Selasa, 29 September 2015

Hyperbaric Oxygen Therapy for Post-Concussion Syndrome: Contradictory Conclusions from a Study Mischaracterized as Sham-Controlled

Journal of Neurotrauma J Neurotrauma. 2013 Dec 1; 30(23): 1995–1999. doi: 10.1089/neu.2012.2799 PMCID: PMC3837504 Hyperbaric Oxygen Therapy for Post-Concussion Syndrome: Contradictory Conclusions from a Study Mischaracterized as Sham-Controlled Paul G. Harchcorresponding author Author information ► Copyright and License information ► This article has been cited by other articles in PMC. Dear Editor, The recent study by Wolf and associates1 has affirmed the effectiveness of hyperbaric (oxygen) therapy in the treatment of patients with mild traumatic brain injury (mTBI)/post-concussion syndrome (PCS) and post-traumatic stress disorder (PTSD). This affirmation emerges from analysis of the study data, rather than from the study's stated conclusions. Mischaracterized as a sham-controlled (placebo implied) design, the study errs in concluding that “HBO2 at 2.4 ATA pressure had no effect on post-concussive symptoms after mild TBI.” A reconsideration of the science of hyperbaric therapy reveals that the study by Wolf and colleagues1 is neither a sham nor placebo-controlled study. Rather, it is a Phase II study of two composite doses of hyperbaric therapy that demonstrated significant improvements in PCS and PTSD symptoms at the 2.4 atmospheres absolute (ATA) pure oxygen dose as well as the low-pressure 1.3 ATA air/oxygen dose. Hyperbaric (oxygen) therapy (HBOT) is a combination product of increased pressure and increased pressure of oxygen above ambient atmospheric pressure, according to scientific principles and current Food and Drug Administration understanding. Although traditionally misdefined as a treatment for diseases based on the increased oxygen component alone (>1.4 ATA oxygen),2 it is a treatment with hyperbaric pressure and hyperoxia for disease processes2,3 whose primary targets are oxygen and pressure sensitive genes.4–6 Evidence for this dual component nature of hyperbaric therapy is found in the 351-year history of hyperbaric air therapy7 and the recent 60-year history of animal, human tissue, and human experiments that have documented biological effects of pressure, especially in the micropressure range8,9 of the Wolf and coworkers1 “sham” control group and the control groups of the Department of Defense (DoD) HBOT TBI studies.10 Examples of this literature are listed in Tables 1 and ​and22.11–28 Pressures from 1.21–1.26 ATA delivered to human29–31 and 1.0015–1.015 ATA to animal endothelial cells,32 and 1.10 and 1.20 ATA to human platelets33,34 for 15 min or longer have caused the elaboration or suppression of vasoactive substances,29–31 and the elaboration of growth factors,32 inflammatory mediators,33 oxidation products,34 and cell proliferation.32 This literature and biological effects from a 1-min exposure to 1.09 ATA or 3 min at 1.04 ATA17 inform the symptomatic improvements noted in the Wolf and associates1 “sham” group, as do benefits of hyperbaric air on spinal function and PTSD in spinal cord injured veterans during a SCUBA diving training course.28 Table 1. Table 1. In vitro and In vivo Studies on Hyperbaric (Pressure and Oxygen) Effects Table 2. Table 2. Continuation of Table 1 In vitro and in Vivo Studies on Hyperbaric (Pressure and Oxygen) Effects To meet the definition of a true sham,35 any controlled experiment to test HBOT must omit in its control groups the active ingredients of increased pressure and hyperoxia. The Wolf and colleagues1 “sham” control group does neither; rather, it includes both. The “sham” control group is exposed to 1.3/1.2 ATA of air, which is a 20–30% increase in pressure and 28–43% increase in plasma oxygen36 over sea level plasma oxygen and a slightly greater increase over San Antonio (hyperbaric treatment site) atmospheric pressure.37 Because pressure and hyperoxia are non-inert—i.e., are biologically active—the Wolf and coworkers1 “sham” control group cannot test for placebo effects; placebo/placebo response is defined as “The effect that an inactive or inert substance has on a clinical condition.”38 Wolf and associates1 allude to possible bioactivity of the control group, but the lack of discussion indicates a lack of appreciation that the presence of hyperoxia and pressure negate Wolf and colleagues1 characterization as a “sham” control group. Restating the design of the Wolf and coworkers1 study, it is a Phase II comparative dosing study of two composite doses of hyperbaric therapy (four actual doses), compressed air (low dose increased pressure and increased oxygen), and compressed oxygen (high dose pressure and high dose oxygen). Both doses were efficacious in the treatment of mTBI PCS and PTSD. The PTSD data demonstrated 18% and 22% reductions in the PCL-M (interpolated from the Figure 1 graph in Wolf and colleagues1) in the HBOT and “sham” groups, respectively, after 30 2 h treatments. These reductions compared favorably with five other therapies/six studies for PTSD39–44 that used the PCL-M (6–45% reductions). The PCS ImPACT data were similarly significantly improved in both groups, but it is the disparity in component and pattern change on the ImPACT results for the two groups that underscore the dual dose design of the study and efficacy of these two doses: 10 IMPACT scores significantly improved in the low dose group compared with 2 in the high dose group. For all 22 items of the ImPACT, 20 improved, 1 was unchanged, and 1 was worse in the low dose group, while 11 improved, 3 were unchanged, and 8 were worse in the high dose group (Table 1 in Wolf and associates1). The pattern of composite ImPACT scores over the course of the study is also different for the two groups (Figure 2 in Wolf and coworkers1). Subjects in the low dose group experienced initial deterioration then steady improvement until the end of the study while the high dose group showed improvement then a steady reversal of benefit to near baseline, followed by rebound improvement 6 weeks post-treatment. This sinusoidal trajectory in the high dose group suggests a differential dosing effect and possibly an overdose response with partial recovery after removal of the high dose, and is consistent with the worsening of eight scores in this group. It is also consistent with a phenomenon previously described and documented in multiple cases of HBOT treatment of chronic cerebral disorders.45 Since the initial submission of this Letter to the Editor, Wolf and colleagues1 have now confirmed this overdosing effect on PCS symptoms in the 2.4 ATA group in a subset analysis presented on June 14, 2013.46 This demonstration of low dose effectiveness and progressive high dose overdosing is also evident in other animal and clinical studies.25,47,48 Wolf and associates1 list multiple possibilities for the improvements in PCS and PTSD, including “placebo, Hawthorne effect, the natural resolution of symptoms over time,…exposure to sham-control partial pressures of oxygen and nitrogen,…and change in living environment…and daily routine.” While 30 chamber experiences and change in living environment and daily routine are theoretical placebo contributions, the myriad standard clinical pressure/hyperoxia2 and micropressure-induced biological effects demonstrated in both animal and human studies8,9 and Tables 1 and ​and22 suggest that placebo is not the majority effect. At the same time, placebo effects were also present in all six of the aforementioned PTSD/PCL-M studies. Hawthorne effect is also theoretically possible, but the foundation/proofing of the Hawthorne effect has been undermined by re-evaluation of the initial data set.49 Symptoms in veterans with TBI and PTSD, in fact, do not resolve over time, as acknowledged by Wolf and coworkers1 in their conclusion “improved more than would be expected greater than 6 months after mTBI,” and reports on persistent care and even worsening of condition over time in the Veterans Affairs system.50,51 All of the explanations by Wolf and colleagues,1 however, do not explain the disparity in component and pattern change in the ImPACT data and transient overdose effect in the high dose oxygen group. If placebo, Hawthorne effect, and other non-biological etiologies are causally entertained, why wouldn't the component and pattern changes be identical in the two groups? The last choice, effects of increased partial pressures of oxygen and nitrogen, seems most plausible as the dominant etiology for the statistically significant improvements in both groups, but it is not necessarily nitrogen pressure, but pressure, per se, that is involved. Wolf and associates1 state, however, “…it seems very unlikely such a minimal dose of oxygen and nitrogen could influence brain function favorably.” The preceding argument and studies in Table 1 and ​and22 suggest the opposite. In conclusion, the study by Wolf and colleagues1 is a non-sham/non-placebo/non-controlled Phase II two composite dose study of hyperbaric therapy (hyperbaric air and hyperbaric oxygen) in U.S. veterans with PCS from mTBI with or without PTSD. The study demonstrated significant net improvements in PCS and PTSD symptoms with both doses of hyperbaric therapy, improvements that are similar in magnitude to other therapies for PTSD and greater than would be expected for PTSD and PCS over time without treatment based on the natural history of the diseases and published persistence rates in veterans.50,51 Their results are thus comparatively effective to other existing therapies for PTSD and possibly PCS of mTBI. If further evidence for the efficacy of hyperbaric therapy in mTBI PCS and PTSD is deemed necessary, as alternatives to the “pivotal” trial,10 and in light of nearly $1 billion dollars of research and development money already spent by the Department of Defense (DoD) on research seeking effective treatments for TBI and PTSD, this author would suggest two options: (1) Abandoning the pursuit of a “sham” hyperbaric control group and prioritizing the data from the wait-list group in the DoD HOPP study10 (Wolf and coworkers1 mention a wait-list group in their recommendations for future studies). This option is based on the physical impossibility of controlling for a chamber experience because of the inability to control for pressure (no method to duplicate middle ear pressure changes without placement of pressure equalization tubes and no commercially available mechanisms to duplicate adiabatic heating and cooling on compression and decompression). Continued attempts at a “sham” pressure control group will only further confuse the scientific and lay community; and (2) an economical Civilian/DoD/Veterans Affairs (VA) off-label networked hyperbaric treatment program using a Medicare-like Coverage with Evidence Development52 pathway. The safety of HBOT 1.5 and even higher doses is not in issue; hyperbaric oxygen therapy in mTBI PCS/PTSD has satisfied one of the cardinal rules of medicine, “First, Do No Harm.” The Coverage with Evidence pathway would allow the DoD and VA to immediately begin treating active military and veteran casualties with hyperbaric therapy in both military and civilian clinics/hospitals such that this health and quality of life improving therapy can be delivered without further delay to the hundreds of thousands of injured PCS/PTSD casualties and veterans now in need. 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