Hyperbaric Oxygen Therapy for Brain Injury, Cerebral Palsy, and Stroke

Agency for Healthcare Research and Quality

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• Outcomes. We sought articles reporting any clinical endpoint. We focused on health outcomes, including mortality and functional changes that a patient would experience, rather than intermediate outcomes. Intermediate outcomes include physiologic measures, such as intracranial pressure, cerebrospinal fluid lactate levels, or changes in cerebral blood flow, or results of imaging studies. Some clinical measures, such as neuropsychiatric and cognitive tests, are also intermediate measures. We did not assume that any of these intermediate measures of the effect of HBOT on patients with brain injury, cerebral palsy, or stroke was proven to be an indicator of the longterm outcome. Instead, in reviewing articles for inclusion in this report, we were particularly interested in studies that reported both intermediate measures and health outcomes, to assess the strength of evidence about their correlation.
• Design. We included original studies of human subjects that reported original data (no reviews). All study designs except for case reports and small case series were eligible for inclusion. Before-after or time-series studies with no independent control group were included if a) five or more cases were reported, and b) outcome measures were reported for both the pre- and post-HBOT period.

Methodology

Technical Expert Advisory Group (TEAG)
We identified technical experts to assist us in formulating the research questions and identifying relevant databases for the literature search. The expert panelists included a neurologist specializing in stroke, a neurosurgeon specializing in severe brain injury, a pediatric neurologist with expertise in treating patients with cerebral palsy, and a physician with an HBOT practice. Throughout the project period, we consulted individual members of the TEAG on issues that arose in the course of identifying and reviewing the literature.

Literature Search, Study Selection, and Data Extraction
We searched a broad range of databases to identify published and unpublished studies of the effectiveness and harms of HBOT in patients with brain injury, cerebral palsy, and stroke. Each database was searched from its starting date to March 2001. The databases searched were:

• MEDLINE®
• PreMEDLINE®
• EMBASE
• HealthSTAR (Health Service Technology, Administration and Research)
• CINAHL® (Cumulative Index to Nursing & Allied Health)
• Cochrane Database of Systematic Reviews
• Cochrane Controlled Trials Register
• DARE (Database of Abstracts of Reviews of Effectiveness)
• AltHealthWatch
• MANTIS™ (Manual, Alternative and Natural Therapy)
• Health Technology Assessment Database TEAG members identified the following additional databases as potential sources of other material that may not be indexed in other electronic databases:
• The Undersea & Hyperbaric Medical Society: a large bibliographic database
• The Database of Randomised Controlled Trials In Hyperbaric Medicine
• European Underwater and Baromedical Society
• International Congress on Hyperbaric Medicine
• National Baromedical Services, Inc.

Update literature searching of the electronic databases MEDLINE, PreMEDLINE, EMBASE, CINAHL, the Cochrane Library, and the Health Technology Assessment Database was completed on February 26, 2002, using the same search strategy as used for the initial searches. Eight additional references submitted by a peer reviewer were added in May 2003. Finally, a supplemental search of MEDLINE, PreMEDLINE, EMBASE, and CINAHL was conducted in July 2003.

The references of all included papers were hand searched. In addition, two reviewers independently conducted hand searches of the references from the Textbook of Hyperbaric Medicine.1 One TEAG member provided articles and meeting abstracts from his personal library.

Two reviewers independently assessed each title and abstract located through the literature searches for relevance to the review, based on the intervention, population, outcome, and study design criteria. The full-text articles, reports, or meeting abstracts that met the criteria listed above were retrieved and reviewed independently by two reviewers who reapplied the eligibility criteria. Disagreements were resolved through consensus.

Extraction of data from studies was performed by one reviewer and checked by a second reviewer. Disagreements were resolved through consensus.

Internal and External Validity and Quality Rating

The quality of all trials in the review was assessed using a list of items indicating components of internal validity. We modified the standard checklists to address issues of particular importance in studies of HBOT. For randomized controlled trials (RCTs) and nonrandomized controlled trials (NRCTs), the items assessed for internal validity were: randomization/allocation concealment, baseline comparability of groups, timing of baseline measures, intervention, outcome measures, timing of followup measurements (long enough to assess effects), loss to followup, handling of dropouts or missing data, masking, statistical analysis (if any), and general reviewer comments.

For the observational studies, items assessed for internal validity were exposure measurement (whether all subjects were given the same HBOT treatment), other interventions, differences in baseline factors among the groups of subjects compared (if a comparison group was included), discussion of or control for potential confounding, masking, evidence of stable baseline, timing of baseline survey, timing of followup measures, outcome measures used, and general comments of
the reviewer.

Each study was then assigned an overall rating (good, fair or poor) according to the US Preventive Services Task Force method:

• Good: Comparable groups assembled initially (adequate randomization and concealment, and potential confounders distributed equally among groups) and maintained throughout the study; followup at least 80 percent; reliable and valid measurement instruments applied equally to the groups; outcome assessment masked; interventions defined clearly; all important outcomes considered; appropriate attention to confounders in analysis; for RCTs, intention-to-treat analysis.