Dear Laureau, et al,

The conclusion of the Laureau, et al1 review, that “…there is high-level evidence that HBOT does not improve motor function, cognition, and functional performance in children with CP,” is a scientifically invalid conclusion. The review’s analysis is based on the historically flawed understanding of hyperbaric oxygen therapy (HBOT) and hyperbaric therapy (HBT). HBOT and HBT, according to the scientific understanding2 and the FDA’s classification of HBOT as a medical gas,3 are composed of two active components, increased barometric pressure and increased oxygen pressure, with possibly a third component, inert gas pressure, when the FiO2 is less than 100%.2 The authors acknowledged this fact in their introduction: “HBOT is part of the hyperbaric therapies (HBT) overall, consisting in the administration of pressurized gas with variable oxygen content and pressure.” This scientific fact was ignored and Laureau, et al1 proceeded to analyze the studies as randomized controlled trials despite lack of control of any of these components of HBOT and HBT. As shown in Table 1, there were no controls in any of the five reviewed pseudo-RCTs4-8 except for a partial oxygen control in Lacey, et al6 (Collet, et al4 and Hardy, et al5 are the same study; Hardy, et al5 is a subgroup of Collet, et al4 with a different outcome instrument). In addition, Lacey, et al6 did not control for: 1) the individual effect of either dose of HBOT or HBT, 2) the effects of the simultaneous OT, PT, and ST plus other therapies performed on the children, or 3) the interactive effects of HBOT/HBT with all of these therapies. Errors 2 and 3 were duplicated by Hegazi, et al,7 and Azhar, et al.8 It is impossible to consider any of these five studies as randomized controlled trials. Nor can any of them be considered to have placebo control groups because all three components of HBT and HBOT are non-inert and there was no assessment of a positive expectation by the children in any study, the two conditions necessary for a placebo effect.9

Table 1. Randomized “Controlled” Trials analyzed in Laureau, et al.1

Study O2 Control Pressure Ctrl HBOT/HBT treatment control group Control for other therapies Placebo expectation assessment
Collet, et al4 No No No N/A No
Hardy, et al5 No No No N/A No
Lacey, et al6 ? Partial No No No No
Hegazy, et al7 No No No No No
Azhar, et al8 No No No No No


The failure to acknowledge the control groups in Collet/Hardy, et al4,5 and Lacey, et al6 as additional doses of HBT/HBOT has prevented a valid assessment of the data in the studies and the appropriate conclusion that HBOT/HBT is the most effective therapy for CP. The Collet, et al4 publication confused the scientific community until the review of Macdonald-Fraser10 informed the discussion about the bioactivity of “micropressure” <1.3 ATA which is the pressure range of the control group in Collett et al4). According to the science and Pascal’s Law,11 one of the Universal Gas Laws, any human being in a hyperbaric chamber cannot escape the physical effects of increased pressure once the chamber is pressurized. The scientific objections of the clinicians on the study12 were reaffirmed in an independent review of HBOT in traumatic brain injury (TBI) and CP by the U.S. Centers for Medicare and Medicaid Services Agency for Healthcare Research and Quality, the evidence/evaluation division of CMS.13 AHRQ concluded on page 47, “The possibility that pressurized room air had a beneficial effect on motor function should be considered the leading explanation.” This was rejected by the hyperbaric medicine and neurology specialties because it violated the historically flawed definition of HBOT14 that ignored the contribution of pressure and mandated pure oxygen at 1.4 ATA or higher for bioactivity. The result was a perpetuation of the flawed Collet, et al4 design with another pressurized “control” group in Lacey, et al6 and a series of near-identical mal-designed HBOT TBI persistent postconcussion syndrome studies by the U.S. Department of Defense that incorporated Collet, et al4 and Lacey, et al’s6 “control” groups.15-18

The five pseudo-RCT HBOT/HBT CP studies reviewed in Laureau, et al1 are comparative dosing HBOT/HBT studies4,5 with simultaneous other therapies (Lacey, et al)6 and comparative treatment studies of HBOT in combination with physical therapy (PT) to PT alone.7,8 The three primary “RCTs” were discussed above. In the remaining two “RCTs,” Hegazi, et al7 and Azhar, et al,8 the “control” groups both contain an active treatment (PT is a non-inert therapy) and neither controlled for pressure, hyperoxia, or for interactive effects between HBOT and PT (there is no HBOT-only treatment group). Azhar, et al8 is erroneously listed in Laureau, et al1 as a study comparing HBOT alone to PT. It is not. It compared HBOT + PT to PT alone, identical to Hegazi, et al.7

All of the pseudo-controlled and non-controlled studies in Laureau, et al1 should be re-analyzed scientifically as comparative effectiveness studies based on the acknowledged understanding of the bioactivity of pressure and hyperoxia. This was done by Senechal in 200719 who showed that HBOT and hyperbaric air therapy (HBA) have greater effects on GMFM than nearly all traditional therapies for CP except dorsal rhizotomy. In addition, HBOT and HBT have demonstrated cognitive improvements that are not seen with traditional therapies for CP.

Alternatively, the studies should be analyzed by Laureau, et al’s1 recommended method, Marois, et al’s GMFM Evolution Ratio.20 Marois, et al20 performed this analysis at HBOT2017, the 11th International Symposium on Hyperbaric Oxygenation and the Brain Injured Child in New Orleans21 (slides 122-132) and at other scientific meetings. Their analysis is reproduced here by permission (Table 2).

Table 2. GMFM Evolution Ratio calculations for traditional CP therapies and HBOT

Study Therapy GMFM-ER
Trahan, et al22 PT, twice/week 4.46
Knox, Evans, et al23 Bobath Rx, thrice/week 4.55
Tsorlakis, et al24 Neurodevelopmental Rx, 2x/week 5.2
Neurodevelopmental Rx, 5x/week 12.0
Hays, et al25 Selective dorsal rhizotomy & PT 10.8
Wright, et al26 Selective dorsal rhizotomy +
OT and PT 2x/wk vs. 8.9
OT and PT 2x/wk 2.9
Nordmark, et al27 Selective dorsal rhizotomy +
individualized PT 6.3
Montgomery, et al28 HBOT-1.75 ATA 47.0
Collet, et al4 HBOT-1.75 ATA/HBA-1.3 ATA 36.3/25
Marois & Vanasse.29 HBOT-1.75 ATA 36.0
Mukherjee, et al30 Standard Intensive Rehab. 6x/wk vs. 3.8
Standard Inten. Rehab. + HBA-1.3 ATA 34.6
Standard Inten. Rehab. + HBOT 1.5 ATA 16.7
Standard Inten. Rehab. + HBOT 1.75 ATA 21.3

Lacey, et al6 HBOT 1.5 ATA 17.14
HBT 1.5 ATA with 14% O2. 8.46
No control for simultaneous OT, PT, ST.


Marois21 showed that for traditional therapies, including rhizotomy, the GMFM ER was 2.9-12, average of 6.9.22-27 For strictly PT it was an average of 5.8 and for dorsal rhizotomy 8.7. For the HBOT studies: HBOT 1.66 ATA O2 (47);28 HBOT 1.75 ATA (36.3), HBA 1.3 ATA (25);4 HBOT 1.75 ATA (36);29 intensive rehab (3.8), HBA 1.3 ATA (34.6), HBOT 1.5 ATA (16.7), HBOT 1.75 ATA (21.3);30 HBOT 1.5 ATA (17.14), 1.5 ATA 14% O2 (8.46);6 average = 26.9. The rate of improvement in GMFM with multiple different doses of HBOT was nearly four times as fast (3.9x) as the rate of improvement with physical therapy, PT plus dorsal rhizotomy, and other therapies consistent with the analysis of Senechal, et al.19 Even Lacey, et al’s6 pseudo-control group improved at nearly 1.5 times the rate of PT. A careful examination of the GMFM ER by dose of HBOT/HBA suggests that the positive effects of HBOT/HBA are more a function of the pressure than the oxygen dose, contrary to Hardy, et al5 (vide supra) and the traditional understanding, and similar to the systematic review pressure-oxygen dose analysis of the DoD TBI studies.31

Lastly, the above analysis does not address the myriad other improvements seen in CP children treated with HBOT/HBT/HBA: speech,32,33 psychosocial function,5 cognition,5,32 sleep,33,34 and seizures,35 Improvements in these functions are not typically seen with the standard CP therapies, indicating that CP is an injury in many children to more areas of the brain than just the motor tracts and that HBOT acts diffusely on widespread wound targets in the brain.36-8 This is suggested by the response seen on functional imaging in the Asl, et al39 HBOT CP study and multiple case reports of HBOT in CP where global increases in brain blood flow were seen after HBOT.40-42

In summary, the debate should only be over for the scientific misunderstanding of HBOT/HBT/HBA and the flawed analyses of HBOT studies based on this non-science. The systematic review of Laureau, et al1 is critically flawed and inconsistent with the science on HBOT/HBT/HBA. It is the culmination of a series of errors spawned from an historical misunderstanding of this science. The derived conclusions in Laureau, et al,1 Collet, et al,4 and Novak, et al43 are unsubstantiated and invalid. The bulk of the evidence for HBOT in CP is positive across multiple studies and is superior to the motor (and other gains) achieved with accepted therapies for CP when analyzed by rate of GMFM improvement or GMFM ER ratio. According to the AHRQ Report Summary,44 “…for clinical decision making or for insurance coverage decisions…Evidence‐based clinical decisions rely more heavily on comparisons of a treatment to other potentially effective therapies than to placebos.” Those comparisons clearly show a superiority of HBOT/HBT to existing therapies for CP. No further research needs to be done to justify the use of HBOT/HBT alongside other standard less effective therapies for CP. What needs to occur is an appreciation of the science of HBOT, HBT, and HBA, an end to the unscientific analyses of HBOT studies on CP, and the performance of future analyses of HBOT based on this science.

References:

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