Evidence Brief: Hyperbaric Oxygen Therapy for Traumatic Brain Injury and/or Post-traumatic Stress Disorder

Nicholas J. Parr; Johanna Anderson; Stephanie Veazie

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Evidence Brief: Hyperbaric Oxygen Therapy for Traumatic Brain Injury and/or Post-traumatic Stress Disorder

Investigators: Nicholas J. Parr, PhD, MPH, Johanna Anderson, MPH, and Stephanie Veazie, MPH.

Washington (DC): Department of Veterans Affairs (US); 2021 Jul.

The Evidence Synthesis Program (ESP) Coordinating Center is responding to a request from the VA Health Services Research and Development Service for an update to the 2018 ESP evidence brief on the use of hyperbaric oxygen therapy (HBOT) to treat Veterans and non-Veterans with traumatic brain injury (TBI) and/or post-traumatic stress disorder (PTSD), in response to the Commander John Scott Hannon Veterans Mental Health Care Improvement Act of 2019 (“Hannon Act”). A secondary aim of this update was to provide an overview of assessment tools for measuring TBI and PTSD symptoms. Findings from this evidence brief will be used to inform a report to the Committees on Veterans Affairs of the US Senate and the US House of Representatives in response to Section 702 of the Hannon Act.

PREFACE

The VA Evidence Synthesis Program (ESP) was established in 2007 to provide timely and accurate syntheses of targeted healthcare topics of importance to clinicians, managers, and policymakers as they work to improve the health and healthcare of Veterans. These reports help:

Develop clinical policies informed by evidence;
Implement effective services to improve patient outcomes and to support VA clinical practice guidelines and performance measures; and
Set the direction for future research to address gaps in clinical knowledge.

The program comprises three ESP Centers across the US and a Coordinating Center located in Portland, Oregon. Center Directors are VA clinicians and recognized leaders in the field of evidence synthesis with close ties to the AHRQ Evidence-based Practice Center Program. The Coordinating Center was created to manage program operations, ensure methodological consistency and quality of products, and interface with stakeholders. To ensure responsiveness to the needs of decision-makers, the program is governed by a Steering Committee composed of health system leadership and researchers. The program solicits nominations for review topics several times a year via the program website.

Comments on this evidence report are welcome and can be sent to Nicole Floyd, Deputy Director, ESP Coordinating Center at vog.av@dyolF.elociN.

EXECUTIVE SUMMARY

Background

The Evidence Synthesis Program Coordinating Center is responding to a request from the VA Health Services Research and Development Service for an updated evidence brief on the use of hyperbaric oxygen therapy for the treatment of traumatic brain injury and/or post-traumatic stress disorder, in response to the Commander John Scott Hannon Veterans Mental Health Care Improvement Act of 2019 (“Hannon Act”). Findings from this updated evidence brief will be used to inform a report submitted to the Committees on Veterans Affairs of the US Senate and the US House of Representatives in response to Section 702 of the Hannon Act.

Methods

To identify studies, we searched MEDLINE®, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and other sources up to October 2020. We used prespecified criteria for study selection, data abstraction, and rating internal validity and strength of the evidence. See our PROSPERO protocol for full study details.

Key Findings

Acute moderate to severe TBI: For patients hospitalized with acute moderate to severe TBI, available evidence suggests HBOT can reduce mortality and coma severity more than standard care, but it is unclear whether HBOT improves longer-term functionality. In patients with acute TBI, severe pulmonary complications and seizures may occur. Because HBOT protocols varied widely across available trials, clarity is needed on the optimal HBOT protocol for moderate to severe TBI.
Chronic mild TBI (mTBI): When pooled, evidence on HBOT for chronic mTBI shows that HBOT does not lead to short-term improvements in post-concussion and PTSD symptoms compared to sham, and sparse longer-term evidence suggests symptom improvement after HBOT is not durable. HBOT appears to be well-tolerated by patients with chronic mTBI, with the most common side effect being mild barotrauma.
A targeted review of outcome measures for TBI and/or PTSD found that similar measures are used in HBOT trials and studies of other treatments for TBI and/or PTSD, and across VA and non-VA HBOT trials.
Decisions about whether additional research is warranted must consider whether patient, provider, and system resources required for HBOT would be better directed toward other approaches. One future research direction could be to examine whether features of the HBOT treatment experience (eg, coordinated engagement with providers and other patients) are themselves active intervention components that could be incorporated into more widely implementable treatments for chronic post-concussion symptoms.

Traumatic brain injury (TBI) and PTSD can often result in similar prolonged symptoms. Many people with chronic mTBI and/or PTSD do not achieve symptom remission with currently recommended treatments, and HBOT has been explored as a treatment alternative for those with persistent symptoms. HBOT is used to increase the supply of oxygen to blood and tissues by delivering 100% medical-grade oxygen inside a chamber where the air pressure is raised to at least 1.4 times greater than normal. Evidence from case series suggesting that HBOT may lead to improved cerebral blood flow, PTSD and post-concussion symptoms, and patient quality of life has not been well-replicated in randomized clinical trials. HBOT has not been FDA-cleared for treatment of TBI and/or PTSD, and the efficacy of HBOT in this application continues to be debated.

The present review updates a 2018 review by the VA Evidence Synthesis Program (ESP) and includes 2 randomized controlled trials completed since the earlier review. Findings of this updated synthesis align with those of the previous ESP review. The updated findings include:

Acute TBI. For patients hospitalized with acute moderate to severe TBI, available evidence suggests HBOT can reduce mortality and coma severity more than standard neurosurgical care, but it is unclear whether HBOT improves longer-term functionality. Patients with acute severe TBI who receive HBOT may experience significant adverse effects, including severe pulmonary complications and seizures. Most HBOT trials in patients with acute TBI did not include current Service members or Veterans with blast-related TBI or patients with moderate TBI; therefore, evidence may be most applicable to patients with severe TBI from other causes.

Treating patients with acute moderate to severe TBI represents a considerably different clinical scenario than treatment of chronic mTBI (the most common form of TBI in Veterans) and prioritizes life-saving interventions typically delivered to hospitalized patients within hours or days of injury. In this application, evidence suggests HBOT may offer near-term benefits. However, because HBOT protocols varied widely across available trials and severe adverse effects may occur, clarity is needed on the protocol that optimally balances benefits and risks of HBOT for patients with acute moderate to severe TBI.

Chronic mTBI. When pooled, evidence on HBOT for chronic mTBI shows that HBOT does not lead to short-term improvements in post-concussion and PTSD symptoms compared to sham. Sparse longer-term evidence suggests symptom improvement after HBOT is not durable. HBOT appears to be well-tolerated by patients with chronic mTBI, with the most common side effect being mild barotrauma.

In several included sham-controlled trials, short-term symptom improvement was similar in both HBOT and sham groups, which suggests observed symptom change is likely the result of participation and/or placebo effects that occur because of the intensity of the HBOT intervention and its sham equivalent. Participation and placebo effects can result from the experience of accessing and receiving care (including sham treatment); engaging with and being engaged by providers, nurses, and other caring staff (for screening, intervention or sham delivery, and outcome assessment); and from patient and provider expectancies of treatment response.

PTSD without TBI. Available evidence is not applicable to PTSD-diagnosed patients without a co-occurring TBI because no trials included these patients.

Typically, health systems assign a low priority to treatments such as HBOT that have so far failed to show conclusive benefit over placebo, sham intervention, or usual care, and consider manufacturers and advocates to have the burden to prove that the intervention can work. In the VA context, decisions about whether additional research is warranted must consider whether patient, provider, and system resources required for HBOT would be better directed toward other approaches. It is also important to recognize that a lack of effect when an intervention is compared to an inactive condition does not necessarily mean the intervention has no benefits. As noted in our original review, evidence on HBOT (and evidence on other treatments that has similar characteristics, such as acupuncture for chronic pain) suggests that the features of the HBOT therapeutic experience may act together to create conditions that lead to improved patient symptoms, at least in the short term. One future research direction could be to examine whether features of the HBOT treatment experience (eg, coordinated engagement with providers and other patients) are themselves active intervention components that could be incorporated into more widely implementable treatments for chronic post-concussion symptoms.

INTRODUCTION

PURPOSE

The Evidence Synthesis Program (ESP) Coordinating Center is responding to a request from the VA Health Services Research and Development Service for an update to the 2018 ESP evidence brief¹ on the use of hyperbaric oxygen therapy (HBOT) to treat Veterans and non-Veterans with traumatic brain injury (TBI) and/or post-traumatic stress disorder (PTSD), in response to the Commander John Scott Hannon Veterans Mental Health Care Improvement Act of 2019 (“Hannon Act”). A secondary aim of this update was to provide an overview of assessment tools for measuring TBI and PTSD symptoms. Findings from this evidence brief will be used to inform a report to the Committees on Veterans Affairs of the US Senate and the US House of Representatives in response to Section 702 of the Hannon Act.

BACKGROUND

Hyperbaric Oxygen Therapy

HBOT is designed to increase the partial pressure of oxygen in the blood and tissues through inhalation of pure oxygen in an environment pressurized to at least 1.4 times normal atmospheric absolute (ATA) pressure at sea level (most regimens use 2.0-2.8 ATA).² The increase in arterial oxygen partial pressure has widespread effects, including reversal of hypoxia in injured tissues, changes in connective and immune cell function, inhibition of inflammation, reduction in swelling, and release of stem cells.³^–⁵ Delivery of HBOT involves use of medical-grade oxygen, and HBOT chambers are ideally operated by specially trained hyperbaric technicians under the supervision of a clinician.⁶

HBOT is an established treatment for decompression sickness, which can occur in scuba divers who have resurfaced from pressurized environments, and has been used for other indications such as treatment of infections or wounds.⁷ Fourteen indications are currently cleared for HBOT device use by the FDA and maintained by the Undersea & Hyperbaric Medical Society (UHMS), including treatment of air or gas embolism, carbon monoxide poisoning, decompression sickness, and soft tissue necrosis (see Appendix A in supplemental materials for full list).⁸ HBOT protocols vary based on the indication, its severity, and patient treatment tolerance and response. HBOT sessions can last 60 to 90 minutes and be delivered 1 or more times each day up to 5 days per week, for as little as 10 days or as long as 6 to 10 weeks. Over the course of treatment, patients frequently interact with hyperbaric technicians, nurses, and other patients.

Treatment of Prolonged Symptoms of TBI and/or PTSD

Chronic mild TBI (mTBI) and PTSD often result in similar prolonged symptoms. Patients with chronic mTBI experience physical (eg, headache, dizziness, vision), cognitive (eg, memory, focus, judgment), and emotional (eg, depression, anger, anxiety) symptoms that last longer than 3 months following their injury and may take 6 months to a year to completely resolve.⁹^–¹¹ PTSD can also result in cognitive and mood problems, sleep issues, and difficulties with concentration, as well as unique symptoms such as hypervigilance, flashbacks, or re-experiencing of a traumatic event.¹² Moderate to severe TBI may result in similar cognitive impairments and behavioral changes, although patients can also experience disability, elevated risk of neurological diseases that can cause functional impairment, and increased risk of death.¹³^,¹⁴ Nineteen to 36% of patients with moderate to severe TBI do not survive.¹⁵

Despite limited available evidence on efficacious treatments for mTBI,¹⁶^,¹⁷ VA/DoD guidelines recommend a coordinated stepped-care treatment approach using psychoeducation, cognitive rehabilitation, nonpharmacologic interventions (eg, sleep hygiene, education, dietary modification, physical therapy, and relaxation), behavioral health treatments, and/or pharmacologic interventions.¹⁸ VA/DoD guidelines for PTSD recommend trauma-focused psychotherapy as primary treatment over pharmacologic and other non-pharmacologic interventions.¹⁹ (See Appendix B in supplemental materials for full list of relevant guidelines.) Treatment of acute moderate to severe TBI represents a different clinical scenario from treatment of chronic mTBI, and prioritizes life-saving measures such as decompressive craniectomy, barbiturate administration, and seizure prophylaxis.²⁰

Use of HBOT for TBI and/or PTSD

Some patients with chronic mTBI and/or PTSD do not experience symptom improvement with recommended therapies,⁹^–¹¹ and HBOT has been explored as a treatment alternative.²¹^,²² Evidence to support HBOT in this application has been drawn from both animal and human studies. In animal models of acute TBI, HBOT improves intermediate disease markers such as tissue oxygenation, neuronal stem cell proliferation, and inflammation,²³ while in patients hospitalized with acute TBI, HBOT has been shown to reduce markers of central nervous system inflammation.²⁴ In case series of patients with mTBI, substantial improvements in cerebral blood flow, post-concussion symptoms, and quality of life have been reported after HBOT.⁴^,²⁵ Importantly, these large improvements have not been well-replicated in randomized clinical trials,¹ suggesting that results of case series may not accurately characterize HBOT efficacy.

Clinical trials are intended to provide a rigorous assessment of whether HBOT causes improvement in TBI and/or PTSD symptoms, but trial findings have been challenging to interpret and widely debated. An ongoing area of controversy is whether HBOT leads to genuine treatment effects or, given the intensity of the intervention, instead produces participation (or Hawthorne) effects and/or placebo effects.²⁶^–²⁸ These can occur when patients or providers know who has been selected to receive treatment (ie, unblinded), or when patients perceive they are receiving treatment because of sensory stimuli (eg, pressure changes or sounds associated with treatment) or the intensive engagement of providers, nurses, and other staff that accompanies treatment delivery. Activities associated with accessing a trial, such as consenting and completing baseline assessments, may also induce participation effects. Participation effects can impact both treatment and control groups in clinical trials and may lead to inconsistent, misleading, or difficult to interpret trial findings.²⁶^,²⁷^,²⁹

Evidence available at the time of the previous ESP review¹ was inconclusive about the efficacy of HBOT for mTBI and PTSD, and use of HBOT to treat TBI or PTSD has not been FDA-cleared or endorsed by clinical practice guidelines or payer policies. Consequently, use of HBOT for this purpose has remained limited. Research has continued, however, and since the release of the previous ESP review, additional trials have been completed. The purpose of the current review was to determine whether findings of these trials, when synthesized with earlier evidence, provide clarity on HBOT efficacy for TBI and/or PTSD.

METHODS

PROTOCOL

A preregistered protocol for this review can be found on the PROSPERO international prospective register of systematic reviews (http://www.crd.york.ac.uk/PROSPERO/; registration number CRD42020216736).

KEY QUESTIONS

The following key questions (KQs) were the focus of this review:

KQ1.: What are the potential benefits of HBOT for the treatment of TBI and/or PTSD?
KQ2.: What are the potential risks of using HBOT for the treatment of TBI and/or PTSD?
KQ3.: Do the benefits or risks of HBOT differ per patient characteristics (eg, patient demographics, comorbidities, disease severity)?
KQ4.: Do the benefits or risks of HBOT differ per treatment protocol (eg, number of sessions, amount of pressure, inpatient vs outpatient treatment)?

ANALYTIC FRAMEWORK

The analytic framework shown in Figure 1 provides a conceptual overview of this review. The population of interest was patients with TBI and/or PTSD. Eligible outcomes included health and other clinically significant outcomes (Key Question 1) and treatment harms (Key Question 2). We did not consider intermediate outcomes associated with HBOT (eg, tissue oxygenation), as the purported treatment mechanism of HBOT implies that changes in intermediate outcomes results in changes in eligible patient-relevant outcomes. Whether benefits and/or risks of HBOT differ by patient characteristics (eg, patient demographics, comorbidities, disease severity) or treatment protocol (eg, number of sessions, amount of pressure, inpatient vs outpatient treatment) was also of interest (Key Questions 3 and 4).

Figure 1

Analytic Framework. Abbreviations. ATA=atmospheres absolute, KQ=key question, PTSD=post-traumatic stress disorder, TBI=traumatic brain injury, %O₂=percent oxygen.

ELIGIBILITY CRITERIA

The ESP included studies that met the following criteria:

Population: Patients with TBI, PTSD, or the co-occurrence of TBI and PTSD
Intervention: HBOT, any protocol (per Undersea & Hyperbaric Medical Society)
Comparator: Any (eg, sham HBOT, no treatment, standard care)
Outcomes:
- Benefits: Mortality, morbidity, quality of life, functional capacity (eg, social, employment, activities of daily living, etc), TBI and/or PTSD symptom improvement (eg, mean change in symptom response), clinically significant TBI and PTSD clinical symptom response (as defined in included studies [eg, proportion of patients meeting a preset threshold for symptom improvement]), and duration of clinical symptom response or improvement. We accepted any definition of clinically significant clinical symptom response. We excluded intermediate physiologic measures, such as intracranial pressure, cerebrospinal fluid lactate levels, or changes in cerebral blood flow.
- Harms: Any (ear problems, pulmonary complications, headache, nausea, etc)
Timing: Any
Setting: Any
Study design: Systematic reviews, randomized controlled trials, and concurrently controlled cohort studies. We considered case series (ie, N > 1) only to address gaps in evidence from studies with control groups. We excluded case reports (ie, N = 1).

DATA SOURCES AND SEARCHES

To identify articles relevant to the key questions, a research librarian searched Ovid MEDLINE, Ovid PsycINFO, Ovid CENTRAL, ClinicalTrials.gov, and PTSDpubs, as well as AHRQ, Cochrane Database of Systematic Reviews, and HSR&D through October 2020 using terms for hyperbaric oxygen therapy, traumatic brain injury, and post-traumatic stress disorder (see Appendix C in the supplemental materials for complete search strategies). Additional citations were identified from hand-searching reference lists and consultation with content experts. We limited the search to published and indexed articles involving human subjects available in the English language. Study selection was based on the eligibility criteria described above. Titles, abstracts, and full-text articles were reviewed by 1 investigator and checked by another. All disagreements were resolved by consensus or discussion with a third reviewer.

As noted, an objective of the review update was to provide an overview of assessment tools for measuring PTSD and TBI symptoms. We conducted a secondary non-systematic search to identify guidelines and systematic reviews for TBI and PTSD assessment tools through the Cochrane Database of Systematic Reviews and the ECRI Guidelines Trust database. Because we limited our search to these sources, we did not carry out additional quality or strength of evidence assessments on these reports.

DATA ABSTRACTION AND ASSESSMENT

Effect information and population, intervention, and comparator characteristics were abstracted from all included studies, and study authors were queried for missing effect information when necessary. The internal validity (risk of bias) of each included study was rated using the Cochrane’s Risk of Bias 2.0 Tool.³⁰ All data abstraction and internal validity ratings were first completed by 1 reviewer and then checked by another; disagreements were resolved by consensus or discussion with a third reviewer.

We graded the strength of the evidence for each outcome based on the AHRQ Methods Guide for Comparative Effectiveness Reviews.³¹ This approach provides a rating of confidence in reported findings based on trial methodology (design, quality, and risk of bias), consistency (whether effects are in the same direction and have a consistent magnitude), and directness (whether assessed outcomes are clinically important to patients and providers). When information on precision of findings (eg, confidence intervals) is available, certainty of evidence is also evaluated. For this review, we applied the following general algorithm: high strength evidence consisted of multiple, large trials with low risk of bias and consistent and precise findings; moderate strength evidence consisted of multiple trials with low to unclear risk of bias and consistent and precise findings; low strength evidence consisted of a single trial, or multiple small trials, with unclear to high risk of bias and/or inconsistent or imprecise findings; and insufficient evidence consisted of a single trial with unclear or high risk of bias, or no available trials. Directness of findings was addressed by requiring included studies to report clinically relevant outcomes.

SYNTHESIS

Trial findings were organized by condition (mTBI or moderate-severe TBI), comparator (sham or no treatment/standard care), and outcome type (post-concussion or PTSD symptoms). When treatment and comparator protocols were sufficiently similar and 2 or more effect estimates from similar timepoints were available, we quantitatively synthesized (meta-analyzed) available effect information to improve statistical power and overcome potential analytic limitations of included trials (eg, significance levels not adjusted for multiple comparisons). When effect data could not be pooled, evidence was synthesized narratively.

Effect sizes for meta-analyses were mean differences between treatment and comparison groups following the treatment course or control period. Standard deviations of means, when not readily available, were calculated from 95% confidence intervals or independent or dependent t-tests (calculations using dependent t-tests assumed a correlation of 0.8 between baseline and post-treatment means). When the same outcome scale was used across trials, raw mean difference (MD) effect sizes were used; when different measures of the same outcome were available, bias-adjusted standardized mean differences (Hedges’ g) were employed.

Random-effects models were used for all meta-analyses. For independent effect data, exact confidence intervals for small meta-analyses were calculated using the method developed by Michael et al.³² When trials reported multiple effect estimates, multivariate random-effects meta-analyses were used to account for dependency among effect estimates, and cluster-robust confidence intervals were calculated for overall effect estimates. Within-trial correlation among dependent effects was assumed to be 0.8; sensitivity analyses using a correlation of 0.3 were conducted to ensure findings were not impacted by this assumption. Heterogeneity in effects was calculated using the restricted maximum-likelihood estimator and evaluated using 95% prediction intervals.³³^,³⁴ Meta-analyses were conducted using the metafor³⁵ package for R (R Foundation for Statistical Computing, Vienna, Austria).

RESULTS

LITERATURE FLOW

The literature flow diagram (Figure 2) summarizes the results of the study selection process (full list of excluded studies available in Appendix D in supplemental materials).

Figure 2

Literature Flowchart. Notes. ^a14 studies in 21 publications. This reflects fewer publications than the original ESP evidence brief due to exclusion of systematic reviews and focus on primary studies with outcomes of interest. Abbreviations. CCRCT=Cochrane (more...)

LITERATURE OVERVIEW

Our search identified 403 potentially relevant articles. We included 14 trials (in 21 publications),³^,²⁴^,³⁶^–⁵⁴ which are summarized in Table 1 (see Appendix E in supplemental materials for full trial details). Six trials included patients with chronic mTBI,³^,³⁸^,⁴⁰^,⁴³^,⁵¹^,⁵⁴ 7 trials included patients with acute moderate to severe TBI,²⁴^,³⁶^,⁴²^,⁴⁴^–⁴⁷ and 1 trial did not specify TBI severity.⁴⁸ Trials in patients with chronic mTBI included patients with or without PTSD, but no trials included patients with PTSD alone (ie, without a co-occurring TBI). The median sample size of included trials was 60 participants (range: 30-320). We identified 2 underway trials (see Appendix F in supplemental materials) examining HBOT use in patients with TBI.

Mild TBI

Trials examining HBOT for mTBI used 30 to 40 sessions of HBOT and compared the treatment group to either a sham condition or to a no treatment or standard care condition. In a sham-controlled trial, patients randomized to the control group experience an intervention that mimics the active treatment condition but is designed to have no treatment effect; as a result, all patients remain blinded to whether they actually received treatment. Sham conditions in HBOT trials used a hyperbaric chamber filled with normal air (ie, less than 100% oxygen) at a lower pressure (1.2 to 1.3 ATA)⁴³^,⁵¹ or low oxygen (10.5%) delivered at 2.0 ATA³⁹ to simulate hyperbaric effects such as ear pressure and heating and cooling effects of pressurization. All included sham-controlled trials enrolled military members with at least 1 mTBI and persistent post-concussion symptoms lasting at least 3 months since their most recent TBI. Four trials³⁸^,⁴⁰^,⁴³^,⁵¹ assessed the proportion of participants with PTSD symptoms, which ranged from 36% to 65%. Trials using no treatment or standard care control conditions were not limited to military members, and participants in these trials were required to have 1 or more mTBIs with persistent post-concussion symptoms. Sham-controlled trials were generally at low risk of biases from randomization procedures, blinding of participants and outcome assessors, missing outcome data (attrition), and deviations from group assignments and trial protocols, while trials using a no treatment comparator were rated as unclear or high risk of bias primarily due to incomplete blinding and attrition. All trials in patients with mTBI were small (50-72 participants), likely limiting statistical power.

We identified 2 trials among patients with mTBI completed since the previous ESP review.¹ The first, known as BIMA, was a double-blind sham-controlled trial⁵¹ of 71 military Service members with at least 1 mTBI and post-concussion symptoms lasting at least 3 months. According to its registered protocol,⁵⁵ BIMA was a Phase II trial and the primary outcome was adverse events associated with treatment exposure. BIMA was not intended to determine efficacy of HBOT, instead aiming to identify outcomes (endpoints) for future efficacy trials from an extensive battery of outcome measures.⁵¹^,⁵⁵ Consequently, efficacy-related findings were considered exploratory and were derived from numerous statistical tests that were not adjusted to limit the possibility of false positives. In addition, participants receiving HBOT appeared to have more severe traumatic brain injuries, on average, than those assigned to the sham group, and the trial also suffered considerable attrition during extended outcome assessment (only 25% of participants originally allocated to HBOT completed the final long-term assessment).

The second new trial identified was a partially-blinded, Phase III, no treatment-controlled crossover trial⁴⁰ of 60 civilian and military participants with mTBI and post-concussion symptoms persisting for at least 6 months. In this trial, 65% of participants allocated to HBOT completed the final assessment. Participants who dropped out had worse baseline PTSD and post-concussion symptoms than participants in HBOT or control groups. The difference in baseline post-concussion symptoms between drop-outs and control participants was significant, and the authors did not appear to report a statistical test for the difference in baseline post-concussion symptoms between drop-outs and HBOT participants; an overall test of the difference in baseline PTSD symptoms between HBOT, control, and drop-out groups was nonsignificant.

Moderate to Severe TBI

All trials investigating HBOT for moderate to severe TBI were included in the previous ESP review on HBOT efficacy for TBI with/without PTSD.¹ Most trials compared HBOT to standard neurosurgical care; 1 used a medication therapy control condition. In these trials, HBOT was used for acute treatment in hospitalized patients, often just hours or days after injury. HBOT treatment courses varied considerably among these trials. Those using HBOT at 1.5 ATA⁴⁵^–⁴⁷ delivered the therapy in 1-hour sessions spaced 4 to 24 hours apart for as few as 3 days and as long as 2 weeks. Three of the 4 trials using higher-pressure HBOT²⁴^,³⁶^,⁴² (2.0-2.5 ATA) delivered HBOT once daily in longer sessions (70-120 minutes) for 10 to 20 sessions. One trial³⁶ repeated the course until the patient recovered or died. A final higher-pressure trial⁴⁴ administered 10 briefer sessions over 4 days. The majority of moderate to severe TBI trials included patients with severe TBI only; 1 trial⁴² included hospitalized patients with moderate or severe TBI. Findings of these trials were at unclear or high risk of bias due to lack of blinding of participants and/or outcome assessors, unclear or high levels of deviations from HBOT protocols in several trials, and exclusion of patients with complications from the analysis in 1 trial.⁴² Although 2 trials were comparatively large (168-320 participants), the majority of trials were small (30-60 participants).

Outcome Measurement

Across trials, measurement of symptoms varied by TBI severity because of differences in the physiology of injury and main outcomes of interest. In trials among patients with mTBI, symptoms of TBI and PTSD were typically assessed using the Rivermead Post-concussion Symptom Questionnaire-13 (RPQ-13; 3 trials), the Neurobehavioral Symptom Inventory (NSI; 3 trials), and the PTSD Checklist (PCL; 5 trials). One trial⁵³ in mTBI patients used the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) tool, which the VA/DoD guideline on concussion and mild TBI recommends against using for routine diagnosis and care of patients with symptoms attributed to mTBI.¹⁸ Another mTBI trial⁵⁰ developed a composite outcome scale based on several existing tools to assess cognitive, physical, and emotional symptoms. Trials in patients with acute moderate to severe TBI used the Glasgow Coma and Outcome Scales (GCS/GOS; 6 trials) and measured patient mortality (4 trials).

Measurement of symptoms was comparable in trials of military/Veteran and civilian populations. Both groups of trials used similar tools and timing of assessments, and generally assessed symptom improvement using mean outcome scores rather than cut-off values. All trials in patients with mTBI assessed HBOT efficacy post-treatment (ie, immediately following 8- to 12-week treatment course); 2 of 4 sham-controlled trials and 1 of 2 standard care or no treatment-controlled trials conducted longer-term follow-up assessments, although follow-up timing varied considerably across trials. In trials of patients with moderate to severe TBI, timing of outcome assessments ranged from immediately following to 6 months after treatment, or was not reported.

Outcome Measurement in HBOT vs non-HBOT Studies

Measurement of treatment efficacy in trials of HBOT for TBI with/without PTSD uses similar tools to those used for other therapies. Using a targeted search of systematic reviews on treatments (other than HBOT) for TBI and PTSD, we identified 24 tools or measures for TBI symptoms and 30 tools or measures for PTSD symptoms (Appendix G in supplemental materials). A 2018 report on treatment of PTSD by the Agency for Healthcare Research and Quality includes a comprehensive list of PTSD outcome assessment tools.⁵⁶ Measurement tools and scales used in HBOT trials and studies of other treatments included the PTSD Checklist, the Rivermead Post-concussion Symptom Questionnaire, and the Glasgow Coma and Outcomes Scales. The most commonly reported tool not used in HBOT trials was the Clinician Administered PTSD Scale.

Table 1

Characteristics of Included Trials.

EFFICACY OF HBOT FOR TBI WITH/WITHOUT PTSD

Mild TBI

Evidence from clinical trials of HBOT efficacy among patients with chronic mTBI was synthesized quantitatively. Results of meta-analyses of available post-treatment effects from sham-controlled trials, including the trial completed after the previous ESP review¹ (BIMA), are shown in Figure 3 (for post-concussion symptoms) and Figure 4 (for PTSD symptoms).

Overall, available evidence shows that HBOT does not lead to short-term improvements in post-concussion and PTSD symptoms among patients with chronic mTBI compared to sham. Synthesizing effect estimates from 3 sham-controlled RCTs,³⁸^,⁴³^,⁵¹ the overall post-treatment effect of HBOT on post-concussion symptoms (RPQ-13 and NSI) favored HBOT but was nonsignificant and very small (g = −0.09, 95% CI [−0.44, 0.26], p = 0.83), while for PTSD symptoms (PCL), the overall effect using evidence from 4 RCTs³⁸^,⁴³^,⁵¹^,⁵⁴ favored sham control (MD = 0.61, 95% CI [−7.75, 8.96], p = 0.38). Individual trial effects for both outcomes were also nonsignificant, inconsistent, and imprecisely estimated, as shown in Figures 3 and 4.

Sparse longer-term evidence suggests symptom improvement after HBOT is not durable. Longer-term effects on post-concussion symptoms, reported by 2 trials at 5.5 to 6 months from baseline and by 1 trial at 12 months from baseline, shared the same limitations as post-treatment effects. At 5.5 to 6 months,³⁹^,⁵¹ reported between-group differences in RPQ and NSI scores were nonsignificant and favored HBOT or neither group, while RPQ scores at 12 months favored control. Six- to 12-month effects on PTSD symptoms (PCL) were reported by only 1 sham-controlled trial⁵¹ and again were nonsignificant and inconsistent, favoring HBOT at 6 months and control at 12 months. The same trial also reported 24- and 36-month outcomes,⁴¹ but these results were only for a subset of original trial participants and were impacted by severe attrition. Reported confidence intervals for longer-term effects were wide and encompassed both improvement and worsening of symptoms relative to sham control.

Figure 3

Forest Plot of Standardized Mean Differences in Post-concussion Symptoms (RPQ-13 and NSI) from Sham-controlled Trials. Notes. Gray error bars around summary estimate diamond indicate 95% prediction interval (PI). Abbreviations. ATA=atmospheres absolute, (more...)

Figure 4

Forest Plot of Mean Differences in PTSD Symptoms (PCL) from Sham-controlled Trials. Notes. Gray error bars around summary estimate diamond indicate 95% prediction interval (PI). Abbreviations. ATA=atmospheres absolute, CI=95% confidence interval, HBOT=hyperbaric (more...)

Several sham-controlled trials³⁹^,⁴³^,⁵¹^,⁵³ of active-duty military members with mTBI included patients with co-occurring mTBI and PTSD (range: 36-65%). Among these, 2 reported outcomes for PTSD subgroups adjusted for age and other covariates. Using uncorrected significance tests, the newly added trial⁵¹ found that post-concussion symptoms (RPQ-3) significantly favored HBOT immediately following treatment among participants with PTSD but not among those without PTSD. Improvements seen at 6 months (RPQ-3 and NSI) were nonsignificant, while symptoms did not differ or worsened compared to sham at 12 months. PTSD symptom (PCL) improvement in the PTSD subgroup favored HBOT post-treatment and at 6 months, but at 12 months results were nonsignificant and symptoms were again worsened compare to sham. The second trial,³⁹ which reported post-concussion outcomes (RPQ) 5.5 months from baseline, did not find evidence of moderation by PTSD status.

Results of a secondary analysis⁵⁰ of data from 2 of the above PTSD subgroups⁴³^,⁵¹ using a composite outcome (including cognitive, physical, and emotional symptoms and based on several existing measurement tools) reported similar findings, and a pooled analysis⁴¹ of included trials found that a PTSD status-by-intervention group interaction was nonsignificant. Finally, a subgroup analysis⁵⁷ (reported in an abstract only) of a previous trial⁵⁴ found that participants with an indication of PTSD (PCL-Military score of 50 of greater) were significantly more responsive to HBOT (2.4 ATA) than sham. Response was defined as a PCL score reduction of 10 or more points; however, baseline differences in absolute PCL scores between PTSD subgroups in treatment or sham conditions were not reported or accounted for in analyses (ie, PTSD-indicated patients in the HBOT group may have had higher PCL scores than PTSD-indicated patients in the sham group, and consequently responded more readily to intervention).

In the meta-analysis of post-concussion outcomes from sham-controlled trials, the similarity in prediction and confidence intervals (Figure 3) for the overall effect estimate suggests heterogeneity in effects between trials was minimal and most variation resulted from within-trial imprecision. In contrast, the prediction interval for PTSD symptoms (Figure 4) was larger than the confidence interval for the overall effect estimate, suggesting substantial heterogeneity in addition to imprecision within trials. Heterogeneity is likely due to the effects from the BIMA and HOPPS trials, which were comparatively larger than other available effects and were in opposite directions.

Compared to sham-controlled trials, no-treatment or standard care-controlled trials⁴⁰^,⁴³ observed effects that favored HBOT. Pooled effects, however, were nonsignificant for both post-concussion symptoms (g = −1.51, 95% CI [−18.96, 15.94], p = 0.45) and PTSD symptoms (MD = −7.41, 95% [−59.22, 44.41], p = 0.33). The only trial⁴⁰ completed since the previous ESP review¹ used a no treatment comparator and reported a large but imprecise effect in favor of HBOT. Comparisons to no treatment or standard care are vulnerable to biases associated with lack of blinding,²⁷^,²⁸^,⁵⁸ and as a result, provide limited insight into HBOT efficacy. As discussed at length in our original review, the only trial⁴³ that included both a sham control group and a standard care control group suggests both HBOT and sham have similar effects, and both are superior to standard post-concussion care.

In addition to PTSD and post-concussion symptoms, several trials³^,⁴³^,⁵¹ assessed whether HBOT led to improved patient quality of life. A crossover trial³ using a no treatment control condition found that patient quality of life (EQ-5D and EQ-VAS) improved following HBOT (among those assigned to receive HBOT and among control participants who received HBOT after crossing over). Two sham-controlled trials⁴³^,⁵¹ observed some post-treatment improvement in a number of health-related quality of life outcomes (SF-36) in both HBOT and control groups, but differences between groups were either nonsignificant or were not assessed for significance.

Moderate to Severe TBI

Seven previously reported RCTs²⁴^,³⁶^,⁴²^,⁴⁴^–⁴⁷ examined the efficacy of HBOT (1.5, 2.0, or 2.5 ATA) for hospitalized patients with acute moderate to severe TBI. In 2⁴⁶^,⁴⁷ of 4 trials reporting patient mortality following HBOT or standard neurosurgical care, HBOT led to significantly reduced patient mortality at 3 months to 1 year. In 3 trials²⁴^,⁴²^,⁴⁴ comparing HBOT to standard care or medication therapy, improvement in coma severity (GCS) significantly favored HBOT (follow-up periods ranged from post-treatment to 6 months after treatment, or were not reported). Finally, 4 trials assessed changes in functional outcomes (GOS) after HBOT or standard care, and 2⁴⁴^,⁴⁷ reported that improvement in functionality significantly favored HBOT at 6 to 12 months from baseline. A third trial⁴² reported improvement over standard care only among those with the highest functional rating at baseline (GOS-4), while a final trial⁴⁶ found that functional outcomes did not differ between groups. Several published meta-analyses, each including a subset of our included trials, generally agreed with these findings, reporting reduced mortality²²^,⁵⁹ and coma severity²¹^,²² with HBOT but conflicting evidence on improvement in functionality among patients with moderate to severe TBI.²¹^,²²^,⁵⁹ Importantly, in addition to variation in HBOT pressure, available trials differed in treatment frequency (1 or multiple daily sessions), session duration (30-120 minutes), and length of treatment course (3 days to 4 weeks).

Unclear TBI Severity

A trial⁴⁸ that used a medication therapy control condition reported significant TBI symptom and function improvement following HBOT, but baseline TBI severity and outcome measurement details were not reported.

HARMS OR ADVERSE EVENTS OF HBOT FOR TBI WITH/WITHOUT PTSD

In most applications of HBOT, serious side effects are rare.⁶⁰ Among included trials of patients with chronic mTBI with/without PTSD, 5 reported on adverse events. Mild barotrauma (minor ear, sinus, or tooth pain or injury caused by pressurization) and headache appear to be the most common adverse effects of HBOT. In 2 trials,⁵¹^,⁵³ barotrauma was more frequently reported among HBOT group participants than sham group participants, but no other differences in adverse events between intervention groups were reported. Two trials³^,³⁷ reported participant withdrawal from the intervention due to minor adverse events (ear problems, claustrophobia, or headache). Only 1 trial⁴⁰ reported a serious event (psychiatric deterioration and hospitalization of a single patient).

Reporting of adverse effects among patients with severe TBI was carried out by 3 of 7 included trials. Two trials³⁶^,⁴⁶ reported pulmonary complications among those receiving HBOT, and a previously published meta-analysis⁵⁹ of these trials found HBOT was associated with significantly increased risk of severe pulmonary complications compared to standard care (RR = 15.57, 95% CI [2.11, 114.72]; N = 228). Seizures were also reported with HBOT use in 2 trials (2 patients experienced seizures in each trial).⁴²^,⁴⁶ Risk of seizure with HBOT use has been reported in other patient populations (eg, 0.3% of patients experienced seizures in a large retrospective cohort treated with HBOT for a wide variety of conditions⁶¹).

SUMMARY AND DISCUSSION

Findings of this updated synthesis align with those of the previous ESP report.¹ Updated findings include:

Treating patients with acute moderate to severe TBI represents a considerably different clinical scenario than treatment of chronic mTBI (the most common form of TBI in Veterans⁶²) and prioritizes life-saving interventions typically delivered to hospitalized patients within hours or days of injury. In this application, evidence suggests HBOT may offer near-term benefits. However, because HBOT protocols varied widely across available trials and severe adverse effects may occur, clarity is needed on the protocol that optimally balances benefits and risks of HBOT for patients with acute moderate to severe TBI.

In several included sham-controlled trials,³⁸^,⁴³^,⁵⁴ short-term symptom improvement was similar in both HBOT and sham groups, which suggests observed symptom change is likely the result of participation and/or placebo effects that occur because of the intensity of the HBOT intervention and its sham equivalent.⁴³^,⁶³^–⁶⁵ Participation and placebo effects can result from the experience of accessing and receiving care (including sham treatment); engaging with and being engaged by providers, nurses, and other caring staff (for screening, intervention or sham delivery, and outcome assessment); and from patient and provider expectancies of treatment response.⁶⁵^–⁶⁸

PTSD without TBI. Available evidence is not applicable to PTSD-diagnosed patients without a co-occurring TBI because no trials included these patients.

LIMITATIONS

Limitations of Included Trials

Design, measurement, and other methodological issues limit our confidence in the evidence on HBOT efficacy in patients with TBI with/without PTSD. First, trials of HBOT efficacy are generally small, leading to 2 concerns. Small RCTs are susceptible to prognostic imbalance, which occurs when there are unaccounted-for differences in factors that affect patient response to treatment across groups (that is, groups may be imbalanced in the likelihood that patients will improve over time).⁶⁹ Prognostic imbalance can be especially impactful when unadjusted analyses are used, as was often the case in included trials, and can lead to observed treatment effects that are substantially larger or smaller than true treatment effects (or to observed effects when there are no true effects).⁷⁰ A second concern related to sample size is statistical power. Given their sample sizes, most included trials would not be able to detect effects smaller than d = 0.7 (a standardized difference in group outcome means at a nominal power of 0.80 and sample size of 60). Standardized mean differences in post-concussion and PTSD symptoms reported in included sham-controlled trials ranged in size from 0.02 to 0.36 (mean = 0.16). Consequently, it is likely that trials were generally underpowered to detect any true differences between HBOT and control groups of the magnitudes observed. This conclusion is corroborated by the frequently large reported p-values, which indicate low observed power.

Additionally, while existing HBOT trials have conducted baseline assessments, patient symptom and treatment histories were not longitudinally assessed prior to study enrollment. Without a clear picture of patients’ preintervention symptom and treatment trajectories, important clinical variation in study samples may go unnoticed.¹^,⁷¹ If unaccounted for, this variation may lead to any true treatment effects of HBOT being artificially attenuated or exaggerated. Most trials also measured only mean changes in outcome scores, which may yield statistically significant findings, but the magnitude of the difference may not translate into a meaningful outcome for patients. Other methodological concerns include deviations from treatment protocols and lack of blinding of outcome assessors in some trials, and more broadly, methodological variation limited the ability to synthesize results of HBOT reported across trials. Trials varied in patient populations (timing of most recent TBI, length and characteristics of previous treatments, etc), HBOT protocols (chamber pressure, number and duration of sessions, etc), comparison groups (eg, inconsistent sham conditions, no treatment/standard care), and follow-up assessment timing.

Limitations of the Present Review

Limitations of our review methods include use of a second reviewer check during study selection, data abstraction, and quality assessment rather than dual independent review. Additionally, our search for measurement tools was not intended to be comprehensive, but instead focused on databases likely to contain high-quality systematic reviews for our targeted review of assessment measures for TBI and PTSD symptoms.

CONSIDERATIONS FOR FUTURE RESEARCH

Previous reviews¹^,⁷¹ have made suggestions for future sham-controlled efficacy trials that could address some limitations of the existing evidence on HBOT for treating chronic post-concussion symptoms. For example, because trials that randomize patients to HBOT and an inactive comparison condition are likely to have difficulty recruiting participants (participants are offered only a 50% chance of receiving active treatment), recommendations have included assigning a greater proportion of participants to treatment than to control conditions (eg, 80% to HBOT, 20% to sham); using a crossover design, in which all participants will ultimately receive treatment; or employing multiple treatment groups with different HBOT protocols (with a single, small sham group). Such designs could reduce patient resistance to enrolling by increasing the likelihood they would receive active treatment, and would maintain the benefits of a sham-controlled design (ie, patient blinding and the ability to detect potential participation effects). Trials using multiple treatment groups may offer other benefits, including clarifying any dose-response relationships associated with different HBOT pressurizations.

Although these alternative designs may improve some aspects of future HBOT efficacy trials, they are unlikely to address the lack of clinical applicability of traditional efficacy research (ie, trials that compare HBOT to an inactive control condition). These trials study HBOT as a standalone intervention rather than in a treatment context that aligns with VA/DoD guidelines for care of post-concussion symptoms, which recommend a coordinated stepped-care treatment approach incorporating multiple treatment modalities to address the wide array of symptoms attributed to concussion.¹⁸^,⁶⁵ Sham or no treatment comparison conditions also do not reflect typical clinical care options or the continuity of well-coordinated care. Consequently, comparisons between a standalone intervention and an inactive control do not provide a test of the real-world treatment value of the intervention (ie, versus or in addition to other available treatments that may be less resource intensive, less burdensome to patients, or more widely accessible).

In this scenario, the observed symptom improvement is attributed to placebo and/or participation effects. In other words, it is characterized as a response to the treatment ritual,¹^,⁶⁵ and not the treatment itself (ie, its purported biological mechanism). Effects resulting from the treatment ritual could be seen as suggesting the absence of “true” treatment effect, supporting a conclusion that an intervention is not efficacious. An alternative interpretation of effects arising from the treatment ritual is that some patients respond to the context of the intervention and the meaning of the intervention and its context.⁶⁵^,⁷² In this view, the psychological, interpersonal, and environmental features of a treatment ritual or process contribute to patient improvement, and should be identified and cultivated to increase benefit to the patient.⁷²

It is possible to evaluate evidence on HBOT in this framework. First, as described in the previous section, the pattern of symptom improvement in available trials strongly suggests participation and/or placebo effects: mTBI patients tended to improve to a similar degree immediately following HBOT and sham HBOT, and improved after HBOT more than after a period of standard care or no treatment. Second, HBOT and sham HBOT are accompanied by an elaborate treatment ritual that involves substantial patient effort, extensive engagement with providers and other patients, and regular access to treatment facilities and equipment. Third, because of the long duration of the HBOT intervention, this ritual is repeated among treatment and sham participants numerous times, leading to extensive exposure to an environment dedicated to improving the patient’s health. Taken together, then, the features of the intervention appear to be likely antecedents of the observed symptom improvement. What does not appear to be critical is the mechanism of the intervention itself, which in the case of HBOT and post-concussion symptoms, remains unclear.

For treatments with these characteristics, the question that follows is whether the lack of clarity on treatment mechanism and lack of benefit over placebo sufficiently justify disuse of the intervention. The question can also be reframed as Does the observed benefit exceed the uncertainties? If it does, subsequent questions involve the risk of harm of the intervention, and its costs and feasibility. The case of acupuncture for chronic pain is informative about these types of considerations. Although more evidence is available on acupuncture than HBOT, like HBOT, repeated trials have shown acupuncture and sham acupuncture produce demonstrable and similar symptom improvement, and shown that acupuncture leads to greater improvement than standard care.⁷³ At the same time, acupuncture has a poorly understood treatment mechanism, but is relatively low risk.⁷³^,⁷⁴

Acupuncture, which is a fairly low-resource intervention compared to HBOT, is now offered to Veterans despite little difference in effectiveness in sham-controlled trials and considerable controversy over negative results in some sham-controlled trials (debate focuses on the biological effects of various sham controls for acupuncture).⁷³ In practice, acupuncture is implemented consistent with its purported biological mechanism (ie, targeting anatomical points thought to facilitate healing), but is experientially indistinct from its sham equivalent. And, from the patient perspective, it is generally effective at improving the presenting symptoms – much like HBOT. Perhaps the most salient difference between HBOT and acupuncture is that HBOT is not low resource: It is a logistically complex intervention requiring dedicated treatment facilities, trained technicians and providers, and ongoing patient monitoring. This factor alone may limit implementation of HBOT, and from the policy-making perspective, decisions about whether additional research is warranted must consider whether patient, provider, and system resources required for HBOT would be better directed toward other approaches.

The hypothesis that the features of the HBOT therapeutic experience, not HBOT per se, lead to improved patient symptoms underlines that the therapeutic ritual is an important element of treatment, not necessarily an obstacle to it. These features – namely, the coordinated, long-duration engagement with caring providers and settings, high patient and provider expectancies for healing, and ongoing interaction with other patients with similar symptoms and experiences – are likely active components of the intervention.⁶⁵ Future research could examine the feasibility and benefits of incorporating these features into other treatment modalities for chronic post-concussion symptoms that are more widely implementable.

CONCLUSIONS

In hospitalized patients with acute moderate to severe TBI, available evidence suggests HBOT can reduce mortality and coma severity, but effects on longer-term functionality and the optimal HBOT protocol for acute TBI are unclear. Evidence on HBOT for chronic mTBI shows that HBOT does not lead to short-term improvements in post-concussion and PTSD symptoms compared to sham, and sparse longer-term evidence suggests symptom improvement after HBOT is not durable. At present there is no evidence from clinical trials about patients diagnosed to have PTSD without a co-occurring TBI. Decisions about whether additional research is warranted must consider whether patient, provider, and system resources required for HBOT would be better directed toward other approaches. One future research direction could be to examine whether features of the HBOT treatment experience (eg, coordinated engagement with providers and other patients) are themselves active intervention components that could be incorporated into more widely implementable treatments for chronic post-concussion symptoms.

ACKNOWLEDGMENTS

This topic was developed in response to a request from the VA Health Services Research and Development Service for an updated evidence brief on the use of hyperbaric oxygen therapy to treat Veterans and non-Veterans with traumatic brain injury and/or post-traumatic stress disorder, in response to the Commander John Scott Hannon Veterans Mental Health Care Improvement Act of 2019. The scope was further developed with input from Operational Partners (below) and the ESP Coordinating Center review team.

The authors are grateful to Kim Peterson for work on developing the original report, Kathryn Vela for literature searching, Payten Sonnen and Rachel Ward for data abstraction efforts and editorial and citation management support, and the following individuals for their contributions to this project:

Operational Partners

Operational partners are system-level stakeholders who help ensure relevance of the review topic to the VA; contribute to the development of and approve final project scope and timeframe for completion; provide feedback on the draft report; and provide consultation on strategies for dissemination of the report to the field and relevant groups.

Tracy L. Weistreich, PhD, RN, NEA-BC, NPD-BC, VHA-CM
Nurse Executive
14HAP VHA National Center for Healthcare Advancement and Partnerships
Christine Eickhoff
Health System Specialist
14HAP VHA National Center for Healthcare Advancement and Partnerships
Jamie Davis, PhD
Health System Specialist
14HAP VHA National Center for Healthcare Advancement and Partnerships
David Atkins, MD, MPH
Director
VA Health Services Research and Development Service

Peer Reviewers

The Coordinating Center sought input from external peer reviewers to review the draft report and provide feedback on the objectives, scope, methods used, perception of bias, and omitted evidence (see Appendix H in the supplemental materials for disposition of comments). Peer reviewers must disclose any relevant financial or non-financial conflicts of interest. Because of their unique clinical or content expertise, individuals with potential conflicts may be retained. The Coordinating Center works to balance, manage, or mitigate any potential nonfinancial conflicts of interest identified.

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54.: Wolf G, Cifu D, Baugh L, Carne W, Profenna L. The effect of hyperbaric oxygen on symptoms after mild traumatic brain injury. Journal of Neurotrauma. 2012;29(17):2606–2612. [PubMed: 23031217]
55.: Weaver L. mTBI Mechanisms of Action of HBO2 for Persistent Post-Concussive Symptoms (BIMA). U.S. Army Medical Research and Development Command. Clinicaltrials.gov identifier: NCT01611194. Protocol available at: https://www.clinicaltrials.gov/ct2/show/NCT01611194?term=NCT01611194&draw=2&rank=1. Accessed May, 2021.
56.: Forman-Hoffman V, Middleton JC, Feltner C, et al. Psychological and pharmacological treatments for adults with posttraumatic stress disorder: a systematic review update. Rockville (MD): Agency for Healthcare Research and Quality (US); Report No.: 18-EHC011-EFReport No.: 2018-SR-01. 2018. [PubMed: 30204376]
57.: Scorza K, McCarthy W, Miller R, Carne W, Wolf G. Hyperbaric Oxygen Effects on PTSD and mTBI Symptoms: A Subset Analysis. ASM. 2013;40.
58.: Forbes D. Blinding: An essential component in decreasing risk of bias in experimental designs. Evidence Based Nursing. 2013;16(3):70–71. [PubMed: 23696228]
59.: Bennett MH, Trytko B, Jonker B. Hyperbaric oxygen therapy for the adjunctive treatment of traumatic brain injury. Cochrane Database of Systematic Reviews. 2012;12:CD004609. [PubMed: 23235612]
60.: Camporesi EM. Side effects of hyperbaric oxygen therapy. Undersea Hyperb Med. 2014;41(3):253–257. [PubMed: 24984321]
61.: Hadanny A, Efrati S. The efficacy and safety of hyperbaric oxygen therapy in traumatic brain injury. Expert rev. 2016;16(4):359–360. [PubMed: 26900796]
62.: Defense and Veterans Brain Injury Center. DoD Worldwide Numbers for TBI. Defense and Veterans Brain Injury Center. http://dvbic.dcoe.mil/dod-worldwide-numbers-tbi. Published 2017. Updated November 29, 2017. Accessed December 5, 2017.
63.: Miller RS, Weaver LK, Brenner LA. Hyperbaric Oxygen Treatment for Persistent Postconcussion Symptoms--Reply. JAMA Internal Medicine. 2015;175(7):1240–1241. [PubMed: 26146913]
64.: Mitchell SJ, Bennett MH. Unestablished indications for hyperbaric oxygen therapy. Diving Hyperb Med. 2014;44(4):228–234. [PubMed: 25596836]
65.: Hoge CW, Jonas WB. The ritual of hyperbaric oxygen and lessons for the treatment of persistent postconcussion symptoms in military personnel. JAMA Internal Medicine. 2015;175(1):53–54. [PubMed: 25401214]
66.: Benedetti F. Placebo-induced improvements: How therapeutic rituals affect the patient’s brain. J Acupunct Meridian Stud. 2012;5(3):97–103. [PubMed: 22682270]
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Supplemental Materials

APPENDIX A. UHMS INDICATIONS FOR HBOT

UHMS Clearances¹

Air or Gas Embolism
Carbon Monoxide Poisoning or Carbon Monoxide Poisoning Complicated by Cyanide Poisoning
Clostridal Myositis and Myonecrosis (Gas Gangrene)
Crush Injury, Compartment Syndrome, and other Acute Traumatic Ischemias
Decompression Sickness
Enhancement of Healing in Selected Problem Wounds
Exceptional Blood Loss (Anemia)
Intracranial Abscess
Necrotizing Soft Tissue Infections
Osteomyelitis (Refractory)
Delayed Radiation Injury (Soft Tissue and Bony Necrosis)
Skin Grafts & Flaps (Compromised)
Thermal Burns
Idiopathic Sudden Sensorineural Hearing Loss²

: Abbreviation. UHMS=Undersea & Hyperbaric Medical Society

APPENDIX B. GUIDELINES ON HBOT USE

Organization Year	Title	Comments on HBOT in relation to TBI and/or PTSD
VA/DOD 2017³	Clinical Practice Guideline for The Management of Posttraumatic Stress Disorder and Acute Stress Disorder	“There is no conclusive evidence that HBOT is effective for treating PTSD. There have been no RCTs or uncontrolled trials specifically focused on patients with PTSD, and there is disagreement about what constitutes an adequate sham treatment. In a DoD study, 72 soldiers with TBI (66% with PTSD) were randomized to standard care (78%), HBOT (54%), or sham HBOT (64%). Baseline scores on the PCL were less severe than in all-PTSD studies, likely because not everyone had PTSD. Scores were still in the severe range. Based on the evidence to date, and the practical and cost concerns, it does not appear that HBOT is a promising treatment for further study.” “There is insufficient evidence to recommend for or against the following somatic therapies: repetitive transcranial magnetic stimulation (rTMS), electroconvulsive therapy (ECT), hyperbaric oxygen therapy (HBOT), stellate ganglion block (SGB), or vagal nerve stimulation (VNS).”
VA/DOD 2016⁴ (update in progress)	Clinical Practice Guideline for The Management of Concussion-mild Traumatic Brain Injury	NA
Colorado Division of Workers’ Compensation 2012⁵	Traumatic Brain Injury Medical Treatment Guidelines	“Despite evidence of limited physiological changes with hyperbaric oxygen, there is insufficient evidence to suggest that hyperbaric oxygen would functionally benefit stroke or TBI patients. Complications can occur, including tension pneumothorax. Hyperbaric oxygen is not recommended acutely or chronically. Ongoing studies could affect this recommendation.”
Brain Trauma Foundation 2017⁶	Guidelines for the Management of Severe Traumatic Brain Injury, 4^th Edition	Excluded studies on HBOT
Tenth European Consensus Conference on Hyperbaric Medicine 2017⁷	Tenth European Consensus Conference on Hyperbaric Medicine: recommendations for accepted and non-accepted clinical indications and practice of hyperbaric oxygen treatment	It would be reasonable to consider HBOT in acute moderate-severe traumatic brain injury (TBI) patients and in a highly selected group of patients with chronic TBI who have clear evidence of metabolically dysfunctional brain region(s) (Type 3 recommendation, Grade C level of evidence) We recommend HBOT use in TBI to be used only in the context of an investigational study protocol approved by an ethics committee and performed according to clinical research good practice (Type 1 Recommendation, Grade A level of evidence)

APPENDIX C. SEARCH STRATEGIES

1. Search for current systematic reviews (limited to 2012 forward) Date Searched: 10/07/20
Sources:	Evidence:
AHRQ	Search: hyperbaric; HBOT Relevant Results: None
CADTH	Search: hyperbaric; HBOT Relevant Results: CADTH. (2020). Hyperbaric Oxygen Therapy for the Treatment of Chronic Pain: A Review of Clinical Effectiveness and Cost-Effectiveness. Rapid Response. Ottawa, CAN.
NICE	Search: (hyperbaric) AND (post-traumatic stress or PTSD or brain injury or TBI); (HBOT) AND (post-traumatic stress or PTSD or brain injury or TBI) Relevant Results: None
ECRI Institute	Search: hyperbaric; HBOT Relevant Results: ECRI Institute. (2017). VA/DoD clinical practice guideline for the management of posttraumatic stress disorder and acute stress disorder.
VA Products: VATAP, PBM, HSR&D publications, VA ART Database	A. http://www.hsrd.research.va.gov/research/default.cfm Search: hyperbaric; HBOT Relevant Results: None B. http://www.research.va.gov/research_topics/ Relevant Results: None
MEDLINE: Systematic Reviews	Database: Ovid MEDLINE(R) ALL 1946 to October 12, 2020 Search Strategy: ------------------------------------------------------------ (hyperbaric or HBOT).mp. (18029) exp Hyperbaric Oxygenation/ (11866) 1 or 2 (18029) exp stress disorders, post-traumatic/ (33123) exp combat disorders/ (3135) (post-traumatic stress or posttraumatic stress or PTSD).mp. (41197) exp craniocerebral trauma/ (159475) exp Glasgow Coma Scale/ (9571) exp Glasgow Outcome Scale/ (2015) (mTBI or TBI).mp. (29025) ((brain* or capitis or cerebr* or crani* or hemispher* or inter-crani* or intra-crani* or skull) adj4 (contusion or damag* or fractur* or injur* or trauma* or wound* or concuss)).mp. (192159) concuss.mp. (14300) diffuse axonal injur.mp. (1710) (Glasgow adj (coma or outcome) adj (scale or score)).mp. (21045) Ranchos Los Amigos Scale.mp. (4) 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 (320212) 3 and 16 (815) limit 17 to english language (672) limit 18 to yr="2017 -Current" (135) (systematic review.ti. or meta-analysis.pt. or meta-analysis.ti. or systematic literature review.ti. or this systematic review.tw. or pooling project.tw. or (systematic review.ti,ab. and review.pt.) or meta synthesis.ti. or meta-analy.ti. or integrative review.tw. or integrative research review.tw. or rapid review.tw. or umbrella review.tw. or consensus development conference.pt. or practice guideline.pt. or drug class reviews.ti. or cochrane database syst rev.jn. or acp journal club.jn. or health technol assess.jn. or evid rep technol assess summ.jn. or jbi database system rev implement rep.jn. or (clinical guideline and management).tw. or ((evidence based.ti. or evidence-based medicine/ or best practice.ti. or evidence synthesis.ti,ab.) and (((review.pt. or diseases category/ or behavior.mp.) and behavior mechanisms/) or therapeutics/ or evaluation studies.pt. or validation studies.pt. or guideline.pt. or pmcbook.mp.)) or (((systematic or systematically).tw. or critical.ti,ab. or study selection.tw. or ((predetermined or inclusion) and criteri).tw. or exclusion criteri.tw. or main outcome measures.tw. or standard of care.tw. or standards of care.tw.) and ((survey or surveys).ti,ab. or overview.tw. or review.ti,ab. or reviews.ti,ab. or search.tw. or handsearch.tw. or analysis.ti. or critique.ti,ab. or appraisal.tw. or (reduction.tw. and (risk/ or risk.tw.) and (death or recurrence).mp.)) and ((literature or articles or publications or publication or bibliography or bibliographies or published).ti,ab. or pooled data.tw. or unpublished.tw. or cijntion.tw. or cijntions.tw. or database.ti,ab. or internet.ti,ab. or textbooks.ti,ab. or references.tw. or scales.tw. or papers.tw. or datasets.tw. or trials.ti,ab. or meta-analy.tw. or (clinical and studies).ti,ab. or treatment outcome/ or treatment outcome.tw. or pmcbook.mp.))) not (letter or newspaper article).pt. (445238) “Review”/ or “Review Literature as Topic”/ (2824729) 20 or 21 (3050721) 19 and 22 (27) ***************************
PsycINFO	Database: APA PsycInfo 1806 to October Week 1 2020 Search Strategy: ------------------------------------------------------------ (hyperbaric or HBOT).mp. (459) exp Posttraumatic Stress Disorder/ (33541) exp COMBAT EXPERIENCE/ (2946) (post-traumatic stress or posttraumatic stress or PTSD).mp. (50977) exp Traumatic Brain Injury/ (19869) exp Brain Damage/ (17778) exp Head Injuries/ (6614) (mTBI or TBI).mp. (12642) ((brain* or capitis or cerebr* or crani* or hemispher* or inter-crani* or intra-crani* or skull) adj4 (contusion or damag* or fractur* or injur* or trauma* or wound* or concuss)).mp. (56650) concuss.mp. (4059) diffuse axonal injur.mp. (435) (Glasgow adj (coma or outcome) adj (scale or score)).mp. (6230) Ranchos Los Amigos Scale.mp. (11) or/2-13 (110962) 1 and 14 (102) (systematic review.ti. or meta-analysis.pt. or meta-analysis.ti. or systematic literature review.ti. or this systematic review.tw. or pooling project.tw. or (systematic review.ti,ab. and review.pt.) or meta synthesis.ti. or meta-analy.ti. or integrative review.tw. or integrative research review.tw. or rapid review.tw. or umbrella review.tw. or consensus development conference.pt. or practice guideline.pt. or drug class reviews.ti. or cochrane database syst rev.jn. or acp journal club.jn. or health technol assess.jn. or evid rep technol assess summ.jn. or jbi database system rev implement rep.jn. or (clinical guideline and management).tw. or ((evidence based.ti. or evidence-based medicine/ or best practice.ti. or evidence synthesis.ti,ab.) and (((review.pt. or diseases category/ or behavior.mp.) and behavior mechanisms/) or therapeutics/ or evaluation studies.pt. or validation studies.pt. or guideline.pt. or pmcbook.mp.)) or (((systematic or systematically).tw. or critical.ti,ab. or study selection.tw. or ((predetermined or inclusion) and criteri).tw. or exclusion criteri.tw. or main outcome measures.tw. or standard of care.tw. or standards of care.tw.) and ((survey or surveys).ti,ab. or overview.tw. or review.ti,ab. or reviews.ti,ab. or search.tw. or handsearch.tw. or analysis.ti. or critique.ti,ab. or appraisal.tw. or (reduction.tw. and (risk/ or risk.tw.) and (death or recurrence).mp.)) and ((literature or articles or publications or publication or bibliography or bibliographies or published).ti,ab. or pooled data.tw. or unpublished.tw. or cijntion.tw. or cijntions.tw. or database.ti,ab. or internet.ti,ab. or textbooks.ti,ab. or references.tw. or scales.tw. or papers.tw. or datasets.tw. or trials.ti,ab. or meta-analy.tw. or (clinical and studies).ti,ab. or treatment outcome/ or treatment outcome.tw. or pmcbook.mp.))) not (letter or newspaper article).pt. (135282) “Review”/ or “Review Literature as Topic”/ (22719) 16 or 17 (155525) 15 and 18 (10) limit 19 to english language (9) limit 20 to yr="2017 -Current" (5) ***************************
Cochrane Database of Systematic Reviews & Cochrane Methodology Register	Database: EBM Reviews - Cochrane Database of Systematic Reviews 2005 to October 1, 2020 Search Strategy: ------------------------------------------------------------ (hyperbaric or HBOT).mp. (95) (post-traumatic stress or posttraumatic stress or PTSD).mp. (234) (mTBI or TBI).mp. (76) ((brain* or capitis or cerebr* or crani* or hemispher* or inter-crani* or intra-crani* or skull) adj4 (contusion or damag* or fractur* or injur* or trauma* or wound* or concuss)).mp. (679) concuss.mp. (51) diffuse axonal injur.mp. (38) (Glasgow adj (coma or outcome) adj (scale or score)).mp. (125) Ranchos Los Amigos Scale.mp. (0) or/2-8 (966) 1 and 9 (17) limit 10 to last 2 years (3) **************************
Systematic Reviews (Journal)	Search: hyperbaric; HBOT Relevant Results: None

2. Systematic reviews currently under development (forthcoming reviews & protocols)

Date Searched: 10/07/20

Sources:

Evidence:

PROSPERO (SR registry)

http://www.crd.york.ac.uk/PROSPERO/

Search: Hyperbaric; HBOT

Relevant Results:

None

DoPHER (SR Protocols)

Search: Hyperbaric; HBOT

Relevant Results:

None

3. Current Guidelines Date Searched: 10/07/20
Sources:	Evidence:
VA/DoD Clinical Practice Guidelines	Relevant Results:
National Guideline Clearinghouse No longer exists
Google Scholar	Search: “"hyperbaric oxygen therapy" guideline; HBOT guideline Relevant Results: None
Epistemonikos	Search: (title:(hyperbaric or HBOT) OR abstract:(hyperbaric or HBOT)) AND (title:(PTSD) OR abstract:(PTSD)) OR (title:(post-traumatic stress) OR abstract:(post-traumatic stress)) OR (title:(TBI) OR abstract:(TBI)) AND (title:(brain injury) OR abstract:(brain injury)) Relevant Results: None
TRIP	Search: (hyperbaric or HBOT) AND (post-traumatic stress or PTSD or brain injury or TBI) Relevant Results: None
Medline: Guideline Search	Database: Ovid MEDLINE(R) ALL 1946 to October 01, 2020 Search Strategy: ------------------------------------------------------------ (hyperbaric or HBOT).mp. (17557) exp Hyperbaric Oxygenation/ (11854) 1 or 2 (17557) exp stress disorders, post-traumatic/ (33058) exp combat disorders/ (3134) (post-traumatic stress or posttraumatic stress or PTSD).mp. (38761) exp craniocerebral trauma/ (159275) exp Glasgow Coma Scale/ (9560) exp Glasgow Outcome Scale/ (2010) (mTBI or TBI).mp. (27441) ((brain* or capitis or cerebr* or crani* or hemispher* or inter-crani* or intra-crani* or skull) adj4 (contusion or damag* or fractur* or injur* or trauma* or wound* or concuss)).mp. (185930) concuss.mp. (13501) diffuse axonal injur.mp. (1640) (Glasgow adj (coma or outcome) adj (scale or score)).mp. (20135) Ranchos Los Amigos Scale.mp. (4) 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 (310598) 3 and 16 (788) limit 17 to english language (645) exp GUIDELINE/ (34662) guideline.mp. (484539) 19 or 20 (484539) 18 and 21 (11) limit 22 to yr=”2018-Current” (1) ***************************
UpToDate	Search: Hyperbaric; HBOT Relevant Results: https://www.uptodate.com/contents/hyperbaric-oxygen-therapy

4. Current primary literature (limited to 2014 forward) Date Searched: 10/07/20
Sources:	Search Strategy/ Evidence:
Medline	Database: Ovid MEDLINE(R) ALL 1946 to October 12, 2020 Search Strategy: ------------------------------------------------------------ (hyperbaric or HBOT).mp. (18029) exp Hyperbaric Oxygenation/ (11866) 1 or 2 (18029) exp stress disorders, post-traumatic/ (33123) exp combat disorders/ (3135) (post-traumatic stress or posttraumatic stress or PTSD).mp. (41197) exp craniocerebral trauma/ (159475) exp Glasgow Coma Scale/ (9571) exp Glasgow Outcome Scale/ (2015) (mTBI or TBI).mp. (29025) ((brain* or capitis or cerebr* or crani* or hemispher* or inter-crani* or intra-crani* or skull) adj4 (contusion or damag* or fractur* or injur* or trauma* or wound* or concuss)).mp. (192159) concuss.mp. (14300) diffuse axonal injur.mp. (1710) (Glasgow adj (coma or outcome) adj (scale or score)).mp. (21045) Ranchos Los Amigos Scale.mp. (4) 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 (320212) 3 and 16 (815) limit 17 to english language (672) limit 18 to yr="2017 -Current" (135) **************************
Medline: Harms	Database: Ovid MEDLINE(R) ALL 1946 to October 12, 2020 Search Strategy: ------------------------------------------------------------ (hyperbaric or HBOT).mp. (18029) exp Hyperbaric Oxygenation/ (11866) 1 or 2 (18029) exp stress disorders, post-traumatic/ (33123) exp combat disorders/ (3135) (post-traumatic stress or posttraumatic stress or PTSD).mp. (41197) exp craniocerebral trauma/ (159475) exp Glasgow Coma Scale/ (9571) exp Glasgow Outcome Scale/ (2015) (mTBI or TBI).mp. (29025) ((brain* or capitis or cerebr* or crani* or hemispher* or inter-crani* or intra-crani* or skull) adj4 (contusion or damag* or fractur* or injur* or trauma* or wound* or concuss)).mp. (192159) concuss.mp. (14300) diffuse axonal injur.mp. (1710) (Glasgow adj (coma or outcome) adj (scale or score)).mp. (21045) Ranchos Los Amigos Scale.mp. (4) 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 (320212) 3 and 16 (815) exp Patient Harm/ (170) harm.mp. (200920) exp Long Term Adverse Effects/ (584) adverse effect.mp. (1870268) 18 or 19 or 20 or 21 (2047778) 17 and 22 (119) limit 23 to english language (106) limit 24 to yr=”2017-Current” (11) **************************
PsychINFO	Database: APA PsycInfo 1806 to September Week 4 2020 Search Strategy: ------------------------------------------------------------ (hyperbaric or HBOT).mp. (459) exp Posttraumatic Stress Disorder/ (33509) exp COMBAT EXPERIENCE/ (2944) (post-traumatic stress or posttraumatic stress or PTSD).mp. (50917) exp Traumatic Brain Injury/ (19844) exp Brain Damage/ (17776) exp Head Injuries/ (6608) (mTBI or TBI).mp. (12631) ((brain* or capitis or cerebr* or crani* or hemispher* or inter-crani* or intra-crani* or skull) adj4 (contusion or damag* or fractur* or injur* or trauma* or wound* or concuss)).mp. (56614) concuss.mp. (4049) diffuse axonal injur.mp. (434) (Glasgow adj (coma or outcome) adj (scale or score)).mp. (6225) Ranchos Los Amigos Scale.mp. (11) or/2-13 (110860) 1 and 14 (102) limit 15 to english language (98) limit 16 to yr="2014 -Current" (14) **************************
CCRCT	Database: EBM Reviews - Cochrane Central Register of Controlled Trials September 2020 Search Strategy: ------------------------------------------------------------ (hyperbaric or HBOT).mp. (3105) exp Hyperbaric Oxygenation/ (373) 1 or 2 (3105) exp stress disorders, post-traumatic/ (2607) exp combat disorders/ (134) (post-traumatic stress or posttraumatic stress or PTSD).mp. (6169) exp craniocerebral trauma/ (3291) exp Glasgow Coma Scale/ (452) exp Glasgow Outcome Scale/ (149) (mTBI or TBI).mp. (2923) ((brain* or capitis or cerebr* or crani* or hemispher* or inter-crani* or intra-crani* or skull) adj4 (contusion or damag* or fractur* or injur* or trauma* or wound* or concuss)).mp. (10192) concuss.mp. (859) diffuse axonal injur.mp. (74) (Glasgow adj (coma or outcome) adj (scale or score)).mp. (2752) Ranchos Los Amigos Scale.mp. (1) 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 (19409) 3 and 16 (146) limit 17 to english language (86) limit 18 to yr="2017 -Current" (29) **************************
Pedro	Search: Hyperbaric; HBOT (limited to 2018 forward) Relevant Results: None
PTSDpubs	Search: (hyperbaric OR HBOT) AND (post-traumatic stress OR PTSD OR brain injury OR TBI) Relevant Results: None

5. Primary literature currently under development (forthcoming studies & protocols) Date Searched: 10/07/20
Sources:	Search Strategy/ Evidence:
Clinicaltrials.gov	Search: Hyperbaric or HBOT Relevant Results: None
UK Clinical Trials Gateway	Search: Hyperbaric; HBOT Relevant results: None
WHO International Clinical Trials Registry Platform	Search: Hyperbaric or HBOT Relevant results: None

6. Advocacy Groups (HBOT, PTSD, and TBI) Date Searched: 10/07/20
Sources:	Search Strategy/ Evidence:
Brain Injury Association of America	Search: hyperbaric; HBOT Relevant Results: None
Kessler Foundation	Search: hyperbaric; HBOT Relevant Results: None
Concussion Legacy Foundation	Search: hyperbaric; HBOT Relevant Results: None
San Diego Brain Injury Foundation	Search: hyperbaric; HBOT Relevant Results: None
Neuro-Laser Foundation	Relevant Results: None
PTSD Foundation of America	Relevant Results: None
National Center for PTSD	Search: hyperbaric; HBOT Relevant Results: None
The official website of the Military Health System and the Defense Health Agency	Search: hyperbaric; HBOT Relevant Results: Hyperbaric Oxygen Therapy for Mild Traumatic Brain Injury. (2018) HR 3326 5.2.2011
PTSD Alliance	Relevant Results: None
International Hyperbaric Medical Foundation	Relevant Results: None
International Hyperbaric Medical Association	Relevant Results: None
HBOT2017 Conference & Expo	Relevant Results: None
HBOT.com	Relevant Results: None
HBOT for Vets	Relevant Results: None
HBOT in Wound Care	Relevant Results: None
Undersea & Hyperbaric Medical Society	https://www.uhms.org/resources/hbo-indications.html Relevant Results: None
Free The Chamber	Relevant Results: None
Holistic Hyperbaric	Relevant Results: None
Harch Hyperbarics Media	Relevant Results: None
Hyperbaric Link	Relevant Results: None
The American Legion	Relevant Results: None
Treat Now	Relevant Results: None

7. Search for current systematic reviews looking at the effectiveness of interventions (other than HBOT) for PTSD or TBI (limited to 2012 forward)

Date Searched: 12-14-20

Sources:

Evidence:

AHRQ

Search: post-traumatic stress disorder; traumatic brain injury

Relevant Results:

CADTH

Search: post-traumatic stress disorder; traumatic brain injury

Relevant Results:

CADTH Results for PTSD (n=52)
CADTH Results for TBI (n=44)

NICE

Search: (post traumatic stress disorder OR traumatic brain injury OR TBI OR PTSD) AND (treatment OR intervention OR program)

Relevant Results:

ECRI Institute

Search: post-traumatic stress disorder; traumatic brain injury

Relevant Results:

Search results in separate document

VA Products: VATAP, PBM, HSR&D publications, VA ART Database

A. http://www.hsrd.research.va.gov/research/default.cfm

Search: post-traumatic stress disorder; traumatic brain injury

Relevant Results:

B. http://www.research.va.gov/research_topics/

Relevant Results:

None

Cochrane Database of Systematic Reviews & Cochrane Methodology Register

Cochrane Methodology Register not updated past 2012

Database: EBM Reviews - Cochrane Database of Systematic Reviews 2005 to December 10, 2020

Search Strategy:

------------------------------------------------------------

Therapeutics.kw. (49)
(therapy or therapies or treatment or treatments or intervention or interventions or program or programs or medication or medications or drug or drugs or pharmaceutical or pharmaceuticals or therapeutic or therapeutics).mp. (10917)
1 or 2 (10917)
(post-traumatic stress or posttraumatic stress or PTSD).mp. (239)
(mTBI or TBI).mp. (78)
((brain* or capitis or cerebr* or crani* or hemispher* or inter-crani* or intra-crani* or skull*) adj4 (contusion* or damag* or fractur* or injur* or trauma* or wound* or concuss*)).mp. (681)
concuss*.mp. (52)
diffuse axonal injur*.mp. (38)
(Glasgow adj (coma or outcome) adj (scale* or score*)).mp. (127)
Ranchos Los Amigos Scale.mp. (0)
or/4-10 (975)
3 and 11 (973)
limit 12 to last 8 years (636)

***************************

APPENDIX D. LIST OF EXCLUDED STUDIES

Exclude reasons: 1=Ineligible population, 2=Ineligible intervention, 3=Ineligible comparator, 4=Ineligible outcome, 5=Ineligible timing, 6=Ineligible study design, 7=Ineligible publication type 8=Outdated or ineligible systematic review, E9=Non-English language, E10=Unable to locate full-text

#	Citation	Exclude reason
1	Adams E. Hyperbaric Oxygen Therapy for Traumatic Brain Injury and Post Traumatic Stress Disorder. VA Technology Assessment Program. 2010.	E8
2	Adamides AA, Winter CD, Lewis PM, Cooper DJ, Kossmann T, Rosenfeld JV. Current controversies in the management of patients with severe traumatic brain injury. ANZ J Surg. 2006;76(3):163–174. [PubMed: 16626360]	E7
3	Algattas H, Huang JH. Neurotrauma and Repair Research: Traumatic Brain Injury (TBI) and its Treatments. Biomed. 2013;5:51–56. [PMC free article: PMC4147763] [PubMed: 25288902]	E7
4	Algattas H, Huang JH. Traumatic Brain Injury pathophysiology and treatments: early, intermediate, and late phases post-injury. Int. 2013;15(1):309–341. [PMC free article: PMC3907812] [PubMed: 24381049]	E7
5	Alternative Therapy Evaluation Committee for the Insurance Corporation of British C. A review of the scientific evidence on the treatment of traumatic brain injuries and strokes with hyperbaric oxygen. Brain Injury. 2003;17(3):225–236. [PubMed: 12623499]	E8
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*: Included in 2018 ESP report

APPENDIX E. EVIDENCE TABLES

CHARACTERISTICS OF INCLUDED PRIMARY STUDIES

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OUTCOME DATA OF INCLUDED PRIMARY STUDIES

A data table of effect estimates used in meta-analyses is available upon request by contacting vog.av@CC.PSE.

QUALITY ASSESSMENT OF INCLUDED PRIMARY STUDIES

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STRENGTH OF EVIDENCE

APPENDIX F. RESEARCH IN PROGRESS

Status	Study Title	Study Design	Information Resources (Registry #; citation(s) for published protocols; links to project websites)
Active, not recruiting	Hyperbaric Treatment of Traumatic Brain Injury (TBI)	RCT	Barry Miskin, MD, Jupiter Medical Center NCT01847755
Unknown	Hyperbaric Oxygen Therapy and SPECT Brain Imaging in Traumatic Brain Injury	RCT	Paul G. Harch, MD, Louisiana State University Health Sciences Center in New Orleans NCT00594503
Active, recruiting	Hyperbaric Oxygen Brain Injury Treatment Trial (HOBIT)	RCT	Minneapolis Medical Research Foundation NCT02407028
Terminated	Hyperbaric Oxygen Therapy in Chronic Traumatic Brain Injury or Post-Traumatic Stress Disorder (NBIRR-1)	RCT	International Hyperbaric Medical Foundation NCT01105962 (new regulatory requirements will require funding for restart as a new study)

APPENDIX G. TABLE OF MEASURES

PTSD

Acronym	Tool Name	Source
BDI	Beck Depression Inventory	2018 AHRQ PTSD
CAPS	Clinician Administered PTSD	2018 AHRQ PTSD SR Amos 2014 Sin 2017 Suomi 2019
CIDI	Comprehensive International Diagnostic Interview	Amos 2014
DTS	Davidson Trauma Scale	2018 AHRQ PTSD SR
GAF	Global Assessment of Functioning	2018 AHRQ PTSD SR
HADS	Hospital Anxiety and Depression Scale	2018 AHRQ PTSD SR
HAM-A or HAS	Hamilton Anxiety Scale	2018 AHRQ PTSD SR
HAM-D	Hamilton Depression Scale	2018 AHRQ PTSD SR
IES	Impact of Event Scale	2018 AHRQ PTSD SR
MADRS	Montgomery-Asberg Depression Rating Scale	2018 AHRQ PTSD SR
MISS or M-PTSD	Mississippi Scale for Combat-Related PTSD	2018 AHRQ PTSD SR
MPSS-SR	Modified PTSD Symptom Scale	2018 AHRQ PTSD SR
PCL	PTSD Checklist	2017 VA/DoD PTSD and acute stress disorder guideline 2018 AHRQ PTSD SR Suomi 2019
PC-PTSD	PC-PTSD Screen	2017 VA/DoD PTSD and acute stress disorder guideline
PSS-I	PTSD Symptom Scale Interview	2018 AHRQ PTSD SR Suomi 2019 2019
PSS-SR	PTSD Symptom Scale Self-Report Version	2018 AHRQ PTSD SR
PTDS or PDS	Posttraumatic Diagnostic Scale	2018 AHRQ PTSD SR
PTSD-I	PTSD Interview	2018 AHRQ PTSD SR
PTSS-10Q-1	PTSD 10-Questions Inventory	Amos 2014
Q-LES-Q-SF	Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form	2018 AHRQ PTSD SR
SCID	Structured Clinical Interview PTSD Module	2018 AHRQ PTSD SR Amos 2014
SCL-90-R	Symptom Checklist-90-Revised	2018 AHRQ PTSD SR
SDS	Sheehan Disability Scale	2018 AHRQ PTSD SR
SF-12	Medical Outcome Study Self-Report Form	2018 AHRQ PTSD SR
SF-36	36-Item Short Form Health Survey	2018 AHRQ PTSD SR
SI-PTSD or SIP	Structured Interview for PTSD	2018 AHRQ PTSD SR
SPRINT	Short PTSD Rating Interview	2018 AHRQ PTSD SR
STAI	State-Trait Anxiety Inventory	2018 AHRQ PTSD SR
TOP-8	Treatment-Outcome Post-Traumatic Stress Disorder Scale	2018 AHRQ PTSD SR
WAS	Work and Social Adjustment Scale	2018 AHRQ PTSD SR

TBI

Acronym	Tool Name	Source
ACE	Acute Concussion Evaluation	Ontario Neurotrauma Foundation, Guideline for Concussion/Mild Traumatic Brain Injury, 2018
ANAM	Automated Neuropsychological Assessment Metrics	VA/DoD Guideline Concussion-Mild Traumatic Brain Injury, 2016
A-WPTAS	Abbreviated Westmead Post-Traumatic Amnesia Scale	Ontario Neurotrauma Foundation, Guideline for Concussion/Mild Traumatic Brain Injury, 2018
AII	Auditory Immediate Index	CADTH 2007 Acetylcholinesterase
CNT	Cambridge Neuropsychological Test Automated Battery	Dougall 2015
CGI	Clinical Global Improvement	CADTH 2007 Acetylcholinesterase Dougall 2015
CIQ	Community Integration Questionnaire	Brasure 2012
CPT-II	Conner’s Continuous Performance Test II	Dougall 2015
DRS	Disability Rating Scale	Willis 2015
DQ	Dysexecutive Questionnaire	CADTH 2007 Acetylcholinesterase
FIM	Functional Independence Measure	CADTH 2007 Acetylcholinesterase
GCS	Glasgow Coma Scale	Ontario Neurotrauma Foundation, Guideline for Concussion/Mild Traumatic Brain Injury, 2018 Alarcon 2017 CADTH 2007 Acetylcholinesterase
GOS	Glasgow Outcome Scale	CADTH 2007 Acetylcholinesterase Willis 2012 Martin Saborido 2019 Chen 2020
HADS	Hospital Anxiety and Depression Scale	CADTH 2007 Acetylcholinesterase Gertler 2015
HVLT	Hopkins Verbal Learning Test	CADTH 2007 Acetylcholinesterase Gertler 2015
ImPACT	Immediate Post-Concussion Assessment and Cognitive Testing	VA/DoD Guideline Concussion-Mild Traumatic Brain Injury, 2016 Dougall 2015
MPAI	Mayo-Portland Adaptability Index	Brasure 2012
NCAT	Neuro-Cognitive Assessment Tool	VA/DoD Guideline Concussion-Mild Traumatic Brain Injury, 2016
NSI	Neurobehavioral Symptom Inventory	Dougall 2015
PCSS	Post Concussion Symptom Scale	Ontario Neurotrauma Foundation, Guideline for Concussion/Mild Traumatic Brain Injury, 2018
RPQ	Rivermead Post Concussion Symptoms Questionnaire	Ontario Neurotrauma Foundation, Guideline for Concussion/Mild Traumatic Brain Injury, 2018
SF-12	Short Form 12 Item	Dougall 2015
TMT	Trail Making Test	Dougall 2015
WAIS	Wechsler Adult Intelligence Scale	Dougall 2015

APPENDIX H. PEER REVIEW DISPOSITION

Comment #	Reviewer #	Comment	Author Response
Are the objectives, scope, and methods for this review clearly described?
1	2	Yes	None
2	3	Yes	None
3	4	Yes	None
4	5	Yes	None
5	6	Yes	None
6	8	First Review No - Using studies, such as Weaver, et al., (2018) that arrived at results using inappropriate statistics is a major flaw in this Evidence Brief. This reviewer strongly suggests that the ESP team goes back and review the statistical methods used by the authors before releasing the brief. In addition, there may be confusion regarding the use of HBOT for ACUTE severe TBI. Acute severe TBI and chronic mild TBI or PTSD are vastly different clinical situations, more separation should be provided in the brief and these clinical conditions should be discussed separately. Second Review Yes	Specific comments regarding Weaver et al. (2018) and HBOT for acute severe TBI are addressed in comments below.
7	9	Yes	None
Is there any indication of bias in our synthesis of the evidence?
8	2	No	None
9	3	No	None
10	4	No	None
11	5	No	None
12	6	No	None
13	8	First Review Yes - Utilizing the Weaver et al. (2018) paper creates obvious bias since the paper utilizes dozens of comparisons without any corrections. The paper that Weaver et al (2018) cites, Tang, et al. (1993) has had limited citations and those that utilized the method from this paper did so a priori. In addition, the Boussi-Gross, et al. paper had no sham treatment and only a 2 month follow-up. Chronic effects of TBI can be both cognitive and noncognitive in nature. People having chronic impairments are very susceptible to believing, at least in the short-term, that an ineffective treatment is efficacious for various non-cognitive conditions. Non-sham treatment studies are bias when there is a TBI history and the treatment is open-labelled. Taking both these two papers together, it is biased to state that the first sentence on page 8, “Although findings indicate some effect of HBOT is likely…” Second Review No	The report has been revised with a meta-analysis of included studies to overcome some issues with analyses in the individual studies. The conclusions, key findings, and summary of the findings have been revised with findings from the meta-analysis.
14	8	Not clear reason why the Brenner, et al. studies were ineligible publications when the Weaver et al (2018) with obvious statistical flaws is included and Boussi-Gross with the critical flaw of no placebo control were included. This type of selection of evidence gives the appearance of bias.	The Brenner, et al. study (HOPPS) was included as Miller, 2015 – which was the publication with full results from the trial – and is included in Table 1 and the meta-analysis.
15	9	No	None
Are there any published or unpublished studies that we may have overlooked?
16	2	No	None
17	3	No	None
18	4	No	None
19	5	First Review Yes - See my review of the brief for details Second Review No	Addressed in comments below.
20	6	No	None
21	8	No	None
22	9	No	None
Additional suggestions or comments can be provided below. If applicable, please indicate the page and line numbers from the draft report.
23	2	Page 4, line 50 FDA did not determine the indications, the UHMS did and that should be identified for clarity.	This has been revised for clarity.
24	2	Page 6, line 10 The office name has changed to VHA National Center for Healthcare Advancement and Partnerships and was formerly, Office of Community Engagement/Center for Compassionate Care Innovation. The review was requested in response to Section 702 of the Commander John Scott Hannon Veterans Mental Health Care Improvement Act of 2019. This is the same response for page 9, line 11	The requesting office name and purpose have been revised.
25	2	Page 9, line 15 the findings will not be used to inform provision of HBOT. They will be submitted to the Committee on Veterans Affairs of the Senate and the Committee on Veterans Affairs of the House of Representatives a report on the results of the review. This review was not requested to inform future care, specifically.	The purpose and use of the review have been revised.
26	2	Page 33, line 28 I am the Nurse Executive for VHA National Center for Healthcare Advancement and Partnerships. OCE and CCI are former names that are no longer current.	The name of the office has been revised.
27	2	Page 33, line 33 Same organizational name for Christine Eickhoff.	The name of the office has been revised.
28	3	The background section does not accurately reflect the office that requested or identified a need to update the previous report.	The requesting office name has been revised.
29	3	pg 4 line 50: the report correctly describes that FDA “clears” devices for specific indications and the list of indications from Appendix A accurately reflects and references the list of indications maintained by UHMS. The reference to the UHMS list of indications should also be included in the narrative on page 4.	This has been corrected to refer to and cite UHMS as providing indications for HBOT use.
30	4	Page 1, lines 8 - 27, “Background.” Page 4, lines 15 - 19 (same comments as from page 1) The requirement from congress related to S. 785, the Commander John Scott Hannon Veterans Mental Health Care Improvement Act of 2019. Specifically, the Act requires VA to “conduct of a systematic review of published research literature on off label use of hyperbaric oxygen therapy to treat post traumatic stress disorder and traumatic brain injury among veterans and nonveterans.” findings will inform a study on the current program evaluation of HBOT for Veterans diagnosed with PTSD with or without TBI	The office name, purpose, and intended use of report have been revised in the executive summary and purpose sections of the report.
31	4	p. 4, line 15-16: see previous comments	The office name, purpose, and intended use of report have been revised in the executive summary and purpose sections of the report.
32	5	p. 1, line 8: I suggest that in mild TBI another key finding is the caveat that the same short-term improvement in symptoms is seen with the sham exposures used in the sham-controlled trials. I know the authors make this point in the body of the brief, but I think it is a point worth adding in this summary (which is all many users will actually read). I interpret this as suggesting the observed improvements are likely due to a participation effect. I feel this is the key message we need to make interested parties aware of and sorting this out is our primary problem with evidence in this area. You make this point clearly in Table ES1, but I think it is important enough to emphasize here.	The key findings have been revised to reflect the findings from a newly added meta-analysis, which takes into account effects in both HBOT and control groups.
33	5	NOTE on ‘sham’. One of the great controversies in this area is the characterization of the typical control exposures used here as ‘sham’. I think it is an accurate term and use it myself frequently, but as you suggest later in the brief, the proponents of HBO for mTBI muddy the waters by claiming that any exposure in a chamber is potentially therapeutic. I suspect the authors are familiar with this argument. I therefore caution the liberal use of ‘sham’ in this document. I fear it may provoke criticism from the proponents of HBO that would distract from the important message of this brief. I suggest the authors acknowledge the argument if only to reject it and/or suggest the use of those (very safe and cheap) alternatives to true HBO while the evidence emerges more fully. This is a difficult situation. Perhaps the following reference may be useful in this regard: Bennett MH. Hyperbaric medicine and the placebo effect. Diving Hyperb Med. 2014 Dec 1;44(4):235–40 [PubMed: 25596837].	We have refined our use of sham terminology and description of sham conditions, and have added further discussion of potential participation effects, which may occur in both treatment and control groups.
34	5	p.1, line 33: I am not convinced of the need for more sophisticated study designs – just better studies! Is this really a key finding?	We agree that better studies are needed, but also think that more sophisticated design and analysis could help clarify any potential effect of HBOT treatment.
35	5	p. 1, line 55: Same point as line 8 above.	The summary of findings in the executive summary have been revised with results from a newly added meta-analysis of the evidence.
36	5	p. 1, line 59: Same point again. Yes HBOT seems to improve symptoms but so does the sham exposure.	The summary of findings in the executive summary have been revised with results from a newly added meta-analysis of the evidence.
37	5	p. 2, line 15: Line 15: I understand the reason one might feel the applicability to veterans is low, but I am not sure I fully agree. Presumably Veterans have TBIs that are not related to blast injury, so this evidence applies to Veterans in that situation as much as it does to any other group.	We have revised the discussion of applicability to include applicability to Veterans sustaining non-blast severe TBIs.
38	5	p. 3, line 7: I do not see the evidentiary basis for saying an effect of HBO is likely. What is likely is that the observed improvements are due to a participation effect as attested to by the more or less equal efficacy of the sham exposures. I suggest a more accurate statement is that an effect of HBO is possible but unlikely.	We have revised the summary of findings with results from a newly added meta-analysis, and updated our findings with the conclusion that available evidence does not show HBOT leads to durable improvements in symptoms.
39	5	p. 3, line 10-11: I would substitute ‘possible’ for ‘likely’ here. If there is an HBO effect above the level of the general participation effect, then it is likely to be clinically unimportant.	We have revised the summary of findings with results from a newly added meta-analysis, and updated our findings with the conclusion that available evidence does not show HBOT leads to durable improvements in symptoms.
40	5	p. 3, line 13: I agree with the more sophisticated design suggestions for the most part, but I am not supportive of adjusting for baseline differences in severity. A stratified design would be better for that purpose I think. Properly powered studies using a universally accepted sham and on the basis of detecting the minimum clinically important effect are the most important features for the future.	We agree and have clarified that stratification by baseline severity and adjustment for other covariates would be optimal.
41	5	p. 4, line 25: This characterization of HBO is slightly inaccurate. It is not really ‘designed to increase the supply of oxygen’. This and the subsequent text perpetuate the misunderstanding that HBO is all about the relief of hypoxia. This is part of the mechanism of action for some conditions, but there is a lot more to it than that. High oxygen tensions (pressures) in the blood and tissues result in a very complex suite of pharmacological effects that are only very loosely associated with the achievement of normoxia in previously hypoxic situations as your phrase suggests. For a brief outline of this I suggest the authors consider the appropriate section of the chapter in Harrison’s Textbook of Medicine (Bennett MH, Mitchell SJ. Hyperbaric and Diving Medicine. In: Harrison’s Principles of Internal Medicine Part 22, Chapter S11,20^th Ed 2018). My suggestion is something like: “Hyperbaric oxygen therapy is designed to greatly increase the partial pressure of oxygen in the blood and tissues through the inhalation of pure oxygen in a pressurized environment. Most HBO regimens involve oxygen breathing at between 2 and 2.8 atmospheres and the resultant substantial increase in arterial oxygen partial pressure (often >1000 mmHg) has widespread physiologic and pharmacologic consequences. One direct consequence is the reversal of hypoxia in injured tissues, but others include pharmacologic effects that persist after removal from the pressure vessel, including changes in fibroblast and leukocyte function, the release of vasculogenic stem cells from bone marrow and the upregulation of antioxidant defenses. Oxygen accelerates healing processes, reduces swelling and promotes cellular growth and repair.13,14,15”	We have revised this section to include these other mechanisms of HBOT and have reviewed the textbook chapter as a reference.
42	5	p. 4, line 36: Probably just a US usage I am not used to, but is ‘urethrane’ a common term for a plastic chamber? From Wikipedia I learn that ‘Urethane is most commonly used in a liquid form as a coating, adhesive, or sealant’. I am not aware of plastic chambers in use, but may be wrong about that! I do see online some references to chambers incorporating urethane coated components so I guess they could loosely be referred to as ‘urethane chambers’.	We have removed the discussion of the different types of chambers to avoid confusion, as we are focusing on the medically used chambers.
43	5	p. 4, line 43: How about ‘will have frequent interactions…’? Hard to see how this can be avoided and it is important of course.	We have removed “may” here for clarity that interactions with staff, etc. are inevitable.
44	5	p. 5, line 50: The statement here is a bit circular when one knows the background. The UHMS definition of the lower limit for HBOT is 1.4ATA precisely because that group wants (quite reasonably) to distinguish what they do as quite different from what is sometimes called ‘mild HBO’ – but should really be called mild hyperbaric therapy, mild oxygen-enriched air therapy or similar. Concerned about the claim that 1.2 or 1.3 ATA of air or oxygen-enriched air could be therapeutic, they changed the definition to exclude such ‘treatments’. I suggest deleting ‘and near the treatment threshold for HBOT (1.4 ATA)’ to make a simpler and accurate statement. Also, it is a bit redundant as anything between 1.0 and 1.4 ATA will be ‘near’ 1.4. (of course, the ‘sham’ therapies used are air at these pressures rather than oxygen, so 1.4 ATA of air contains nowhere near the same oxygen pressure as 1.4 ATA of 100% oxygen). Many proponents of HBO for mTBI like to avoid this distinction.	We have deleted “and near the treatment threshold…” and added some further context to this section for clarity.
45	5	p. 5, line 52: It is worth noting that a therapeutic effect of 1.2 or 1.3 ATA of air would be absolutely extraordinary (as opposed to 100% oxygen at these pressures where such a notion is possible).	We have added a statement about the use of room air reducing the overall oxygen pressure in sham treatment.
46	5	p. 8, line 9: I presume the HBOT in the inclusion criteria is according to the UHMS definition?	Yes. We have added a statement about this for clarity.
47	5	p. 9, line 34: I understood that this RoB tool is only for the assessment of RCTs and not non-random comparative trials. There are validated instruments for the latter purpose. (Wells, G. et al. The Newcastle-Ottawa Scale (Nos) for Assessing the Quality of Nonrandomised Studies in Meta-Analyses. Ottawa Hospital Research Institute: Ottawa, ON, Canada.; Sterne JA, Hernán MA, Reeves BC, et al. ROBINS-I: A tool for assessing risk of bias in non-randomised studies of interventions. BMJ 2016;355:1–7).	All of our included studies were randomized controlled trials or randomized crossover trials and so we used the RCT RoB tool.
48	5	Included studies: The relevant publications are very difficult to identify due to multiple reports of a number of trials – often for ‘extra’ outcomes not reported in the main paper. My apologies if the authors have seen all these, but potentially missed studies I have identified include: Holbach KH, Wassman H, Kolberg T. Improved reversibility of the traumatic mid-brain syndrome following the use of hyperbaric oxygen. Acta Neurochirurgica 1974; 30:247–256. [PubMed: 4432786] Shandley S, Wolf EG, Schubert-Kappan CM, Baugh LM, Richards MF, Prye J, Arizpe HM, Kalns J. Increased circulating stem cells and better cognitive performance in traumatic brain injury subjects following hyperbaric oxygen therapy. Undersea & hyperbaric medicine: journal of the Undersea and Hyperbaric Medical Society, Inc. 2017;44(3):257–69. [PubMed: 28779582] Wares D, Cifu DX, Hole KW, Wetzel PA, Wares JR, Gitchel G, Carne W. Effects of hyperbaric oxygen on eye tracking abnormalities in males after mild traumatic brain injury. Journal of Rehabilitation Research and Development 2014;51(7):1047–1056 [PubMed: 25436771] Churchill S, Miller RS, Deru K, Wilson SH, Weaver LK. Simple and procedural reaction time for mild traumatic brain injury in a hyperbaric oxygen clinical trial. Military Medicine. 2016 May 1;181(suppl_5):40–4. [PubMed: 27168551]	Holbach KH, et al. – Unable to locate an English language full-text Shandley S, et al. – Excluded as PTSD/Post-concussion symptom outcomes are only reported in relation to stem cell levels Wares D, Cifu DX, et al. – We included the main outcomes from the Cifu study, but excluded this publication as we did not include eye tracking outcomes Churchill S, et al. – We included the main outcomes from the Miller study (HOPPS), but excluded this publication as we did not focus on reaction time outcomes
49	5	p. 15, line 12-14: I think this statement is somewhat misleading given the complexity of this paper and the stated aim of being exploratory in order to identify good outcome measures for use in future trials. There were 71 participants and >600 outcomes calculated for this paper, with no attempts to statistically account for this large number – calling any interpretation of p-values or 95% CI into question. I think any conclusion that the HBOT group did better is highly qualified to say the least. I suggest modifying the description of the paper with some disscussion to this effect. (Appraisal of that paper is contained in the word document).	We have revised our synthesis of the results based on a newly added meta-analysis and have added some discussion of these methodological limitations of the analyses in the BIMA trial.
50	5	p. 16, line 25: Agree, but perhaps you should add the obvious problem previously mentioned of the facility in the design to promote a positive bias through a participation/placebo effect.	We have revised our synthesis of the results based on a newly added meta-analysis and have discussed the no comparator/standard care treatment separately, with an in-depth discussion of potential placebo/participation effects in the summary and discussion.
51	5	p. 23, line 48: I think this conclusion expressed in the first phrase is too strong given the evidence. Given the bias issues with RCTs not controlled with sham, and the very high number of comparisons made in BIMA, I think that such a benefit is possible rather than likely and if present likely to be evanescent. Although you do go on to explain in the next line that the benefits are likely to be due to a placebo effect, that modification comes too late. The enthusiastic proponents of HBO can and will selectively quote the first phrase in isolation.	We have revised our synthesis of the results based on a newly added meta-analysis and have added some discussion of these methodological limitations of the analyses in the BIMA trial.
52	5	p. 24, paragraph 1: Agree with your logic and that this is a very complicated area. Please consider adding that a universally agreed sham treatment that has been validated to be to be effective as a sham (ie not distinguishable from HBOT by participants) has an important role in clarifying the problems described here. This is under active discussion in the field.	We have added language on the need for consensus on treatment and sham protocols as a need for future research.
53	5	p. 25, line 51: I can’t quite grasp how a crossover trial could possibly work given the therapeutic intention to show long-lasting benefit.	We have refined discussion of trial designs suggested for future research.
54	6	None. Excellent summary.	None
55	8	No additional suggestions, but the use of reports should have a test of quality, especially regarding the design and statistical rigor.	We have incorporated a meta-analysis to overcome some of the limitations in the analyses within individual studies, and expanded discussion of design and rigor of included trials.
56	8	When discussing the use of HBOT in acute severe TBI, it should be more strongly stated that the studies being describe are in the acute time after the injury and clinical state of the participants is vastly different than in chronic phase.	We have added clarification that the studies in severe TBI were in the acute time after injury and that this differs from the use of HBOT for (chronic) mild TBI.
57	8	Second Review Major improvement in analysis of the literature and assessment of limitations. Only additional information that should be included is: How many treatment sessions are required for HBOT approved indications, e.g., decompression sickness, gas embolism, CO poisoning, or soft tissue necrosis?	We have added a brief overview of the treatment protocols for the approved HBOT indications to the background section.
58	9	It seems important to note that this topic has been revisited multiple times over the last many years. Major Concern: Whereas relevant evidence is presented, my major concern is with the Executive Summary and in particular the Key Findings.	Comments addressed individually below.
59	9	Key Findings: Bullet 1: “In patients with mild TBI and persistent post-concussion symptoms, current evidence suggests that HBOT can lead to short-term improvement in post-concussion and PTSD symptoms. It is unclear whether symptom improvements are clinically meaningful, and there is uncertainty in effects due to variations in patient, intervention, and comparator characteristics.” What is missing from this is that “genuine treatment effects or placebo effects induced by the intensive nature of the HBOT intervention.” Would most strongly recommend a revision of this bullet to include the information stated later in the summary. That is, similar findings were identified in the sham groups.	We have revised the summary of findings with results from a newly added meta-analysis, and updated our findings with the conclusion that available evidence does not show HBOT leads to durable improvements in symptoms.
60	9	Key Findings: Bullet 2: As noted, outcomes from this study are much more focused on measures related to hospitalization vs TBI-specific outcomes – this should be more strongly stated. That is, indications highlighted are more in line with “wound care” that HBOT has been found to be effective for vs longer-term functional TBI outcomes. Such treatments would be administered in the ICU or other acute settings.	We have added language to clarify that treatment was for hospitalized patients with acute injury.
61	9	Key Findings: Final Bullet: Additional information regarding the goals for future research would be helpful – in terms of mTBI and PTSD – findings appear to be consistent over many trials. It is unclear that future research is required. Might suggest that existing data could be used to evaluate the cost-effectiveness of HBOT for mild TBI and/or PTSD (vs traditional effective tx).	We have expanded on the goals of future research, which are to overcome some of the design and methodological limitations of the existing evidence and clarify any potential true effect of HBOT.
62	9	Background: Discussion of mechanisms (both related to TBI and PTSD) still remain elusive (see Xie et al 2007 – inflammation) – this does not appear to be sufficiently addressed in this brief.	We agree this is an important area to address and have added a discussion around future research on the etiologies of chronic post concussive symptoms to the discussion section.
63	9	Future Research: It is not clear to this reviewer that additional research to identify “small but clinically meaningful” change is warranted in light of current findings and evidence which suggests that patients with PTSD and/or mTBI DO benefit from more cost effective – efficacious treatments for conditions on whole (PTSD: CPT; or specific symptoms, MTBI, insomnia, CBTi). As such further clarification regarding the basis for this recommendation would be useful. Moreover, within the Brief the “well-conducted, sham-controlled RCT’s” are noted (p. 16). If further research were to be conducted, which this reviewer would NOT recommend, it is suggested that this work be conducted primarily by teams without clear conflicts related to outcomes.	We removed the statement regarding “well-conducted” trials and have expanded on how future research could overcome some of the design and methodological limitations of the existing evidence and clarify any potential true effect of HBOT. Future research is required by the Hannon Act, and so we feel recommendations for future research are warranted.
64	9	Page 2. “It is unclear whether observed short- and longer term symptom improvements among those with mTBI, regardless of PTSD status, are clinically meaningful.” … or related to oxygen exposure	We have revised the executive summary with findings from a newly added meta-analysis to better reflect the findings from HBOT and sham conditions.
65	9	Page 4. Symptoms: some are overlapping and others are quite distinct (e.g., hypervigilance) this should be clarified.	We have revised the sentence on PTSD symptoms to distinguish between overlapping and unique symptoms.
66	9	Page 23. Line 6 – information re: similar improvements with SHAM is missing.	We have revised the discussion to more clearly state that similar improvements were seen in sham groups and to describe how this is likely the result of participation effects.
67	9	Figure 3. PTSD Module of SCID was use for Miller et al. Is this figure meant to be all inclusive?	This figure was not meant to be all inclusive, but to show common scales across studies. We have statements to clarify that these were “commonly” used scales or tools. In Miller et al, it appears the SCID tool was used for baseline PTSD assessment, but not outcome assessment, and so it was not included in the figure.

REFERENCES

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2.: Piper S, Legross T, Murphy-Lavoie H. Idiopathic Sudden Sensorineural Hearing Loss (New! approved on October 8, 2011 by the UHMS Board of Directors. Undersear & Hyperbaric Medical Society. Indications for Hyperbaric Oxygen Therapy Web site. https://www.uhms.org/resources/hbo-indications.html. Updated 2020. Accessed.
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Prepared for: Department of Veterans Affairs, Veterans Health Administration, Health Services Research & Development Service, Washington, DC 20420 Prepared by: Evidence Synthesis Program (ESP) Coordinating Center, Portland VA Health Care System, Portland, OR, Mark Helfand, MD, MPH, MS, Director

Suggested citation:

Parr NJ, Anderson J, Veazie S. Evidence Brief: Hyperbaric Oxygen Therapy for Traumatic Brain Injury and/or Post-traumatic Stress Disorder. Washington, DC: Evidence Synthesis Program, Health Services Research and Development Service, Office of Research and Development, Department of Veterans Affairs. VA ESP Project #09-199; 2021. Available at: https://www.hsrd.research.va.gov/publications/esp/reports.cfm.

This report is based on research conducted by the Evidence Synthesis Program Center located at the VA Portland Health Care System, Portland, OR, funded by the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development. The findings and conclusions in this document are those of the author(s) who are responsible for its contents; the findings and conclusions do not necessarily represent the views of the Department of Veterans Affairs or the United States government. Therefore, no statement in this article should be construed as an official position of the Department of Veterans Affairs. No investigators have any affiliations or financial involvement (eg, employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties) that conflict with material presented in the report.

This publication is in the public domain and is therefore without copyright. All text from this work may be reprinted freely. Use of these materials should be acknowledged.

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Evidence Brief: Hyperbaric Oxygen Therapy for Traumatic Brain Injury and/or Post-traumatic Stress Disorder

PREFACE

EXECUTIVE SUMMARY

Background

Methods

Key Findings

INTRODUCTION

PURPOSE

BACKGROUND

Hyperbaric Oxygen Therapy

Treatment of Prolonged Symptoms of TBI and/or PTSD

Use of HBOT for TBI and/or PTSD

METHODS

PROTOCOL

KEY QUESTIONS

ANALYTIC FRAMEWORK

Figure 1

ELIGIBILITY CRITERIA

DATA SOURCES AND SEARCHES

DATA ABSTRACTION AND ASSESSMENT

SYNTHESIS

RESULTS

LITERATURE FLOW

Figure 2

LITERATURE OVERVIEW

Mild TBI

Moderate to Severe TBI

Outcome Measurement

Outcome Measurement in HBOT vs non-HBOT Studies

Table 1

EFFICACY OF HBOT FOR TBI WITH/WITHOUT PTSD

Mild TBI

Figure 3

Figure 4

Moderate to Severe TBI

Unclear TBI Severity

HARMS OR ADVERSE EVENTS OF HBOT FOR TBI WITH/WITHOUT PTSD

SUMMARY AND DISCUSSION

LIMITATIONS

Limitations of Included Trials

Limitations of the Present Review

CONSIDERATIONS FOR FUTURE RESEARCH

CONCLUSIONS

ACKNOWLEDGMENTS

Operational Partners

Peer Reviewers

REFERENCES

Supplemental Materials

APPENDIX A. UHMS INDICATIONS FOR HBOT

APPENDIX B. GUIDELINES ON HBOT USE

APPENDIX C. SEARCH STRATEGIES

APPENDIX D. LIST OF EXCLUDED STUDIES

APPENDIX E. EVIDENCE TABLES

CHARACTERISTICS OF INCLUDED PRIMARY STUDIES

OUTCOME DATA OF INCLUDED PRIMARY STUDIES

QUALITY ASSESSMENT OF INCLUDED PRIMARY STUDIES

STRENGTH OF EVIDENCE

Mild TBI

Moderate to Severe TBI

Unclear TBI Severity

APPENDIX F. RESEARCH IN PROGRESS

APPENDIX G. TABLE OF MEASURES

PTSD

TBI

APPENDIX H. PEER REVIEW DISPOSITION

REFERENCES

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