Treatment of Traumatic Brain Injury With Hyperbaric Oxygen Therapy

Treatment of Moderate to Mild Cognitive Dysfunction Caused by Traumatic Brain Injury (TBI) With Hyperbaric Oxygen Therapy (HBOT)

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00810615

Enrollment

Registered

2008-12-18

Start date

2009-02-28

Completion date

2011-01-31

Last updated

2018-08-13

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Brain Injury, Chronic

Keywords

chronic TBI, cognitive function, PTSD, HBO, hyperbaric, oxygen, chronic brain injury

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.

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

Interventions

OTHERHyperbaric 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.

OTHERSham treatment

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

SINGLE (Subject)

Eligibility

Sex/Gender

ALL

Age

19 Years to 60 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.

Secondary

Measure	Time frame	Description
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.
Functional MRI	six weeks post hyperbaric exposure series	—

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).

Participants by arm

Arm	Count
Sham Treatment 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.	25
Hyperbaric Oxygen 2.4 ATA 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.	25
Total	50

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Withdrawal by Subject	1	1

Baseline characteristics

Characteristic	Hyperbaric Oxygen 2.4 ATA	Sham Treatment	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	25 Participants	25 Participants	50 Participants
Age, Continuous	28.3 years STANDARD_DEVIATION 8.1	28.4 years STANDARD_DEVIATION 7.4	28.3 years STANDARD_DEVIATION 7.7
Region of Enrollment United States	25 participants	25 participants	50 participants
Sex: Female, Male Female	1 Participants	1 Participants	2 Participants
Sex: Female, Male Male	24 Participants	24 Participants	48 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	4 / 25	10 / 25
serious Total, serious adverse events	0 / 25	0 / 25

Outcome results

Primary

Computer Cognitive Test Scores - BrainCheckers Code Sub Recall

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.