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Patient Blinding During Hyperbaric Trials is Possible and Essential

The Evidence-Based Medicine Hierarchy
The Evidence-Based Medicine Hierarchy

Pioneering cardiac surgery within a pressurized chamber heralded the modern era of hyperbaric medicine. While the almost immediate introduction of cardiopulmonary bypass technology proved hyperbaric surgery short-lived, its hyper-oxygenation mechanism was adopted to treat several other acute ischemic states. Identification of additional therapeutic mechanisms associated with hyperbaric hyperoxia led to its use elsewhere, with hyperbaric medicine emerging as accepted practice despite a paucity of robust supportive evidence. That its early proponents included highly regarded academicians may well have played an influencing role.

The advent of evidence-based medicine (EBM) has changed the medical practice calculus. There is increasing expectation that therapeutic interventions be proven efficacious, safe and cost-effective. While this applies to medicine in general, the continued failure to produce convincing data in support of its common indications finds hyperbaric oxygen (HBO) therapy firmly beneath the evidence ‘microscope’. Within the United Kingdom for example, once at the forefront of hyperbaric research and clinical activity, the National Health Service, the UK’s principal underwriter of health care, has whittled down reimbursement to a single condition, decompression sickness. All previously approved uses have been delisted.

Need for better data

While the UK example is extreme, frustration regarding evidence shortcomings is widely apparent elsewhere. Ready acceptance of negative studies otherwise noted to suffer patient selection, study design, protocol compliance, and data interpretation flaws (Scheinkestel et al. 1999; Annane et al. 2002; Fedorko et al. 2016; Glover et al. 2016 as examples) has clearly influenced policy makers, authoritative practice guidelines, meta-analyses, invited editorials, and others who purchase healthcare. With few exceptions, there has been a failure to undertake well designed and executed randomized sham-controlled double-blind trials. As noted in the accompanying evidence hierarchy diagram, this study type is considered the highest level and most reliable form of research methodology. In its absence, hyperbaric medicine will continue its struggle for broad acceptance within ‘mainstream’ medicine.

Sham vs placebo

You are likely more familiar with the term placebo, which is defined as an entirely inert substitute to active therapy. Placebo studies are common during new drug investigations, with the inactive agent often referred to as a sugar pill. One cannot employ placebo during hyperbaric research, although some studies have incorrectly used this term. As patients are required to enter a chamber rather than swallow a pill, they will be exposed to incidental and potentially harmful effects. During the 2010 Londahl et al. DFU trial for example, one sham (which the authors termed placebo) patient fell while in the chamber suffering a head injury requiring hospitalization. Several sham patients experienced ear barotrauma, necessitating surgical intervention (needle myringotomy) in two patients, and four others suffered hypoglycemia: all hardly representing inert blinding.

Sham studies are those in which blinding is required during investigation of a procedure or intervention. As one cannot feign entering a chamber, one must simulate aspects associated with it. Sham is defined, therefore, as a fake procedure that omits the step thought to be therapeutically necessary. Sham patients should ideally, therefore, experience the incidental effects of chamber exposure absent hyperoxia (active therapy).

How can sham exposures be undertaken?

Several methods have been employed.

  1. Air breathing compression to equivalent pressure of the active treatment group, thereby exposing sham patients to compression/barotrauma issues and chamber warming/cooling. Its drawback is that patients will experience elevated oxygen tensions (Dalton’s Law), thereby confounding assessment of magnitude of any oxygen effect between groups. There is also a risk of decompression sickness, the degree of which being dependent upon chamber pressure/duration. Attempts to mitigate this risk with oxygen breathing during slowed decompression may result in unblinding.

  2. Air breathing compression to equivalent pressure of the active treatment group, then switching from air to a percentage of oxygen, balance nitrogen, equal to that of normal atmospheric pressure (examples: 7% at 3.0 ATA - 8.75% at 2.4 ATA - 10.5% at 2.0 ATA).This serves to eliminate the elevated oxygen issue but increases risk of decompression sickness. It also adds a degree of technical complexity.

  3. Maintaining sham patients within an unpressurized chamber while breathing air. The shortcoming of this approach is that incidental effects are absent. This would become all too readily apparent having undergone the informed consent process (where such effects are described) and should patients from each group encounter one another.

  4. Air breathing compression to an intermediate pressure (commonly 1.34 ATA) in order to produce incidental effects, then immediate gradual decompression to normal atmospheric pressure for the remainder of the planned exposure period. This approach has been statistically validated as an effective blinding technique (Clarke, at al. 2008; Weaver et al. 2002), and recommended for subsequent trials. It also serves to eliminate decompression sickness risk, as it does the confounding elevated oxygen pressure exposure.

In summary:

  1. A validated method exists to effectively blind patients during hyperbaric trials, and

  2. Randomized sham controlled double blind trials are the ‘proof of evidence’ gold standard and required to fully validate HBO therapy in this modern era

This current lack of efficacy evidence does not mean lack of clinical effectiveness if appropriate research is yet to be undertaken. It does mean that proof of evidence studies are essential for the continued availability and viability of HBO therapy, in order that select patients continue to gain access and benefit.

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