HBO indicates hyperbaric oxygen; mTBI, mild traumatic brain injury; PTSD, posttraumatic stress disorder; and RPQ, Rivermead Post-Concussion Symptoms Questionnaire.
eMethods 1. Study Inclusion and Exclusion Criteria
eMethods 2. Hyperbaric Oxygen and Sham Administration Procedures
eMethods 3. Patient Reported Outcomes and Neuropsychological Testing Battery
eFigure 1. Histogram of the Number of Hyperbaric Chamber Sessions Completed Within Study Period
eFigure 2. Comparison of Change From Baseline Scores for Postconcussion Symptoms at the Midpoint (20 Sessions) and the End of the Study
eTable. Summary of Chamber Intervention–Related Adverse Events
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Miller RS, Weaver LK, Bahraini N, et al. Effects of Hyperbaric Oxygen on Symptoms and Quality of Life Among Service Members With Persistent Postconcussion Symptoms: A Randomized Clinical Trial. JAMA Intern Med. 2015;175(1):43–52. doi:10.1001/jamainternmed.2014.5479
Improvement has been anecdotally observed in patients with persistent postconcussion symptoms (PCS) after mild traumatic brain injury following treatment with hyperbaric oxygen (HBO). The effectiveness of HBO as an adjunctive treatment for PCS is unknown to date.
To compare the safety of and to estimate the efficacy for symptomatic outcomes from standard PCS care alone, care supplemented with HBO, or a sham procedure.
Design, Setting, and Participants
Multicenter, double-blind, sham-controlled clinical trial of 72 military service members with ongoing symptoms at least 4 months after mild traumatic brain injury enrolled at military hospitals in Colorado, North Carolina, California, and Georgia between April 26, 2011, and August 24, 2012. Assessments occurred before randomization, at the midpoint, and within 1 month after completing the interventions.
Routine PCS care was provided in specialized clinics. In addition, participants were randomized 1:1:1 to 40 HBO sessions administered at 1.5 atmospheres absolute (ATA), 40 sham sessions consisting of room air at 1.2 ATA, or no supplemental chamber procedures.
Main Outcomes and Measures
The Rivermead Post-Concussion Symptoms Questionnaire (RPQ) served as the primary outcome measure. A change score of at least 2 points on the RPQ-3 subscale (range, 0-12) was defined as clinically significant. Change scores from baseline were calculated for the RPQ-3 and for the total RPQ. Secondary measures included additional patient-reported outcomes and automated neuropsychometric testing.
On average, participants had sustained 3 lifetime mild traumatic brain injuries; the most recent occurred 23 months before enrollment. No differences were observed between groups for improvement of at least 2 points on the RPQ-3 subscale (25% in the no intervention group, 52% in the HBO group, and 33% in the sham group; P = .24). Compared with the no intervention group (mean change score, 0.5; 95% CI, −4.8 to 5.8; P = .91), both groups undergoing supplemental chamber procedures showed improvement in symptoms on the RPQ (mean change score, 5.4; 95% CI, −0.5 to 11.3; P = .008 in the HBO group and 7.0; 95% CI, 1.0-12.9; P = .02 in the sham group). No difference between the HBO group and the sham group was observed (P = .70). Chamber sessions were well tolerated.
Conclusions and Relevance
Among service members with persistent PCS, HBO showed no benefits over sham compressions. Both intervention groups demonstrated improved outcomes compared with PCS care alone. This finding suggests that the observed improvements were not oxygen mediated but may reflect nonspecific improvements related to placebo effects.
clinicaltrials.gov Identifier: NCT01306968
Although most military service members sustaining mild traumatic brain injury (mTBI) fully recover within 30 days,1 some report chronic symptoms following deployment-related injury.2-4 Common postconcussion symptoms (PCS) include headaches, balance problems, sleep disturbance, fatigue, forgetfulness, poor concentration, irritability, and anxiety.5,6 While symptom presentation is heterogeneous, data suggest that the frequency and severity of symptoms may be more related to concomitant emotional distress or pain than to a specific mechanism or severity of injury.7-11 Regardless of contributing factors, few established therapies exist for those with persistent PCS.12
Based on previous work for other neurological conditions, interest emerged in hyperbaric oxygen (HBO) as a potential treatment for chronic PCS.13,14 Clinicians observed improvement in mTBI symptoms following 40 HBO sessions at 1.5 atmospheres absolute (ATA) for 60 minutes.14 Subsequently, Harch et al15 demonstrated symptomatic and modest cognitive improvement in a case series of 15 service members with PCS using this regimen. These favorable anecdotes prompted the Department of Defense and the Department of Veterans Affairs to develop a clinical research program to evaluate the safety and efficacy of HBO by treating service members with persistent PCS in a series of randomized, sham-controlled trials.16 We report the symptom and quality-of-life outcomes from the largest and most rigorous of these preliminary clinical trials to date.
The study protocol was approved by the institutional review boards at the US Army Medical Research and Materiel Command and the University of Colorado, as well as local institutional reviews. All study volunteers signed written informed consent. The Hyperbaric Oxygen Therapy for Persistent Post-concussive Symptoms After Mild Traumatic Brain Injury (HOPPS) trial was designed as a 3-group, randomized, double-blind, sham-controlled trial to evaluate changes in baseline concussion symptoms after an intervention period of 8 to 10 weeks (Figure). The intervention groups included routine PCS care as practiced within the Department of Defense, routine PCS care supplemented with HBO at the dose of 1.5 ATA for 60 minutes administered weekdays for 40 sessions, and routine PCS care supplemented with an otherwise identical 40 sham sessions of room air pressurized to 1.2 ATA. Randomization used a permuted block method of 1:1:1, stratified by site. The study was conducted at 4 military hospitals using multiplace hyperbaric chambers under an investigational new drug application held by the US Army Office of the Surgeon General.17
The HOPPS trial participants were at least 18 years old and still serving in the military and were recruited through hospital-based TBI clinics, referrals from unit medical officers, or self-referrals. Interested service members contacted a civilian study hotline to learn about the study and screen for eligibility after verbal informed consent. Medical history, TBI history determined by a structured clinical interview (Ohio State University TBI Identification),18 and ongoing symptoms were self-reported. All participants required a history of 1 or more lifetime mTBIs with persistent symptoms, with at least 1 mTBI occurring during deployment to Operation Iraqi Freedom or Enduring Freedom and the most recent at least 4 months before randomization. Comorbidities, such as posttraumatic stress disorder (PTSD) or depressive symptoms, were assessed at enrollment and were not exclusionary, but medication use had to be stable for 30 days. Exclusion criteria included lifetime history of moderate to severe TBI, relative or absolute contraindications to HBO, or current drug abuse. Before randomization, each participant experienced brief chamber pressurization to assess for claustrophobia and ability to equalize ear pressure (eMethods 1 in the Supplement lists detailed inclusion and exclusion criteria).
Hyperbaric oxygen was administered daily in an air-filled multiplace chamber at 1.5 ATA for 60 minutes. Participants breathed 100% oxygen delivered by a hood designed for that purpose. Details of the procedure and blinding methods are described in eMethods 2 in the Supplement, and only chamber operators knew the chamber treatment allocation. The sham followed identical chamber procedures; however, the chamber was pressurized to 1.2 ATA (a depth previously shown to mask the pressurization process19), and participants breathed room air administered through the hoods. Participants completed 40 sessions within a 10-week period that allowed for other medical and job-related commitments. After completion, volunteers were asked via questionnaire to guess their assignment to HBO or air during chamber sessions.
Validated outcome measures for interventional trials in PCS are not established to date. The primary outcome was change in concussion symptom scores after the intervention using the Rivermead Post-Concussion Symptoms Questionnaire (RPQ), which queries about symptoms during the past 24 hours compared with preinjury health.20,21 Because no validated change scores exist, we prespecified a cutoff of a 15% improvement that we deemed clinically relevant, translating to a change score of at least 2 points on the RPQ-3 subscale (score range, 0-12). Change scores over time in patient-reported outcomes are anchored individually from the baseline values, and a positive change indicates a favorable response by convention.
Secondary self-reported symptom outcomes included the Neurobehavioral Symptom Inventory, which asks about symptoms during the past 2 weeks without any pre-TBI comparison,22,23 as well as patient-reported outcomes focusing on specific domains (eMethods 3 in the Supplement). One study objective was to define change scores for the Neurobehavioral Symptom Inventory for further validation. A battery of neurocognitive tests was assessed using the Automated Neuropsychological Assessment Metrics (Automated Neuropsychological Assessment Metrics, version 4, TBI Military battery).24,25 Traditional neuropsychological testing results will be published separately.
Outcomes were administered at baseline and after completion of 40 chamber sessions (or at 10 weeks if all sessions were not completed). The PCS questionnaires and the Automated Neuropsychological Assessment Metrics, version 4, were also administered after 20 sessions to explore the number of required sessions. Measures were administered in a standardized order by research coordinators and neuropsychometrists blinded to allocation. The assessment team monitored for symptoms of heightened stress or suicidal thoughts using the University of Washington Risk Assessment Protocol.26
This phase 2 trial was designed to enable a preliminary assessment of safety and feasibility, and no formal sample size calculation for efficacy was performed. The change score of at least 2 points on the RPQ-3 subscale (measuring headaches, dizziness, and nausea) was selected to establish a point estimate and refine the sample size requirements for future studies. Allowing for an anticipated dropout rate of 20%, a group size of 24 volunteers was selected to provide sufficient power (>80%) to detect a 50% difference in volunteers achieving that threshold in this pilot study.21
Descriptive statistics summarize the population enrolled, including baseline characteristics of each intervention group. Frequencies and percentages are reported for categorical data. Means, medians, and SDs are reported for continuous data. Comparisons of the primary and secondary outcomes were performed using paired t test. Change from baseline scores was compared using Wilcoxon signed rank test. The percentage of volunteers achieving a change score of at least 2 points on the RPQ-3 subscale was compared using Fisher exact test. Because this was a phase 2 trial designed to explore outcome measure performance, no correction for multiplicity was performed. Analyses were conducted using statistical software (SAS, version 9.2; SAS Institute). Reported P values are 2-sided, and P < .05 was considered significant.
Two hundred eighty-six individuals contacted the hotline, and 190 were referred to the site research teams; 163 service members provided informed consent and were screened, and 72 were eligible and randomized (Figure). Enrollment started April 26, 2011, at the following 4 sites: Fort Carson, Colorado; Camp Lejeune, North Carolina; Camp Pendleton, California; and Fort Gordon, Georgia. The last study visit occurred August 24, 2012.
The baseline characteristics of the 3 intervention groups were similar (Table 1). The median age was 31 years, 96% were men, and 94% were enlisted. Nineteen percent had a college degree. They had experienced a mean of 3 lifetime concussion events, with the most recent mTBI occurring on average 23 months before randomization. Comorbidities were common. Using the PTSD module of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition), 66% met criteria for PTSD. Concurrent interventions for PCS and PTSD showed no difference between groups, although medications were used liberally for pain, sleep, and anxiety. Only 24% had entered into the Department of Defense medical disability process for possible separation from military service.
Two participants experienced an additional mTBI during the 10-week study period. Their data are included in the primary analyses. Eight individuals were unable to complete the study, as outlined in the Figure. In addition, owing to conflicts with medical appointments or work schedules, some participants could not complete all 40 planned chamber sessions within the allotted 10-week period. The number of chamber sessions completed did not differ between the sham and HBO groups (eFigure 1 in the Supplement). All randomized participants were included in the intent-to-treat analysis, while only those completing all 40 chamber sessions and outcomes testing were included in the per-protocol analysis.
The group randomized to no supplemental chamber intervention showed no improvement during the 3-month observational period, with a mean RPQ-3 subscale change score of 0.0 (95% CI, −1.0 to 1.0; P = .97) and a mean total RPQ change score of 0.5 (95% CI, −4.8 to 5.8; P = .91) (Table 2). The group receiving HBO improved symptomatically, with mean change scores of 1.2 (95% CI, 0.0 to 2.4; P = .04) on the RPQ-3 subscale and 5.4 (95% CI, −0.5 to 11.3; P = .008) on the total RPQ. The group receiving sham sessions also improved on the RPQ-3 subscale (mean change score, 1.5; 95% CI, 0.1-2.9; P = .03) and on the total RPQ (mean change score, 7.0; 95% CI, 1.0-12.9; P = .02). Among those in the no chamber intervention group, 25% (95% CI, 11% to 47%) met the prespecified change of at least 2 points on the RPQ-3 subscale. While greater, no meaningful differences (P = .24) were detected in the percentage who met the prespecified change of at least 2 points between the HBO group (52%; 95% CI, 33% to 71%) and the sham group (33%; 95% CI, 17% to 55%). Favorable change scores on the total RPQ were higher for the HBO group but no difference between the HBO group and the sham group was observed (P = .70). The magnitude of symptom improvement was greater among those who completed all 40 chamber sessions, with no difference (P = .95) in change scores between the HBO group (11.0; 95% CI, 3.2-18.8) and the sham group (10.7; 95% CI, 3.9-17.5). An exploratory analysis showed that most improvement occurred within the first 20 chamber sessions of either chamber intervention (eFigure 2 in the Supplement).
The Neurobehavioral Symptom Inventory scores, measuring concussion-related symptoms during the past 2 weeks, showed slight worsening from baseline in the no chamber intervention group (−1.1; 95% CI, −7.3 to 5.2) compared with the mean symptom improvement after chamber interventions (3.7; 95% CI, −3.7 to 11.2 for the HBO group and 6.9; 95% CI, 1.4-12.4 for the sham group) (Table 3). These change scores were not statistically different (P = .49). Analysis of the Neurobehavioral Symptom Inventory cognitive, affective, and somatic symptom subscales showed no differential clustering of change effects between the 2 chamber interventions. The PTSD symptoms improved after the interventions, favoring the sham group (mean change, 11.4; 95% CI, 5.9 to 16.9) over the HBO group (mean change, 5.0; 95% CI, −1.7 to 11.6).
The patient-reported outcomes of depression, generalized anxiety, pain, and sleep are listed in Table 4. Improvements in change scores trended in favor of the sham group for all measures compared with the HBO group. Health-related quality-of-life outcomes (physical functioning, bodily pain, social functioning, and emotionality domains on the 36-Item Short Form Health Survey [SF-36]) improved, also favoring the sham group over the HBO group. The Global Satisfaction With Life Scale demonstrated similar improvement with both chamber interventions compared with routine PCS care.
No statistical differences were observed between the 2 treatment groups at baseline or on change from baseline scores in any of the cognitive testing measured by the Automated Neuropsychological Assessment Metrics, version 4, standardized throughput scores after 10 weeks. These results are summarized in Table 4.
Two individuals withdrew from the study before chamber sessions were initiated owing to time commitments, leaving safety populations of 24 in the HBO group and 23 in the sham group. The HBO and hyperbaric air sham sessions were well tolerated. No serious adverse events occurred, although 2 adverse events (claustrophobia and worsening of intensity and frequency of headaches) were troubling enough for participants to withdraw from chamber sessions. Fourteen adverse events were attributable to the hyperbaric procedures, equally distributed between the HBO and sham groups (eTable in the Supplement). No participant reported cognitive decline or increased suicidal thoughts.
Pilot efficacy trials serve many purposes, including to develop the safety and tolerability of a product, to develop a point estimate for efficacy in the study population for sample size determinations in pivotal trials, and to refine and validate outcomes measures. At times, surprising outcomes data are generated. Our results support the conclusion that supplemental administration of breathing 100% oxygen at 1.5 ATA (HBO procedure) or air at 1.2 ATA (sham procedure) for 60 minutes is well tolerated and improves symptoms and quality of life compared with local care management of PCS without chamber intervention. However, we observed no difference between HBO and sham. We postulate that improvement in the chamber intervention groups was due to placebo effects or the potential benefit of daily interactions with the study staff.
The test article in this study (HBO at 1.5 ATA) increases oxygen tension in plasma to approximately 1000 mm Hg27 and in brain tissue approximately 3-fold28 despite oxygen-induced vasoconstriction. The HBO also alters regulation of blood flow for a period thereafter.15 Anecdotes and case series have described improvements in PCS and PTSD symptoms and cognitive performance after varying numbers of HBO sessions.13-15,29 Based on these observations, Harch and colleagues15 postulated that HBO heals the brain, speculating on mechanisms akin to soft-tissue healing of chronic hypoxic diabetic wounds described by Warriner and Hopf.30 A recent randomized, wait-list, crossover study29 demonstrated improvements that were owing to aspects of the hyperbaric chamber procedure, although the protocol was not designed to assess if oxygen or other facets of the procedure contributed. Unfortunately, these studies lack adequate control designs to prove that the observed benefits are due to pharmacological effects of HBO rather than nonspecific treatment effects.
This double-blind, randomized clinical study was designed to determine the effect size of the symptomatic improvements by HBO delivered at 1.5 ATA compared with a sham delivery of pressurized room air at 1.2 ATA when supplementing routine mTBI care. A second control group that received mTBI care without chamber intervention was included to evaluate the magnitude of the expected placebo effects from this complex procedure. The design of the procedural blind in studies with self-reported outcomes is critical to managing bias and is described in detail elsewhere.16
Taken as a solitary finding in a small multicenter study, concerns about a type II error are valid. However, similar results were obtained in simultaneously conducted, single-site, randomized clinical trials using alternate HBO doses and sham designs.31-34 Wolf et al31 also observed improvement in PCS in a military population undergoing 30 chamber sessions at a higher pressure dose than we offered. Volunteers were randomized to receive HBO at 2.4 ATA for 90 minutes or a sham procedure of room air pressurized to 1.3 ATA, slowly falling to 1.2 ATA. Outcome measures included a concussion computerized battery and the Post-traumatic Disorder Check List–Military Version. Postintervention outcomes demonstrated no significant differences in PCS or PTSD symptom improvement. Cifu and colleagues32 conducted a single-site, dose-ranging study among symptomatic concussed marines who relocated to Pensacola, Florida, for 40 hyperbaric sessions. This 3-group randomized clinical trial evaluated an intervention of daily 2.0 ATA pressurizations of 60 minutes’ duration. Volunteers were randomized to 100% oxygen, 75% oxygen (an oxygen tension equivalent to 1.5 ATA used in this study), or 10.5% oxygen (an oxygen tension equivalent to breathing room air at sea level). Overall, modest improvement in symptoms was observed, suggesting that the benefit was not a pressurization effect32 and that HBO was not superior to oxygen dosing equivalent to room air. No evidence of symptomatic improvement was manifest on reevaluation after 3 months.33 Likewise, no statistical improvements were observed in neurological, balance, or cognitive outcomes from HBO over those observed in the sham procedure group.34
How do we reconcile the anecdotes with the outcomes from a series of small randomized clinical trials? One of the strengths of this study is the inclusion of a routine care PCS group, which allows conclusions to be drawn regarding the observed symptomatic improvement that may occur following participation in daily chamber sessions (HBO or sham) during 8 to 10 weeks in addition to routine mTBI rehabilitation. The observed improvement after chamber sessions is most likely due to placebo responses from the intensive rituals of these repetitive medical procedures. Similar responses have been observed owing to participation in sham acupuncture therapies, which have been associated with substantial response in pain reduction and improved quality of life.35 Injection placebos are generally more active than pill placebos in migraine investigations.36 The hyperbaric chamber procedure in a research study is an intense ritual experience consisting of 2 hours of daily social interactions with a dedicated team of nurses and hyperbaric technicians, as well as other participants, in the multiplace hyperbaric chamber. This experience likely triggered a marked placebo response.
It has been argued that the sham designs used in this trial and other Department of Defense studies are not inert and represent dose-ranging trials of pressurized air.37 We recognize that a sham is not inert, and we cannot completely discount the physiological effects of minimal increases in nitrogen or oxygen from pressurized room air. However, we believe it is biologically implausible that air at 1.2 ATA (equivalent to 2 m of seawater pressure) has a beneficial effect on healing the damaged brain remotely after mTBI. The study by Cifu et al,32 which varied pressure, oxygen, and nitrogen, demonstrated no dose-response effect to suggest that the sham responses are due to gas or pressure. Placebo responses are more likely, but unfortunately our study was not designed to evaluate the components of a placebo response such as response expectancy, verbal suggestion, and stimulus conditioning.38 This is an area for further research.
Our trial was not an efficacy trial but rather a pilot study designed to define significant PCS change scores and to determine an effect size to inform sample sizes for potential pivotal trials. The multicenter design improves the generalizability of the findings, but they remain restricted to symptomatic military populations. An additional concern is the absence of validation of a PCS score and defined responsiveness (clinically relevant change scores), but a lack of difference between HBO and sham across all the evaluated domains suggests that the findings are not test specific. A confirmatory trial intended to validate the selected outcome measures is under way (clinicaltrials.gov identifier NCT01611194).
Among service members with PCS, HBO showed no benefits over an air sham compression procedure, but symptoms in both groups improved compared with mTBI care without supplemental chamber interventions. This outcome suggests that the observed improvements were not oxygen mediated but may reflect nonspecific improvements related to placebo effects. Taken with results from other concurrent investigations, our study does not support phase 3 trials of HBO for the treatment of PCS at this time.
Accepted for Publication: July 28, 2014.
Corresponding Author: R. Scott Miller, MD, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd, Bethesda, MD 20814 (email@example.com).
Published Online: November 17, 2014. doi:10.1001/jamainternmed.2014.5479.
Author Contributions: Dr Miller and Mr Hetzell had full access to all the data and take responsibility for the integrity of the data and accuracy of the data analysis.
Study concept and design: Miller, Weaver, Bahraini, Churchill, Deru, Ricciardi, Fracisco, Close, Brenner.
Acquisition, analysis, or interpretation of data: Weaver, Bahraini, Churchill, Price, Skiba, Caviness, Mooney, Hetzell, Surrett, Bartos, Ryan, Brenner.
Drafting of the manuscript: Miller, Weaver, Hetzell, Deru, Brenner.
Critical revision of the manuscript for important intellectual content: Miller, Weaver, Bahraini, Churchill, Skiba, Mooney, Hetzell, Deru, Brenner.
Statistical analysis: Miller, Hetzell, Liu.
Obtained funding: Miller, Weaver, Ricciard.
Administrative, technical, or material support: Miller, Weaver, Bahraini, Churchill, Deru, Fracisco, Close, Brenner.
Study supervision: Miller, Weaver, Churchill, Brenner.
Conflict of Interest Disclosures: None reported.
Funding/Support: The HOPPS trial was funded by the Defense Health Program and was managed by the US Army Medical Materiel Development Activity. The Naval Health Research Center and Army Contracting Command contracted support throughout this trial.
Role of the Funder/Sponsor: The sponsor of this trial is the US Army Office of the Surgeon General, who holds the investigational new drug application for hyperbaric oxygen to treat traumatic brain injury. The sponsor’s representative is the US Army Medical Research and Materiel Command. The sponsor had no role in the design of the study and provided support staff to ensure good clinical practice compliance. The sponsor and representative had the right to review the manuscript but had no authority to change any aspect of it.
Group Information: The HOPPS Trial Team Investigators were the following: Recruiting Center, Hyperbaric Medicine Department, LDS Hospital: Susan Churchill, Kayla Deru, and Kate Hak. Fort Carson Army Community Hospital: Heidi Terrio, Laura Grogan, Mike Anderson, and Simon Robertson. Naval Hospital Camp Lejeune: Jason Gordon, Dan Lesley, Tom Johnson, and Dawn Mitchell. Naval Hospital Camp Pendleton: Peter Zamfirescu, Scott Sparks, Illy Dominitz, Stephen Fischer, Jason Roby, James Chung, Lisa Tangredi, and William Howes. Eisenhower Army Medical Center: Joel Raintree, Michael Madsen, Jack Rigg, Austin Chhoeu, Otto Boneta, Eric Helling, Eric Martin, Herb Yeager, and Matthew Salak. Veterans Integrated Service Network 19: Maria Devore and Leah Russell. Henry M. Jackson Foundation: Jami Egan, Mark Greeder, Jennifer Gardino, Caron Wilbur, Kris Spalloni, Barbara Mayhugh, Tiffany Cripps, Ashlea Raynor, Karen Bartku, Linda Corkhill, Delia Marshall, Kilwanna Bush-Brown, Nancy Sickafoose, Rachael Anderson, and Alayna Capo. OxyHeal Health Group: Dana Hahn, Phil Treadway, Debbie Treadway, John Gross, Robert Samonte, James Rife, Michael Eastman, Dustin Halper, Eddie Johnson, Mike Fogie, Arturo Morales, Carlos Lewis, Daniel Jarmillo, Nicole Garrett, and Preston Burrell. Regulatory: Cheryl Dicks, Belinda Wagner, and Kevin Marrs. Clinical Operations: Lorena DiRienzo, Melissa Askin, Shannon Berg, Ernest Yribe, Kirsten Smith, Jim Bell, and Brendan Murphy. Data and Safety Management: Devin Hunt, Dixion Rwaksyaguri, and Doug Domalik. Administrative Support: Kyle Martin, Ilka DeLeon, Krista Mormon, and Christie Lawrence.
Disclaimer: The authors are solely responsible for the content of this article, which does not necessarily reflect the views of the US Army, the US Navy, the Department of Defense, or the Department of Veterans Affairs.
Additional Contributions: OxyHeal Health Group supported the installation, maintenance, and use of the additional hyperbaric chambers used in this study. We thank our study service members who not only sacrificed in combat in defense of our country but volunteered to help others struggling from the effects of traumatic brain injury and posttraumatic stress disorder.