Treatment of Traumatic Brain Injury With Hyperbaric Oxygen Therapy

• Sponsor: San Antonio Military Medical Center (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT00810615
• Collaborator: (none)
• Enrollment: 50
• Arms: 2
• Duration (Months): 23

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if hyperbaric oxygen therapy (HBOT) improves the cognitive function of OIF/OEF individuals who have chronic mild to moderate traumatic brain injury (TBI). Cognitive function includes such things as thinking, remembering, recognition, concentration ability and perception. Traumatic brain injury is common with head injuries caused by blows to the head, nearby explosions, or concussion. Subjects will be assigned to an intervention or sham arm. Computer based cognitive tests will be used as outcome measures. Subjects are enrolled by invitation only.

Condition or Disease	Intervention/Treatment	Phase
Brain Injury, Chronic	Other: Hyperbaric oxygen @ 2.4 ATA; Other: Sham treatment	Phase 1/Phase 2

Detailed Description

The Agency for Healthcare Research and Quality (AHRQ) did a comprehensive review of the literature focusing on TBI, stroke and cerebral palsy in Sep 2003. The study design and goals were based on the AHRQ recommendations for future hyperbaric oxygen for TBI research. This report stated, "The most important gap in the evidence is a lack of a good quality time-series study or controlled trial of the effects of HBOT on cognition, memory, and functional status in patients with deficits due to mild and moderate chronic TBI." The AHRQ Evidence Report further stated, "Lack of agreement on the dosage of HBOT and the duration of treatment is an important barrier to conducting good-quality clinical studies…Good-quality dose-ranging studies of HBOT for brain injury can be done, based on the model used by pharmaceutical manufacturers and the FDA. It is likely that the dosage of HBOT needs to be individualized based on the patient's age, clinical condition, and other factors". Although there are many anecdotal cases of TBI improvement with HBO, this case is backed with non-subjective data. The biological basis for why breathing 100% oxygen under pressurized conditions improves chronic neurological trauma remains unclear. There is some evidence that chronic TBI effects are related to the demyelization effect linked to the expression of a specific protease, calpain. This protease is also seen in demyelination delayed effects of carbon monoxide poisoning which is slowed by treatment with HBO. The "idling neuron" theory advocated in neurological studies suggest that HBO may increase metabolic performance of chronically impaired neurons that were marginally capable, enabling restoration of full function leading in turn to increased integrative plasticity. HBO has been shown to increase recruitment of stem cells from the bone marrow, suggesting that HBO may increase the rate at which damaged neuronal tissue can be reconstituted de novo. The proposed research will treat 25 subjects using HBO (2.4 ATA breathing 100% oxygen) and 25 subjects in a sham HBO treatment (1.3 ATA breathing air). Computer-based cognitive testing and the Post-traumatic Stress Disorder Checklist for Military (PCL-M) will be administered pre- and post-HBOT as well as at intervals throughout the treatment. The cognitive test results and stem cell results will be analyzed within each subject at the various treatment points as well as cohort groups between each treatment leg. Cognitive test scores will also be compared to cognitive test population reference bases matched for gender and age. The Agency for Healthcare Research and Quality 2003 report also stated, "If there is a 1 percent chance that the treatment works, a rational decision maker would try it-there is a potential gain and no potential loss. On the other hand, if there are proven harms, and their severity and frequency are well described, the probability that the treatment works would have to be higher before most people would try it"

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: Treatment of Moderate to Mild Cognitive Dysfunction Caused by Traumatic Brain Injury (TBI) With Hyperbaric Oxygen Therapy (HBOT)
• Study Start Date: Feb 1, 2009
• Actual Primary Completion Date: Jan 1, 2011
• Actual Study Completion Date: Jan 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Sham Comparator: Sham treatment Subject will breathe air at less than 1.3 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at less that 1.3 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures.	Other: Sham treatment; Other Names: sham exposure; 1.3 ATA air
Experimental: Hyperbaric oxygen 2.4 ATA Subject will breathe 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures.	Other: Hyperbaric oxygen @ 2.4 ATA; Subject will breath 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures.; Other Names: hyperbaric oxygen HBOT HBO

Outcome Measures

Primary Outcome Measures

1. Computer Cognitive Test Scores - ImPACT Verbal Memory [Baseline and six weeks post hyperbaric exposure series]

   The Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) battery was developed at the University of Pittsburgh. It has a sensitivity of 81.9% and specificity of 89.4% in discriminating between concussion and non-concussion groups. It consists of a medical history questionnaire regarding concussions and resultant symptoms including loss of consciousness, memory loss, confusion, headache, seizure activity, emotional state, and sleep patterns. There are four subtests given and scored by computer. These include verbal and visual memory, visual motor speed, and response time. The composite scores are specifically designed to determine changes within the individual, better or worse, over time. The verbal memory score demonstrates improvement as the score increases. The score range was 36.8 to 98.6.

2. Posttraumatic Stress Disorder Checklist - Military Version (PCL-M) Scores [baseline compared to the change at post hyperbaric exposures (30) series and the six weeks post hyperbaric exposure series]

   The PCL-M is a self reported test in which a list of 17 problems and complaints are offered to the individual to score on a 1 to 5 scale with 1 designating "not at all", 2= "a little bit", 3= "moderately", 4= "quite a bit" and 5 designating "extremely". A sample complaint would be "repeated, disturbing dreams of a stressful military experience". Hence there is a possible total score range from 17 to 85. For military members, a score of 50 or above is indicative of PTSD. A change from baseline of 5-9 represents a reliable change and change of 10 or greater is a significant change.

3. Computer Cognitive Test Scores - ImPACT Visual Memory [Baseline and six weeks post hyperbaric exposure series]

   The Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) battery was developed at the University of Pittsburgh. It has a sensitivity of 81.9% and specificity of 89.4% in discriminating between concussion and non-concussion groups. It consists of a medical history questionnaire regarding concussions and resultant symptoms including loss of consciousness, memory loss, confusion, headache, seizure activity, emotional state, and sleep patterns. There are four subtests given and scored by computer. These include verbal and visual memory, visual motor speed, and response time. The composite scores are specifically designed to determine changes within the individual, better or worse, over time. The visual memory score demonstrates improvement as the score increases. The score range was 31.2 to 92.7.

4. Computer Cognitive Test Scores - ImPACT Processing Speed [Baseline and six weeks post hyperbaric exposure series]

   The Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) battery was developed at the University of Pittsburgh. It has a sensitivity of 81.9% and specificity of 89.4% in discriminating between concussion and non-concussion groups. It consists of a medical history questionnaire regarding concussions and resultant symptoms including loss of consciousness, memory loss, confusion, headache, seizure activity, emotional state, and sleep patterns. There are four subtests given and scored by computer. These include verbal and visual memory, visual motor speed, and response time. The composite scores are specifically designed to determine changes within the individual, better or worse, over time. The Processing Speed score demonstrates improvement as the score increases. The score range was 9.7 to 52.4.

5. Computer Cognitive Test Scores - ImPACT Reaction Time [Baseline and six weeks post hyperbaric exposure series]

   The Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) battery was developed at the University of Pittsburgh. It has a sensitivity of 81.9% and specificity of 89.4% in discriminating between concussion and non-concussion groups. It consists of a medical history questionnaire regarding concussions and resultant symptoms including loss of consciousness, memory loss, confusion, headache, seizure activity, emotional state, and sleep patterns. There are four subtests given and scored by computer. These include verbal and visual memory, visual motor speed, and response time. The composite scores are specifically designed to determine changes within the individual, better or worse, over time. The reaction time score demonstrates improvement as the score decreases. The score range was 0.42 to 1.84.

6. Computer Cognitive Test Scores - BrainCheckers Simple Reaction Time [Baseline and six weeks post hyperbaric exposure series]

   Braincheckers is a PDA version of the Automated Neuropsychological Assessment Metrics (ANAM) supported by the Army Medical Research and Materiel Command in 2000. It was validated against ANAM for the individual tests used. Throughput is defined as correct responses per minute of time available to respond. Higher scores indicate higher accuracy in each of the subtest. The simple reaction time range is 30 to 255.

7. Computer Cognitive Test Scores - BrainCheckers Code Substitution [Baseline and six weeks post hyperbaric exposure series]

   Braincheckers is a PDA version of the Automated Neuropsychological Assessment Metrics (ANAM) supported by the Army Medical Research and Materiel Command in 2000. It was validated against ANAM for the individual tests used. Throughput is defined as correct responses per minute of time available to respond. Higher scores indicate higher accuracy in each of the subtest. The range is 9 to 66. The scores in this section represent results of the code substitution subtest.

8. Computer Cognitive Test Scores - BrainCheckers Procedural Reaction Time [Baseline and six weeks post hyperbaric exposure series]

   Braincheckers is a PDA version of the Automated Neuropsychological Assessment Metrics (ANAM) supported by the Army Medical Research and Materiel Command in 2000. It was validated against ANAM for the individual tests used. Throughput is defined as correct responses per minute of time available to respond. Higher scores indicate higher accuracy in each of the subtest. The range is 25 to 118. The scores in this section represent results of the procedural reaction time.

9. Computer Cognitive Test Scores - BrainCheckers Go-NoGo Reaction Time [Baseline and six weeks post hyperbaric exposure series]

   Braincheckers is a PDA version of the Automated Neuropsychological Assessment Metrics (ANAM) supported by the Army Medical Research and Materiel Command in 2000. It was validated against ANAM for the individual tests used. Throughput is defined as correct responses per minute of time available to respond. Higher scores indicate higher accuracy in each of the subtest. The range is 41 to 174. The scores in this section represent results of the Go-NoGo reaction time subtest.

10. Computer Cognitive Test Scores - BrainCheckers Matching To Sample [Baseline and six weeks post hyperbaric exposure series]

    BrainCheckers is a PDA version of the Automated Neuropsychological Assessment Metrics (ANAM) supported by the Army Medical Research and Materiel Command in 2000. It was validated against ANAM for the individual tests used. Throughput is defined as correct responses per minute of time available to respond. Higher scores indicate accuracy in each of the subtest. The range is 6 to 50. The scores in this section represent results of the matching to sample subtest.

11. Computer Cognitive Test Scores - BrainCheckers Code Sub Recall [Baseline and six weeks post hyperbaric exposure series]

    BrainCheckers is a PDA version of the Automated Neuropsychological Assessment Metrics (ANAM) supported by the Army Medical Research and Materiel Command in 2000. It was validated against ANAM for the individual tests used. Throughput is defined as correct responses per minute of time available to respond. Higher scores indicate accuracy in each of the subtest. The range is 6 to 135. The scores in this section represent results of the code sub recall subtest.

Secondary Outcome Measures

1. Functional MRI [six weeks post hyperbaric exposure series]

2. Stem Cells: CD_34 [six weeks post hyperbaric exposure series]

   A non-parametric regression 14 using the Theil estimator was fit to the observed data in order to demonstrate general trends for relations between measures of cognitive functioning and increased stem cells.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 19 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• neurology diagnosis of mild to moderate TBI

• injury sustained during OIF/OEF military activities

• perception of cognitive dysfunction following their injury

• stable mental status for at least two months

• stable psychotropic medication history for at least one month

• ability to perform computer based cognitive testing (must be capable using a mouse and PDA pointer and readily view the displays)

• TBI occurrence since 7 October 2001

• ability to consent

Exclusion Criteria:

• medical conditions that prevent subject from participating in hyperbaric environments

• previous hyperbaric oxygen treatments since being diagnosed with TBI

• history of alcohol abuse

• history of drug abuse

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• San Antonio Military Medical Center

Investigators

• Study Director: E. George Wolf, M.D., SAMMC Hyperbaric Medicine
• Principal Investigator: Leonardo C Profenna, M.D., SAMMC Hyperbaric Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: George Wolf, Study Director, San Antonio Military Medical Center
• ClinicalTrials.gov Identifier: NCT00810615
• Other Study ID Numbers: FWH20080137H
• First Posted: Dec 18, 2008
• Last Update Posted: Aug 13, 2018
• Last Verified: Nov 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by George Wolf, Study Director, San Antonio Military Medical Center: chronic TBI; cognitive function; PTSD; HBO; hyperbaric; oxygen; chronic brain injury
• Additional relevant MeSH terms: Brain Injuries; Brain Injuries, Traumatic; Brain Injury, Chronic; Wounds and Injuries

Study Results

Participant Flow

Recruitment Details	Recruitment occurred from Nov 2008 - Nov 2010. Candidate subjects with a diagnosis of chronic truamatic brain injury (TBI) were identified by DoD neurologists. Those interested were screened for inclusion/exclusion criteria. 103 candidates were screened. 22 did not qualify; 31 were deferred (psychotropic medication or mental status unstable).

Arm/Group Title	Sham Treatment	Hyperbaric Oxygen 2.4 ATA
Arm/Group Description	Subjects breathed air at less than 1.3 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at less that 1.3 ATA. Hyperbaric exposures were done up to 5 times per week with a total number of 30 exposures. Pressurization time was seven minutes to a depth of 11 feet of sea water (fsw) or 1.3 ATA. The chamber pressure was slowly decreased over 10 minutes to 6 fsw (1.2 ATA). The final depressurization to surface was done over a 10 minute period. To simulate the treatment 2.4 ATA pressurization, pressurizations and depressurizations were done using venting techniques that would be nearly identical with the noise and temperature as that experienced with the treatment pressure. The inside observers simulated pressure equalization measures (Valsalva) every 10 to 30 seconds and breathed oxygen by mask (required in the 2.4 ATA pressure to prevent decompression sickness) at the same frequency as if they were in the treatment exposure pressure.	Subject breathed 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. Hyperbaric exposures were done up to 5 times per week with a total number of 30 exposures. Pressurization time was seven minutes to a depth of 45 feet of sea water (fsw) or 2.4 ATA. The final depressurization to surface was done over a 10 minute period. Inside observers used pressure equalization measures (Valsalva) every 10 to 30 seconds and breathed oxygen by mask (required in the 2.4 ATA pressure to prevent decompression sickness) three times (10/15/5 minute durations) during the exposure.
Period Title: Overall Study
STARTED	25	25
COMPLETED	24	24
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Sham Treatment	Hyperbaric Oxygen 2.4 ATA	Total
Arm/Group Description	Subjects breathed air at less than 1.3 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at less that 1.3 ATA. Hyperbaric exposures were done up to 5 times per week with a total number of 30 exposures. Pressurization time was seven minutes to a depth of 11 feet of sea water (fsw) or 1.3 ATA. The chamber pressure was slowly decreased over 10 minutes to 6 fsw (1.2 ATA). The final depressurization to surface was done over a 10 minute period. To simulate the treatment 2.4 ATA pressurization, pressurizations and depressurizations were done using venting techniques that would be nearly identical with the noise and temperature as that experienced with the treatment leg. The inside observers simulated pressure equalization measures (Valsalva) every 10 to 30 seconds and breathed oxygen by mask (required in the 2.4 ATA pressure to prevent decompression sickness)at the same frequency as if they were in the treatment exposure pressure.	Subject breathed 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. Hyperbaric exposures were done up to 5 times per week with a total number of 30 exposures. Pressurization time was seven minutes to a depth of 45 feet of sea water (fsw) or 2.4 ATA. The final depressurization to surface was done over a 10 minute period. Inside observers used pressure equalization measures (Valsalva) every 10 to 30 seconds and breathed oxygen by mask (required in the 2.4 ATA pressure to prevent decompression sickness) three times (10/15/5 minute durations)during the exposure.	Total of all reporting groups
Overall Participants	25	25	50
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	25 100%	25 100%	50 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	28.4 (7.4)	28.3 (8.1)	28.3 (7.7)
Sex: Female, Male (Count of Participants)
Female	1 4%	1 4%	2 4%
Male	24 96%	24 96%	48 96%
Region of Enrollment (participants) [Number]
United States	25 100%	25 100%	50 100%

Outcome Measures

1. Primary Outcome

Title	Computer Cognitive Test Scores - ImPACT Verbal Memory
Description	The Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) battery was developed at the University of Pittsburgh. It has a sensitivity of 81.9% and specificity of 89.4% in discriminating between concussion and non-concussion groups. It consists of a medical history questionnaire regarding concussions and resultant symptoms including loss of consciousness, memory loss, confusion, headache, seizure activity, emotional state, and sleep patterns. There are four subtests given and scored by computer. These include verbal and visual memory, visual motor speed, and response time. The composite scores are specifically designed to determine changes within the individual, better or worse, over time. The verbal memory score demonstrates improvement as the score increases. The score range was 36.8 to 98.6.
Time Frame	Baseline and six weeks post hyperbaric exposure series

Outcome Measure Data

Analysis Population Description

one subject withdrawal from each group due to personal reasons

Arm/Group Title	Sham Treatment	Hyperbaric Oxygen 2.4 ATA
Arm/Group Description	Subject will breathe air at less than 1.3 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at less that 1.3 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures. Sham treatment	Subject will breathe 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures. Hyperbaric oxygen @ 2.4 ATA: Subject will breath 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures.
Measure Participants	24	24
Baseline	70.48 (13.05)	74.21 (12.03)
six weeks post hyperbaric exposure series	78.12 (16.087)	75.36 (15.230)

2. Primary Outcome

Title	Posttraumatic Stress Disorder Checklist - Military Version (PCL-M) Scores
Description	The PCL-M is a self reported test in which a list of 17 problems and complaints are offered to the individual to score on a 1 to 5 scale with 1 designating "not at all", 2= "a little bit", 3= "moderately", 4= "quite a bit" and 5 designating "extremely". A sample complaint would be "repeated, disturbing dreams of a stressful military experience". Hence there is a possible total score range from 17 to 85. For military members, a score of 50 or above is indicative of PTSD. A change from baseline of 5-9 represents a reliable change and change of 10 or greater is a significant change.
Time Frame	baseline compared to the change at post hyperbaric exposures (30) series and the six weeks post hyperbaric exposure series

Outcome Measure Data

Analysis Population Description

Per protocol. The study was a pilot.

Arm/Group Title	Sham Treatment	Hyperbaric Oxygen 2.4 ATA
Arm/Group Description	Subjects breathed air at less than 1.3 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at less that 1.3 ATA. Hyperbaric exposures were done up to 5 times per week with a total number of 30 exposures. Pressurization time was seven minutes to a depth of 11 feet of sea water (fsw) or 1.3 ATA. The chamber pressure was slowly decreased over 10 minutes to 6 fsw (1.2 ATA). The final depressurization to surface was done over a 10 minute period. To simulate the treatment 2.4 ATA pressurization, pressurizations and depressurizations were done using venting techniques that would be nearly identical with the noise and temperature as that experienced with the treatment pressure. The inside observers simulated pressure equalization measures (Valsalva) every 10 to 30 seconds and breathed oxygen by mask (required in the 2.4 ATA pressure to prevent decompression sickness) at the same frequency as if they were in the treatment exposure pressure.	Subject breathed 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. Hyperbaric exposures were done up to 5 times per week with a total number of 30 exposures. Pressurization time was seven minutes to a depth of 45 feet of sea water (fsw) or 2.4 ATA. The final depressurization to surface was done over a 10 minute period. Inside observers used pressure equalization measures (Valsalva) every 10 to 30 seconds and breathed oxygen by mask (required in the 2.4 ATA pressure to prevent decompression sickness) three times (10/15/5 minute durations) during the exposure.
Measure Participants	24	24
Baseline measurement	48.88 (12.59)	50.38 (14.53)
Post 30 hyperbaric exposures	-10.125 (10.759)	-8.875 (8.789)
6 Week Follow-up	-8.292 (10.960)	-8.625 (10.761)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sham Treatment, Hyperbaric Oxygen 2.4 ATA
	Comments	ANCOVA, baseline measurement was considered as a covariate and group (sham or 2.4 ATA), treatment (15 treatments, 30 treatments, and 6 weeks) as well as the interaction between group and treatment were considered as the independent variables.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	ANCOVA
	Comments	A repeated measures model was designed so as to incorporate the adjust for the repeated (dependent) measures within individuals over time.

3. Primary Outcome

Title	Computer Cognitive Test Scores - ImPACT Visual Memory
Description	The Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) battery was developed at the University of Pittsburgh. It has a sensitivity of 81.9% and specificity of 89.4% in discriminating between concussion and non-concussion groups. It consists of a medical history questionnaire regarding concussions and resultant symptoms including loss of consciousness, memory loss, confusion, headache, seizure activity, emotional state, and sleep patterns. There are four subtests given and scored by computer. These include verbal and visual memory, visual motor speed, and response time. The composite scores are specifically designed to determine changes within the individual, better or worse, over time. The visual memory score demonstrates improvement as the score increases. The score range was 31.2 to 92.7.
Time Frame	Baseline and six weeks post hyperbaric exposure series

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sham Treatment	Hyperbaric Oxygen 2.4 ATA
Arm/Group Description	Subject will breathe air at less than 1.3 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at less that 1.3 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures. Sham treatment	Subject will breathe 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures. Hyperbaric oxygen @ 2.4 ATA: Subject will breath 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures.
Measure Participants	24	24
Baseline	56.56 (14.86)	59.8 (12.17)
six weeks post hyperbaric exposure series	64.72 (15.19)	66.8 (14.72)

4. Primary Outcome

Title	Computer Cognitive Test Scores - ImPACT Processing Speed
Description	The Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) battery was developed at the University of Pittsburgh. It has a sensitivity of 81.9% and specificity of 89.4% in discriminating between concussion and non-concussion groups. It consists of a medical history questionnaire regarding concussions and resultant symptoms including loss of consciousness, memory loss, confusion, headache, seizure activity, emotional state, and sleep patterns. There are four subtests given and scored by computer. These include verbal and visual memory, visual motor speed, and response time. The composite scores are specifically designed to determine changes within the individual, better or worse, over time. The Processing Speed score demonstrates improvement as the score increases. The score range was 9.7 to 52.4.
Time Frame	Baseline and six weeks post hyperbaric exposure series

Outcome Measure Data

Analysis Population Description

one subject withdrawal from each group due to personal reasons

Arm/Group Title	Sham Treatment	Hyperbaric Oxygen 2.4 ATA
Arm/Group Description	Subject will breathe air at less than 1.3 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at less that 1.3 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures. Sham treatment	Subject will breathe 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures. Hyperbaric oxygen @ 2.4 ATA: Subject will breath 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures.
Measure Participants	24	24
Baseline	30.26 (8.50)	29.62 (9.61)
Six weeks post hyperbaric exposure series	36.71 (10.47)	33.84 (10.30)

5. Primary Outcome

Title	Computer Cognitive Test Scores - ImPACT Reaction Time
Description	The Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) battery was developed at the University of Pittsburgh. It has a sensitivity of 81.9% and specificity of 89.4% in discriminating between concussion and non-concussion groups. It consists of a medical history questionnaire regarding concussions and resultant symptoms including loss of consciousness, memory loss, confusion, headache, seizure activity, emotional state, and sleep patterns. There are four subtests given and scored by computer. These include verbal and visual memory, visual motor speed, and response time. The composite scores are specifically designed to determine changes within the individual, better or worse, over time. The reaction time score demonstrates improvement as the score decreases. The score range was 0.42 to 1.84.
Time Frame	Baseline and six weeks post hyperbaric exposure series

Outcome Measure Data

Analysis Population Description

one subject withdrawal from each group due to personal reasons

Arm/Group Title	Sham Treatment	Hyperbaric Oxygen 2.4 ATA
Arm/Group Description	Subject will breathe air at less than 1.3 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at less that 1.3 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures. Sham treatment	Subject will breathe 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures. Hyperbaric oxygen @ 2.4 ATA: Subject will breath 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures.
Measure Participants	24	24
Baseline	0.739 (0.322)	0.725 (0.199)
Six weeks post hyperbaric exposure series	0.677 (0.186)	0.712 (0.266)

6. Primary Outcome

Title	Computer Cognitive Test Scores - BrainCheckers Simple Reaction Time
Description	Braincheckers is a PDA version of the Automated Neuropsychological Assessment Metrics (ANAM) supported by the Army Medical Research and Materiel Command in 2000. It was validated against ANAM for the individual tests used. Throughput is defined as correct responses per minute of time available to respond. Higher scores indicate higher accuracy in each of the subtest. The simple reaction time range is 30 to 255.
Time Frame	Baseline and six weeks post hyperbaric exposure series

Outcome Measure Data

Analysis Population Description

One subject withdrawal from each group due to personal reasons

Arm/Group Title	Sham Treatment	Hyperbaric Oxygen 2.4 ATA
Arm/Group Description	Subject will breathe air at less than 1.3 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at less that 1.3 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures. Sham treatment	Subject will breathe 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures. Hyperbaric oxygen @ 2.4 ATA: Subject will breath 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures.
Measure Participants	24	24
Baseline	142.21 (60.68)	135.79 (61.48)
Six weeks post hyperbaric exposure series	174.96 (57.75)	171.83 (54.66)

7. Primary Outcome

Title	Computer Cognitive Test Scores - BrainCheckers Code Substitution
Description	Braincheckers is a PDA version of the Automated Neuropsychological Assessment Metrics (ANAM) supported by the Army Medical Research and Materiel Command in 2000. It was validated against ANAM for the individual tests used. Throughput is defined as correct responses per minute of time available to respond. Higher scores indicate higher accuracy in each of the subtest. The range is 9 to 66. The scores in this section represent results of the code substitution subtest.
Time Frame	Baseline and six weeks post hyperbaric exposure series

Outcome Measure Data

Analysis Population Description

One subject withdrawal from each group due to personal reasons

Arm/Group Title	Sham Treatment	Hyperbaric Oxygen 2.4 ATA
Arm/Group Description	Subject will breathe air at less than 1.3 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at less that 1.3 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures. Sham treatment	Subject will breathe 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures. Hyperbaric oxygen @ 2.4 ATA: Subject will breath 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures.
Measure Participants	24	24
Baeline	39.20 (12.08)	37.42 (13.74)
Post hyperbaric exposure 6 week follow up throughp	43.39 (13.56)	40.71 (12.10)

8. Primary Outcome

Title	Computer Cognitive Test Scores - BrainCheckers Procedural Reaction Time
Description	Braincheckers is a PDA version of the Automated Neuropsychological Assessment Metrics (ANAM) supported by the Army Medical Research and Materiel Command in 2000. It was validated against ANAM for the individual tests used. Throughput is defined as correct responses per minute of time available to respond. Higher scores indicate higher accuracy in each of the subtest. The range is 25 to 118. The scores in this section represent results of the procedural reaction time.
Time Frame	Baseline and six weeks post hyperbaric exposure series

Outcome Measure Data

Analysis Population Description

One subject withdrawal from each group due to personal reasons

Arm/Group Title	Sham Treatment	Hyperbaric Oxygen 2.4 ATA
Arm/Group Description	Subject will breathe air at less than 1.3 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at less that 1.3 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures. Sham treatment	Subject will breathe 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures. Hyperbaric oxygen @ 2.4 ATA: Subject will breath 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures.
Measure Participants	24	24
Baseline	81.63 (20.82)	81.17 (21.66)
Post hyperbaric exposure 6 week follow up throughp	85.78 (23.16)	86.78 (16.63)

9. Primary Outcome

Title	Computer Cognitive Test Scores - BrainCheckers Go-NoGo Reaction Time
Description	Braincheckers is a PDA version of the Automated Neuropsychological Assessment Metrics (ANAM) supported by the Army Medical Research and Materiel Command in 2000. It was validated against ANAM for the individual tests used. Throughput is defined as correct responses per minute of time available to respond. Higher scores indicate higher accuracy in each of the subtest. The range is 41 to 174. The scores in this section represent results of the Go-NoGo reaction time subtest.
Time Frame	Baseline and six weeks post hyperbaric exposure series

Outcome Measure Data

Analysis Population Description

One subject withdrawal from each group due to personal reasons

Arm/Group Title	Sham Treatment	Hyperbaric Oxygen 2.4 ATA
Arm/Group Description	Subject will breathe air at less than 1.3 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at less that 1.3 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures. Sham treatment	Subject will breathe 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures. Hyperbaric oxygen @ 2.4 ATA: Subject will breath 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures.
Measure Participants	24	24
Baseline	119.67 (31.03)	116.52 (23.33)
Post hyperbaric exposure 6 week follow up throughp	131.70 (31.43)	129.17 (25.67)

10. Primary Outcome

Title	Computer Cognitive Test Scores - BrainCheckers Matching To Sample
Description	BrainCheckers is a PDA version of the Automated Neuropsychological Assessment Metrics (ANAM) supported by the Army Medical Research and Materiel Command in 2000. It was validated against ANAM for the individual tests used. Throughput is defined as correct responses per minute of time available to respond. Higher scores indicate accuracy in each of the subtest. The range is 6 to 50. The scores in this section represent results of the matching to sample subtest.
Time Frame	Baseline and six weeks post hyperbaric exposure series

Outcome Measure Data

Analysis Population Description

One subject withdrawal from each group due to personal reasons

Arm/Group Title	Sham Treatment	Hyperbaric Oxygen 2.4 ATA
Arm/Group Description	Subject will breathe air at less than 1.3 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at less that 1.3 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures. Sham treatment	Subject will breathe 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures. Hyperbaric oxygen @ 2.4 ATA: Subject will breath 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures.
Measure Participants	24	24
Baseline	20.00 (10.70)	23.71 (11.86)
Post hyperbaric exposure 6 week follow up throughp	28.22 (10.63)	24.42 (8.08)

11. Primary Outcome

Title	Computer Cognitive Test Scores - BrainCheckers Code Sub Recall
Description	BrainCheckers is a PDA version of the Automated Neuropsychological Assessment Metrics (ANAM) supported by the Army Medical Research and Materiel Command in 2000. It was validated against ANAM for the individual tests used. Throughput is defined as correct responses per minute of time available to respond. Higher scores indicate accuracy in each of the subtest. The range is 6 to 135. The scores in this section represent results of the code sub recall subtest.
Time Frame	Baseline and six weeks post hyperbaric exposure series

Outcome Measure Data

Analysis Population Description

One subject withdrawal from each group due to personal reasons

Arm/Group Title	Sham Treatment	Hyperbaric Oxygen 2.4 ATA
Arm/Group Description	Subject will breathe air at less than 1.3 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at less that 1.3 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures. Sham treatment	Subject will breathe 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures. Hyperbaric oxygen @ 2.4 ATA: Subject will breath 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. Hyperbaric exposures will be done up to 5 times per week with a total number of 30 exposures.
Measure Participants	24	24
Baseline	29.88 (16.63)	36.38 (19.77)
Post hyperbaric exposure 6 week follow up throughp	47.57 (24.02)	44.08 (12.07)

12. Secondary Outcome

Title	Functional MRI
Time Frame	six weeks post hyperbaric exposure series

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Secondary Outcome

Title	Stem Cells: CD_34
Description	A non-parametric regression 14 using the Theil estimator was fit to the observed data in order to demonstrate general trends for relations between measures of cognitive functioning and increased stem cells.
Time Frame	six weeks post hyperbaric exposure series

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

14. Post-Hoc Outcome

Title	PCL-M Relative Risk of Improvement of 2.4 ATA Exposures vs. Sham, All Participants With Only One Concussive Event
Description	The purpose of a pilot study is to identify potential subgroups who may respond to treatment. The various composite scores were ranked and separated by subject and within groups for those who improved and those who did not. This allowed the application relative risk analysis using MedCalc (http://www.medcalc.org) to identify potential subgroups. Relative Risk of Improvement (RROI) was calculated against the concussion history items. Main categories were the number of concussive events, whether the subject had multiple non-concussive events or not, if there were two concussive events within a 48 hour period, the time expired from the last concussion to consent, the etiology of the event, and loss of consciousness. A concussive event was defined as one immediately followed with symptoms. This outcome measure analyzed PCL-M score decreases of 10 or more (significantly improved) in the individuals who experienced only one concussive event.
Time Frame	Baseline values compared to 30 post hyperbaric exposure or 6 week follow-up

Outcome Measure Data

Analysis Population Description

Participants with significant improvement (PCL-M composite scores demonstrating a decrease by 10 or greater) or participants not meeting this criterion.

Arm/Group Title	Sham Treatment Improved	Sham Treatment Not Improved	Hyperbaric Oxygen 2.4 ATA Improved	Hyperbaric Oxygen 2.4 ATA Not Improved
Arm/Group Description	Subjects breathed air at less than 1.3 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at less that 1.3 ATA. See previous description for details. PCL-M composite scores demonstrated a significant (decrease by10 or greater)improvement or a reliable (decrease by 5 or greater) from baseline at 30 post hyperbaric exposure or 6 week follow-up.	Subjects breathed air at less than 1.3 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at less that 1.3 ATA. See previous description for details. PCL-M composite scores demonstrated a decrease of 4 or less from baseline at 30 post hyperbaric exposure or 6 week follow-up.	Subject breathed 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. See previous description for details. PCL-M composite scores demonstrated a significant (decrease by10 or greater)improvement or a reliable (decrease by 5 or greater) from baseline at 30 post hyperbaric exposure or 6 week follow-up.	Subject breathed 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. See previous description for details. PCL-M composite scores demonstrated a decrease of 4 or less from baseline at 30 post hyperbaric exposure or 6 week follow-up.
Measure Participants	15	9	13	11
Number [participants]	4 16%	2 8%	4 8%	7 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sham Treatment, Hyperbaric Oxygen 2.4 ATA, Hyperbaric Oxygen 2.4 ATA Improved, Hyperbaric Oxygen 2.4 ATA Not Improved
	Comments	Relative Risk of Improvement in 2.4 ATA group vs. Sham in subjects with one significant event (blast or impact resulting in concussion symptoms) per Concussion History. PCL-M with significant improvement defined as a score decrease 10 or more.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.5455
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Post-Hoc Outcome

Title	PCL-M Relative Risk of Improvement of 2.4 ATA Exposures vs. Sham, All Participants With Two Concussive Events
Description	The purpose of a pilot study is to identify potential subgroups who may respond to treatment. The various composite scores were ranked and separated by subject and within groups for those who improved and those who did not. This allowed the application relative risk analysis using MedCalc (http://www.medcalc.org) to identify potential subgroups. Relative Risk of Improvement (RROI) was calculated against the concussion history items. Main categories were the number of concussive events, whether the subject had multiple non-concussive events or not, if there were two concussive events within a 48 hour period, the time expired from the last concussion to consent, the etiology of the event, and loss of consciousness. A concussive event was defined as one immediately followed with symptoms. This outcome measure analyzed PCL-M score decreases of 10 or more (significantly improved) in individuals who experienced two concussive events.
Time Frame	Baseline values compared to 30 post hyperbaric exposure or 6 week follow-up

Outcome Measure Data

Analysis Population Description

Participants with significant improvement (PCL-M composite scores demonstrating a decrease by 10 or greater) or participants not meeting this criterion.

Arm/Group Title	Sham Treatment Improved	Sham Treatment Not Improved	Hyperbaric Oxygen 2.4 ATA Improved	Hyperbaric Oxygen 2.4 ATA Not Improved
Arm/Group Description	Subjects breathed air at less than 1.3 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at less that 1.3 ATA. See previous description for details. PCL-M composite scores demonstrated a significant (decrease by10 or greater)improvement or a reliable (decrease by 5 or greater) from baseline at 30 post hyperbaric exposure or 6 week follow-up.	Subjects breathed air at less than 1.3 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at less that 1.3 ATA. See previous description for details. PCL-M composite scores demonstrated a decrease of 4 or less from baseline at 30 post hyperbaric exposure or 6 week follow-up.	Subject breathed 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. See previous description for details. PCL-M composite scores demonstrated a significant (decrease by10 or greater)improvement or a reliable (decrease by 5 or greater) from baseline at 30 post hyperbaric exposure or 6 week follow-up.	Subject breathed 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. See previous description for details. PCL-M composite scores demonstrated a decrease of 4 or less from baseline at 30 post hyperbaric exposure or 6 week follow-up.
Measure Participants	15	9	13	11
Number [participants]	6 24%	5 20%	3 6%	2 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sham Treatment, Hyperbaric Oxygen 2.4 ATA, Hyperbaric Oxygen 2.4 ATA Improved, Hyperbaric Oxygen 2.4 ATA Not Improved
	Comments	Relative Risk of Improvement in 2.4 ATA group vs. Sham in subjects with two significant events (blast or impact resulting in concussion symptoms) per Concussion History. PCL-M with significant improvement defined as a score decrease 10 or more.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.10
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Post-Hoc Outcome

Title	PCL-M Relative Risk of Improvement of 2.4 ATA Exposures vs. Sham, All Participants With Three Concussive Events
Description	The purpose of a pilot study is to identify potential subgroups who may respond to treatment. The various composite scores were ranked and separated by subject and within groups for those who improved and those who did not. This allowed the application relative risk analysis using MedCalc (http://www.medcalc.org) to identify potential subgroups. Relative Risk of Improvement (RROI) was calculated against the concussion history items. Main categories were the number of concussive events, whether the subject had multiple non-concussive events or not, if there were two concussive events within a 48 hour period, the time expired from the last concussion to consent, the etiology of the event, and loss of consciousness. A concussive event was defined as one immediately followed with symptoms. This outcome measure analyzed PCL-M score decreases of 10 or more (significantly improved) in individuals who experienced three concussive events.
Time Frame	Baseline values compared to 30 post hyperbaric exposure or 6 week follow-up

Outcome Measure Data

Analysis Population Description

Participants with significant improvement (PCL-M composite scores demonstrating a decrease by 10 or greater) or participants not meeting this criterion.

Arm/Group Title	Sham Treatment Improved	Sham Treatment Not Improved	Hyperbaric Oxygen 2.4 ATA Improved	Hyperbaric Oxygen 2.4 ATA Not Improved
Arm/Group Description	Subjects breathed air at less than 1.3 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at less that 1.3 ATA. See previous description for details. PCL-M composite scores demonstrated a significant (decrease by10 or greater)improvement or a reliable (decrease by 5 or greater) from baseline at 30 post hyperbaric exposure or 6 week follow-up.	Subjects breathed air at less than 1.3 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at less that 1.3 ATA. See previous description for details. PCL-M composite scores demonstrated a decrease of 4 or less from baseline at 30 post hyperbaric exposure or 6 week follow-up.	Subject breathed 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. See previous description for details. PCL-M composite scores demonstrated a significant (decrease by10 or greater)improvement or a reliable (decrease by 5 or greater) from baseline at 30 post hyperbaric exposure or 6 week follow-up.	Subject breathed 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. See previous description for details. PCL-M composite scores demonstrated a decrease of 4 or less from baseline at 30 post hyperbaric exposure or 6 week follow-up.
Measure Participants	15	9	13	11
Number [participants]	3 12%	2 8%	4 8%	2 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sham Treatment, Hyperbaric Oxygen 2.4 ATA, Hyperbaric Oxygen 2.4 ATA Improved, Hyperbaric Oxygen 2.4 ATA Not Improved
	Comments	Relative Risk of Improvement in 2.4 ATA group vs. Sham in subjects with three significant events (blast or impact resulting in concussion symptoms) per Concussion History. PCL-M with significant improvement defined as a score decrease 10 or more.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.1111
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Post-Hoc Outcome

Title	PCL-M Relative Risk of Improvement of 2.4 ATA Exposures vs. Sham, All Participants With Four or More Concussive Events
Description	The purpose of a pilot study is to identify potential subgroups who may respond to treatment. The various composite scores were ranked and separated by subject and within groups for those who improved and those who did not. This allowed the application relative risk analysis using MedCalc (http://www.medcalc.org) to identify potential subgroups. Relative Risk of Improvement (RROI) was calculated against the concussion history items. Main categories were the number of concussive events, whether the subject had multiple non-concussive events or not, if there were two concussive events within a 48 hour period, the time expired from the last concussion to consent, the etiology of the event, and loss of consciousness. A concussive event was defined as one immediately followed with symptoms. This outcome measure analyzed PCL-M score decreases of 10 or more (significantly improved) in individuals who experienced four or more concussive events.
Time Frame	Baseline values compared to 30 post hyperbaric exposure or 6 week follow-up

Outcome Measure Data

Analysis Population Description

Participants with significant improvement (PCL-M composite scores demonstrating a decrease by 10 or greater) or participants not meeting this criterion.

Arm/Group Title	Sham Treatment Improved	Sham Treatment Not Improved	Hyperbaric Oxygen 2.4 ATA Improved	Hyperbaric Oxygen 2.4 ATA Not Improved
Arm/Group Description	Subjects breathed air at less than 1.3 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at less that 1.3 ATA. See previous description for details. PCL-M composite scores demonstrated a significant (decrease by10 or greater)improvement or a reliable (decrease by 5 or greater) from baseline at 30 post hyperbaric exposure or 6 week follow-up.	Subjects breathed air at less than 1.3 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at less that 1.3 ATA. See previous description for details. PCL-M composite scores demonstrated a decrease of 4 or less from baseline at 30 post hyperbaric exposure or 6 week follow-up.	Subject breathed 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. See previous description for details. PCL-M composite scores demonstrated a significant (decrease by10 or greater)improvement or a reliable (decrease by 5 or greater) from baseline at 30 post hyperbaric exposure or 6 week follow-up.	Subject breathed 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. See previous description for details. PCL-M composite scores demonstrated a decrease of 4 or less from baseline at 30 post hyperbaric exposure or 6 week follow-up.
Measure Participants	15	9	13	11
Number [participants]	2 8%	0 0%	2 4%	0 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sham Treatment, Hyperbaric Oxygen 2.4 ATA, Hyperbaric Oxygen 2.4 ATA Improved, Hyperbaric Oxygen 2.4 ATA Not Improved
	Comments	Relative Risk of Improvement in 2.4 ATA group vs. Sham in subjects with four or more significant events (blast or impact resulting in concussion symptoms) per Concussion History. PCL-M with significant improvement defined as a score decrease 10 or more.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.0
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

18. Post-Hoc Outcome

Title	PCL-M Relative Risk of Improvement of 2.4 ATA Exposures vs. Sham, All Participants With Multiple Non-concussive Blast and/or Impact Exposures.
Description	The purpose of a pilot study is to identify potential subgroups who may respond to treatment. The various composite scores were ranked and separated by subject and within groups for those who improved and those who did not. This allowed the application relative risk analysis using MedCalc (http://www.medcalc.org) to identify potential subgroups. Relative Risk of Improvement (RROI) was calculated for the number of concussive events, whether the subject had multiple non-concussive events or not, if there were two concussive events within a 48 hour period, the time expired from the last concussion to consent, the etiology of the event, and loss of consciousness. Many subjects had multiple blast and/or impact events without a concussion (asymptomatic), but had a flight or flight (danger response) experience. This outcome measure analyzed PCL-M score decreases of 10 or more (significantly improved) in individuals who experienced multiple non-concussive blast and/or impact events.
Time Frame	Baseline values compared to 30 post hyperbaric exposure or 6 week follow-up

Outcome Measure Data

Analysis Population Description

Participants with significant improvement (PCL-M composite scores demonstrating a decrease by 10 or greater) or participants not meeting this criterion who had multiple blast and/or impact event that did not result in a concussion (asymptomatic), but had a flight or flight (danger response) experience.

Arm/Group Title	Sham Treatment Improved	Sham Treatment Not Improved	Hyperbaric Oxygen 2.4 ATA Improved	Hyperbaric Oxygen 2.4 ATA Not Improved
Arm/Group Description	Subjects breathed air at less than 1.3 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at less that 1.3 ATA. See previous description for details. PCL-M composite scores demonstrated a significant (decrease by10 or greater)improvement from baseline at 30 post hyperbaric exposure or 6 week follow-up.	Subjects breathed air at less than 1.3 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at less that 1.3 ATA. See previous description for details. PCL-M composite scores demonstrated a significant (decrease by 9 or less)improvement from baseline at 30 post hyperbaric exposure or 6 week follow-up.	Subject breathed 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. See previous description for details. PCL-M composite scores demonstrated a significant (decrease by10 or greater)improvement from baseline at 30 post hyperbaric exposure or 6 week follow-up.	Subject breathed 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. See previous description for details. PCL-M composite scores demonstrated a significant (decrease by 9 or less)improvement from baseline at 30 post hyperbaric exposure or 6 week follow-up.
Measure Participants	17	7	7	17
Number [participants]	11 44%	5 20%	2 4%	9 NaN

19. Post-Hoc Outcome

Title	PCL-M Relative Risk of Improvement of 2.4 ATA Exposures vs. Sham, Measuring Time to Consent From the Last Concussion in Subjects With Multiple Concussions.
Description	The purpose of a pilot study is to identify potential subgroups who may respond to treatment. The various composite scores were ranked and separated by subject and within groups for those who improved and those who did not. This allowed the application relative risk analysis using MedCalc (http://www.medcalc.org) to identify potential subgroups. Relative Risk of Improvement (RROI) was calculated for the number of concussive events, whether the subject had multiple non-concussive events or not, if there were two concussive events within a 48 hour period, the time expired from the last concussion to consent, the etiology of the event, and loss of consciousness. This outcome measure analyzed PCL-M score decreases of 10 or more (significantly improved) with consent within one year from the last concussion in subjects who had multiple concussions.
Time Frame	Baseline values compared to 30 post hyperbaric exposure or 6 week follow-up

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sham Treatment Improved	Sham Treatment Not Improved	Hyperbaric Oxygen 2.4 ATA Improved	Hyperbaric Oxygen 2.4 ATA Not Improved
Arm/Group Description	Subjects breathed air at less than 1.3 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at less that 1.3 ATA. See previous description for details. PCL-M composite scores demonstrated a significant (decrease by10 or greater)improvement or a reliable (decrease by 5 or greater) from baseline at 30 post hyperbaric exposure or 6 week follow-up.	Subjects breathed air at less than 1.3 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at less that 1.3 ATA. See previous description for details. PCL-M composite scores demonstrated a decrease of 9 or less from baseline at 30 post hyperbaric exposure or 6 week follow-up.	Subject breathed 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. See previous description for details. PCL-M composite scores demonstrated a significant (decrease by10 or greater)improvement or a reliable (decrease by 5 or greater) from baseline at 30 post hyperbaric exposure or 6 week follow-up.	Subject breathed 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. See previous description for details. PCL-M composite scores demonstrated a decrease of 9 or less from baseline at 30 post hyperbaric exposure or 6 week follow-up.
Measure Participants	17	7	17	7
Number [participants]	1 4%	3 12%	3 6%	2 NaN

Adverse Events

Arm/Group Title	Sham Treatment		Hyperbaric Oxygen 2.4 ATA
Arm/Group Description	Subjects breathed air at less than 1.3 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at less that 1.3 ATA. Hyperbaric exposures were done up to 5 times per week with a total number of 30 exposures. Pressurization time was seven minutes to a depth of 11 feet of sea water (fsw) or 1.3 ATA. The chamber pressure was slowly decreased over 10 minutes to 6 fsw (1.2 ATA). The final depressurization to surface was done over a 10 minute period. To simulate the treatment 2.4 ATA pressurization, pressurizations and depressurizations were done using venting techniques that would be nearly identical with the noise and temperature as that experienced with the treatment pressure. The inside observers simulated pressure equalization measures (Valsalva) every 10 to 30 seconds and breathed oxygen by mask (required in the 2.4 ATA pressure to prevent decompression sickness) at the same frequency as if they were in the treatment exposure pressure.		Subject breathed 100% oxygen at 2.4 Atmospheres Absolute (ATA) in three 30 minute periods separated by 10 minutes of breathing air at 2.4 ATA. Hyperbaric exposures were done up to 5 times per week with a total number of 30 exposures. Pressurization time was seven minutes to a depth of 45 feet of sea water (fsw) or 2.4 ATA. The final depressurization to surface was done over a 10 minute period. Inside observers used pressure equalization measures (Valsalva) every 10 to 30 seconds and breathed oxygen by mask (required in the 2.4 ATA pressure to prevent decompression sickness) three times (10/15/5 minute durations) during the exposure.
All Cause Mortality
	Sham Treatment		Hyperbaric Oxygen 2.4 ATA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Sham Treatment		Hyperbaric Oxygen 2.4 ATA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/25 (0%)
Other (Not Including Serious) Adverse Events
	Sham Treatment		Hyperbaric Oxygen 2.4 ATA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/25 (16%)		10/25 (40%)
Ear and labyrinth disorders
Ear block	4/25 (16%)	8	10/25 (40%)	44

Limitations/Caveats

Caveats: Analysis used both repeated measures of analysis of covariance (ANCOVA) and repeated measures analysis of variance (RMANOVA). Due to the results, analysis is currently identifying potential subgroups which may demonstrate significance.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.