Hyperbaric Oxygen for 

SMs with PCS after mTBI: 

A Randomized, Double-Blinded, Sham-Controlled, 

Variable Dose Prospective Trial

David X. Cifu, MD

Herman J. Flax, MD Professor and Chairman

Department of PM&R

Virginia Commonwealth University

National Director

PM&R Program Office

Department of Veterans Affairs
Poll Question #1

• What is your primary role in VA? 

– student, trainee, or fellow

– clinician

– researcher 

– manager or policy-maker 

– Other 
Use of HBO2 : Animal Research 

• Systemic review of animal (rodent, cat, dog) 

research supports HBO2 use in acute TBI

• Acutely, HBO2 significantly 

• Reduces acute cerebral edema 

• Reduces markers of cerebral inflammation

• Increases cerebral perfusion 

• Enhances spatial learning / task

• Also shown to enhance cognitive outcomes in 

chronic moderate-severe TBI
Use of HBO2 : Animal Research 

• Caveats in examining animal literature:

• HBO2 treatment initiation 

• Animals usually begun minutes to 2 hours post injury 

• Humans usually 6+ hours to days post-injury 

• No HBO2 research in mTBI (acute or chronic)

• mTBI animal model lacking and PCS hard to 

understand in animal

• No direct translation of animal TBI work to 

humans
Use of HBO2 : Human Research 

• Four Systematic Reviews

• Included 23 publications (1972-2001)

• Only four studies (382 subjects, 199 HBO2 & 183 

controls) met review criteria for scientific evaluation

• Assessed acute, traumatic, moderate-severe TBI

• Concluded current scientific evidence insufficient to 

prove effectiveness / ineffectiveness of HBO2 for TBI

• Two reviews and two trials published since 2001.
Use of HBO2 : Human Research 

• Summary of acute human usage (in severe 

TBI): 

• One trial showed trend (P < 0.08) towards favorable outcome 

at 1.5 years post-injury.

• Three trials showed a significant reduction (RR 0.69, 

95%CI 0.54-0.88) in risk of dying (mortality) with 

‘numbers needed to treat’ being 7.

• No reduction in coma persistence or duration. 

• Enhanced mortality seems to be related to effects 

on ICP and pulmonary status
Use of HBO2 : Human Research 

• Caveats of Human Literature:

• Overall study quality assessed as low

• No sham therapy included

• Randomization inadequate

• Blinding not used

• Non-standard inclusion criteria across trials

• No scientifically rigorous human research has 

been published in acute mild/moderate TBI or 

chronic TBI of any severity. 
Current Clinical Trials in the DoD and VA

• There are presently 4 DoD supported HBOT trials 

for persistent symptoms after mTBI.

– Pilot study (HBOT vs Sham) completed : No effect

– Pilot study (outcome measure validation) completed

– Pilot study (HBOT [2 dose] vs Sham) underway –

completed

– Definitive trial begun January 2012

• There is also 1 non-DoD open-label trial (Harch – 

LSU) underway.

– Non-randomized

– No sham or control
Richmond-Pensacola HBO2 Study

Design: 

• Three arm, single-center, double blinded, dose-ranging study with 

sham control

• Randomly assigned to one of three conditions

• 10.5 % at 2 ATA to mimic Sham Air; 75% O2 at 2ATA to mimic 

 1.5ATA at 100% O2; versus100% O2 at 2.0 ATA 

• 40 exposures of 60 minutes each on separate days over 8-10 weeks

• Block randomization to minimize differential effects over time

Population: 

• 60 active duty Marines

• mTBI in last three years (M-8.5 mos, range 3-39 mos) 

• Mean age= 23.2 (SD=2.95)

• 97% of group was E1-E6 

9 
Outcome Measures

Primary: 

• Rivermead Postconcussive Questionnaire (RPQ)

• 16 Likert-type scale items 

Secondary: 

• PTSD Checklist Military (PCL-M) 

• 17 Likert-type scale items

• Both instruments are self-report measures

• Lower score indicates improvement

Tertiary: 

• CPT balance, eye tracking, neuropsychological testing 
Sample Selection

• Recruited primarily at MCB Camp Lejeune

• Inclusion Criteria

– Sustained mTBI in past 3 months to 3 yrs

– Post-Concussion Syndrome (PCS) present

– Stable psychiatric & psychotropic medication status

• Exclusion Criteria

– Moderate or severe TBI

– Prior exposure to HBO2 (hyperbaric oxygen)

– Contraindications to HBO2 (such as pulmonary “air 

trapping condition)

11
12

128 Screened for Eligibility

59 Excluded

 30 Refused to Participate

 29 Failed to Meet Inclusion Criteria

61 

Randomized

21 Randomized to Sham Condition

 21 Received Intervention as Assigned

21 Randomized to 1.5 ATA Condition

 21 Received Intervention as Assigned

19 Randomized to 2.0 ATA Condition

 19 Received Intervention as Assigned

21 Assessed at 2-week Follow-Up

 

20 Assessed at 12-week Follow-Up

 1 Lost to Follow-Up; Not located

21 Included in This Analysis

21 Assessed at 2-week Follow-Up

 

20 Assessed at 12-week Follow-Up

 1 Lost to Follow-Up; Declined Participation

21 Included in This Analysis

18 Assessed at 2-week Follow-Up

 1 Lost to Follow-up; Unavailable 

19 Assessed at 12-week Follow-Up

 

19 Included in This Analysis
Sample (n=61) characteristics

• Demographics 

– Age mean 23.3 years (SD=3.24). 

– 20 (33%) married, 3 (5%) divorced, and 38 (62%) single. 

– All were Marines and 97% had E1-E6 pay grades. 

– ANOVA and chi square analysis: no between group differences

• All had >= one mTBI during deployment from blast

– 85% from improvised explosive device (IED)

– 3.0% from rocket propelled grenade,

– 1.7% from mortar attack

– 10% not categorizable. 

– At “pre” assessment s participants were mean 8.5 months (SD= 6.6, 

range= 3-39) after most recent (or only) mTBI 13
Results

• There were no differences between any of the groups on any 

aspect of the primary outcome measure (RPQ), including subscales 

RPQ-3 and RPQ-13

• - within group comparisons (pre/post) were not significant 

• No differences between any of the groups on the total score of the 

secondary measure (PCL-M)

• Within group differences (pre/post):

• Sham: 6.7 point improvement

• HBO2 1.5 ATA: 6.2 point improvement

• HBO2 2.0 ATA: 13.9 point improvement (statistically 

improved)

One-way ANOVA conducted on total RPQ score, subscales RPQ-3 and RPQ-13, and all individual items

One-way ANOVA conducted on total PCL-M score
Results

RPQ Sub-analysis: Within group differences 

on individual symptoms

• Sham group showed no significant differences 

between pre-post compression scores

• 1.5 ATA equivalent group showed a significant 

increase (worsening) in light sensitivity 

• 2.0 ATA equivalent group showed a significant 

decrease (improvement) on noise sensitivity and 

frustration/ impatience

robert.s.miller@us.army.mil FOUO (PRE-DECISIONAL: DO NOT RELEASE) 15
Results

PCL-M Sub-analysis: Within group differences 

on individual symptoms 

• Sham group showed significant improvement on super 

alertness/watchfulness and being easily startled between 

pre-post compression scores

• 1.5 ATA equivalent group showed a significant 

improvement on super alertness/watchfulness

• 2.0 ATA equivalent group showed a significant 

improvement on being upset when reminded of a 

stressful event, super alertness/watchfulness and total 

score
Results

• Secondary Outcomes: There were no differences 

between any of the groups on any aspect of the 

secondary outcome measures, including subscales 

neuropsychological tests, balance testing and eye 

tracking. 

• There were interactions between changes in the 

RPQ and the descriptive and secondary outcome 

measures, however this was not influenced by the 

intervention group they were in.
Statistical Methods

• Repeated measures mixed-effect model was used to determine 

efficacy of outcomes

• Primary hypothesis: RPQ-16 scores differ between intervention groups 

(Sham, 1.5 ATA, 2.0 ATA) across time points (0 wks, 1 wks, 12 wks)

• Model included all of the explanatory variables as well as time (0 wks, 

1 wks, 12 wks), intervention group (Sham, 1.5 ATA, 2.0 ATA), and the 

interaction between time and intervention group.

• Evidence of intervention efficacy was determined if the parameters 

corresponding to the interaction term were non-zero at the 0.05 level

• This model is adjusted for following subjects longitudinally, through an 

unstructured covariance structure and a random effect accounting for 

the cohort

18
Variable Level Sham 1.5 ATA 2.0 ATA P

Blast Exposure High (≥ 4) 8 (38%) 8 (38%) 6 (32%) 0.887

Low (< 4) 13 (62%) 13 (62%) 13 (68%)

LOC Yes 8 (38%) 12 (57%) 6 (32%) 0.231

No 13 (62%) 9 (43%) 13 (68%)

PTA Yes 13 (62%) 15 (71%) 8 (42%) 0.161

No 8 (38%) 6 (29%) 11 (58%)

PTSD Yes (PCL ≥ 50) 6 (29%) 6 (29%) 10 (53%) 0.359

No (PCL < 50) 15 (71%) 15 (71%) 9 (47%)

TOMM Pass 19 (90%) 18 (86%) 14 (74%) 0.340

Fail 2 (10%) 3 (14%) 5 (26%)

Time Elapsed ≤ 6 mos 11 (52%) 9 (43%) 11 (58%) 0.627

> 6mos 10 (48%) 12 (57%) 8 (42%)

Drinking Status High Risk 11 (52%) 11 (52%) 11 (58%) 0.923

Low Risk 10 (36%) 10 (48%) 8 (42%)

Previous Head Injury Yes 3 (15%) 6 (32%) 7 (33%) 0.349

No 17 (85%) 13 (68%) 14 (67%)

Age 24 (1.2) b 22.9 (2.9) b 22.9 (3.3) b 0.326a

WTAR (baseline) 33.9 (6.1) b 32.9 (6.5) b 34.0 (6.0) b 0.828a

McGill Score (baseline) 11.9 (8.3) b 12.0 (6.0) b 10.4 (8.8) b 0.780a

Explanatory variable distribution by intervention group

19
Explanatory Variable F-ratio(df1, df2) P-value

Time 0.9 (2, 55.5) 0.426

Intervention Group 0.5 (2, 47.2) 0.590

Blast Exposure 2.6 (1, 48.2) 0.112

PTA 4.8 (1, 48.4) 0.033

LOC 0.9 (1, 48.1) 0.350

PTSD 7.3 (1, 48.5) 0.009

Injury Elapse 2.4 (1, 48.3) 0.131

Alcohol Use 1.5 (1, 129) 0.219

Age 0.0 (1, 50.1) 0.925

Previous Head Injury 0.0 (1, 48.1) 0.937

McGill 33.4 (1,143) <0.001

WTART 1.2 (1,119) 0.278

TOMM 0.1 (1, 47.7) 0.730

Explanatory variable main effects on RPQ-16.

20
RPQ-16 by intervention group over time (baseline, 1 wk, 3 month)

Time by intervention group effect = (F(4, 63.7)=1.0, P=0.410) 21
Predictor F-ratio (df1, df2) P

RPQ-3 0.7 (4, 64.0) 0.592

RPQ-13 1.0 (4, 63.8) 0.400

Mayo 0.6 (4, 62.8) 0.702

Balance (SOT) 1.0 (4, 58.9) 0.443

WAIS 1.8 (4, 59.4) 0.141

Trail-Making B 0.7 (4, 64.9) 0.621

Stroop 0.6 (4, 60.2) 0.664

CPT-II 0.6 (4, 60.9) 0.685

CVLT Long Delay Free Recall 0.8 (4, 63.1) 0.523

PASAT 1.4 (4, 52.9) 0.256

BVMT Delay Recall 0.5 (4, 62.3) 0.753

COWAT 1.6 (4, 64.1) 0.197

Grooved Peg Board 0.5 (4, 47.5) 0.724

SWLS 0.5 (4, 61.2) 0.751

Depression (CESD) 0.5 (4, 63.8) 0.767

GOSE 0.8 (4, 57.7) 0.503

Hypothesis tests for secondary outcomes (treatment 

by time interaction)

22
Explanatory Variable F-ratio(df1, df2) P

Blast Exposure 0.57 (4, 62.8) 0.685

PTA 1.00 (4, 62.9) 0.416

LOC 0.20 (4, 63.4) 0.938

PTSD 0.13 (4, 63.9) 0.971

Injury Elapse 0.67 (4, 63.1) 0.618

Alcohol Use 0.27 (4, 65.4) 0.898

Age 0.78 (4, 69.3) 0.539

Previous Head Injury 2.06 (4, 62.1) 0.097

McGill 0.12 (4, 72.6) 0.975

WTAR 0.67 (4, 69.1) 0.618

TOMM 0.83 (4, 66.5) 0.510

Hypothesis tests for subgroup efficacy analysis (RPQ-16) 

[3 way interaction between explanatory variable, time, and treatment group]

23
Results

• RPQ was influenced by a number of secondary factors, 

however was not influenced by intervention group.

– RPQ decreased over time

– RPQ was higher when there was a marker of more significant mTBI (# 

of blast-related mTBI, presence or absence of PTA)

– RPQ was higher when there was an increased report of body pain.

– RPQ was higher when there was evidence of PTSD
Results

• There were interactions between changes in the RPQ and the descriptive and 

secondary outcome measures, however this was not influenced by the 

intervention group they were in. 

• In the full analyses of secondary outcomes there was significant main effects 

for:

• Time on multiple neuropsychological tests (WAIS III working memory, Trails 

B, CVLT LD Free Recall, PASAT 2.0 sec, BVMT Del Recall, COWAT Let 

Fluency). These tests improved over time but were not influenced by group.

• LOC for SOT (computerized posturography). Worsened if subject had more 

mTBI or longer PTA but not influenced by group.

• # Blast Exposures for Trails B. Worsened if subject had more mTBI or longer 

PTA but not influenced by group.
Conclusions

• Study duplicated total oxygen doses most often used clinically, and 

recommended by advocates 

• No main-effect treatment differences in post-concussion symptoms 

were found between sham compression, 1.5 ATA or 2.0 ATA groups

• In addition to the expected significant association between PCS and 

PTSD symptom measures there was also an association between PCS 

and Pain (McGill) and mTBI with PTA versus without PTA status

26
1

TITLE: The Effect of Hyperbaric Oxygen on Persistent Post‐Concussive Symptoms

RUNNING TITLE: The Effect of Hyperbaric Oxygen on Persistent Post-Concussive Symptoms 

AUTHORS: David X. Cifu, MD1,2,3

 National Director, PM&R Program Office, Department of Veterans Affairs 

 Chairman and Professor, Department of PM&R, Virginia Commonwealth 

 University, 1223 East Marshall Street, Richmond, Virginia 23298 

 Office: 804-828-4231 

 FAX: 804-828-6755 

 Email: dcifu@vcu.edu

Brett B. Hart, CAPT, MC, USN4

Hyperbaric Medicine Department, Naval Medicine Operational Training Center 

220 Hovey Road, Pensacola, Florida, 32508 

Office: 850-452-3297 

 FAX: 850-452-4541 

Email: Brett.Hart@med.navy.mil 

Steven L. West, PhD2 

Associate Professor, Department of PM&R, Virginia Commonwealth University 

 1223 East Marshall Street, Richmond, Virginia 23298 

 Office: 804-827-2562 

 FAX: 804-828-6755 

Email: slwest2@vcu.edu

William Walker, MD2,3,5 

Professor, Department of PM&R, Virginia Commonwealth University 

 1223 East Marshall Street, Richmond, Virginia 23298 

 Office: 804-828-4231 

 FAX: 804-828-6755 

Email: wcwalker@vcu.edu

William Carne, PhD2,3,5

 Assistant Professor, Department of PM&R, Virginia Commonwealth University 

 1223 East Marshall Street, Richmond, Virginia 23298 

 Office: 804-828-4231 

 FAX: 804-828-6755wilford hall 

 Email: lasile@aol.com

1

PM&R Program Office, Department of Veterans Affairs, Washington DC 

2

Department of PM&R, Virginia Commonwealth University, Richmond, VA 

3

Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, VA 

4 Naval Medicine Operational Training Center, Pensacola, FL 5

Richmond Defense and Veterans Brain Injury Center, Richmond, VA 
2

CORRESPONDENCE TO: David X. Cifu, MD 

Department of Physical Medicine and Rehabilitation 

1223 East Marshall Street 

Richmond, VA 23298-0677 

Office: 804-828-4231 

FAX: 804-828-6755 

Email: dcifu@vcu.edu

Funding was provided for the primary study by a Defense Advanced Research Projects Agency 

grant (N66001-09-2-206), U.S. Navy Bureau of Medicine and Surgery for contract funding 

temporary duty requirements, and the U.S. Army Medical Materiel Development Activity for 

end of study contract funding. Dr. Carne’s and Walker’s efforts were additionally supported 

through a contract from the Defense and Veterans Brain Injury Center. The funding sources had 

no role in the study design, analysis, interpretation of the data, the writing of the paper, or the 

decision to submit the paper for publication. 

Disclaimer: The views expressed herein do not necessarily represent the views of the Department 

of Veterans Affairs, Department of Defense, or the U.S. Government.
3

Abstract 

The effects of hyperbaric oxygen (HBO2) on persistent post-concussion symptoms in 60 military 

service members with at least one combat-related, mild traumatic brain injury were examined in 

a single-center, double-blind, randomized, sham-controlled, prospective trial at the Naval 

Medicine Operational Training Center (NMOTC) at Naval Air Station Pensacola. Over a 10-

week period, subjects received a series of 40, once daily, hyperbaric chamber compressions at 

2.0 atmospheres absolute (ATA). During each session, subjects breathed one of 3 pre-assigned 

oxygen fractions (10.5%, 75%, or 100%) for 60 minutes, resulting in an oxygen exposure 

equivalent to breathing surface air, 100% oxygen at 1.5 ATA or 100% oxygen at 2.0 ATA, 

respectively. Individual, subscale and total item responses on the Rivermead Postconcussive 

Symptom Questionnaire (RPQ) and individual and total Post-Traumatic Disorder Check ListMilitary Version (PCL-M) were measured just prior to intervention and immediately postintervention. Between groups testing of pre- and post-intervention means revealed no significant 

differences on individual or total scores on the PCL-M or RPQ, demonstrating a successful 

randomization and no significant main effect for HBO2 at 1.5 ATA or 2.0 ATA equivalent 

compared with the sham compression. Within group testing of pre- and post-intervention means 

revealed significant differences on three individual items and 2.0 ATA HBO2 PCL-M total score. 

This study demonstrated that HBO2 at either 1.5 or 2.0 ATA equivalent had no effect on postconcussive symptoms after mild TBI when compared with a sham compression. 

Key words: hyperbaric oxygen therapy, traumatic brain injury, post-concussive syndrome 
4

INTRODUCTION 

With the onset of the Afghanistan and Iraq Wars in October 2001, the U.S. Departments 

of Defense (DoD) and Veterans Affairs (VA) have established a worldwide system of care to 

assess and manage the significant numbers of service members (SMs) and Veterans who have 

sustained mild traumatic brain injury (mTBI).1

 Aggregated screening data of all Operation 

Enduring Freedom (OEF; Afghanistan War) and Operation Iraqi Freedom (OIF; Iraq War) 

Veterans enrolled in the VA system of care through 2011 reveal that 9.6% experienced at least 

one mTBI during their deployments.2

 Of note, more than 90% of these individuals have at least 

one concomitant secondary diagnosis (e.g., post-traumatic stress disorder (PTSD), pain) that may 

confound both the clinical presentation and subsequent treatment.2,3 This condition has been 

labeled Post-Deployment Multi-Symptom Disorder,4 or more commonly Post-Deployment 

Syndrome5 and may be one of the reasons for the higher rate of persistent post-concussive 

syndrome (PPCS) in military personnel compared to civilian individuals.3 The broad range and 

high frequency of various symptoms is the clinical hallmark of these syndromes. Additionally, 

many in the military have had repetitive blast exposures, potentially with associated head trauma 

and associated cumulative brain injury, that may further complicate symptom attribution and 

recovery.6

 

In an effort to evaluate the effectiveness of innovative treatments for the array of 

symptoms seen with PPCS in U.S. combatants, the DoD and VA have developed an initiative 

involving three ongoing independent, randomized, blinded trials to assess the utility of 

hyperbaric oxygen (HBO2).7

 Together these complementary investigations objectively study the 

effect on symptoms of a range of hyperbaric exposures on military and Veteran populations. 
5

HBO2 administration involves breathing high levels of oxygen, usually 100%, at an increased 

pressure at least 1.4 times greater than the atmospheric absolute pressure at sea level (1 

atmospheres absolute or ATA, which is equivalent to 760 mmHg partial pressure of oxygen).8

The partial pressure of oxygen will increase proportionally with an increase in the hyperbaric 

chamber compression pressure, consequently the intent of HBO2 is to increase the oxygenation 

of the patient’s blood and tissues to supraphysiologic levels as a stimulus to cellular growth and 

repair. The use of HBO2 in treating TBI is based on the still unproven theory that functionally 

retrievable neurons, adjacent to severely damaged or dead neurons, exposed to hyperbaric 

oxygen may return to normal function or near normal function by reactivating metabolic or 

electrical pathways. Other possible mechanisms of benefit to TBI patients include stem cell 

mobilization to sites of injury, immune modulation, and impact on fundamental 

neurotransmitters such as nitric oxide.9 While these theories hold promise for future 

identification of those patients most likely to respond, in practical terms symptom improvement 

remains the current metric for a positive therapeutic outcome.7 

To date, the evidence for efficacy of HBO2 in TBI is inconclusive. Randomized trials 

support the use of HBO2 to improve survival after acute, severe TBI, however there is no 

appreciable effect in functional outcomes.10,11 Primarily anecdotal evidence exists to support 

HBO2 for chronic traumatic brain injury (i.e., more than three months post event), and the only 

published randomized clinical trial investigating HBO2 for post-concussion syndrome 

demonstrated no effect.9

A typical HBO2 clinical treatment uses oxygen at 2.0 to 3.0 ATA for durations of 90 to 

120 minutes, however individualization based on diagnosis and patient symptoms has been 

advocated8

 and anecdotal evidence exists to support efficacy in TBI at lower dosages (1.5 
6

ATA).10, 12,13 A randomized, controlled trial using 2.4 ATA HBO2 exposure compared with sham 

(room air at 1.3 ATA) failed to demonstrate any differences in symptoms in SMs with PPCS.9

Given these results and the anecdotal reports of efficacy at lower, potentially safer pressures, the 

second phase of the VA-DoD research initiative focused on the effect of 1.5 and 2.0 ATA 

equivalent HBO2 dosing. To this end, this investigation examined the effects of HBO2 exposure 

on a population of active duty SMs with PPCS following combat-related mTBI in a three-arm, 

randomized, blinded, sham-controlled trial. 

 
7

MATERIALS AND METHODS 

Commencing in 2009, the Defense Advanced Research Projects Agency and U.S. Navy 

Bureau of Medicine and Surgery (as part of the DoD-VA collaborative research program) 

sponsored this single center, three-arm, randomized, blinded, sham-controlled trial of HBO2

exposure on symptomatic mTBI. The logistics and challenges of double blinding hyperbaric 

chamber interventions have been described previously.14 This study received appropriate 

institutional review board and governmental approvals. Sixty-one active duty military SMs with 

PPCS were recruited from United States military bases. Inclusion criteria were TBI specialistconfirmed diagnosis of mTBI based on the DoD definition of TBI (Health Affairs 2007), postconcussive symptoms from mTBI for at least 3 months, injury occurrence in the past 3 years, 

psychiatric status (if any) stable for 2 months, stable psychotropic medication history for at least 

one month, and ability to use computerized testing. The diagnosis of TBI was confirmed by the 

study physiatrist’s history, physical examination and a review of all the acute medical records, 

including any available battlefield information, from the time of the traumatic event to the 

present, using the DoD definition of TBI. The only exclusion criteria were the presence of a 

disorder that contraindicated hyperbaric exposure or previous exposure to HBO2. Volunteers 

were recruited from a pool of full-duty Marines from Camp Lejeune Marine Base (NC) and a 

few from Marine Base Quantico (VA) whose symptoms were being managed by the TBI clinic 

but who were otherwise without medical or military limitations. The Marines from Quantico 

received additional duty orders to relocate to Naval Medicine Operational Training Center 

(NMOTC) at Naval Air Station Pensacola, Florida for two months to receive the investigative 

exposures in a hyperbaric chamber. 
8

Demographic information, clinical parameters, and baseline physical, cognitive, and 

behavioral functioning measures were obtained. Participants were randomly assigned to breathe 

one of three oxygen mediums in the hyperbaric chamber at 2.0 ATA, specifically 10.5%, 75% or 

100% oxygen. The sham-control (10.5% oxygen at 2.0 ATA) simulated a placebo exposure. The 

intervention dosing used in this study was chosen based on the consensus opinion of the DoD 

and VA.15 To maximize participant blinding, oxygen concentrations were varied while 

maintaining 2.0 ATA in order to minimize the likelihood of participants noting differential 

pressures. Randomization to one of the three groups was accomplished using a computergenerated number assignment (randomizer.org©). 

Exposures were conducted in a multiplace chamber with the breathing medium delivered 

at gas flow rates of >20 l/min using an oxygen treatment hood once the 2.0 ATA exposure 

pressure was reached, to ensure a consistent dose (Amron International Inc., Vista, CA). The 

NMOTC hyperbaric chamber was elevated less than 50 feet above mean sea level. Exposures in 

this study were delivered using modifications of established protocols developed by the Navy's 

Bureau of Medicine and Surgery (BUMED) Undersea Medicine department. In order to ensure 

distributional uniformity among the three experimental exposures, subjects were accessioned in 

five separate blocks of 11-15 subjects, based on subject availability. Each group of subjects was 

randomly assigned to receive one of the three experimental conditions. Once assigned to a 

particular treatment group, the subjects’ experimental condition did not vary over the 40 

exposure course. To ensure subject and investigator blinding to the specific treatment exposure 

being received, all subjects were pressurized inside the chamber to a pressure equivalent of 2.0 

ATA. This is equivalent to the atmospheric pressure attained during underwater diving to 33 feet 

of seawater. Subjects breathed an oxygen-nitrogen treatment gas blended to achieve the oxygen 
9

pressure equivalents to which they were assigned. Specifically, three gas mixtures were 

employed: 1) a sham air equivalent of 10.5% oxygen (balance 89.5% nitrogen), 2) a 1.5 ATA 

oxygen equivalent of 75% oxygen (balance 25% nitrogen) and 3) a 2.0 ATA oxygen equivalent 

of 100% oxygen (0% nitrogen). Chamber compression to 2.0 ATA generally required <3 

minutes to attain. Once at 2.0 ATA of pressure, each subject was instructed to sit quietly and 

breathed the assigned gas mixture for a period of 60 minutes (+/- 1 minute). Chamber 

decompression to 1.0 ATA (i.e., an average room air pressure of 759 mmHg) similarly required 

<3 minutes to attain. Each participant underwent 40 compressions lasting 60 minutes over a tenweek period. During compression to and decompression from 2.0 ATA, all subjects breathed 

ambient chamber air. Taking into account National Fire Protection Agency, US Navy Diving 

Manual Class A chamber operation standards and local NMOTC control levels, the oxygen 

content of chamber air was closely regulated to remain between 19-23.5% surface equivalents 

(i.e., sea level). This protocol was selected as it most closely approximated the community 

standard of care and meets all safety guidelines7,8 . 

Any subject unable to complete a scheduled treatment due to transient contraindications 

to hyperbaric chamber exposure (i.e. fevers, congestion, inability to equalize sinus or ear 

pressure), was allowed to make up the missed treatment at the next available opportunity (i.e. 

later the same day, on weekends when treatments were not normally scheduled or, if necessary, 

during the transition period between the five, 12-subject blocks). 

Statistical Analyses 

This segment of the study focused on an analysis of the effects of these exposures on the 

primary outcome measure, the RPQ, by comparing baseline measures to initial post-compression 

outcomes. Subsequent analyses of all outcome measures at both the initial and 3-month time 
10

periods will be completed later. Initial post-compression outcome measurements were obtained 

within the first week following last exposure. While a broad array of outcome batteries was 

utilized for all participants, this initial paper presents main findings on the symptomatic effects 

of the chamber exposures measured by the primary outcome tool, the RPQ.16 The RPQ is a 

widely used Likert-type symptom inventory consisting of 16 items (and a 17th narrative item) 

designed to evaluate the somatic, cognitive and emotional functioning of individuals who have 

PPCS following a brain injury.16 A study of the psychometric properties of the RPQ found it is 

most appropriately scored and analyzed using two sub-scales, items 1-3 constituting the RPQ-3 

and the remaining 13 items constituting the RPQ-13.16 The appropriate sample size estimates 

were calculated for a 10% difference (equal to a decrease of 7 total score points) on the primary 

outcome of postconcussive symptom severity as measured by the Rivermead Postconcussive 

Symptom Questionnaire (RPQ),16which required 20 subjects in each group after adjusting for 

10% attrition (one way ANOVA; Power 0.80; alpha 0.05). Given the significant co-occurrence 

of PTSD in military populations with mTBI1-4 and the overlap of many symptoms to either 

condition, a number of behavior measures were included in this investigation. For this paper, we 

selected the Post-Traumatic Disorder Check List-Military Version (PCL-M) to assess symptoms 

associated with PTSD.15,17 The PCL-M is a 17-item self-report measure of symptoms suggestive 

of post-traumatic stress disorder (PTSD) and is often used as an aid in screening for and 

measuring PTSD. For both the RPQ and PCL-M, improvement in symptoms is denoted by lower 

scores. 

All analyses were conducted using SPSS 16.0. Demographic characteristics were 

analyzed using descriptive statistics. Main effect concussive symptom changes were examined 

using one-way ANOVA of pre and post scores on RPQ individual items, RPQ subscales (RPQ-3; 
11

RPQ-13) and RPQ total score. Potential secondary effects of hyperbaric treatment on posttraumatic stress was analyzed using one-way ANOVA on pre and post PCL individual item 

scoresas well as PLC total score. Statistical level of significance was set at .05.

RESULTS 

One hundred and twenty eight SMs met preliminary study eligibility and consented for 

evaluation. Sixty-one of 128 candidates met the full study criteria and were randomly assigned 

into the sham-control or one of two HBO2 exposure groups. The primary reasons for exclusion 

were the inability to confirm the diagnosis of mTBI, active medication changes and schedule 

conflicts. One participant was unavailable for the immediate post-intervention assessment 

leaving a total of 60 subjects for the present analysis. All study subjects experienced at least one 

mTBI, with the most recent TBI occurring a mean of 8.5 months (SD= 6.58 months, range= 3-39 

months) prior to the baseline assessments. All subjects were male. Etiology of concussion 

included improvised explosive device (IED) blast (85.3%), rocket propelled grenades (3.0%), 

and mortar attacks (1.7%). The remaining 10% were uncategorized blasts. Slightly more than 

one-quarter of the participants self-reported concussions (M = 2.1, SD=.95, range=1-4) prior to 

the most recent blast injury. Of the 60 subjects who completed the pre- and post-compression 

procedures, there were 21 subjects in the sham-compression group, 18 in the 1.5 ATA equivalent 

group and 21 in the 2.0 ATA equivalent group. There were no pre-compression between group 

differences on these variables. 

The final sample of 60 subjects had a mean age of 23.2 years (SD=2.95). Two (3.0%) 

were African-American, 47 (78.3%) were Caucasian, 10 (16.6%) were Hispanic, and one (1.6%) 

was Native American. Of the 60, 19 were married, three were divorced, and 38 were single. Pay 
12

grades E1-E6 comprised 97% of the sample. One-way analysis of variance (ANOVA) and chi 

square analysis revealed no between group differences with respect to age, pay grade, marital 

status, or race /ethnicity. 

To determine if a main effect existed, between group analyses, using SPSS with one-way 

ANOVA, were conducted for the pre-compression and post-compression RPQ items, subscales 

(RPQ-3; RPQ-13) and total scores. As a secondary analysis, PCL-M item responses and total 

score, again using SPSS with one-way ANOVA, were also conducted. At pre-treatment there 

were no significant differences between groups for symptom inventory items, verifying the 

efficacy of randomization. At post-compression, no significant differences were found between 

the three groups on any individual symptom inventory items, subscale scores (RPQ-3; RPQ-13) 

or total scores on the RPQ or PCL-M. 

*****Insert Tables 1 and 2 here  

Within group analyses were conducted for all three groups using paired t-tests, 

comparing pre-compression and post-compression RPQ item responses. The Sham (2.0 ATA10.5% O2) group showed no significant differences on symptom inventory items, subscale scores 

(RPQ-3; RPQ-13) or total score. The 1.5 ATA equivalent (2.0 ATA-75% O2) group showed a 

statistically significant increase (i.e., worsening) on item 14 (light sensitivity), but no significant 

differences were noted for other symptom individual items, subscale scores (RPQ-3; RPQ-13) or 

total score. The 2.0 ATA equivalent (2.0 ATA-100% O2) group showed a statistically significant 

decrease on items 4 (noise sensitivity) and 9 (frustration, impatience), but no other significant 
13

differences were noted for symptom individual items, or subscale scores (RPQ-3; RPQ-13) or 

total score. 

** ***Insert Table 3 here  

Within group analyses were then conducted for all three groups using paired t-tests, 

comparing pre-compression and post-compression PCL-M item responses. Items 16 (being super 

alert; watchful) and 17 (easily startled) were significantly decreased within the Sham (2.0 ATA10.5% O2) group, but no other significant differences were noted for individual symptom 

inventory items or total score. The 1.5 ATA equivalent (2.0 ATA-75% O2) group showed a 

significant decrease on item 16 (being super alert; watchful), but no other significant differences 

were noted for individual symptom inventory items or total score. The 2.0 ATA equivalent (2.0 

ATA-100% O2) group demonstrated significant decreases on PCL-M items 4 (upset when 

reminded of stressful past event), 16 (being super alert; watchful) and total score. 

** ***Insert Table 4 here**** 

DISCUSSION 

This investigation represents the second DoD-VA collaborative, randomized, controlled 

clinical trial studying clinically relevant effects of HBO2 on PPCS. In this study, none of the 

groups achieved the hypothesized clinically significant improvement (i.e., 7 points) on the 

primary outcome measure for PPCS (i.e., RPQ). Additionally, there were no significant 

differences between groups on any of the RPQ-3, RPQ-13 or PCL-M total scores post-
14

compression. While there were within group improvements on several of the items for each of 

the three compression groups, analysis of individual symptom items revealed that there were no 

between group differences. These findings are similar to the first DoD-VA collaborative trial.9

The lack of between group differences among the three experimental conditions on the primary 

outcome measure suggests that there was no treatment effect that could be attributed to the 

hyperbaric oxygen parameters studied. These current findings, which parallel the earlier work of 

Wolf and colleagues,9 are particularly important in that this study utilized the more typical 

treatment pressures advocated by hyperbaric clinicians.8,10,12,13 

While no main treatment effect was found at any exposure level, within group analyses 

were noteworthy for improvements on 1-2 items from both the RPQ and the PCL-M within each 

experimental condition. Additionally, the total score for the 2.0 ATA equivalent group for the 

PCL-M was found to improve. A statistical argument could be made that the total score is 

subject to family wise error rate and a post hoc test (e.g., Bonferonni correction or a similar test) 

should have been conducted to reduce the likelihood of false positives by lowering the alpha 

value. It was determined, given the exploratory nature of this feasibility study, that doing so 

would have increased the number of false negatives, obscuring statistically significant results. 

Future studies should apply the more rigorous post hoc corrections in order to ensure that false 

positives are not included (i.e., type I error). However, it is interesting to note that even with a 

more “liberal” alpha value these significant results represented only a small fraction of the item 

inventory and a restricted symptom array. The six symptoms that significantly varied within any 

of the groups were; noise sensitivity, light sensitivity, easily frustrated, easily upset by past 

events, being super alert and easily startled. Three of these symptoms (being super alert, easily 

upset and easily startled) are hallmarks of PTSD, but are not typical for mTBI. One of them 
15

(easily frustrated) may be seen in either condition and the remaining two symptoms (noise and 

light sensitivity) are more commonly associated with mTBI. The finding of symptoms consistent 

with either (or both) mTBI and PTSD was expected in this cohort due to the nature of postdeployment syndrome.1-6 While one of the symptoms (noise sensitivity) that improved within the 

2.0 ATA equivalent exposure group is most commonly associated with mTBI, none of the 

symptoms improved differentially in the main analysis between groups. 

The decision to use the RPQ as the primary outcome measure was driven by its 

worldwide acceptance in the study of mTBI and specifically PPCS.15,18-19 However, it is most 

commonly utilized in individuals who are within one year of their symptom-generating mTBI, 

when these symptoms are most likely to improve or resolve. In this investigation, while the mean 

time post-mTBI was 8.5 months, many of the subjects had multiple mTBI’s, some as distant as 

39 months previously, and symptom onset could not be easily discerned. Moreover, these 

subjects had most likely already experienced the bulk of the recovery typically seen following 

mTBI, but persistent residual symptoms remained at time of study enrollment. However, the 

baseline mean individual item score on the RPQ for all groups was 1.93, therefore these subjects 

could only have improved in a limited fashion, as compared to individuals with the more typical 

moderate-severe symptoms seen with acute concussion. The pre-established clinically significant 

RPQ total score criterion threshold of a 7-point improvement was not approached in any of the 

groups. Of interest, we found that the Sham and 1.5 ATA equivalent groups demonstrated nonsignificant increase (worsening) in their raw total RPQ scores, whereas the 2.0 ATA equivalent 

group demonstrated a 3.77 point non-significant decrease (improvement). 

We believe that the improvements seen in this investigation, as well as the Wolf study 

and prior case reports11,12,20-22 can be best explained by factors other than the HBO2’s effect on 
16

PPCS. As has been reported in depression, anxiety, and PTSD randomized sham-controlled 

trials, one would expect a placebo and/or Hawthorne effect on symptoms given the intense 

nature of the intervention.23-25 For example, the Marines in this study were temporarily 

reassigned to Pensacola Naval Air Station and had greatly reduced duty schedules. Additionally, 

they had enhanced access to leisure time and activities in a non-combat, semi-tropical beach 

environment. The significant improvement on the PCL-M total score in the 2.0 ATA equivalent 

group is of interest, but its implications are unclear. Given evidence from animal research on the 

positive effects of HBO2 on behavioral factors26 and the minor benefits seen on the PCL-M in the 

2.4 ATA DoD trial,9 further prospective investigations may be warranted.

This trial represents the second randomized, double-blinded, sham-controlled, 

prospective study of HBO2 in the symptomatic chronic mTBI population and demonstrates no 

significant symptomatic improvements from PPCS of HBO2 at either 1.5 or 2.0 ATA equivalent 

over sham-control. This investigation incorporated many features lacking in prior studies, to 

include randomization, blinding, and control groups. The inclusion of this level of scientific rigor 

in this study and Wolf’s support the conclusion that the minor benefit seen on the RPQ, PCL-M 

and other similar measures are not the result of the hyperbaric oxygen. 

These studies demonstrated that individuals with PPCS could be recruited into and safely 

tolerate this study protocol. Future studies, which are currently underway, will benefit from the 

addition of a waiting list or standard concussion care third arm to account for the nonspecific 

effects possible in sham-control treatment and longer duration of follow-up to assess for the 

durability of any initial improvements. 

This study has a number of inherent limitations. The small sample size limits the power 

of the study. Generalizability may be limited by gender. Additionally, the high follow-up rate 
17

seen secondary to the paid travel and active duty status (i.e., they received additional duty orders 

to be on the base) may be atypical of non-military populations. The combat exposure 

experienced by all study participants introduces the possible influence of post-traumatic stress, 

depression, anxiety, substance abuse, and pain, which have been associated with deployment,3,4 

likely had confounding effects on HBO2. The diagnosis of TBI relies on participant self-report, 

which is sensitive to subjective patient interpretation, memory, social desirability and other 

covariates such as personality factors and willingness to reveal problems. As noted, a 

confounding role of PTSD symptoms may be especially important, as our study demonstrated a 

significant reduction of some individual items on both the RPQ and PCL-M that are commonly 

attributed to stress in both the sham-control and HBO2 groups over time. Better understanding of 

this influence and other possible variables, time post-injury, medication usage and adjustments 

and the role of repetitive mTBI in post-concussion recovery, would allow for a greater 

refinement of treatment protocols. 

CONCLUSIONS

Hyperbaric oxygen treatment is a proven intervention for select acute and chronic 

ischemic injuries that have well-established theoretical underpinnings and a well-documented 

role in dive-related injuries, soft tissue healing, and carbon monoxide poisoning treatment. Prior 

human research trials with acute severe TBI have been inconclusive and previous studies in 

participants with long-standing post-concussive syndrome have demonstrated no symptom relief 

with hyperbaric oxygen. This study, which utilized a randomized, controlled, double-blinded 

design conducted at total oxygen doses most commonly by used by clinicians, did not 
18

demonstrate significant effects of hyperbaric oxygen in individuals with symptoms of chronic 

mTBI, when compared to sham compression. 

 
19

ACKNOWLEDGMENTS 

The authors would like to recognize and thank Ms. Sheila Galvin, Traumatic Brain Injury 

Program Coordinator for the Wounded Warrior Regiment USMC for her superb service in 

coordinating participant requirements; Ms. Karen Guenther and the Injured Marine Semper Fi 

Fund for transportation support for participants; Dr. Jason Cromar, USAFSAM, for coordinating 

the protocol; the members of the Naval Aerospace Medicine Institute Hyperbaric Medicine 

Department for supporting the 705 chamber dives and 139 man days of "bottom time" needed to 

complete this project; and Dr. R. Scott Miller (U.S. Army Medical Material Development 

Activity (USAMMDA), Ft. Detrick, MD) for manuscript review. 

 
20

Table 1

Between Group Analysis of RPQ Item Means

Pre‐Compression Post‐Compression

Item

number

Sham 1.5 ATA

Equivalent

2.0 ATA

Equivalent

Significance Sham 1.5 ATA

Equivalent

2.0 ATA

Equivalent

Significance

1 2.9 3 2.83 .83 2.62 2.90 2.39 .35

2 1.57 1.43 1.22 .63 1.76 1.52 1.28 .27

3 0.76 0.62 0.55 .78 0.71 0.76 0.33 .24

4 2.7 2.10 2.72 .28 2.43 2.48 2.00 .32

5 2.52 2.86 2.83 .63 2.86 2.86 2.61 .75

6 2.24 1.7 1.72 .28 2.24 1.76 1.78 .31

7 2.62 2.38 3.05 .16 2.48 2.62 2.50 .92

8 1.38 1.0 1.17 .60 1.24 1.10 0.94 .77

9 2.52 2.43 2.67 .78 2.33 2.19 2.11 .79

10 3.14 3.05 3.06 .94 3.05 3.0 2.78 .67

11 2.43 2.19 2.44 .75 2.52 2.29 2.39 .75

12 2.57 2.29 2.39 .69 2.33 2.38 2.06 .58

13 1.29 0.71 0.67 .15 1.48 1.0 0.67 .06

14 1.62 1.10 0.94 .18 1.90 1.62 1.11 .16

15 0.48 0.43 0.28 .58 0.81 0.33 0.22 .07

16 2.05 2.05 1.94 .96 2.10 1.76 1.50 .36

RPQ‐3 5.20 5.04 4.6 .72 5.10 5.19 4.00 .20

RPQ‐13 27.57 24.29 25.83 .48 27.76 25.38 22.67 .23

Total Score 32.81 29.33 30.44 .53 32.86 30.57 26.67 .19

   
21

                                                                                   

Table 2

Between Group Analysis of PCL‐M Item Means

Pre‐Compression Post‐Compression

Item

number

Sham 1.5 ATA

Equivalent

2.0 ATA

Equivalent

Significance Sham 1.5 ATA

Equivalent

2.0 ATA Significance

Equivalent

1 2.95 2.81 3.39 .24 2.71 2.67 2.83 .90

2 2.43 2.86 3.16 .11 2.38 2.76 3.00 .25

3 2.10 1.76 2.39 .15 1.90 1.95 2.00 .96

4 2.52 2.52 2.94 .46 2.48 2.48 2.28 .80

5 2.71 2.57 2.72 .93 2.76 2.52 2.52 .56

6 2.57 2.57 2.72 .92 2.52 2.57 2.39 .89

7 2.0 2.05 2.22 .82 1.90 2.14 1.83 .62

8 2.0 2.38 2.28 .63 2.24 2.43 2.17 .82

9 2.19 2.10 2.61 .49 2.19 1.71 2.17 .31

10 2.29 2.33 3.00 .15 2.42 2.29 2.50 .87

11 2.57 2.33 2.89 .47 2.48 2.19 2.33 .80

12 1.71 1.57 1.61 .91 1.71 1.81 1.28 .23

13 3.71 3.86 3.83 .93 3.95 3.76 3.50 .53

14 3.38 3.38 3.55 .87 3.14 3.05 3.14 .91

15 3.33 3.10 3.44 .58 3.43 3.24 3.33 .86

16 3.24 3.29 3.11 .88 2.76 2.86 2.39 .52

17 3.43 3.19 3.43 .69 2.90 2.86 3.00 .94

Total Score 45.14 44.67 49.39 .45 43.9 43.29 42.56 .96
22

Table 3

Within Group Analysis of RPQ Item Means

Sham 1.5 ATA Equivalent 2.0 ATA Equivalent

Item

Number

Pre

Mean

Post

Mean

Sig Pre

Mean

Post

Mean

Sig Pre

Mean

Post

Mean

Sig

1 2.9 2.62 .23 3.00 2.90 .71 2.83 2.39 .12

2 1.57 1.76 .33 1.43 1.53 .73 1.22 1.28 .83

3 0.76 0.71 .83 0.62 0.76 .48 0.55 0.33 .33

4 2.7 2.43 .21 2.10 2.48 .23 2.72 2.00 .04*

5 2.52 2.86 .18 2.86 2.86 1.0 2.83 2.61 .33

6 2.24 2.24 1.0 1.71 1.76 .88 1.72 1.77 .88

7 2.62 2.48 .51 2.38 2.62 .26 3.06 2.50 .10

8 1.38 1.24 .42 1.00 1.10 .72 1.17 0.94 .22

9 2.52 2.33 .38 2.43 2.19 .37 2.67 2.11 .05*

10 3.14 3.05 .65 3.05 3.00 .72 3.06 2.78 .45

11 2.43 2.52 .68 2.19 2.29 .68 2.44 2.39 .88

12 2.57 2.33 .40 2.29 2.38 .75 2.38 2.06 .33

13 1.29 1.48 .30 0.71 1.00 .21 0.67 0.67 1.0

14 1.62 1.90 .28 1.10 1.62 .04* 0.94 1.11 .64

15 0.48 0.81 .11 0.43 0.33 .49 0.22 0.22 1.0

16 2.05 2.10 .87 2.05 1.76 .44 1.94 1.50 .15

RPQ‐3 5.20 5.10 .84 5.04 5.19 .8 4.6 4.0 .32

RPQ‐13 27.57 27.76 .91 24.29 25.38 .59 25.83 22.67 .21

Total Score 32.81 32.86 .98 29.33 30.57 .61 30.44 26.67 .19

          

*Significant

n.b.: Significant items were #4 (noise sensitivity), #9 (frustration, impatience) and #14 (light sensitivity)

   
23

Table 4

Within Group Analysis of PCL‐M Item Means

Sham 1.5 ATA Equivalent 2.0 ATA Equivalent

Item

Number

Pre

Mean

Post

Mean

Sig Pre

Mean

Post

Mean

Sig Pre

Mean

Post

Mean

Sig

1 2.95 2.71 .37 2.81 2.67 .63 3.39 2.83 .14

2 2.43 2.38 .86 2.86 2.76 .68 3.16 3.00 .51

3 2.10 1.90 .46 1.76 1.95 .43 2.39 2.00 .13

4 2.52 2.48 .88 2.52 2.48 .85 2.94 2.28 .02*

5 2.71 2.76 .88 2.57 2.52 .83 2.72 2.52 .30

6 2.57 2.52 .88 2.57 2.57 1.0 2.72 2.39 .21

7 2.0 1.90 .68 2.05 2.14 .75 2.22 1.83 .15

8 2.0 2.24 .46 2.38 2.43 .89 2.28 2.17 .54

9 2.19 2.19 1.0 2.10 1.71 .23 2.61 2.17 .16

10 2.29 2.42 .64 2.33 2.29 .87 3.00 2.50 .07

11 2.57 2.48 .72 2.33 2.19 .65 2.89 2.33 .22

12 1.71 1.71 1.0 1.57 1.81 .17 1.61 1.28 .11

13 3.71 3.95 .33 3.86 3.76 .80 3.83 3.50 .32

14 3.38 3.14 .31 3.38 3.05 .23 3.55 3.14 .32

15 3.33 3.43 .74 3.10 3.24 .58 3.44 3.33 .71

16 3.24 2.76 .03* 3.29 2.86 .05* 3.11 2.39 .04*

17 3.43 2.90 .03* 3.19 2.86 .15 3.43 3.00 .19

Total Score 45.14 43.9 .67 44.67 43.29 .64 49.39 42.56 .05*

        

        *Significant

    n.b.: Significant items were #4 (upset when reminded of past stressful event), #9 (being super alert; watchful) and                     

    #17 (easily startled)
24

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