**7. NOTE BENE: the sham and placebo controversies in HBOT**

Expert commentary on the issues surrounding the HBOT "sham" revealed the fundamental flaws in the DoD/VA/Army research [60]. In a sham treatment, the researcher goes through the motions without actually performing the treatment. The intent is to have an inert or medically inactive procedure or substance used to compare results with active substances. A placebo is often used with half the people in a drug trial to help show whether the drug being studied is more effective than an inactive "sugar pill." The results of each group are compared. [NOTE: Debate continues on whether it is possible, under the circumstances of HBOT treatment, to construct a true sham-controlled study.]

The placebo effect is very difficult, if not impossible, to prove in HBOT studies on patients suffering from PPCS that accompanies TBI. Further studies cannot ignore a placebo, but the overwhelmingly positive effects in so many, and so widely different studies, make the likelihood of a placebo unusual. [NOTE: when physiologic changes, such as both structural and functional increases in brain mass and activity are noted – as they were not in DoD/VA/Army studies, since they refuse to perform such objective science – it is impossible to ascribe the changes to the placebo effect. In numerous of the non-government published peer-reviewed studies on the use of HBOT for TBI, however, such positive transformations have been noted in the treated patients. Objective evidence of changes are shown in peerreviewed research using such methods as SPECT scans, RightEye, qEEG, etc. Those changes can only be the effect of exposure to HBOT [61].]

A worldwide surge of challenges arose when the DoD/Army/VA studies purported to use a sham in their studies and reported that HBOT "does not work." [62] International researchers and authorities could read that both the data and the discussion in all the purported randomized controlled studies said virtually the same thing: "Both intervention groups [sham and treated] demonstrated improved outcomes compared with PCS care alone" [63] Dr. Pierre Marois spoke for many: "By definition "sham" is "something false or empty". Hyperbaric treatments at 1.2 ATA substantially increase the amount of dissolved oxygen in the blood and simultaneously induce cascades of metabolic changes and genes activation. Therefore, the supposedly sham treatment of Miller's study is not close to being a placebo." [64].

The clearest example to date that demonstrates that these gas/pressure combinations have a therapeutic effect on brain injury models is the article by Malek et al. [65] They demonstrated that HBO (100% O2) and HBA (21% O2/79% N2) were equivalent in protecting neurons after transient forebrain ischemia in the gerbil using 2.5 ATA. The role of a potential placebo effect was ruled out in this study and demonstrates the activity of HBO and HBA in a neurologic injury model.

The certainty that hyperbaric medicine begins with any increase in oxygen concentration and/or pressure is further substantiated by on-going work at the University of Wisconsin [66]. Animal studies already show a significant increase in mobilized stem progenitor cells and decrease in Inflammatory cytokines when HBOT and HBAT (room-air) are applied at pressures as low as 1.2ata. Together these findings support the likelihood of biologic activity, consubstantial with HBOT, being activated at much lower dose of hyperoxia than previously postulated. Those results, coupled with decades of experiments by the US Navy and US Air Force [67], demonstrate that the Army's and UHMS's claims that hyperbaric medicine only occurs at pressures higher than 1.4ata are fallacious. Any increase in oxygen concentration and/or pressure is a medical intervention.

The USAF TBI study used the Agency for Healthcare Quality and Research recommendations for future HBOT research for TBI. One pertinent comment was the following: "Whether placebo-controlled trials are necessary to evaluate HBOT has received a great deal of attention in discussions about HBOT. Participants on all sides of this debate make the assumption that an "evidence-based" approach implies devotion to double-blind, placebo-controlled trials without regard to practical or ethical considerations. This assumption is false. Double-blind, placebo-controlled trials are the "gold standard" for government regulators overseeing the approval of new pharmaceuticals, but not for clinical decision-making or insurance coverage decisions. Evidence-based clinical decisions rely more heavily on comparisons of one treatment to other potentially effective therapies, not to placebos." [68].
