PREFACE

The VA Evidence-based Synthesis Program (ESP) was established in 2007 to provide timely and accurate syntheses of targeted healthcare topics of particular importance to clinicians, managers, and policymakers as they work to improve the health and healthcare of Veterans. QUERI provides funding for four ESP Centers, and each Center has an active University affiliation. Center Directors are recognized leaders in the field of evidence synthesis with close ties to the AHRQ Evidence-based Practice Centers. The ESP is governed by a Steering Committee comprised of participants from VHA Policy, Program, and Operations Offices, VISN leadership, field-based investigators, and others as designated appropriate by QUERI/HSR&D.

The ESP Centers generate evidence syntheses on important clinical practice topics. 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 ESP disseminates these reports throughout VA and in the published literature; some evidence syntheses have informed the clinical guidelines of large professional organizations.

The ESP Coordinating Center (ESP CC), located in Portland, Oregon, was created in 2009 to expand the capacity of QUERI/HSR&D and is charged with oversight of national ESP program operations, program development and evaluation, and dissemination efforts. The ESP CC establishes standard operating procedures for the production of evidence synthesis reports; facilitates a national topic nomination, prioritization, and selection process; manages the research portfolio of each Center; facilitates editorial review processes; ensures methodological consistency and quality of products; produces “rapid response evidence briefs” at the request of VHA senior leadership; collaborates with HSR&D Center for Information Dissemination and Education Resources (CIDER) to develop a national dissemination strategy for all ESP products; and interfaces with stakeholders to effectively engage the program.

Comments on this evidence report are welcome and can be sent to Nicole Floyd, ESP CC Program Manager, at vog.av@dyolF.elociN.

EXECUTIVE SUMMARY

Hyperbaric oxygen therapy (HBOT) is designed to increase the supply of oxygen to our blood and tissues and is thought to have osmotic and angiogenesis effects. In normal air, the oxygen level is only around 21% and the atmospheric absolute (ATA) pressure at sea level is 760 mmHg. HBOT delivers 100% medical grade oxygen inside a chamber where the air pressure is raised at least 1.4 times greater than normal. HBOT has been described as a high-tech, high-touch treatment that can require daily 2-hour sessions for 8 to 10 weeks in which participants are assisted by one or more specially-trained HBOT technicians and are sometimes accompanied by other patients in ‘multiplace’ chambers.

Following certain types of injuries, our bodies may demand more oxygen than is available in the normal air we breathe to supply our cells with the fuel necessary for healing processes (eg, metabolism, cellular growth and repair). The FDA has cleared HBOT, commonly at 100% oxygen delivered between 1.5 and 3.0 ATA, as a combination treatment of increased oxygen (hyperoxia) at increased hydrostatic pressure for several types of injury indications such as wound healing, necrotizing infections, burns, radiation injury, and carbon monoxide poisoning.

Given the microscopic and macroscopic wounds to the white matter of the brain that have been attributed to traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD), HBOT has also been explored as a therapy for these conditions. It has been used anywhere from between 3 to 71 months post-injury for mild TBI and within 24 hours for moderate to severe TBI. Among people who sustain mild TBI, up to 85% report persistent post-concussion symptoms (PPCS). Of those with PPCS, at least 90% have at least one co-occurring behavioral health condition, such as PTSD, and together these conditions have been labeled ‘post-deployment syndrome’. Among people with PPCS, mild TBI, PTSD, and post-deployment syndrome, many do not achieve remission with recommended treatments; thus, there remains a great need for innovative therapies.

In case series of TBI and/or PTSD populations, HBOT, mostly at 1.5 ATA, has statistically significantly improved cerebral blood flow and mean scores on post-concussion symptoms (PCS), PTSD, depression, and anxiety symptom checklists, as well as cognitive functioning and quality of life. Statistically significant mean improvement on physiological outcomes and checklists does not always equal clinically significant symptom benefits. To best demonstrate a net benefit, ideally HBOT would significantly improve clinically significant symptom response, function, and quality of life over a control group in randomized controlled trials (RCTs) of patients with mild to severe TBI and/or PTSD, without increasing risk of serious harm.

Available RCT evidence on using HBOT for TBI and/or PTSD has been controversial, widely debated, and potentially confusing. Department of Veterans Affairs/Department of Defense (VA/DoD)-affiliated researchers, a 2015 US Government Accountability Office report, and a June 2017 independent systematic review have concluded that HBOT is no better than sham. HBOT proponents have raised concerns that (1) HBOT's lack of effectiveness is due to use of a mischaracterized sham in the control groups – shams that were not true shams, but were actually therapeutic treatments and (2) bias against HBOT in VA/DoD RCT investigators that has led to flaws in the design and interpretation of HBOT research. Our independent and objective re-analysis of 16 RCTs found inconclusive evidence of HBOT's benefits at least for mild TBI and PTSD, no obvious indication that bias led to flaws in VA/DoD RCTs, and that current evidence does not clearly support any one argument over another for or against HBOT.

For mild TBI, in the most recent fully published VA/DoD-funded RCT (HOPPS – ‘Hyperbaric Oxygen Therapy for Persistent Post-concussive Symptoms After Mild Traumatic Brain Injury’), neither HBOT at 1.5 ATA nor room air at 1.2 ATA (sham) significantly improved the proportion of military service members with a clinically relevant improvement in post-concussive symptoms after 8 to 10 weeks (≥ 2-point improvement in Rivermead Post-Concussion Symptoms Questionnaire (RPQ—3)) compared to a no-chamber group – which an HBOT proponent described as the “only acceptable control group” (52% vs 33% vs 25%; P=0.24) because it lacks the potentially bioactive components of pressure and hyperoxia. Although this finding would seem to negate the ‘mischaracterized sham’ argument, we cannot rule out that the lack of improvement was due to a lack of adequate statistical power in the HOPPS RCT. Compared to sham (10.5% oxygen [O₂] at 2.0 ATA, room air at 1.2-1.3 ATA), HBOT given at 1.5 ATA or 2.4 ATA for mild TBI has also not significantly improved mean scores on other post-concussive symptom checklists or quality of life outcomes in other fully published VA/DoD RCTs. Although an Israeli civilian RCT had more positive findings, we have more doubt about its reliability due to its greater methodological limitations.

HBOT also did not significantly improve PTSD symptoms compared to sham in 2 VA/DoD RCTs with concomitant mild TBI and PTSD (mean difference in PTSD score change, -1.49 points, 95% CI -5.79 to 2.80), but interpretation of these findings is limited by imprecision, as only 37% to 65% of study participants had documented PTSD.

In patients with moderate to severe TBI, to best demonstrate a clinically important benefit over usual care, ideally (1) HBOT would significantly reduce risk of mortality, (2) improve the functional status and quality of life of the survivors, and (3) these benefits could be attributed specifically to HBOT and not between-group differences in the intensity level of medical care and decisions about life-sustaining treatment. Per the most recent and comprehensive systematic reviews, only one of these conditions has been met.

HBOT may increase risk of some serious harms when used in moderate to severe TBI. In patients with moderate to severe TBI, HBOT increased risk of severe pulmonary complications, but not seizures or ear barotrauma, compared to sham. In mild TBI, no serious adverse effects were reported and there were no significant differences between HBOT and control groups in specific adverse events

Proponents of HBOT for mild TBI and/or PTSD claim that the main confusion in interpreting the findings of HBOT RCTs is that the control groups of 1.2 to 1.3 ATA have been mischaracterized as sham. Although the Hyperbaric Oxygen Committee of the Undersea and Hyperbaric Medical Society (UHMS) defines HBOT treatment pressure as at least 1.4 times higher than sea level, proponents of the ‘mischaracterized sham’ argument have suggested that lower pressures are actually active treatments with documented physiological and clinical effects. But the reliability of this claim is unclear because the documentation the proponents provide is not directly from patients with TBI and/or PTSD, but is from in vitro samples or patients with different conditions whose experiences with 1.2 to 1.3 ATA may or may not be comparable to TBI and/or PTSD, including chronic toxic encephalopathy, autism, cerebrovascular injury, epilepsy, or migraine.

Opponents claim HBOT has consistently shown no significant differences compared to sham, and thus is no more than a high-tech, high-touch ritual with “powerful nonspecific placebo effects”. We find 2 factors that preclude interpreting these findings as consistent evidence of no effect: (1) heterogeneity in HBOT protocol (1.5 ATA to 2.4 ATA), outcome assessment methods, timing (immediately following therapy, up to 6 weeks after discontinuation), and patient populations (most recent TBI ranged from 3 to 71 months) and (2) important methodological limitations.

In summary, the large treatment benefits demonstrated for HBOT in uncontrolled case series have not been easily replicated in well-controlled RCTs. Potential explanations for this include that the potential benefits are subtle and demonstration requires larger RCTs, HBOT is in fact ineffective, and/or the sham design has indeed been problematic. We disagree with both sides of the ongoing debate that the current evidence clearly points to one explanation over another. We simply still don't know. Pooling data from the HOPPS trial and the yet unpublished BIMA trial – both of which compared HBOT 1.5 ATA to room air at 1.2 ATA, and used the RPQ to measure PCS symptoms – could shed light on the debate. Broad usage of HBOT as an initial treatment for mild or moderate to severe TBI and/or PTSD in lieu of conventional treatments still does not appear warranted. When patients do not respond to and/or do not tolerate adequate trials of multiple conventional therapy options and are considering emerging treatment options, offering HBOT to Veterans with mild or moderate to severe TBI and/or PTSD is reasonable. Prior to HBOT use, clinicians and patients should consider its potential increased risk of barotrauma and/or pulmonary complications. A small-scale clinical demonstration may provide the opportunity to improve data collection on comorbidities, clinically relevant patient outcomes, patient expectations, and documentation of the types and durations of previous and ongoing treatments.

PURPOSE

The ESP Coordinating Center (ESP CC) is responding to a request from the Center for Compassionate Innovation (CCI) for an evidence brief on the use of hyperbaric oxygen therapy (HBOT) to treat Veterans with traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) in whom other treatments have not been successful. Findings from this evidence brief will be used to inform considerations of clinical use of HBOT in Veterans with TBI and/or PTSD.

BACKGROUND

SCOPE

Objective: To synthesize the evidence regarding the potential benefits and risks of hyperbaric oxygen therapy (HBOT) for traumatic brain injury (TBI), post-traumatic stress disorder (PTSD), or their co-occurrence.

ANALYTIC FRAMEWORK

The analytic framework below (Figure 1) illustrates the Population, Interventions, Comparators, Outcomes, Timing, Setting, and Study designs (PICOTSS) of interest that guided this review and their relationship to the key questions. This evidence brief addresses the evidence evaluating the direct link between HBOT and health and clinically significant outcomes (Key Question 1) and potential risks (Key Question 2). Key Questions 3 and 4 examines whether the benefits and/or risks of HBOT differ per patient characteristics (eg, patient demographics, comorbidities, disease severity) or per treatment protocol (eg, number of sessions, amount of pressure, inpatient vs outpatient treatment).

Figure 1

Analytic Framework.

METHODS

We followed the steps in the systematic review process outlined below. For complete search strategies, see Appendix C in supplemental materials. A draft version of this report was reviewed by peer reviewers as well as clinical leadership. Their comments and our responses are presented in the Supplemental Materials, Appendix G.

Figure 2Review Methods

1

Robinson et al. Twelve recommendations for integrating existing systematic reviews into new reviews: EPC guidance. J Clin Epidemiol. 2016 [PubMed: 26261004];

2

Whiting et al. ROBIS: A new tool to assess risk of bias in systematic reviews was developed. J Clin Epidemiol. 2016 [PMC free article: PMC4687950] [PubMed: 26092286];

3

McDonagh et al. Methods for the drug effectiveness review project. BMC Med Res Methodol. 2012 [PMC free article: PMC3532217] [PubMed: 22970848];

4

Berkman et al. Grading the Strength of a Body of Evidence When Assessing Health Care Interventions for the Effective Health Care Program of the Agency for Healthcare Research and Quality: Agency for Healthcare Research and Quality;2013 [PubMed: 24404627].

RESULTS

The literature flow diagram (Figure 1) summarizes the results of the search and study selection processes. See Appendix D in supplemental materials for full list of excluded studies.

LITERATURE FLOW

Figure 3Literature Flowchart

LITERATURE OVERVIEW

Our search identified 282 unique, potentially relevant articles. We included 3 good-quality systematic reviews^26,50,51 which included 15 RCTs (in 19 publications),^{23-25,29,52-68} and one subsequently published RCT (in 4 publications),^69,70 for a total of 26 publications (Table 1; see supplemental materials Appendix E for full evidence tables). Five RCTs^{23-25,53-55,63,66,67,69,70} reported outcomes for patients with mild TBI with or without PTSD, 10 RCTs^{29,52,57-62,64,65,68} reported outcomes for patients with moderate to severe TBI, and 1 RCT⁵⁶ failed to report on TBI severity. No studies focused exclusively on patients with PTSD or separately analyzed PTSD subgroups, and the prevalence of PTSD in these studies was 36%⁶⁶ to 65%.⁶³ The majority of studies were in mostly male populations with a mean age range from 20 to 44 years. The number of HBOT sessions ranged from 3 to 84 and exposure lasted from 1 to 2 hours. We generally concurred with the ratings from previous systematic reviews that most studies had ‘few’ or acceptable levels of methodological limitations. The majority of RCTs were short-term (≤ 10 weeks) and none evaluated durability of effects.

Table 1

Characteristics of Included Studies.

We identified one potentially relevant study on mild TBI (BIMA) that is pending publication, and additional ongoing studies (see Appendix F in supplemental materials for details).⁷¹ None of the ongoing studies are expected to address important gaps in the literature. We sent requests for scientific information to 20 HBOT chamber manufacturers to identify additional published, unpublished, and supplemental data on published studies, but did not receive any submissions.

KQ1. WHAT ARE THE POTENTIAL BENEFITS OF HBOT FOR THE TREATMENT OF TBI AND/OR PTSD?

Mild TBI

The 39% to 96% increase in perceived quality of life and percentage back to normal cognitive, physical, and emotional function reported in case series²⁸ have not been easily replicated in the most well-controlled RCTs with the greatest relevance to Veterans, which were conducted by the VA/DoD (Table 2). HBOT has not significantly led to a clinically important improvement in TBI and/or PTSD symptoms, function, or quality of life compared to an adequate control group, and RCTs have not shown that any such improvements are durable beyond the few weeks following therapy discontinuation.^23-25,63 Neither has HBOT been shown to be consistently ineffective. Although HBOT given at 1.5 ATA to 2.4 ATA generally did not significantly improve post-concussive symptom or quality of life outcomes compared to control groups of 1.2-1.3 ATA in the 3 published VA/DoD RCTs, heterogeneity in HBOT protocol (1.5 ATA to 2.4 ATA), outcome assessment methods and timing (immediately following therapy, up to 6 weeks after discontinuation), and patient populations (most recent TBI ranged from 3 to 71 months), and important methodological limitations preclude interpreting findings as consistent evidence of no effect. Although an Israeli civilian RCT had more positive findings, we have more doubt about its reliability due to its greater methodological limitations.

Table 2

Post-concussive Symptom and Quality of Life Outcomes for HBOT versus Sham in VA/DoD RCTs.

VA/DOD Studies

Four VA/DoD RCTs have compared HBOT to conditions characterized as sham in which room air was delivered at low-pressure ATA (1.2 to 1.3)^25,63,71 or low oxygen (10.5%) was delivered at 2.0 ATA²⁴ to simulate “middle ear pressure effects and adiabatic heating and cooling effects of pressurization and depressurization”. In the most recent fully published DoD-funded RCT (HOPPS), neither HBOT 1.5 ATA nor room air at 1.2 ATA (sham) significantly improved the proportion of military service members with a clinically relevant improvement in post-concussive symptoms after 8 to 10 weeks (≥ 2-point improvement in Rivermead Post-Concussion Symptoms Questionnaire (RPQ—3)) compared to a no-chamber group – which an HBOT proponent described as the “only acceptable control group because it is the only control group which lacks the potential bioactive components of pressure and hyperoxia”⁷² (52% vs 33% vs 25%; P=0.24). Although this finding would seem to negate the ‘mischaracterized sham’ argument, we cannot rule out that the lack of improvement was due to a lack of adequate statistical power in the HOPPS RCT. Although this study required 72 patients for adequate statistical power, only 64 were included in their analysis. No significant differences between HBOT, low-pressure, and no-chamber groups were found in various quality of life SF-36 subscales, but results generally favored the low-pressure group over the HBOT group. Otherwise, compared to the low-pressure 1.2 to 1.3 ATA control groups in the other VA/DoD RCTs, HBOT significantly improved post-concussion symptoms only when delivered as 100% oxygen at 1.5 ATA, as described in the most recent VA/DoD RCT, which has not yet been fully published in a peer-reviewed journal (BIMA, Brain Injury and Mechanisms of Action study).⁷¹ According to the RPQ-3 2-point threshold used in the Miller 2015 RCT, though, this 1.5 difference in BIMA, while statistically significant, may not be clinically relevant. In the 3 other VA/DoD RCTs,^24,25,63 1.5 ATA, 2.0 ATA, and 2.4 ATA HBOT did not significantly improve PCS symptom response or quality of life. Factors including (1) heterogeneity in HBOT protocol (1.5 ATA to 2.4 ATA), outcome assessment methods and timing (immediately following therapy, up to 6 weeks after discontinuation), and patient populations (most recent TBI ranged from 3 to 71 months), and (2) important methodological limitations preclude interpreting these findings as consistent evidence of no effect. Also, the generalizability of the VA/DoD RCT findings to Veteran population is unclear, as the majority of participants in the VA/DoD studies were active-duty service members who were receiving paid travel, greatly reduced duty schedules, and enhanced access to leisure time during their participation the in the RCTs.²⁴

Perhaps most important is that HBOT still lacks evidence from RCTs on the durability of its potential benefits. HBOT's improvements in the RPQ-3 compared with sham in the unpublished BIMA have been reported to “regress” at 6 and 12 months.⁷¹

Israeli Civilian RCT

HBOT has shown promise in Israeli civilians at the late chronic stage of mild TBI (mean of 33 months post-injury) after a protocol of 40 sessions, 5 days a week, 60 minutes each, with 100% oxygen at 1.5 ATA.²³ This HBOT protocol improved quality of life compared to a control group of ‘no treatment’ (-17.7% vs +4.7%; P=not reported; baseline = 7.70 to 7.87 on European Quality of Life-5 Dimensions (EQ-5D), score of 5 = no problems; score 25 = extreme difficulties).²³ This same HBOT protocol also improved quality of life in the ‘no treatment’ control group when they crossed over to HBOT (-16.3% vs +4.7%; P=not reported). While encouraging, this RCT has several methodological limitations, the greatest of which is that we can't rule out the ‘participation effect’, as the only comparison was to an unblinded, no-treatment control group. Second, this is a single, underpowered study. The number of patients analyzed in the control group was lower than the N=31 needed to detect a 10% or greater improvement on the neurocognitive test score, and it is unclear how that power calculation applies to the EQ-5D. Finally, the analysis excluded more patients in the control group overall (22% vs 11%), the majority of which were due to “technical performance problems in their cognitive tests” (16% vs 5%), which could have been related to poorer neurocognitive and quality of life outcomes. Additionally, the applicability of the findings from these studies to Veterans with mild TBI is unclear because this study included 57% women with a higher mean age than the VA/DoD populations, and the comparability of the potential cumulative effects of multiple TBIs, their concomitant secondary diagnoses (ie, PTSD), or other previous or concurrent TBI treatment are unknown because they were not reported.

Moderate to Severe TBI

In patients with moderate to severe TBI, to best demonstrate a clinically important benefit over usual care, ideally (1) HBOT would significantly reduce risk of mortality, (2) improve the functional status and quality of life of the survivors, and (3) these benefits could be attributed specifically to HBOT and not between-group differences in the intensity level of medical care and decisions about life-sustaining treatment. According to the 3 good-quality systematic reviews, only one of these conditions has been met.^26,50,51 HBOT (1.5 to 2.55 ATA) consistently reduced odds of death in 2 meta-analyses.^26,50 HBOT reduced the relative risk of mortality in the earlier meta-analysis of 3 RCTs published between 1974 and 1992 (0.69, 95% CI 0.54 to 0.88, P = 0.003).²⁶ In the 2016 review by Wang et al of 3 newer RCTs published between 1992 and 2013, HBOT reduced the odds of mortality by 68% (OR=0.32, 95% CI 0.18 to 0.57)⁵⁰ and improved Glasgow Coma Scale (GOS) by 278% (OR=3.78, 95% CI 1.23 to 11.63) compared to the control groups based on 3 overall good-quality RCTs.⁵⁰ The GOS improvement was driven by a single study⁶⁵ performed in China with a control group where the mortality rate was almost double that observed in other included studies.⁵⁰ A sensitivity analysis after removal of this study⁶⁵ found no significant difference in GOS improvement (OR [random effects]=2.18, 95% CI 0.92 to 5.17).⁵⁰

The applicability of these results to Veterans is likely low because none of these studies included current service members or Veterans or those with blast-induced TBI. Furthermore, the majority of TBIs in Veterans are mild – moderate to severe TBIs only make up 9.4% and 1.1%, respectively, of TBIs sustained by service members since 2000.⁷⁴

PTSD

Little is known about the benefits of HBOT in patients with PTSD. While no studies focused exclusively on patients with PTSD, several studies included patients with concomitant TBI and PTSD. None of these studies did a responder analysis of clinically important PTSD improvements. A meta-analysis of the 2 RCTs^{24,25,53,66,67} by Cifu et al and Wolf et al that reported complete pre- and post-treatment PTSD score data showed no significant difference in PTSD score change between HBOT and control groups (pooled difference in means (fixed effects) = -1.45, 95% CI -5.79 to 2.80).⁵⁰ The applicability of these findings to patients with PTSD is unclear because the prevalence of PTSD in these studies was only 36%⁶⁶ to 65%⁶³ and PTSD subgroups were not separately analyzed. HBOT also did not significantly improve PTSD symptoms compared to sham in the most recent HOPPS trial, which was not included in the meta-analysis.⁶³

SUMMARY AND DISCUSSION

HBOT has the potential to fill a great need by improving the health and well-being of the many patients with TBI and/or PTSD who are refractory to recommended treatments. Interpretation of evidence on using HBOT for TBI/PTSD has been controversial, widely debated, and potentially confusing. Our independent and objective examination of 16 RCTs found that the large treatment benefits demonstrated for HBOT in uncontrolled case series have not been easily replicated in well-controlled RCTs. Potential explanations for this include that the potential benefits are subtle and demonstration requires larger RCTs, HBOT is in fact ineffective, and/or the sham design has indeed been problematic. We are unconvinced that the current evidence clearly points to one explanation over another. We simply still don't know.

For mild TBI, in the most recent fully published VA/DoD-funded RCT (HOPPS), neither HBOT 1.5 ATA nor room air at 1.2 ATA (sham) significantly improved the proportion of military service members with a clinically relevant improvement in post-concussive symptoms after 8 to 10 weeks (≥ 2-point improvement in Rivermead Post-Concussion Symptoms Questionnaire [RPQ—3]) compared to a no-chamber group (52% vs 33% vs 25%, P=0.24). Although the lack of difference between sham and no chamber had the potential to negate the ‘mischaracterized sham’ argument, the imprecision in HOPPS RCT precluded any conclusions. Compared to sham (10.5% O₂ at 2.0 ATA, room air at 1.2-1.3 ATA) HBOT given at 1.5 ATA to 2.4 ATA for mild TBI also has not significantly improved mean scores on other post-concussive symptom checklists or quality of life outcomes in other fully published VA/DoD RCTs.^24,25,63 HBOT also did not significantly improve PTSD symptoms compared to sham in 2 VA/DoD studies with concomitant mild TBI and PTSD (mean difference in PTSD score change, -1.49 points (95% CI -5.79 to 2.80)), but interpretation of these findings is limited by imprecision, as only 37% to 65% of study participants had documented PTSD. In patients with moderate to severe TBI, although HBOT may significantly reduce risk of mortality, it is unclear whether the reduction is due to HBOT and not differences in intensity level of medical care and decisions about life-sustaining treatment, or whether functional status and quality of life is meaningfully improved in survivors. Serious harms of HBOT appear limited to use in moderate to severe TBI, in which HBOT increased risk of severe pulmonary complications (13% vs 0%, RR=15.57, 95% CI 2.11 to 114.72, N=228), but not seizures or ear barotrauma. In mild TBI, no serious adverse effects were reported and there were no significant differences between HBOT and control groups in specific adverse events.

Proponents of HBOT for mild TBI and/or PTSD suggest that the main confusion in interpreting the findings of controlled HBOT trials is that the 1.2 to 1.3 ATA control groups have been mischaracterized as sham. Although the Hyperbaric Oxygen Committee of the Undersea and Hyperbaric Medical Society defines HBOT treatment pressure as at least 1.4 times higher than sea level,^1,24 proponents of the ‘mischaracterized sham’ argument have suggested that lower pressures are actually active treatments with documented physiological and clinical effects. The evidence of increased blood flow effects of the low-pressure room air conditions that support the ‘mischaracterized sham’ argument are from samples with chronic toxic encephalopathy, autism, cerebrovascular injury, epilepsy, or migraine and not specific to TBI, and also have the potential to be the result of participation effects.⁷⁹

HBOT proponents have also claimed that VA/DoD RCT investigators (and the medical field in general) are biased against HBOT (and other emerging treatments)^43,44 and that this bias has led to flaws in the design and interpretation of the VA/DoD RCTs that intentionally or unintentionally underestimate HBOT's effects.⁴¹ In order to be complete, any systematic review needs to investigate and address any concerns about the quality, relevance, and integrity of its included studies. One claim is that a VA/DoD investigator bias against HBOT led to a design that intentionally underestimated HBOT's effects in the Cifu RCT^24,55,66,67 because it didn't match the HBOT parameters used in the prior Wolf RCT.^25,53,54 We disagree with the claim that HBOT parameters used in Cifu RCT clearly reflect levels known to be sub- or supra-therapeutic. First, as HBOT parameter best practices for TBI have not yet been identified, some variability among RCTs is inevitable. Second, as the HBOT parameters used in the Wolf RCT did not produce clinically relevant improvement, replication is not clearly warranted. Finally, we interpret the selection of the pressures for the Cifu RCT (2.0 and 1.5 ATA equivalent) as reflecting an attempt to improve the chances of HBOT's effectiveness. This is because the pressure levels used in the Cifu RCT were closer than in the Wolf RCT to the levels that the HBOT proponent also identified as “the ideal pressure that proponents of HBOT normally use for neurological treatments” (≤ 1.5 ATA). We also identified the claim that VA/DoD bias against HBOT led to misinterpretation of the Cifu RCT results: “The conclusion of Cifu et al. that HBOT is ineffective on mTBI is not supported by the data they acquired.”⁴¹ To refute the Cifu RCT conclusion and demonstrate HBOT's effectiveness, this claim provides data on within-group, uncontrolled changes from before to after in the HBOT arms from both Cifu and Wolf and from another uncontrolled series of HBOT patients.²⁸ We disagree that these within-group data demonstrate a misinterpretation of results in the Cifu RCT. In fact, in the Cifu RCT publication, the investigators' interpretation of the within-group changes is identical to those of this HBOT proponent, as noted by this quote from the abstract: “Within-group testing of pre- and postintervention means revealed significant differences on several individual items for each group and difference in the Posttraumatic Disorder Checklist—Military Version total score for the 2.0 ATA HBO2 group.” The difference is that the conclusion from the Cifu RCT that HBOT is ineffective is based on a between-group's comparison of HBOT versus sham, which we agree was not statistically significant. The problem with relying on within-group changes is that – as even noted by a HBOT proponent – without a control group, placebo or participation effects “cannot be entirely ruled out”²⁸ and “need confirmation with larger numbers of subjects or with a stronger design such as a randomized or Bayesian study.”²⁸

Skeptics claim HBOT has consistently shown no significant differences compared to sham and is no more than a high-tech, high-touch ritual³⁶ with “powerful nonspecific placebo effects.”³⁷ Factors such as (1) heterogeneity in HBOT protocol (1.5 ATA to 2.4 ATA), outcome assessment methods, timing (immediately following therapy, up to 6 weeks after discontinuation), and patient populations (most recent TBI ranged from 3 to 71 months) and (2) important methodological limitations preclude interpreting these findings as consistent evidence of no effect. We are not suggesting that it is incumbent on the skeptics to prove ineffectiveness. We are only noting the limitations that preclude clear interpretation of the VA/DoD RCTs as demonstrating consistent evidence of no effect.

CONCLUSIONS

Current evidence does not clearly point to one explanation over another for why well-controlled RCTs have not easily replicated the large treatment benefits demonstrated for HBOT in uncontrolled case series. Although our independent and objective examination of 16 RCTs found a lack of compelling evidence of effectiveness for mild TBI and PTSD, we disagree that it can be fully explained by potential physiological effects of sham specific to TBI and/or PTSD or consistent evidence of ineffectiveness that points to a nonspecific participation effect. Pooling data from the HOPPS trial and the as-yet-unpublished BIMA trials could shed light on the debate. Broad usage of HBOT as an initial treatment for mild or moderate to severe TBI or PTSD in lieu of conventional treatments still does not appear clearly warranted. When patients do not respond to and/or do not tolerate adequate trials of multiple conventional therapy options and are considering emerging treatment options, offering HBOT to Veterans with mild or moderate to severe TBI and/or PTSD appears reasonable – with careful consideration of potential increased risk of certain harms. A small-scale clinical demonstration may provide the opportunity to improve data collection on comorbidities, clinically relevant patient outcomes, patient expectations, and documentation of the types and durations of previous and ongoing treatments.

Acknowledgements

We would like to thank Julia Haskin, MA for editorial support and Katherine Mackey, MD, MPP for providing clinical review.

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Supplemental Materials

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Prepared for: Department of Veterans Affairs, Veterans Health Administration, Quality Enhancement Research Initiative, Health Services Research & Development Service, Washington, DC 20420.

Prepared by: Evidence-based Synthesis Program (ESP), Coordinating Center, Portland VA Health Care System, Portland, OR, Mark Helfand, MD, MPH, MS, Director.

Recommended citation: Peterson K, Bourne D, Anderson J, Boundy E, Helfand M. Evidence Brief: Hyperbaric Oxygen Therapy (HBOT) for Traumatic Brain Injury and/or Post-traumatic Stress Disorder. VA ESP Project #09-199; 2018.

This report is based on research conducted by the Evidence-based Synthesis Program (ESP) Coordinating Center located at the Portland VA Health Care System, Portland, OR, funded by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Quality Enhancement Research Initiative. 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.