HBOT and DVA Richards.PNG

 

MEMORANDUM FOR RECORD                                                                            

 

SUBJECT: HBOT and the Department of Veterans of Affairs

 

1.  Executive Summary: The purpose of this memorandum is to provide common situational understanding on the state of Hyperbaric Oxygen Therapy (HBOT) for the treatment of combat-related Traumatic Brain Injury (TBI)/ Post-Concussion Syndrome (PCS) and Post Traumatic Stress Disorder (PTSD) within the VA/DOD and private medical

 

a. As of the end of FY2017, the US Department of Veterans Affairs reported that 964,038 veterans had a current diagnosis of PTSD. This number does not include service members currently on active duty with PTSD. This number included 388,700 veterans of the Global War on Terror (GWOT) and 395,201 veterans of the war in Vietnam. At least 120,000 veterans are disabled by TBI. Due to the way TBI was evaluated historically and the continuing paucity of adequately-equipped and staffed military and veteran medical facilities able to appropriately evaluate combat-related TBI, this number of veterans disabled by TBI is likely substantially higher.

 

b. The DOD and VA are currently unable to effectively treat either combat-related TBI/PPCS or combat-related PTSD with existing first line treatments. Even when administered under ideal conditions, existing treatments rarely produce meaningful reductions in symptoms. VA researchers assessing the effectiveness of current treatment recently concluded that “There is an urgent need for innovative treatment strategies.” Symptom management is generally conducted using “off-label” medications that have not been approved by the US Food and Drug Administration (FDA) for the purposes they are used for and are often used in violation of the VA’s own treatment guidelines due to the high-risk of serious adverse effects.

 

c. Hyperbaric Oxygen Therapy (HBOT) is the most promising “innovative treatment strategy” available for treating the invisible wounds of combat-related TBI and PTSD. In seven consecutive peer-reviewed clinical trials of HBOT for chronic TBI/PPCS published since 2012, HBOT has demonstrated both statistically and clinically significant treatment effects. Five of these studies specifically studied the effect of HBOT on combat-related TBI. Each of these five studies also demonstrated that HBOT effectively improved the symptoms of PTSD to the extent that the majority of participants with PTSD no longer met the clinical criteria for PTSD.

 

d. Furthermore, in terms of the both the magnitude of improvement and the probability that a patient will improve, HBOT is more effective “than any non-hyperbaric intervention previously reported.”

 

e. “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.” (VA evidence 3) Note that this is the majority of the population.


f. The largest obstacle to full acceptance of HBOT as a first line treatment for chronic TBI/PPCS and PTSD is the problematic design of the four clinical trials conducted by the DOD/VA which employed an alleged “sham” dose that the DOD/VA concedes may be an effective, biologically active treatment dose. In two of the four DOD/VA trials, the alleged “sham” group improved sufficiently to cause researchers to attribute improvement to “powerful non-specific treatment effects.” Current resistance within the DOD/VA to HBOT is based on these claims even thought a recent VA evidence review not that the assumption of a “sham” is not supported.

 

g. The second largest obstacle to full acceptance of HBOT is an assumption that HBOT is unaffordable based on common reimbursement rates at US hospitals that are typically around $3,000 per treatment. Multiple cost analysis conducted by Hyperbaric Medicine International and other HBOT professional societies confirms that HBOT can be profitably administered at between $100 and $250 per treatment depending on the local market costs and clinic efficiency. The average cost of treatment would be between $4,000 and $10,000 for standard course of 40 treatments. This is substantially less the current cost of a typical VA specialized PTSD treatment program.

 

h. HBOT is safe. HBOT safety profiles are well understood for currently-approved conditions which typically employ higher pressures and hyperoxia than used to treat TBI and PTSD. Not a single serious adverse effect was noted in the any of the seven consecutive trials.

 

i. The use of HBOT as a first line treatment for chronic TBI and PTSD is endorsed by the majority of national professional hyperbaric medical associations in the US.

   

2. Neither the US Departments of Defense or Veterans Affairs are currently able to effectively treat combat veterans with chronic Traumatic Brain Injury (TBI)/Post Concussion Syndrome (PCS) and/or Post Traumatic Stress Disorder (PTSD) even when veterans are treated under ideal conditions.

 

a. In 2014 the Institute of Medicine of the National Academy of Science reported: “[N]either department knows whether it is providing effective, appropriate, or adequate care for PTSD.” (IOM 2014, p.7)

 

b. There are only two sources of data on the effectiveness of VA treatment programs. These are data reported by the VA’s top-tier Specialized Intensive PTSD Treatment Programs (SIPP) and data reported in clinical trials of treatments.

 

c. On average the SIPPs failed to produce clinically significant improvement after an average of 46 days of treatment and $23,578 per veteran. (IOM 2014, p.100)

 

d. In 2013 and 2015 VA researchers published two meta-analysis reviews of effectiveness of the VA’s frontline PSTD treatments including Prolonged Exposure Therapy, Cognitive Processing Therapy, and Eye Movement Desensitization and Reprocessing Therapy. These reviews found that these treatments were mostly ineffective in treating PTSD. Excerpts of their findings include:

 

i. “[M]ean posttreatement scores for CPT and prolonged exposure therapy remained at or above clinical criteria for PTSD, and approximately two-thirds of patients receiving CPT or prolonged exposure retained their diagnosis after treatment.” Symptom remission was rare. (Steenkamp, et al., p.489)

 

ii. “In the RCTs conducted to date, with one exception, mean symptom scores at the end of treatment or at the latest follow-up (when available) indicated that PTSD symptoms were still substantial.” (Steenkamp and Litz, p.49)

 

iii. “[T]he outcomes from RCTs suggest that only a minority of veterans can be expected to lose their PTSD diagnosis as a result of getting CPT or PE, arguable administered in an ideal fashion…” (Steenkamp and Litz, p.49)

 

iv. “Attaining high end-state functioning may be the exception rather than the rule.” (Steenkamp and Litz, p.49)

 

v. The authors concluded that, “There is an urgent need for innovative treatment strategies.” (Steenkamp, et al., p.498)

 

3. The VA is currently unable to deal with the veteran suicide epidemic. This failure is due to the VA’s inability to effectively treat TBI and/or PTSD which are the smoking guns behind the veteran suicide epidemic.

 

a. In September 2018 the VA reported that the suicide rate among veterans of the Global War on Terror including Operation Iraqi Freedom (Iraq) and Operation Enduring Freedom (Afghanistan) had increased by more than 10 percent between 2015 and 2016. (VA National Suicide Data Report 2005-2016).

 

b. In 2012 the Institute of Medicine reported that combat veterans with PTSD and two or more comorbidities are 25.7 times more likely to have suicidal ideations then their combat veteran peers. (IOM 2012, p.45) This population includes almost combat veterans with PTSD and TBI. The average combat veteran with PTSD has 3-4 comorbid disorders. (Steenkamp, et al., p.497).

 

4. VA clinical practice in treating both TBI and PTSD is currently based on “off-label” treatments not approved by the FDA that often violate the VA’s own published PTSD treatment guidelines.

 

a. Only two medications are approved by the FDA for the treatment of PTSD. These are the SSRIs Sertraline (Zoloft) and Paroxetine (Paxil).

 

b. Only four medications have even a moderate level of evidence supporting efficacy in treating PTSD (three SSRIs and one SNRI). Notably none of this evidence is based on clinical trials with veterans. (VA/DOD Clinical Practice Guideline for the Management of PTSD 2017, p. 53)

 

c. Despite the lack of evidence, in practice the VA/DOD treats veterans with PTSD and TBI with cocktails of medications that often do more harm than good. The majority of medications regularly provided to veterans are not only “off-label,” but are recommended against by the VA PTSD Treatment Guidelines because of significant harmful side effects.

 

d. The VA/DOD treatment guidelines for mild TBI are poorly supported by evidence. Of 23 recommendations in the guidelines, only three have strong evidence supporting them. For seven recommendations the evidence is against the recommendation and for three recommendations there is no evidence at all. (VA/DOD Clinical Practice Guideline for the Management of Mild Traumatic Brain Injury, 2017, 19-21).

 

e. Actual symptom management of TBI is based on pharmacological uses that have not been approved by the FDA.

 

6. HBOT has consistently and substantially outperformed the VA’s front-line treatments in effectively treating both TBI and PTSD both in terms of the magnitude of improvement and the probability of improvement.

 

a. The authors of the final and largest DOD/VA clinical trial reported, “In all four military-sponsored studies, participants exposed to HBO2 reported symptom improvement.” And “The magnitude of improvement in self-reported assessments by 13 weeks is larger than any non-hyperbaric intervention previously reported.” (Weaver, 152)

 

b. In each of seven consecutive clinical trials of HBOT for treating TBI or TBI and PTSD published since 2012, HBOT caused both statistically and clinically significant improvement in both TBI and PTSD symptoms. Five of these studies specifically evaluated the effects of HBOT on combat veterans.

 

c. In contrast to exiting VA/DOD frontline therapies, the majority of combat veterans with PTSD experienced such substantial improvement that they no longer met the criteria for PTSD as defined in each study.

 

d. Studies that employed functional and/or structural brain imaging revealed that HBOT significantly improved brain function and caused the generation of new neural pathways.

 

e. The outcomes reported in the studies are consistent with clinical outcomes of 943 veterans or active duty service members in addition to those treated in the clinical trials known to have been treated in private clinics with HBOT for TBI and/or PTSD. The treatment outcomes of over four hundred of these veterans were measured and recorded using the same or similar metrics as the VA and DOD used in their studies.

 

Impact on PTSD. May be due to brain injury. 

 

Although the first pilot study and the four subsequent DOD/VA clinical trials were designed to investigate the use HBOT specifically to treat TBI/PPCS, the majority of patients enrolled in all but one of the studies also had comorbid PTSD. Each of the trials included assessments to that measured the effect of treatment on PTSD symptoms. In all five clinical trials with combat veterans, a majority of veterans with PTSD experienced symptomatic improvement to the extent that they no longer met the clinical threshold for having PTSD. This lead many of the investigators to recommend HBOT be considered as a treatment for PTSD even in the absence of TBI.

 

Dr. Lindell Weaver, the primary investigator of the fourth DOD/VA clinical trial noted, “Because almost all participants with PTSD had blast injury, the effect of HBO2 on blast injury in participants with PTSD cannot be determined, but those results suggest a correlation between blast and PTSD.” (BIMA 147)

 

Dr. Weaver’s insight is consistent with ground-breaking findings on distinctive physiological effects of blast on the brain published in the Lancet in 2016. “This distinctive pattern of scarring may indicate specific areas of damage from blast exposure consistent with the general principles of blast biophysics, and further, could account for aspects of the neuropsychiatric clinical sequelae reported.” (p. 944) Specifically these included “neuroanatomical areas associated with PTSD.” (p.950) (Perl, et al., “Characteristics of interface astroglial scarring in the human brain after blast exposure: a post-mortem case series,” Lancet Neural 15:944-53, 2016).

 

These insights support HBOT as an effective treatment for blast-related TBI.

Background.

 

a. In 2008 the RAND Corporation published DOD-funded research that revealed that rates of both combat-related TBI and PTSD were substantially higher than anticipated. The study revealed that morbidity rates for both conditions were around 20 percent of the total deployed force. In response to the DOD and VA began a series of initiatives to mitigate the impact of the invisible wounds of war. By 2008 around 400,000 US service members in Iraq and Afghanistan had experienced combat-related traumatic brain injuries.

 

b. As part a part of this response, in December 2008 the DOD and VA held a consensus conference with 60 leading hyperbaric medicine clinicians and researchers on hyperbaric oxygen therapy as a prospective treatment for chronic traumatic brain injury/ persistent post-concussion syndrome (PPCS). The conference concluded that hyperbaric oxygen had significant potential has effective treatment for chronic TBI and that it was safe, but the conference failed to achieve consensus that there was sufficient evidence at that time to immediately adopt the treatment.

 

c. The DOD and VA agreed to fund additional research to determine the efficacy of hyperbaric oxygen therapy for chronic traumatic brain injury. The Defense Centers of Excellence for Psychological Health ant Traumatic Brain Injury established a plan for a multi-site study with 500 combat veterans with chronic traumatic brain injury to be concluded by October 2009.

 

d. At that time there was significant divergence on the desirability of hyperbaric oxygen therapy between key interest group within the services with the Marine Corps and Navy supporting and the Army opposing. As a result the majority of participants in the first two studies were Marines. The Marine Corps’ official charity, the Semper Fi Fund, provided a significant portion of the funding as well as 29 wounded Marines for the first pilot study conducted by Dr. Paul Harch at Louisiana State University.

 

e. Responsibility for further HBOT research was transferred to the US Army Medical Research and Material Readiness Command (USAMRMC) which oversaw four subsequent DOD/VA funded clinical trials of HBOT for chronic TBI/PPCS. The execution of HBOT research under Army leadership departed significantly from plan established in December 2008 by the DOD Defense Centers of Excellence. No single study was large enough to establish efficacy in accordance with FDA guidelines and instead of determining efficacy by October 2009, the initial report of the fourth DOD study stemming from the 2008 consensus conference was not published until July 2018. In a February 2018 review of HBOT for TBI and PTSD the VA Evidence-based Synthesis Program concluded that differences in trial design, specifically the trials were underpowered and “heterogeneity in HBOT protocol, outcome assessments methods, timing, and patient populations and important methodological limitations” made it impossible to clearly interpret results. (Evidence Review, p. 20) Given the close oversight by a single agency, the unexplained abandonment of the DCOE research program to verify efficacy by the end of 2009, and the fact that all each of the studies’ primary investigators began closely collaborating and reviewing each other’s study designs at least as early as 2011,  it is difficult to explain how ten years and more than  $120 million later, the DOD/VA cannot reach conclusions on the effectiveness of HBOT because of failures in the design of their own sequentially-conducted clinical trials.

 

Resistance with the DOD/VA to the adoption of HBOT as a first line treatment is based on unsupported assumptions behind problematic study designs.

 

a. As previously noted, problems in the designs the DOD/VA clinical trials are the largest obstacle to the acceptance of the HBOT as first line treatment for TBI/PPCS and PTSD. The most significant flaw was the attempt to control the clinical trials with a sham or placebo does of HBOT that is potentially an effective treatment dose. Each of the four DOD/VA trials used a different “sham/placebo” dose that differed either pressure, hyperoxia, or time of treatment. In two of the four trials the “sham” group improved sufficiently compared to the “treatment” group to lead investigators to suggest that the improvements were the result of “power non-specific treatment effects” (or placebo effect). Given that HBOT has consistently produced improvements greater in terms of both magnitude of improvement and probability of improvement than any other existing treatment for either TBI/PPCS or PTSD, these conclusions are the single largest impediment to wide-scale adoption of the HBOT for the treatment.

 

b. DOD/VA investigators adopted the sham designed based one of several possible definitions of HBOT proposed by the Undersea and Hyperbaric Medical Society (UHMS). “Hyperbaric oxygen treatment, in which a patient breathes 100% oxygen intermittently while inside a treatment chamber at a pressure higher than sea level pressure (1 atmosphere), can be viewed as the new application of an old established technology to resolve certain recalcitrant, expensive, or otherwise hopeless medical problems… pressurization should be at 1.4 atmospheres or higher.” (UHMS HBOT Committee Report, 1999) It is important to note that UHMS selection of 1.4 ATA was based on practical concerns over regulation and insurance compensation, not on the science of hyperbaric medicine within which there is no clear point where combinations of hyperbaric pressure and hyperoxia abruptly cease to be biological active.

 

c. Critics of DOD/VA clinical trials have argued that laboratory tissue studies, animal studies, and clinical trials of HBOT for other neurological conditions such as Cerebral Palsy, chronic toxic encephalopathy, autism, cerebrovascular injury, epilepsy, and migraines have all demonstrated that that the pressure/oxygen combinations used as “shams” in the DOD/VA studies were biological active in ways that supported predicted treatment effects. However, no dosing studies specifically for TBI/PPCS and/or PTSD have been conducted to date.

 

d. When reviewing the use of the same “sham” dose in prior clinical trials of HBOT for cerebral palsy, the Agency for Healthcare Research and Quality (AHRQ), part of the US Department of Health and Human Services, issued an opinion the “sham” was an effective treatment dose. They wrote, “The Canadian Trial of HBOT for cerebral palsy has important implications for the design of future research. In the trial there was significant benefit in the control group.” (6) “The possibility that pressurized room air (21% O2 at 1.3 ATA) had a beneficial effect on motor function should be considered the leading explanation.” (44) (Agency for Healthcare Research and Quality (AHRQ) #85 Hyperbaric Oxygen Therapy for Brain Injury, Cerebral Palsy, and Stroke, 2003.)

 

e. The variation in hyperbaric pressure, hyperoxia, and time-in-treatment among protocols for treating indications accepted with the United States and internationally demonstrates that the ideal dosing of HBOT varies based on location and nature of the condition treated. The fundamental problem with the use of a HBOT “sham” in the DOD/VA clinical trials is that the DOD/VA admits that they do not know whether their “sham” is in fact an effective treatment dose. In February 2018 the VA acknowledged “the sham design has indeed been problematic,” and “We simply still don’t know” [if it is an effective dose]. (VA Evidence, 19)

 

f. Dr. George Wolf, the primary investigator of the first DOD/VA clinical trial, reported, “One factor to consider is that the sham could be considered an oxygen treatment in that the partial pressure of oxygen is increased (as well as that of nitrogen). Another factor is the increased hydrostatic pressure created with both the sham and the treatment groups.” (Wolf, 318).

 

“Our design could be considered a treatment comparison vs. a true sham with a therapeutic effect from both increased partial oxygen pressure and hydrostatic pressure. A Type II statistical error cannot be ruled out.” 328 Wolf (Note: Dr. Wolf has been publicly advocating for the use of HBOT in treating TBI/PPCS and PTSD since completing his study.)

 

g. Dr. Lindell Weaver, the primary investigator of the fourth DOD/VA clinical trial known as the BIMA Study, concluded, “BIMA does not support placebo effects or sham exposures improving patient-reported outcomes.” (BIMA 147) He continued, “Whether the associated sham exposures have a therapeutic effect on the chronically damaged human brain is not known.” (BIMA 150) He suggested, “Future clinical trials could be designed to investigate therapeutic properties of low pressure air “sham” hyperbaric exposures in brain-injured individuals.” (BIMA 150)

 

h. Several experienced HBOT researchers and clinicians not involved with DOD/VA clinical trials have published peer-reviews analyses criticizing the DOD/VA trial designs.

 

i. “Unfortunately, in the application of HBOT in neurologic issues, where lower pressures appear to be efficacious, what appears as a control group to those accustomed to indications utilizing HBOT at > 2.0 ATM, is actually a therapeutic group. This leads to confounding results and inappropriate abandonment of HBOT as a potentially valid therapy.” (Mychaskiw, Editor of the UHM Journal, “Editorial Perspective,” UHM 39(4), 2012.)

 

ii. “Hyperbaric oxygen and hyperbaric air have demonstrated therapeutic effects on mTBI/PPCS symptoms secondary to brain injury in 5 out of 5 peer-reviewed clinical trials. The current use of pressurized air (1.2-1.3 ATA) as a placebo or sham in clinical trials biases the results due to biological activity that favors healing.” And “Some of the recently published clinical trials are mischaracterized as sham-controlled clinical trials (i.e., sham = 21% O2/1.2-1.3 ATA), but are best characterized as dose-varying (variation in oxygen concentration, pressure applied, or both) clinical trials.” (Figueroa and Wright, “Hyperbaric Oxygen: B-Level Evidence in Mild Traumatic Brain Injury Clinical Trials.” Neurology 87(13): 1400-1406. 2016.)

 

iii. “It is worth pointing out that again even the control group is undergoing HBT, and all the patients showed improvements in working, delayed verbal and visual memory, and executive function.” (Eve, et al. “Hyperbaric Oxygen Therapy as a Potential Treatment for Post-Traumatic Stress Disorder with Traumatic Brain Injury.” Neuropsychiatric Disease and Treatment 12:2689+. 2016.

 

9. Cost. A significant deterrent to acceptance of hyperbaric oxygen therapy for first-line treatment of combat veterans with chronic TBI and/or PTSD is assumptions about the cost of treatment.

 

a. Hospitals with the United States typically charge between $1,800 and $10,000 for a single treatment of hyperbaric oxygen therapy with the mean price around $3,000 per treatment. At least one of the professional societies representing some hyperbaric medical providers strongly advocates with the US Government to maintain these lucrative pricing schemes. This successful lobbying effort has shaped the perception of government healthcare agencies that hyperbaric oxygen therapy would be too expensive to adopt regardless over efficacy.  

 

b. Hyperbaric Medicine International has conducted multiple assessments of the costs of treatment of hyperbaric oxygen therapy across different regions and metropolitan areas within the United States and across of variety of treatment settings. Even in the most expensive markets, one-hour treatments of hyperbaric oxygen therapy can be provided profitable at $250 per treatment. The more efficient clinics in lower-cost markets are able to profitably provide one-hour treatments for $100 per treatment.

 

c. US Government reimbursement through Medicare for a single treatment of hyperbaric oxygen therapy is typically between $200-250 depending on the location. US Military reimbursement through TRICARE insurance is around $400 per treatment.

 

d. The costs of hyperbaric oxygen therapy are very sensitive to economies of scale and decline rapidly with patient throughput. Volume-based cost savings could be easily achieved.

 

8. The use of HBOT as frontline treatment from chronic TBI and PTSD is endorsed by the majority of national professional hyperbaric medical associations in the US to include:

 

a. The International Hyperbaric Medical Association

b. The National Hyperbaric Medical Association

c. The American College of Hyperbaric Medicine

d. The American Association for Hyperbaric Awareness

e. Prominent individual members of the Undersea and Hyperbaric Medical Association

 

10. The point of contact for this memorandum is the undersigned at b.richards@hyperbaricmedicineinternational.org.

 

                                                                       

R. Benjamin Richards

President,

Hyperbaric Medicine International

 

 

Source Cited in this Memorandum:

Steenkamp, et al. “Psychotherapy for Military-Related PTSD: A Review of Randomized Clinical

Trials.” JAMA. 2015:314(5):489-500.

Steenkamp and Litz. “Psychotherapy for military-related posttraumatic stress disorder: Review

of the evidence.”  Clinical Psychology Review 33 (2013): 45-53.

Institute of Medicine. Treatment for Posttraumatic Stress Disorder in Military and Veteran

Populations: Initial Assessment. The National Academies Press: 2012.

Institute of Medicine. Treatment for Posttraumatic Stress Disorder in Military and Veteran

Populations: Final Assessment. The National Academies Press: 2014.

VA National Suicide Data Report 2005-2016 (updated)

VA/DOD Clinical Practice Guideline for the Management of PTSD 2017

“Out of Thin Air” ESPN The Magazine July 20 2015

“DOD, VA research again finds hyperbaric oxygen therapy ineffective at treating concussion-

related injuries.”https://www.research.va.gov/currents/winter2015/winter2015-9.cfm