What the <#$*&!> Is Wrong with the DoD/VA HBOT Studies?!!

Xavier A. Figueroa, Ph.D.

iron lungThe iron lung was a desperate and ingenious solution for the ravages of polio. It allowed those infected and affected by the polio virus to continue to live, even with the loss of nerve function to their diaphragm.

It was only with the development of mass vaccination campaign against polio that the iron lung was made obsolete or rare.

Vaccination was once thought to be unscientific, unproven and dangerous technology, yet it is standard today and has saved the lives of billions of people. HBOT is at a similar cross-road with the treatment for TBI.

For all of you that have come back to follow up on the last blog post, thanks for sticking around. For the new people here, it might be worthwhile to go back to our first post in this series here.

Here we are, back at it again, trying to understand what the *bleep* is going in with hyperbaric oxygen therapy (HBOT).

On the last blog post, I mentioned that we were going to discuss two major topics:

  1. The relevant biological data on how hyperbaric oxygen therapy (HBOT) works.
  2. The three remaining DoD studies using HBOT to treat traumatic brain injury.

    1. Cifu DX, Hart BB, West SL, Walker W, Carne W. The Effect of Hyperbaric Oxygen on Persistent Postconcussion Symptoms. J Head Trauma Rehabil. 2013. (DoD) (USA)
    2. Walker WC, Franke LM, Cifu DX, Hart BB. Randomized, Sham-Controlled, Feasibility Trial of Hyperbaric Oxygen for Service Members With Postconcussion Syndrome: Cognitive and Psychomotor Outcomes 1 Week Postintervention. Neurorehabil Neural Repair. 2013. (DoD) (USA)
    3. Cifu DX, Walker WC, West SL, Hart BB, Franke LM, Sima A, et al. Hyperbaric oxygen for blast-related postconcussion syndrome: Three-month outcomes. Ann Neurol. 2014;75(2):277-86. (DoD) (USA)

Now, before I get started, the intent of these blog posts is to provide as clear an analysis of the existing data on HBOT used for brain injury as possible (without having anyone fall asleep!). We are here to simplify, teach and untangle the morass of studies, spin and myths that have arisen over time with HBOT, and have a little fun in the process.

Onwards to the nerdy but fundamental stuff!

The Effects of Hyperbaric Oxygen on the Body

Effects_HBOTWhat do we breathe, day in and day out? It is a mix of Oxygen/Nitrogen at roughly 21%/79%. Every cell in our body utilizes oxygen to metabolize (build, destroy and maintain). Oxygen is an essential metabolic component that is used in over +5,000 unique pathways in the body. We even have a very elegant and complex system to capture oxygen from the air (our lungs and the red blood cells; see image below).

Red blood cells in our body are specialized oxygen capturing cells. They are completely dedicated to do two things: capture oxygen from the lungs and remove carbon dioxide from the body. All the oxygen that our cells use is delivered by the red blood cells under normal circumstances.

In healthy adults and children, the red blood cells are 97-98% saturated with oxygen. When we breathe pure oxygen (100% oxygen versus air), we can reach 99% saturation levels. The only know and safe method to increase oxygen levels in the body is through hyperbaric oxygen.

For those that want a little more detail on how HBOT works, you can go to our very first blog post here.

In the simplest terms possible, an HBOT chamber works in the same way a soda water maker works:  It dissolves a gas into the water of the body!  In the case of an HBO chamber, the gas is 100%, USP Medical grade oxygen.

When you dissolve oxygen into the water portion of the body (the plasma), you are adding to the overall amount of oxygen that can be delivered into the tissues.  Why?  Remember that in order for us to live and breathe, we need the red blood cells to deliver the oxygen to our tissues. Very little oxygen is dissolved into the plasma of the blood under normal circumstances (At sea level, were pressure is 1.0 ATA, we breathe 21% Oxygen/79% Nitrogen. That is “normal”). When we increase the pressure and/or increase the amount of oxygen, we can increase the amount of dissolved oxygen in the plasma. This increase allows for more oxygen to reach the tissues.

How_It_WorksHow much difference can there be when we breathe in a pressurized environment?  Well, quite a bit.

Hemoglobin has an upper limit in the amount of oxygen it can carry. The theoretical maximum, if the red blood cells were 100% saturated (they never are) would be 203 mL oxygen/L of blood (Upper half of Table 1). Even with increases in the amount of oxygen and pressure, hemoglobin has a finite carrying capacity for oxygen. All the excess oxygen is provided by the dissolved fraction in the plasma (the lower half of Table 1). Even a modest pressure increase of 1.5 ATA (the equivalent pressure experienced underwater at 16 feet) increases the total amount of oxygen to the tissues to 228 mL Oxygen/L blood (a 14% increase in total oxygen).

Gas_Mix_ChartWhat does the body do with that increase in oxygen? A lot.

  • Increases the production of stem cells (both local and global) [1-13].
  • Induces a state of analgesia (hyperbaric treatments reduce the sensation of pain) [14-18].
  • Inhibits inflammation (HBOT stops inflammatory cells from entering the site of injury) [19-26].
  • Reduces swelling (HBOT causes blood vessels to constrict, reducing edema) [27-30].
  • Protects cells from dying (inhibits apoptosis and necrosis) [31-37].
  • Promotes new blood vessel growth (angio- and vasculogenesis) [5, 38-47].
  • Increases cellular metabolism [48-54].
  • Accelerates bone knitting and wound healing [41, 55-65].
  • Increases the number of enzymes that stop reactive oxygen species (oxygen radicals) [66-72].

Most of the effects we see with HBOT are due to signaling from reactive oxygen species (OH-, NO•, H2O2), changes in gene/protein expression and increased mitochondrial respiration. The production of oxygen radicals are essential for the effects we see in HBOT as they are the signals for cells to adapt or change. Other effects are still not fully understood, such as why HBOT increases red blood cell rigidity and blood viscosity [73, 74]. Hyperbaric oxygen induces a profound change in cell behavior, gene expression and healing, all by increasing the total amount of oxygen in the body and the pressure exerted on cells.

Going the Other Way With Oxygen

So, if we see a reduction in oxygen concentration, do we see biological effects on the body, too? 

Absolutely!

Hypoxia is the term used when the overall oxygen level drops below 21% or the atmospheric pressure is less than 1.0 ATA (with 21 % oxygen). Hypoxia induces a number of changes in the body, mostly to counteract the loss of oxygen, such as an increase in red blood cells [75-78] and the switching of gene expression in blood cell precursors [79] that are better able to grab oxygen.

Hypoxia has been used to prepare high performance athletes in endurance training [80] and may have reparative properties in preconditioning. Indeed, preconditioning may induce protection against other injuries such as stroke and TBI [81]. The role of oxygen is diverse and still poorly understood.

The reason to bring up hypoxia in this blog post is to demonstrate a simple fact: The body and brain are sensitive to changes in oxygen concentration. It is this ability to respond to those changes that makes HBOT such a powerful treatment tool. More important to the discussion, is the fact that a placebo or shams are nearly impossible to simulate with HBOT trials, let alone with a pressure treatment of any kind.

How Much Oxygen/Pressure Is Enough?

Would_You_BelieveWait a minute?!!

Did you say it is nearly impossible to simulate a sham treatment?

Yes.  Cells in the body are finely attuned to changes in oxygen concentration and pressure changes.

As we have seen, changes in oxygen concentration and gas pressure can affect the body. But how much is required to show a detectable level of change?  The Wolf et al. study [82] showed that modest changes in pressure (an increase of 0.2-0.3 ATA) with 21% Oxygen was sufficient to improve symptoms associated with a TBI. Remember that the oxygen dose in the “sham” dissolved ~30% more oxygen into the plasma than just breathing room air. This was enough to induce a significant change in symptoms scores in two independent assessment scales.

In the research literature, changes smaller than 0.1 ATA have induced growth factor production and an increase in cell division [83] in epithelial  cell cultures when compared to the control cultures. Studies of smooth muscle cells derived from human aorta reported that 1.1 ATA of room air (an increase of 0.1 ATA) was sufficient to increase growth rates [84, 85]. Cells can sense these subtle changes.

The cell culture data is supported by evidence from studies of lung function and oxygenation with chronic obstructive pulmonary disease, cystic fibrosis, pulmonary fibrosis and pulmonary hypertension (thromboembolic). Moving patients from cities located 800 meters above sea-level (0.91 ATA) to locations 400 meters below sea-level (1.05 ATA) improved oxygenation and lung function [86, 87]. In a recent pilot study looking at the effects of SCUBA diving on veterans, a large reductions in post-traumatic stress disorder (PTSD) symptoms were observed [88], with pressure ranges from 1.3 to 1.5 ATA with Nitrox (32-36% Oxygen/ 68-64% Nitrogen). Not only do small changes affect the cardiopulmonary system, they appear to affect the central nervous system in a manner that promotes repair to the brain.

So, if small changes in air pressure can have a measureable effect in cell behavior and human health, why would a “sham”, as described by the Wolf et al. study, be a “sham”? 

Simple:  It can’t. REMEMBER:  A "sham" is a treatment or procedure that is performed as a control and that is similar to but omits a key therapeutic element of the treatment or procedure under investigation.

The positive outcomes of the Wolf et al. study are due to the fact that oxygen and/or pressure have a biological effect and probably why the remaining DoD/VA sponsored studies used a different control group:  A sham that controlled for oxygen concentration (10.5% Oxygen at 2.0 ATA=21% Oxygen equivalent) to a very fine degree.

Pressure still remains to be addressed: how much effect does it have in promoting healing?  This remains an under-investigated area. All these controls on variables are difficult, but necessary to address. The sham treatment was not cheap or easy to achieve, which explains why many of the previous reports of TBI treatment with HBOT do not use a placebo (do you have a spare $1 million for the sham treatments?)

The DoD/VA Sponsored Clinical Trial

Let’s take a look at the study design of the single clinical trial that was published as three independent articles. Yup, the authors got a lot of mileage out of one study.

  1. Cifu, D.X., et al., The effect of hyperbaric oxygen on persistent postconcussion symptoms. J Head Trauma Rehabil, 2014. 29(1): p. 11-20.
  2. Walker, W.C., et al., Randomized, Sham-Controlled, Feasibility Trial of Hyperbaric Oxygen for Service Members With Postconcussion Syndrome: Cognitive and Psychomotor Outcomes 1 Week Postintervention. Neurorehabil Neural Repair, 2013.
  3. Cifu, D.X., et al., Hyperbaric oxygen for blast-related postconcussion syndrome: Three-month outcomes. Ann Neurol, 2014. 75(2): p. 277-86.

DoD_TestingThe single clinical trial design is graphically represented in the figure above.  Study participant were assigned into three different treatments groups (10.5 % Oxygen, 75% Oxygen and 100% Oxygen). The participants were given the exact same pressure (2.0 ATA) but given different oxygen mixtures to simulate different treatments. This single clinical trial did not attempt to replicate previous reports but approximated the process. This single clinical trial did not try to match what had been done in the previous report by Wolf et al. or other studies.

The three DoD/VA sponsored articles reported on one group of Marines (N=61(83,84); N=60(85)). These articles reported on the outcomes of a follow-up analysis (post-HBOT treatment) at 1 week, 3 months and an independent analysis of the secondary outcome measures. The two primary measures they looked at were the Rivermead post-concussion questionnaire (RPQ) and the PTSD Checklist-Military Version (PCL-M). The Walker et al. paper [89] looked at secondary outcomes measures of neurocognitive performance, which we will not discuss or go into in this blog. Secondary measures are more complex and dependent on multiple neuromuscular and neurocognitive pathways.

The RPQ is a self-administered test that asks the study subject to rate symptoms associated with a TBI on a 0 to 4 point scale. The worse the symptoms severity the higher the score the participant should assign. The total maximum for points in the RPQ is 64. Higher is worse, lower is better.

The PCL-M is another self-administered test that rates PTSD symptoms on a 1-5 scale with 17 questions and has a total maximum value of 85 points. Again, higher is worse, lower is better.

In each of the articles by Cifu et al. and Walker et al., the conclusions from the authors were that there was no effect from HBOT…nothing, zero, zilch, nada. Not even the supposed placebo or Hawthorne effect showed up in any of their trials.

So, how does the Cifu study [90, 91] compare to the Wolf et al. study [82]?  Please remember that all the information is taken directly from the published data and not from “unnamed sources”. We just arrived at a very different set of conclusions from the exact same data.

Wolf_vs_CIFUJust remember conclusions and discussions are like opinions: everyone has one, but it needs to be backed-up by data. Although the Cifu et al. study concludes that the results are clinically non-significant, the aggregate PTSD scores were significant (right side), just like in the Wolf et al. study (left side).

The lack of change in the other conditions for the Cifu study (75% and 100% Oxygen) could be due to insufficient number of study participants. The Wolf et al. study had 6 and 3 more study participants per group (N=24 for the “sham” and 2.4 ATA group) than the Cifu study (N=18 for the 75% oxygen and N=21 for the 100% group). Given how close the results were between both studies, the addition of 6 and 3 more study participants by the Wolf et al. study could explain the difference seen between both articles.

Another factor at play is the relatively high pressures used by both Wolf and Cifu. Around the world, scientists who have been doing research with HBOT for decades have consistently pointed out that lower pressure treatments, ideally 1.5 ATA or lower, should have greater efficacy, as higher pressures of oxygen may actually be too harsh for the injured brain. For Cifu and Wolf, the HBOT intervention doses were at or above 2.0 ATA in pressure. The lower “sham” treatment was much closer to the ideal pressure that proponents of HBOT normally use for neurological treatments [92-95].

Now, what is really very surprising with the Wolf et al. study is the  effect seen with hyperbaric air (1.3 ATA, 21% Oxygen), which critics claim is a placebo or Hawthorne effect. The effects were large (41% difference between pre and post testing on the RPQ), but they were not reported as significant in the aggregate scores, although 9 symptoms showed significant differences in the “sham” treatment group. The PTSD scores are also very close in overall effect between pre and post treatment (16% improvement in the Wolf study and 14% in the Cifu study; both statistically significant when compared between pre and post treatment.)

The changes in RPQ and PTSD score are in agreement with another published report. Harch et al. [93] treated 15 Marines with bomb-blast induced mTBIs and produced results that were in agreement with the Wolf and Cifu studies.

Wolf_CIFU+HarchThe conclusion of Cifu et al. that HBOT is ineffective on mTBI is not supported by the data they acquired. Although the RPQ results from Cifu et al. are different from the Wolf and Harch studies, the PTSD changes are significant and in agreement with previously published outcomes. The RPQ results of Cifu et al. are puzzling, but could be due to the small size of the study sample that was used. Obviously this is an area for research, but research can be performed while treating. Still, the overall trend between these three studies favors a clinically positive outcome with HBOT treatment.

Even more intriguing is the following thought: Was the number of treatments sufficient to produce the best outcome? Thirty, 90-minute sessions were done with the Wolf et al study; forty 60-minute sessions with the Cifu et al. and Harch et al. studies (2700 minutes vs. 2400 minutes of HBOT treatment). Would more sessions produce greater improvements? 

We don’t know. Only a limited number of HBOT case reports demonstrate improved outcomes with more than 40 treatments [96].

So What?! It’s Still Just a Placebo!

The lack of a placebo or sham group with the majority of HBOT studies has always been held up as a major deficiency when it comes to the results obtained with neurological injuries. The placebo effect is a well recognized component of medical treatment, sometimes superseding the effects of the actual treatment. Controls are an essential component of most clinical trials, but sometimes the controls are just not feasible or too costly to set up (especially with HBOT). Placebos are not always used (cancer studies compare new drugs or procedures against standard of care all the time) and comparing pre and post measures, although not deemed the most stringent, are acceptable and valuable in medicine [97].

Wolf_CIFU_Harch_No_PlaceboBut the placebo objection may be a superfluous point. What was overlooked in the discussion of Cifu et al was the lack of any change in the 2.0 ATA, 10.5% Oxygen group (the 21% Oxygen equivalent). The Cifu et al study clearly demonstrated that being in the presence of a hyperbaric chamber did not induce a placebo effect in the study participants. The increased attention by the study technician and doctors did not produce a Hawthorne effect on the study participants, either (see graph above). On the contrary,

“…we found that the sham and the 1.5 ATA equivalent groups demonstrated nonsignificant [underline is mine] increase (worsening) in their raw total RPQ scores,…” (P.18) [91]

The 2.0 ATA, 10.5% Oxygen group did not produce any statistically significant changes in the RPQ or PTSD scores (placebo or nocebo), as would be expected when simulating a 21% oxygen equivalent. The sham control was a real sham control! The lack of a placebo effect and the significant effect found with the PTSD results renders the PTSD effect highly significant for the Cifu et al. study.

The concerns and criticisms leveled at the earlier HBOT studies for a lack of a sham or placebo control are greatly diminished by the Cifu et al. report. Apparently being placed inside a pressure chamber for an hour every day for 5 days does not promote the sorts of psychobiological signals that can initiate spontaneous self-healing (like a placebo should). But it does point to the fact that we are witnessing a real and powerful neurological repair/reactivation mechanism with HBOT.

How Science and Medicine Move Forward

World_Looks_DifferentWhen we talk about scientific and medical research, first and foremost we are talking about people. We all carry some sort of bias when we look at the world and try to make sense it.

Our personality, education, feelings and attitudes always alter how we perceive facts about the world. Everything we perceive around us is always filtered by the glasses we wear in our lives. Take for example the picture of the rose colored glasses. If you wore such glasses (and forgot that you were wearing them) you would come to the objective conclusion that the sky was indeed pink. Others not wearing glasses (or other colored glasses) would disagree with you and be equally valid in their objections (what a case of mass forgetfulness about glasses!)

Proponents and opponents of HBOT use different sets of filters when analyzing data and evaluating information. In many cases, researchers only see and find what they are looking for. I can safely say that as a former skeptic of the field of HBOT, I only reviewed or selected information that supported my preconceived belief about HBOT: HBOT had limited utility and could not be used for neurological treatments. Heck, I would gloss over the data and rely on the conclusion of the author’s (a very bad thing for any scientist to do. Always check over the data…always.)

It was only when I was forced to review the literature, dig through the archives and immerse myself in the decades of research publications that my bias regarding HBOT began to shift. There is an immense amount of basic biological information, of very high quality, that reports the positive and negative effects of HBOT. Decades of case reports and clinical trials point to an overall positive effect of HBOT on a wide variety of neurological conditions (stroke, TBI, PTSD). Even the reports that claim no effect, when you look them over in detail, turn out to have significantly positive results!  Bias can crop up in unexpected ways. Conclusions in published reports leave a lot of room for opinions to be applied and given the patina of fact. Unfortunately, the stakes in this field are very high in terms of human cost and the promises made by a Nation to all it serving members, past and present.

Why TBI Treatment is Literally Life-And-Death

CemetaryA large fraction of the current epidemic of military suicides (22+ service members a day take their lives) are more than likely due to misdiagnosed TBI and PTSD. Although the DoD and VA have spent billions (actually, $ 9.2 billion since 2010) trying to diagnose and treat the problem, the epidemic of suicide and mental illness are larger than ever. Drug interventions are woefully inadequate, as more and more studies continue to find that pharmacological interventions are not effective in treating the varied symptoms of TBI or PTSD [98-100]. In many cases suicide of veterans have been linked through prescribed overmedication [101, 102].

On top of the military epidemic there is a large existing civilian population of TBI survivors (now ~10 million in the US alone). How many in the civilian population take their lives because the pain is just too much?  How many can’t work because their brain injury won’t allow them to work?  We don’t know because we, as a society, are just starting to realize how prevalent brain injuries have become. And how many care-givers are equally and negatively affected by caring for their brain injuried relatives? And what is the COST of continuing to deny a safe and effective treatment that is constantly mischaracterized?

HBOT is a safe and effective treatment with low-to-no side effects (after all, even the DOD accepted the safety of HBOT back in 2008). Access to HBOT is available within most major metropolitan centers, but the major sticking point is money. Who pays for the treatment?  Those that are willing to pay for it out-of-pocket and state taxpayers picking up the tab for brain-injured service members forced back into society without sufficient care (or forced out on a Chapter 10, when it should have been treated as a medical condition).

The continued reports of studies like the DoD/VA sponsored trials allow denial of coverage and provide adequate cover for public officials to claim that more study needs to be done. As we have seen, the conclusions of the authors of the DoD/VA sponsored studies downplay the results of effectiveness. There are sufficient studies (and growing) showing a strong positive effect of HBOT in TBI. More will be forthcoming.

The cardinal rule of medicine is “First, Do No Harm”. With HBOT, this rule is satisfied. Now, by denying or blocking a treatment that has proven restorative and healing effects, countless physicians and organizations, from the VA to DoD, Congress and the White House, could be accused of causing harm. Never mind how many experiments “fail” to show results (even when they actually show success). Failure to replicate a result is just that…a failure to replicate, not a negation of a treatment or other positive results. You can’t prove a negative and there are many clinical trials that do show the efficacy of HBOT.

The practice of medicine and the use of HBOT should not be dependent on the collective unease of a medical profession and the dilatory nature of risk adverse politicians, but on the evidence-based results that we are seeing. Within the VA, there are hard working physicians that are trying to change the culture of inertia and implement effective treatments for TBI and PTSD, using evidence based medicine. Unfortunately, evidence-based medicine only works when we accept the evidence presented to us and not on mischaracterized conclusions of a single study (or any other study). Our veterans, our citizens and our communities deserve better than what we are currently giving them: bad conclusions, institutions too scared to act in the interests of the people it serves and too many physicians unwilling to look at the accumulated evidence.

HBOT works for the treatment of mild-to-moderate TBI and PCS.

Treat now.

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6 comments for “What the <#$*&!> Is Wrong with the DoD/VA HBOT Studies?!!

  1. July 25, 2014 at 4:55 pm

    We are just glad there is SOME HOPE for our veterans w TBI. And that Dr. Figueroa is speaking out!

  2. July 6, 2014 at 7:14 pm

    Thank you, Dr. Figueroa, for this thorough and informative article!

    I have had a TBI for over 30 years. I was in a HBOT chamber, years ago, in FL, for two days, which I paid for on my own. I had positive results in my scans and memory.

    When I returned to Rochester, NY, where I live, I begged my doctor and insurance to approve that form of treatment for me but I was declined. Your article gives me renewed hope for this type of research and for others suffering with TBI. I would be honored and blessed to interview you as a Special Guest on the Brain Injury Radio show. I host the Thursday 10pm EST "From Flawed to Fantastic" show.

    Your colleague, Dr. Maria Romanos, was recently interviewed by my colleague, radio host Kim Justice, who does the Wednesday evening show on the same network.

    Fantastic Frank Johnson

    • Dana E. Harper
      August 15, 2014 at 1:07 pm

      How do we tune you in when the interview is scheduled?

  3. July 3, 2014 at 11:00 pm

    It is unbelievable the DoD and VA are still dragging their feet on HBOT. The treatment has been around since the 40's and to my knowledge, no one has ever recorded adverse affects while following standard protocols for the various indications. I have completed nearly 240 treatments the last 4+ years for serious traumatic brain injuries from my 9 NFL-caused emergency VP shunt brain surgeries, which include having gran mal seizures. Not only have I NOT had an adverse reaction, my micro cognitive memory scores improved over 15% in the first 2 years alone (all documented by the way!). And I quit the four dementia medicines I was on: Arricept, Namenda, Resperdal & Lexapro.

    We owe it to our veteran heros to offer any and all available treatment after their service. Everyone is concerned with liability. Who is liable for the several veteran suicides which occur daily?!!

    Shame on the DoD and VA for dragging their heels.

    George Visger

    The Visger Group

    Traumatic Brain Injury Consulting

    • Kerry Mischka
      July 4, 2014 at 7:38 pm

      I completely concur with everything that George Visger has stated… Although my severe TBI was the result of a car accident, I wonder to this day if HBOT could help my major depression. It is impossible to know, because I am on disability now and cannot afford it. It's almost like being murdered TWICE!!! What is going on with this world?

      Kerry Mischka

    • don summerlin
      July 27, 2014 at 1:43 pm

      Damn straight

Comments are closed.