Hyperbaric oxygen therapy (HBOT) is the
inhalation of 100 percent oxygen inside a hyperbaric chamber that is
pressurized to greater than 1 atmosphere (atm). HBOT causes both
mechanical and physiologic effects by inducing a state of increased
pressure and hyperoxia. HBOT is typically administered at 1 to 3
atm. While the duration of an HBOT session is typically 90 to 120
minutes, the duration, frequency, and cumulative number of sessions
have not been standardized.
HBOT is administered in two primary ways, using a monoplace chamber
or a multiplace chamber. The monoplace chamber is the lesscostly
option for initial setup and operation but provides less opportunity
for patient interaction while in the chamber. Multiplace chambers
allow medical personnel to work in the chamber and care for acute
patients to some extent. The entire multiplace chamber is
pressurized, so medical personnel may require a controlled
decompression, depending on how long they were exposed to the
hyperbaric air environment.
The purpose of this report is to provide a guide to the strengths
and limitations of the evidence about the use of HBOT to treat
patients who have brain injury, cerebral palsy, and stroke. Brain
injury can be caused by an external physical force (also known as
traumatic brain injury, or TBI); rapid acceleration or deceleration
of the head; bleeding within or around the brain; lack of sufficient
oxygen to the brain; or toxic substances passing through the
blood-brain barrier. Brain injury results in temporary or permanent
impairment of cognitive, emotional, and/or physical functioning.
Cerebral palsy refers to a motor deficit that usually manifests
itself by 2 years of age and is secondary to an abnormality of at
least the part of the brain that relates to motor function. Stroke
refers to a sudden interruption of the blood supply to the brain,
usually caused by a blocked artery or a ruptured blood vessel,
leading to an interruption of homeostasis of cells, and symptoms
such as loss of speech and loss of motor function.
While these conditions have different etiologies, prognostic
factors, and outcomes, they also have important similarities. Each
condition represents a broad spectrum, from barely perceptible or
mild disabilities to devastating ones. All three are characterized
by acute and chronic phases and by changes over time in the type and
degree of disability. Another similarity is that the outcome of
conventional treatment is often unsatisfactory. For brain injury in
particular, there is a strong sense that conventional treatment has
made little impact on outcomes.
Head Injuries Improved With Hyperbaric Oxygen Therapy
Predicting the outcome of brain injury, cerebral palsy, and stroke
is difficult. Prognostic instruments, such as the Glasgow Coma Scale
(GCS) for brain injury, are not precise enough to reliably predict
an individual patient’s mortality and long-term functional status.
Various prognostic criteria for the cerebral palsy patient’s
function have been developed over the years. For example, if a
patient is not sitting independently when placed by age 2, then one
can predict with approximately 95 percent confidence that he/she
never will be able to walk. However, it is not possible to predict
precisely when an individual patient is likely to acquire a
particular ability, such as smiling, recognizing other individuals,
or saying or understanding a new word.
Mortality and morbidity from a stroke are related to older age,
history of myocardial infarction, cardiac arrhythmias, diabetes
mellitus, and the number of stroke deficits. Functional recovery is
dependent on numerous variables, including age, neurologic deficit,
comorbidities, psychosocial factors, educational level, vocational
status, and characteristics of the stroke survivor’s environment.
The report focuses on the quality and consistency of studies
reporting clinical outcomes of the use of HBOT in humans who have
brain injury, cerebral palsy, or stroke. This information can be
used to help providers counsel patients who use this therapy and to
identify future research needs.
Reporting the Evidence
This review addresses the following questions:
Does HBOT improve mortality and morbidity in patients who have
traumatic brain injury or nontraumatic brain injury, such as anoxic
ischemic encephalopathy?
Does HBOT improve functional outcomes in patients who have cerebral
palsy? (Examples of improved functional outcomes are decreased
spasticity, improved speech, increased alertness, increased
cognitive abilities, and improved visual functioning.)
Does HBOT improve mortality and morbidity in patients who have
suffered a stroke?
What are the adverse effects of using HBOT in these conditions?
To identify the patient groups, interventions, and outcomes that
should be included in the review, we read background material from
diverse sources including textbooks, government reports, proceedings
of scientific meetings, and Web sites. We also conducted focus
groups and interviews to improve our understanding of the clinical
logic underlying the rationale for the use of HBOT. In the focus
groups, we identified outcomes of treatment with HBOT that are
important to patients, caregivers, and clinicians and examined
whether patients, caregivers, and clinicians who have experience
with HBOT value certain outcomes differently from those who have not
used HBOT. A broader goal of the focus groups was to better
understand the disagreement between supporters and nonsupporters of
HBOT.
The following interventions, populations, outcomes, and study design
criteria were used to formulate the literature search strategy and
to assess eligibility of studies.
Intervention. Hyperbaric oxygen therapy: any treatment using 100
percent oxygen supplied to a patient inside a hyperbaric chamber
that is pressurized to greater than 1 atm.
Population. Patients with: brain injury from any cause and in any
stage (acute, subacute, or chronic). cerebral palsy of any etiology.
thrombotic stroke.
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.
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.
Fair: Generally comparable groups assembled initially (inadequate or
unstated randomization and concealment methods) but some question
remains whether some (although not major) differences occurred with
followup; measurement instruments acceptable (although not the best)
and generally applied equally; outcome assessment masked; some, but
not all, important outcomes considered; appropriate attention to
some, but not all, potential confounders; for RCTs,
intention-to-treat analysis.
Poor: Groups assembled initially not close to being comparable or
not maintained throughout the study; measurement instruments
unreliable or invalid or not applied equally among groups; outcome
assessment not masked; key confounders given little or no attention;
for RCTs, no intention-to-treat analysis.
For each study, the reviewer’s assessment of external validity is
given, including an assessment of the evidence that the study
population reflects the underlying patient population (agerange,
co-morbidities, co-interventions, etc.). External validity indicates
the applicability of the results of the study to clinical practice.
For example, if the study recruited a narrowly defined group of
patients, the results may not be generalizable to a broader spectrum
of patients. A study can have high internal validity but low
external validity. There are no well-defined criteria for assessing
external validity, and clinicians must assess the applicability of
the results to the patient population for which the intervention is
intended.
Findings
Brain Injury
For traumatic brain injury, one randomized trial provided fair
evidence that HBOT might reduce mortality or the duration of coma in
severely injured TBI (traumatic brain injuries) patients. However,
in this trial, HBOT also increased the chance of a poor functional
outcome. A second fair quality randomized trial found no difference
in mortality or morbidity overall, but a significant reduction in
mortality in one subgroup. Therefore, they provide insufficient
evidence to determine whether the benefits of HBOT outweigh the
potential harms.
The quality of the controlled trials was fair, meaning that
deficiencies in the design add to uncertainty about the validity of
results.
Due to flaws in design or small size, the observational studies of
HBOT in TBI do not establish a clear, consistent relationship
between physiologic changes after HBOT sessions and measures of
clinical improvement.
The evidence for use of HBOT in other types of brain injury is
inconclusive. No good- or fair quality studies were found.
Cerebral Palsy
There is insufficient evidence to determine whether the use of HBOT
improves functional outcomes in children with cerebral palsy. The
results of the only truly randomized trial were difficult to
interpret because of the use of pressurized room air in the control
group. As both groups improved, the benefit of pressurized air and
of HBOT at 1.3 to 1.5 atm should both be examined in future studies.
The only other controlled study compared HBOT treatments with 1.5
atm to delaying treatment for 6 months. As in the placebo-controlled
study, significant improvements were seen, but there was not a
significant difference between groups.
Cerebral Palsy Testimonials
Two fair-quality uncontrolled studies (one time-series, one
before-after) found improvements in functional status comparable to
the degree of improvement seen in both groups in the controlled
trial.
Although none of the studies adequately measured caregiver burden,
study participants often noted meaningful reductions in caregiver
burden as an outcome of treatment.
Stroke
Although a large number of studies address HBOT for the treatment of
stroke, the evidence is insufficient to determine whether HBOT
reduces mortality in any subgroup of stroke patients because no
controlled trial assessed was designed to assess mortality.
Among controlled trials, the evidence about morbidity is
conflicting. The three best-quality trials found no difference in
neurological measures in patients treated with HBOT versus patients
treated with pressurized room air.
Two other controlled trials, one randomized and one nonrandomized,
found that HBOT improved neurological outcomes on some measures.
However, both were rated poor-quality.
Most observational studies reported favorable, and sometimes
dramatic, results, but failed to prove that these results can be
attributed to HBOT. For example, one retrospective study found
better mortality rates in patients who received HBOT than a
comparison group of patients from a different hospital who did not.
The study did not provide information on mortality rates from other
causes in each hospital; this information would have made it easier
to judge whether the improved survival was due to HBOT or to
differences in overall quality of care at the HBOT hospital.
The observational studies of HBOT provided insufficient evidence to
establish a clear relationship between physiologic changes after
HBOT sessions and measures of clinical improvement. Few studies
established that patients were stable at baseline.
Adverse Events
Evidence about the type, frequency, and severity of adverse events
in actual practice is inadequate. Reporting of adverse effects was
limited, and no study was designed specifically to assess adverse
effects.
The few data that are available from controlled trials and cohort
studies of TBI suggest that the risk of seizure may be higher in
patients with brain injuries treated with HBOT.
No study of HBOT for brain injury, cerebral palsy, or stroke has
been designed to identify the chronic neurologic complications.
Pulmonary complications were relatively common in the trials of
brain-injured patients. There are no reliable data on the incidence
of aspiration in children treated for cerebral palsy with hyperbaric
oxygen.
Ear problems are a known potential adverse effect of HBOT. While ear
problems were reported in brain injury, cerebral palsy, and stroke
studies the incidence, severity and effect on outcome are not clear.
However, the rates reported among cerebral palsy patients were
higher (up to 47 percent experiencing a problem) than reported with
brain injury or stroke. However, the data in brain injury are
limited by the use of prophylactic myringotomies.
Supplemental Qualitative Analysis
Opinions about the frequency and severity of risks of HBOT vary
widely.
Several participants emphasized the importance of continued
treatments to maximize results.
Patients and caregivers value any degree of benefit from HBOT
highly. An improvement that may appear small on a standard measure
of motor, language, or cognitive function can have a very large
impact on caregiver burden and quality of life.
Future Research
Outcome Studies
We identified several barriers to conducting controlled clinical
trials of HBOT for brain injury, particularly cerebral palsy:
Lack of agreement on the dosage and the duration of treatment.
Need for better measures of relevant outcome measures, such as
caregiver burden.
Lack of independent, reliable data on the frequency and severity of
adverse events.
Patients’ unwillingness to be assigned to a placebo or sham
treatment group.
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.
In addition to needing improved design, future trials of HBOT need
better reporting. This would aid interpretation and the application
of the research results. Two types of information are essential: a
clear description of the research design, particularly of the
control and comparison groups, and a detailed description of the
patient sample. It is frequently difficult to tell from published
studies how comparable the patient populations are, not only
demographically but also
clinically, in order to interpret the diagnosis and prognosis.
Studies of Diagnosis and Nonclinical Endpoints
An independent, critical assessment of the body of animal
experiments and human case studies supporting the “idling neuron”
theory of brain injury and recovery should have been done. A large
body of studies supports the theory underlying the use of HBOT, but
the interpretation of these studies is also disputed. Most of these
studies use experimental animal models of brain injury and are
designed to provide support for the hypothesis that HBOT redirects
blood flow to, and promotes recovery and growth of, “idling neurons”
at the border of the damaged brain tissue.
There is sharp disagreement in the medical literature over the
validity of these experimental models. One major issue is the
significance of improvements in patterns of cerebral blood flow. The
principle that redirecting flow toward ischemic areas can help
damaged tissue recover is well established in cardiology. However,
in critical care generally, drugs and maneuvers that redirect flow
to ischemic organs (e.g., brain and kidney) do not always improve
recovery at the cellular level. For this reason, improved blood flow
must be linked to other measures of cellular and organ recovery.
HBOT for brain injury is not likely to gain acceptance in routine
clinical use until a clinical method of assessing its effectiveness
in the individual patient is validated.Specifically, the diagnostic
value of SPECT scans and of other intermediate indicators of the
effects of HBOT should be examined in goodquality studies. Like all
other diagnostic tests, SPECT scans have a measurable false positive
and false negative rate in relation to clinical outcomes. Controlled
trials are not needed as the ideal study design to measure the
accuracy of a diagnostic test. Rather, a longitudinal cohort study
in which all patients undergo scans as well as standardized followup
tests would be a feasible and ideal approach.Source