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We identified several barriers to conducting controlled clinical trials of HBOT for brain injury, particularly cerebral palsy:
As described below, strategies can be developed to conduct good-quality studies to overcome each of these barriers.
Dose and duration of treatment. Oxygen, the “active ingredient” in HBOT, is fundamentally a drug. As for any drug, dose and duration of treatment must be determined in carefully designed dose-ranging studies before definitive studies demonstrating clinical efficacy can be started. Good-quality dose-ranging studies of HBOT for brain injury can be done, based on the model used by pharmaceutical manufacturers and the FDA. It is likely that the dosage of HBOT needs to be individualized based on the patient‘s age, clinical condition, and other factors. This is the case for many other drugs and does not pose an insurmountable barrier to designing dosefinding trials. In fact, the need to individualize therapy makes it essential to base the design of long-term studies of clinical outcomes on the results of dose-ranging studies.
Better outcome measures. In describing the course of their patients, experienced clinicians who use HBOT to treat patients with brain injury, cerebral palsy, and stroke refer to improvements that may be ignored in standardized measures of motor and neuro-cognitive dysfunction. These measures do not seem to capture the impact of the changes that clinicians and parents perceive. Caregivers’ perceptions should be given more weight in evaluating the significance of objective
improvements in a patient’s function. Unfortunately, studies have not consistently measured caregiver burden, or have assessed it only by self-report. Studies in which the caregivers’ burden was directly observed would provide much stronger evidence than is currently available about treatment outcome.
Adverse events. Uncertainty about the frequency and severity of serious adverse events underlies much of the controversy about HBOT. The case against HBOT is based on the reasoning that, because HBOT may be harmful, it must be held to the highest standard of proof. A corollary is that, if HBOT can be shown to be as safe as its supporters believe it to be, the standard of proof of its efficacy can be lowered.
Good-quality studies of adverse effects are designed to assess harms that may not be known or even suspected. The most common strategy is to use a standard template of several dozen potential adverse effects affecting each organ system. Other characteristics of a good study of adverse events are a clear description of patient selection factors, independent assessment of events by a neutral observer, and the use of measures for the severity (rather than just the occurrence) of each event.
Unwillingness to be in a placebo group. The issue of placebo groups has been the subject of a great deal of debate. Participants on both sides 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 for insurance coverage decisions. Evidence-based clinical decisions rely more heavily on comparisons of a treatment to other potentially effective therapies than to placebos.
Several alternatives to the double blind, placebo-controlled trial can be used to examine effectiveness. One approach is to compare immediate to delayed treatment with HBOT, as was done in the Cornell trial. Another is to design a trial in which patients are randomly assigned to several alternative HBOT regimens. Because of uncertainty about the dosage and duration of treatment, such a trial would be preferable to a trial that offered a choice between one particular regimen and no treatment at all. It is also easier to incorporate a sham therapy arm in such a trial: patients may be more willing to enter a trial if they have a 10 percent or 20 percent chance of being assigned to sham treatment instead of a 50 percent chance. Other alternatives to a placebo include conventional physical, occupational, and recreational therapy, or another alternative therapy, such as patterning.
The Canadian trial of HBOT for cerebral palsy has important implications for the design of future research. In the trial there was a clinically significant benefit in the control group. Debate about the trial centers largely on how the response in the control group should be interpreted. The trial investigators believe that the beneficial effect was the result of the psychological effect of participating in the trial and extra attention paid the children in and out of the hyperbaric chamber. Alternatively, the slightly pressurized air (that is, “mild” hyperbaric oxygen) may have caused the improvement. A third possibility is that the slightly increased oxygen concentration, not the pressure per se, was responsible for the benefit.
A trial that could sort out which of these explanations was true would have a major impact on clinical practice. Such a trial might compare (1) room air under slightly elevated pressure, delivered in a hyperbaric chamber, to (2) elevated oxygen concentration alone, delivered in a hyperbaric chamber, and to (3) an equal amount of time in a hyperbaric chamber, with room air at atmospheric pressure. From the perspective of a neutral observer, the third group is not a “sham” but rather an attempt to isolate the effect of the social and psychological intervention cited by the Canadian investigators.
Summary, Evidence Report/Technology Assessment: Number 85. AHRQ Publication Number 03-E049, September 2003. Agency for Healthcare Research and Quality, Rockville, MD. Used with permission. www.ahrq.gov/clinic/epcsums/hypoxsum.htm.