Health Sciences Center in New Orleans)

Severity of TBI addressed in study Not specified

Study start date and estimated study 

completion datea January 2007 to December 2016

Purpose to test the hypothesis that single-photon emission computerized tomography brain 

imaging tracksb and is consistent with clinical improvements in patients receiving 

hyperbaric oxygen therapy for chronic TBI

Title 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)

Sponsor (sponsor affiliation) U.S. Army Medical Research and Materiel Command

Severity of TBI addressed in study Mild TBI

Study start date and estimated study 

completion datea September 2012 to January 2017

Purpose to investigate the mechanisms of action of hyperbaric oxygen therapy for persistent postconcussive symptomsc after mild TBI

Title Phase 1-2 Study of Hyperbaric Treatment of Traumatic Brain Injury 

(https://clinicaltrials.gov/show/NCT01847755)

Sponsor (sponsor affiliation) Barry Miskin, M.D. (Jupiter Medical Center, Florida)

Severity of TBI addressed in study Not specified

Study start date and estimated study 

completion datea April 2013 to April 2017

Purpose to test the hypothesis that patients with TBI treated with hyperbaric oxygen will show 

improvement in function and an increased blood flow as evidenced by single-photon 

emission computerized tomography scanb

Title Hyperbaric Oxygen Therapy Treatment of Chronic Mild Traumatic Brain Injury/Persistent 

Post-Concussion Syndrome (https://clinicaltrials.gov/show/NCT02089594)

Sponsor (sponsor affiliation) Louisiana State University Health Sciences Center in New Orleans

Severity of TBI addressed in study Mild TBI

Study start date and estimated study 

completion datea May 2014 to March 2015d

Purpose to determine whether an eight-week course of forty low-pressure hyperbaric oxygen 

treatments can significantly improve symptoms and cognitive function in subjects with the 

persistent-post concussion syndrome of mild TBI

Title A Double-Blind Randomized Trial of Hyperbaric Oxygen Versus Sham in Civilian PostConcussive Syndrome (https://clinicaltrials.gov/show/NCT01986205)

Sponsor (sponsor affiliation) Lindell Weaver (Intermountain Health Care, Inc., Utah)

Severity of TBI addressed in study Mild TBI
Appendix II: Ongoing Interventional and 

Observational Studies on Hyperbaric Oxygen 

Therapy to Treat Traumatic Brain Injury (TBI)

Page 27 GAO-16-154 Hyperbaric Oxygen Therapy

Study start date and estimated study 

completion datea February 2015 to December 2018

Purpose to examine whether 40 hyperbaric oxygen sessions have an effect on long-term 

symptoms after concussion

Title Hyperbaric Oxygen Brain Injury Treatment (HBOIT) Trial 

(https://clinicaltrials.gov/show/NCT02407028) 

Sponsor (sponsor affiliation) Gaylan Rockswold (Minneapolis Research Foundation)

Severity of TBI addressed in study Not specified

Study start date and estimated study 

completion datea December 2015 to December 2017

Purpose to determine the optimal hyperbaric oxygen treatment paradigm to be instituted in terms of 

atmospheric pressure, frequency of treatment and whether normobaric hyperoxiae

following hyperbaric oxygen treatments enhances the treatment effect

Source: ClinicalTrials.gov, accessed by the National Institutes of Health on July 22, 2015. | GAO-16-154

a

The ClinicalTrials.gov definition of “study start date” is the date that enrollment of participants for a 

clinical study begins and the definition of “estimated study completion date” is the anticipated date of

final data collection for the last participant during the final visit to the study location.

b

Single-photon emission computerized tomography scan is a type of nuclear imaging test, which uses 

a radioactive chemical and a special camera to create 3-D images of organ function.

c

Postconcussive symptoms are physical, cognitive, and emotional or behavioral symptoms reported 

by individuals who suffer from mild TBI. The most commonly reported are headache, dizziness, 

decreased concentration, memory problems, irritability, fatigue, visual disturbances, sensitivity to 

noise, judgment problems, depression, and anxiety.

d

The information for this trial had not been updated as of September 30, 2015 to indicate if it was 

completed or the completion date was extended and it is still ongoing.

e

Normobaric hyperoxia is the use of oxygen at a higher-than-normal level without pressure, which 

results in greater oxygen content in the tissues and organs than normally exists at sea level.

Table 5: Ongoing Observational Studies on Hyperbaric Oxygen Therapy to Treat Traumatic Brain Injury (TBI), Enrolling 

Participants from Jan. 1, 2005 to July 22, 2015 

Title Development of Normative Datasets for Assessments Planned for Use in Patients with 

Mild Traumatic Brain Injury (NORMAL) (https://clinicaltrials.gov/show/NCT01925963)

Sponsor (sponsor affiliation) Lindell Weaver (Intermountain Health Care, Inc., Utah)

Severity of TBI addressed in study Mild TBI

Study start date and estimated study 

completion datea October 2013 to February 2016

Purpose to collect information about brain function and structure among active duty military 

personnel or civilians who are healthy. Researchers want to develop a database from 

normal volunteers that will be used in comparison with a similar database from active duty 

military with postconcussive syndromeb from a mild traumatic brain injury. Findings from 

this study may be used to design larger studies that will evaluate whether hyperbaric 

oxygen treatments actually improve postconcussive syndromeb

Title 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) 

Sponsor (sponsor affiliation) Assaf-Harofeh Medical Center
Appendix II: Ongoing Interventional and 

Observational Studies on Hyperbaric Oxygen 

Therapy to Treat Traumatic Brain Injury (TBI)

Page 28 GAO-16-154 Hyperbaric Oxygen Therapy

Severity of TBI addressed in study Not specified

Study start date and estimated study 

completion datea March 2015 to June 2015c

Purpose to evaluate the perfusion magnetic resonance imaging (MRI) changes in addition to the 

cognitive tests before and after the treatment

Source: ClinicalTrials.gov, accessed by the National Institutes of Health on July 22, 2015. | GAO-16-154

a

The ClinicalTrials.gov definition of “study start date” is the date that enrollment of participants for a 

clinical study begins and the definition of “estimated study completion date” is the anticipated date of

final data collection for the last participant during the final visit to the study location.

b

Postconcussion syndrome (or postconcussive syndrome) is when postconcussive symptoms are 

persistent in nature, it is also called persistent post-concussion symptoms. Postconcussive symptoms 

are physical, cognitive, and emotional/behavioral symptoms reported by individuals who suffer from 

mild TBI. The most commonly reported are headache, dizziness, decreased concentration, memory 

problems, irritability, fatigue, visual disturbances, sensitivity to noise, judgment problems, depression, 

and anxiety.

c

The information for this trial had not been updated as of September 30, 2015 to indicate if it was 

completed or the completion date was extended and it is still ongoing.
Appendix III: Relevant Case Report Articles on 

Hyperbaric Oxygen Therapy

Page 29 GAO-16-154 Hyperbaric Oxygen Therapy

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.

Table 6: Case Report Articles on Hyperbaric Oxygen Therapy to Treat Traumatic Brain Injury (TBI) or Post-Traumatic Stress 

Disorder (PTSD), Published from Jan. 1, 2005 to Apr. 6, 2015

Title (year) Pilot Case Study of the Therapeutic Potential of Hyperbaric Oxygen Therapy on Chronic Brain Injury (2007)

Authors Hardy, P., K.M. Johnston, L. DeBeaumont, D.L. Montgomery, J. M., Lecomete, J.P. Soucy, D. Bourbonnais, 

and M. Lassonde

Case(s) 1 participant with TBI (severity not specified)

Conclusion The single-case study provided preliminary evidence of improvements after a series of 20 and 60 hyperbaric 

oxygen therapy treatments. 

Title (year) 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 (2009)

Authors Harch, P.G., E.F. Fogarty, P.K. Staab, and K. Van Meter

Case(s) 1 participant with mild-moderate TBI, post-concussive syndrome, and PTSD

Conclusion Hyperbaric oxygen therapy treatments caused a reduction in symptoms and signs of chronic mild or moderate 

blast-induced TBI, postconcussive syndrome, and PTSD. The study showed improvement of symptoms and 

signs of TBI, postconcussive syndrome, and PTSD reflected improvements in brain blood flow imaging.

Title (year) Case Report: Treatment of Mild Traumatic Brain Injury with Hyperbaric Oxygen (2009)

Authors Wright, Col. J,K., E. Zant, K. Groom, R.E. Schlegel, and K. Gilliland

Case(s) 2 participants (airmen) with mild TBI and post-concussive syndrome 

Conclusion Both airmen had substantive improvement within 10 days of hyperbaric oxygen treatment.

Title (year) Hyperbaric Oxygen Ameliorates Worsening Signs and Symptoms of Post-Traumatic Stress Disorder (2010)

Authors Eovaldi, B., and C. Zanetti

Case(s) 1 participant with PTSD

Conclusion Hyperbaric oxygen therapy improved the signs and symptoms of agitation, confusion, and emotional distress in 

a 27-year-old male 7 days following a traumatic accident. 

Title (year) Hyperbaric Oxygen Therapy in the Management of Paroxysmal Sympathetic Hyperactivity after Severe 

Traumatic Brain Injury: A Report of 6 Cases (2011)

Authors Lv, LQ., LJ. Hou, MK. Yu, XH. Ding, XQ Qi, and YC. Lu

Case(s) 6 participants with severe TBI

Conclusion Symptoms of a syndrome that affects patients with severe TBI quickly disappeared after several hyperbaric 

oxygen therapy treatments. Five other patients with the same syndrome were then consecutively treated, and 

all showed positive responses.

Title (year) Hyperbaric Oxygen Therapy (1.5 ATA) in Treating Sports Related TBI/CTE: Two Case Reports (2011)

Authors K. Stoller

Case(s) 2 participants (football players) with TBI (severity not specified)

Appendix III: Relevant Case Report Articles 

on Hyperbaric Oxygen Therapy
Appendix III: Relevant Case Report Articles on 

Hyperbaric Oxygen Therapy

Page 30 GAO-16-154 Hyperbaric Oxygen Therapy

Conclusion Two football players with TBI were shown to benefit from being treated with hyperbaric oxygen as documented 

by neurocognitive examinations and functional brain imaging. 

Title (year) Tension Pneumocephalus as a Complication of Hyperbaric Oxygen Therapy in a Patient with Chronic 

Traumatic Brain Injury (2012)

Authors Lee, LC., FK. Lieu, YH. Chen, TH. Hung, and SF. Chen 

Case(s) 1 participant with TBI (severity not specified) 

Conclusion Tension pneumocephalusa is a rare but potentially fatal complication of hyperbaric oxygen therapy. Before 

conducting hyperbaric oxygen therapy for a TBI patient, thorough evaluation of the patient is imperative to 

ensure that the expected benefits outweigh potential risks.

Source: GAO review of published articles. | GAO-16-154

Note: GAO has paraphrased the conclusions of these articles. For the complete, original version of 

these conclusions, refer to the articles. Full references for each article are included in appendix I.

a

Tension pneumocephalus is a rare form of pneumocephalus in which air in the head creates a mass 

effect on the brain and may cause neurologic compromise, brain herniation, or even death, if not 

treated promptly.
Appendix IV: Relevant Literature Review 

Articles on Hyperbaric Oxygen Therapy

Page 31 GAO-16-154 Hyperbaric Oxygen Therapy

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.

Table 7: Literature Review Articles on Hyperbaric Oxygen Therapy to Treat Traumatic Brain Injury (TBI), Published from Jan. 

1, 2005 to Apr. 6, 2015

Title (year) Current Controversies in the Management of Patients with Severe Traumatic Brain Injury (2006)

Authors Adamides, A.A., C.D. Winter, P.M. Lewis, D.J. Cooper, T. Kossmann, and J.V. Rosenfeld

Purpose to examine the evidence base behind each intervention for TBI, including hyperbaric oxygen therapy

Conclusion Large, multicenter, randomized trials in TBI are challenging, but are required before practice may change and 

outcomes improve.

Title (year) A Systematic Review of the Use of Hyperbaric Oxygen Therapy in the Treatment of Acute Traumatic Brain 

Injury (2006)

Authors Bennett, M. H., B. E. Trytko, and B. Jonker.

Purpose to assess the randomized clinical evidence for the benefit or harm of adjunctive hyperbaric oxygen therapy in 

the treatment of acute TBI

Conclusion Hyperbaric oxygen therapy reduced the risk of death, but there is no clear evidence of improved functional 

outcome. More research is needed in order to confirm or refute the findings of this review. 

Title (year) Hyperbaric Oxygen in Traumatic Brain Injury (2007)

Authors Rockswold, S.B., G. L. Rockswold, and A. Defillo

Purpose to examine historical and current investigations on the efficacy and mechanisms of hyperbaric oxygen 

treatment in TBI

Conclusion Hyperbaric oxygen treatments at a depth of 1.5 atmospheres absolute (ATA) can be delivered to severe TBI 

patients with relative safety and low risk of oxygen toxicity.

Title (year) Normobaric Hyperoxia Therapy for Traumatic Brain Injury and Stroke: A Review (2009)

Authors Kumaria, A. and C.M. Tolias

Purpose to survey studies, using hyperbaric oxygen therapy for TBI and stroke, which formed the basis for early studies 

on normobaric hyperoxia (increased oxygen without pressure). Clinical studies are presented on the efficacy of 

normobaric hyperoxia on TBI and stroke, emphasizing their safety, efficacy and practicality

Conclusion Conclusions about hyperbaric oxygen therapy are limited and more research is needed. Normobaric hyperoxia 

(increased oxygen without pressure) has been proposed as a more feasible alternative. 

Title (year) Hyperbaric Oxygen Therapy for Traumatic Brain Injury (2011)

Authors Huang, L., and A. Obenaus

Purpose to review the experimental and clinical hyperbaric oxygen research relevant to TBI

Conclusion Research of hyperbaric oxygen therapy in a variety of TBI models has shown positive effects. Due to the 

variability of human TBI, the efficacy of clinical hyperbaric oxygen therapy and an optimal regimen for 

hyperbaric oxygen therapy remains difficult to understand. However, all human studies have involved severe 

TBI patients and it is likely that there may be increased efficacy in mild or moderate TBI patients.

Appendix IV: Relevant Literature Review 

Articles on Hyperbaric Oxygen Therapy
Appendix IV: Relevant Literature Review 

Articles on Hyperbaric Oxygen Therapy

Page 32 GAO-16-154 Hyperbaric Oxygen Therapy

Title (year) Hyperbaric Oxygen Therapy for the Adjunctive Treatment of Traumatic Brain Injury (2012)

Authors Bennett, M.H., B. Trytko, and B. Jonker

Purpose to assess studies on the effects of adjunctive hyperbaric oxygen therapy for TBI 

Conclusion In people with TBI, while the addition of hyperbaric oxygen therapy may reduce the risk of death and improve 

the final Glasgow Coma Scale ratinga there is little evidence that the survivors have a good outcome. Given 

these findings, there is a case for additional research in order to define the true extent of the benefit of 

hyperbaric oxygen therapy.

Title (year) Brain Tissue Oxygen Monitoring and Hyperoxic Treatment in Patients with Traumatic Brain Injury (2012) 

Authors Beyon, C., K.L. Kiening, B. Orakcioglu, A.W. Unterberg, and O.W. Sakowitz 

Purpose to summarize studies which have examined the impact of hyperbaric oxygen and normobaric oxygen (oxygen 

administered without pressure) on TBI patients

Conclusion Although controlled clinical trials have not yet been carried out, the available study results suggest that a brain 

tissue oxygen-directed therapy may improve mortality and functional outcomes in these patients. The efficacy 

of oxygen-directed treatment in TBI patients remains to be proven, and further studies as well as controlled and 

prospective clinical trials are needed.

Title (year) Hyperbaric Oxygen (HBO2) for Post-Concussive Syndrome/Chronic TBI Product Summary (2013)

Authors McCrary, Col. B.F., L. Weaver, LCDR K. Marrs, Col. R. S. Miller, C. Dicks, K. Deru, N. Close, and Col. M. 

DeJong

Purpose to provide study researchers with information from published literature in support of prospective controlled 

clinical evaluations of hyperbaric oxygen treatment for persistent postconcussion syndrome following mild TBI 

by summarizing the relevant safety and efficacy information available from non-clinical and clinical experience 

to date

Conclusion Published literature regarding hyperbaric oxygen for chronic sequelae (conditions) following TBI in adults is 

limited. More information from clinical trials is needed.

Title (year) Therapeutic Options to Enhance Coma Arousal after Traumatic Brain Injury: State of the Art of Current 

Treatments to Improve Coma Recovery (2014)

Authors Cossu, G.

Purpose to examine the literature to clarify the indications for the various techniques and to guide the clinical practice 

towards an earlier coma arousal after a severe TBI

Conclusion The selected articles had limitations due to the limited number of cases analyzed in each study. A need 

remains for well-designed, multicentered, and sufficiently rigorous trials enrolling specific subtypes of brain 

trauma to help clinicians in the everyday clinical practice and to offer the patient the best treatment protocol.

Title (year) Hyperbaric Oxygen Therapy Applied Research in Traumatic Brain Injury: From Mechanisms to Clinical 

Investigation (2014)

Authors Wang, Y., D. Chen, and G. Chen

Purpose to assess the literature to examine the key role of hyperbaric oxygen therapy in treating TBI on the basis of 

animal studies, clinical research, complications from hyperbaric oxygen therapy and oxygen toxicity

Conclusion Increasing evidence has shown that hyperbaric oxygen therapy is a key contributor in the treatment of TBI. The 

authors believe that hyperbaric oxygen therapy will be increasingly accepted by patients and approved by 

clinicians. Further research should be undertaken into mechanisms and efficacy of hyperbaric oxygen therapy, 

as it could offer a clinically promising therapeutic approach to TBI.

Source: GAO review of published articles. | GAO-16-154

Notes: GAO has paraphrased the conclusions of these articles. For the complete, original version of 

these conclusions, refer to the articles. Full references for each article are included in appendix I.
Appendix IV: Relevant Literature Review 

Articles on Hyperbaric Oxygen Therapy

Page 33 GAO-16-154 Hyperbaric Oxygen Therapy

a

The Glasgow Coma Scale was designed and is used to assess the depth and duration of the coma 

and impaired consciousness. This scale helps to gauge the impact of a wide variety of conditions, 

such as acute brain damage due to traumatic injuries, vascular injuries, or both.
Appendix V: Relevant Interventional Study or 

Clinical Trial Articles on Hyperbaric Oxygen 

Therapy

Page 34 GAO-16-154 Hyperbaric Oxygen Therapy

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).

Table 8: Eight Articles on Interventional Studies or Clinical Trials on Hyperbaric Oxygen Therapy to Treat Mild Traumatic

Brain Injury (TBI) or Post-Traumatic Stress Disorder (PTSD), Published from Jan. 1, 2005 to Apr. 6, 2015

DOD-Funded Study (Air Force)

Title (year) The Effect of Hyperbaric Oxygen on Symptoms after Mild Traumatic Brain Injury (2012)

Authors Wolf, G., D. Cifu, L. Baugh, W. Carne, and L. Profenna

Purpose to examine the effects of 2.4 atmospheres absolute (ATA) hyperbaric oxygen on post-concussion 

symptoms in 50 military service members 

Conclusion This study demonstrated no improvement in symptom relief with hyperbaric oxygen at an exposure 

pressure of 2.4 ATA in comparison to the sham control group.a

DOD-Funded Study (Navy)

Title (year) The Effect of Hyperbaric Oxygen on Persistent Postconcussion Symptoms (2014)

Authors Cifu, D.X., B.B. Hart, S.L. West, W. Walker, and W. Carne

Purpose to examine the effects of hyperbaric oxygen on persistent postconcussion symptomsb in 60 military service 

members with at least one combat-related mild TBI 

Conclusion This study demonstrated that hyperbaric oxygen had no effect on postconcussion symptomsb after mild 

TBI when compared with patients in the sham control group.a

Title (year) Effects of Hyperbaric Oxygen on Eye Tracking Abnormalities in Males after Mild Traumatic Brain Injury

(2014)

Authors Cifu, D.X., K.W. Hoke, P.A. Wetzel, J. R. Wares, G. Gitchel, and W. Carne

Purpose to examine the effects of hyperbaric oxygen on eye movement abnormalities in 60 military servicemembers

with at least one mild TBI from combat were examined 

Conclusion This study demonstrated that hyperbaric oxygen did not have an effect on eye movement abnormalities 

after mild TBI when compared with the sham control group.a

Title (year) Hyperbaric Oxygen for Blast-Related Postconcussion Syndrome: Three-Month Outcomes (2014)

Authors Cifu, D.X., W.C. Walker, S.L. West, B.B. Hart, L.M. Franke, A. Sima, C.W. Graham, and W. Carne

Purpose to determine the effects of hyperbaric oxygen therapy after 3 months on 60 military servicemembers; 

whether specific subgroups may have benefited; and if no overall effect was found, whether benefit is 

masked by other conditions 

Conclusion This study results showed no evidence of efficacy by 3 months post-compression (after therapy) to treat 

the symptomatic, cognitive, or behavioral sequelae of postconcussion syndromec after combat-related mild 

TBI. 

Title (year) Randomized, Sham-Controlled, Feasibility Trial of Hyperbaric Oxygen for Service Members with 

Postconcussion Syndrome: Cognitive and Psychomotor Outcomes 1 Week Postintervention (2014) 

Authors Walker, W.C., L.M. Franke, D.X. Cifu, and B.B. Hart

Appendix V: Relevant Interventional Study or 

Clinical Trial Articles on Hyperbaric Oxygen 

Therapy
Appendix V: Relevant Interventional Study or 

Clinical Trial Articles on Hyperbaric Oxygen 

Therapy

Page 35 GAO-16-154 Hyperbaric Oxygen Therapy

Purpose to examine for possible effects on balance, fine motor, and cognitive performance one week after a 

hyperbaric oxygen intervention in 60 service members with post-concussion symptomsb after mild TBI

Conclusion This study demonstrated no beneficial effect of exposure to hyperbaric oxygen therapy compared to the 

sham control groupa when examining deficits associated with mild TBI and postconcussionsyndrome.c

DOD Funded-Study (Army)

Title (year) Effects of Hyperbaric Oxygen on Symptoms and Quality of Life Among Service Members with Persistent 

Postconcussion Symptoms A Randomized Clinical Trial (2015) 

Authors 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

Purpose to compare the safety of and to estimate the efficacy for symptomatic outcomes from standard post 

concussive syndromec care alone, care supplemented with hyperbaric oxygen or a sham procedure

Conclusion This study demonstrated that hyperbaric oxygen showed no benefits over a sham control group,a but 

symptoms in both groups improved compared to servicemembers with mild TBI that did not use hyperbaric 

oxygen therapy. 

Israeli Study

Title (year) Hyperbaric Oxygen Therapy Can Improve Post Concussion Syndrome Years after Mild Traumatic Brain 

Injury-Randomized Prospective Trial (2013) 

Authors 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

Purpose to test the effectiveness of hyperbaric oxygen therapy in improving brain function and quality of life in 50 

mild TBI patients 

Conclusion This study demonstrated that hyperbaric oxygen therapy results in brain function improvements for mild 

TBI patients, years after injury. 

United States Study

Title (year) A Phase I Study of Low-Pressure Hyperbaric Oxygen Therapy for Blast-Induced Post-Concussion 

Syndrome and Post-Traumatic Stress Disorder (2012) 

Authors 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

Purpose to report on the safety and efficacy of hyperbaric oxygen therapy in 16 military subjects with mild to 

moderate TBI/post-concussion symptomsb and PTSD

Conclusion This study demonstrated that hyperbaric oxygen therapy was safe and that servicemembers experienced 

significant improvements in areas, such as physical exams and self-reporting on quality of life 

measurements. 

Source: GAO review of published articles. | GAO-16-154

Notes: GAO has paraphrased the conclusions of these articles. For the complete, original version of 

these conclusions, refer to the articles. Full references for each article are included in appendix I.

a

A sham control group is a group of participants that receives a treatment or procedure that is similar 

to the treatment or procedure under investigation, but is lacking the component(s) of the intervention 

being studied.

b

Postconcussion symptoms are physical, cognitive, and emotional/behavioral symptoms reported by 

individuals who suffer from mild TBI. The most commonly reported are headache, dizziness, 

decreased concentration, memory problems, irritability, fatigue, visual disturbances, sensitivity to 

noise, judgment problems, depression, and anxiety.

c

Postconcussion syndrome (or postconcussive syndrome) is when postconcussive symptoms are 

persistent in nature, such symptoms are also referred to as persistent postconcussion symptoms.
Appendix V: Relevant Interventional Study or 

Clinical Trial Articles on Hyperbaric Oxygen 

Therapy

Page 36 GAO-16-154 Hyperbaric Oxygen Therapy

Table 9: Four Articles on Interventional Studies or Clinical Trials on Hyperbaric Oxygen Therapy to Treat Severe Traumatic 

Brain Injury (TBI) or Non-Specified TBI, Published from Jan. 1, 2005 to Apr. 6, 2015

Severe TBI

Title (year) 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 (2010)

Authors Rockswold, S.B., G.L. Rockswold, D.A. Zaun, X. Zhang, C.E. Cerra, T.A. Bergman, and J. Liu

Purpose to compare hyperbaric oxygen and normobaric hyperoxiaa treatment effects for 69 patients 

Conclusion This study demonstrated that hyperbaric oxygen has a more robust post-treatment effect than normobaric 

hyperoxiaa on issues related to the brain. However, it appears that oxygen treatment for severe TBI 

improved over time.

Title (year) A Prospective, Randomized Phase II Clinical Trial to Evaluate the Effect of Combined Hyperbaric and 

Normobaric Hyperoxia on Cerebral Metabolism, Intercranial Pressure, Oxygen Toxicity, and Clinical 

Outcome in Severe Traumatic Brain Injury (2013)

Authors Rockswold, S.B., G.L. Rockswold, D.A. Zaun, and J. Liu

Purpose to evaluate the combination of hyperbaric oxygen and normobaric hyperoxiaa as a single treatment for 42 

patients

Conclusion This study demonstrated that combined hyperbaric oxygen and normorbaric hyperoxiaa treatments 

(increased oxygen without pressure) significantly improved brain related issues. There was also significant 

reduction in mortality.

Non-Specified TBI

Title (year) Evaluation of Hyperbaric Oxygen Treatment of Neuropsychiatric Disorders Following Traumatic Brain Injury

(2006)

Authors Xia-yan, S. T. Zhong-quan, S. Da, and H. Xiao-ju

Purpose to study the effects of hyperbaric oxygen on cerebral blood flow and the usefulness of a specific type of 

brain images in the diagnosis and assessment of neuropsychiatric disordersa after TBI for 310 patients 

Conclusion This study demonstrated that a specific type of picture (image) of the brain was much more sensitive than 

other types in the diagnosis of neuropsychiatric disordersb following hyperbaric oxygen treatment of 

neuropsychiatric disordersb arising from TBI.

Title (year) Use of Hyperbaric Oxygen in Traumatic Brain Injury: Retrospective Analysis of Data of 20 Patients Treated 

at a Tertiary Care Centre (2012)

Authors Sahni, T., M. Jain, R. Prasad, S.K. Sogani, and V. P. Singh

Purpose to determine whether addition of hyperbaric oxygen therapy to standard treatment plan of 20 patients with 

TBI improves outcomes 

Conclusion This study demonstrated significant improvement for patients; however, it is a retrospective study and the 

small numbers precludes a statistical conclusion.

Source: GAO review of published articles. | GAO-16-154

Notes: GAO has paraphrased the conclusions of these articles. For the complete, original version of 

these conclusions, refer to the articles. Full references for each article are included in appendix I.

a

Normobaric hyperoxia is the use of oxygen at a higher-than-normal oxygen level without pressure, 

which results in greater oxygen content of the tissues and organs than normally exists at sea level.

b

Neuropsychiatric disorders are mental disorders attributable to diseases of the nervous system.
Appendix V: Relevant Interventional Study or 

Clinical Trial Articles on Hyperbaric Oxygen 

Therapy

Page 37 GAO-16-154 Hyperbaric Oxygen Therapy

Table 10: Three Articles on Interventional Studies or Clinical Trials on the Safety of Hyperbaric Oxygen Therapy to Treat 

Traumatic Brain Injury (TBI), Published from Jan. 1, 2005 to Apr. 6, 2015

Title (year) The Safe Treatment, Monitoring and Management of Severe Traumatic Brain Injury patients in a Monoplace 

Chamber (2010)

Authors Gossett, W.A., G.L. Rockswold, S.B. Rockswold, C.D. Adkinson, T.A. Bergman, and R.R. Quickel

Purpose to examine our unique experience in the management, monitoring and safety of patients with severe TBI 

undergoing hyperbaric oxygen treatment 

Conclusion Hyperbaric oxygen treatments at a depth of 1.5 ATA (atmospheres absolute) can be delivered repetitively to 

the severe TBI patient with or without multiple injuries in either a monoplace (single person) or multiplace 

(multi-person) chamber with relative safety.

Title (year) Hyperbaric Side Effects in a Traumatic Brain Injury Randomized Clinical Trial (2012)

Authors Wolf, E.G, J. Prye, R. Michaelson, G. Brower, L. Profenna, and O. Boneta

Purpose to examine the side effects of 2.4 ATA hyperbaric oxygen compared to a sham control groupa on 

postconcussion symptoms in military service members with combat-related, mild TBI

Conclusion This study demonstrated no major adverse events. Given the infrequent, mild side effect profile, the authors 

felt the study demonstrated that hyperbaric oxygen therapy was safe at a relatively high treatment pressure 

in TBI subjects, and that these data could be used to evaluate the risk/ benefit calculation when deciding to 

utilize hyperbaric oxygen therapy for treatment of various diseases in the TBI population.

Title (year) A Prospective Trial of Hyperbaric Oxygen for Chronic Sequelae after Brain Injury (2013)

Authors Churchill, S., L.K. Weaver, K. Deru, A.A. Russo, D. Handrahan, W.W. Orrison, J.F. Foley, H.A. Elwell

Purpose to examine recruitment, tolerance, and safety in preparation for a randomized control trial

Conclusion The results of this study found that a brain-injured population with disability can complete a 60-session 

course of daily hyperbaric oxygen at 1.5 ATA for 60 minutes and can tolerate extensive testing to assess 

efficacy.

Source: GAO review of published articles. | GAO-16-154

Notes: GAO has paraphrased the conclusions of these articles. For the complete, original version of 

these conclusions, refer to the articles. Full references for each article are included in appendix I.

a

A sham control group is a group of participants that receives a treatment or procedure that is similar

to the treatment or procedure under investigation, but is lacking the component(s) of the intervention 

being studied.
Appendix VI: Comments from the Department 

of Defense

Page 38 GAO-16-154 Hyperbaric Oxygen Therapy

Appendix VI: Comments from the 

Department of Defense
Appendix VII: Comments from the Department 

of Veterans Affairs

Page 39 GAO-16-154 Hyperbaric Oxygen Therapy

Appendix VII: Comments from the 

Department of Veterans Affairs
Appendix VII: Comments from the Department 

of Veterans Affairs

Page 40 GAO-16-154 Hyperbaric Oxygen Therapy
Appendix VIII: GAO Contact and Staff

Acknowledgments

Page 41 GAO-16-154 Hyperbaric Oxygen Therapy

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. 

Appendix VIII: GAO Contact and Staff 

Acknowledgments

GAO contact

Staff 

Acknowledgments

(291279)
The Government Accountability Office, the audit, evaluation, and 

investigative arm of Congress, exists to support Congress in meeting its 

constitutional responsibilities and to help improve the performance and 

accountability of the federal government for the American people. GAO 

examines the use of public funds; evaluates federal programs and 

policies; and provides analyses, recommendations, and other assistance 

to help Congress make informed oversight, policy, and funding decisions. 

GAO’s commitment to good government is reflected in its core values of 

accountability, integrity, and reliability.

The fastest and easiest way to obtain copies of GAO documents at no 

cost is through GAO’s website (http://www.gao.gov). Each weekday 

afternoon, GAO posts on its website newly released reports, testimony, 

and correspondence. To have GAO e-mail you a list of newly posted 

products, go to http://www.gao.gov and select “E-mail Updates.”

The price of each GAO publication reflects GAO’s actual cost of 

production and distribution and depends on the number of pages in the 

publication and whether the publication is printed in color or black and 

white. Pricing and ordering information is posted on GAO’s website, 

http://www.gao.gov/ordering.htm. 

Place orders by calling (202) 512-6000, toll free (866) 801-7077, or 

TDD (202) 512-2537.

Orders may be paid for using American Express, Discover Card, 

MasterCard, Visa, check, or money order. Call for additional information.

Connect with GAO on Facebook, Flickr, Twitter, and YouTube.

Subscribe to our RSS Feeds or E-mail Updates. 

Listen to our Podcasts and read The Watchblog.

Visit GAO on the web at www.gao.gov.

Contact:

Website: http://www.gao.gov/fraudnet/fraudnet.htm

E-mail: fraudnet@gao.gov

Automated answering system: (800) 424-5454 or (202) 512-7470

Katherine Siggerud, Managing Director, siggerudk@gao.gov, (202) 512-

4400, U.S. Government Accountability Office, 441 G Street NW, Room 

7125, Washington, DC 20548

Chuck Young, Managing Director, youngc1@gao.gov, (202) 512-4800

U.S. Government Accountability Office, 441 G Street NW, Room 7149 

Washington, DC 20548

GAO’s Mission

Obtaining Copies of 

GAO Reports and 

Testimony

Order by Phone

Connect with GAO

To Report Fraud, 

Waste, and Abuse in 

Federal Programs

Congressional 

Relations

Public Affairs

Please Print on Recycled Paper.