| The
Proponents to HBOT:
June
2002
Analysis
of the results of a
randomized study of
hyperbaric oxygen therapy
in the treatment of
children with cerebral
palsy: Placebo or
physiological effect?
Pierre
Marois, MD, FRCP(C),
Physiatrist and Michel
Vanasse, MD, FRCP(C),
Neurologist
Introduction
The results of the study
of the effects of
hyperbaric oxygen therapy
(HBO study) in the
treatment of children with
cerebral palsy have been
known for over six months.
However, these results are
still controversial. The
directors of the "Fonds
de la recherche en santÈ
du Quebec" (FRSQ),
the organization
responsible for overseeing
this study and some
researchers, including the
principal researcher, Dr.
Jean-Paul Collet, are
convinced that the
improvements observed in
both groups of children
involved in the study was
due solely to a placebo
effect. Others, the
authors included, believe
that the cause or causes
of this improvement were
not clearly identified by
this study and suggest the
need to pursue further
research of HBO treatment.
We
have voiced our opinions
on several occasions and
are now compelled to
document our position in
order to enable those
interested in this debate
to familiarize themselves
with our argument,
weighing the pros and the
cons. We would like to
demonstrate that we are
not merely presenting an
empathetic attitude
towards desperate parents
faced with the unfortunate
condition of their child.
Recognizing our
limitations in the area of
research, we associated
ourselves with and
collaborated with a team
of researchers, clinicians
and methodologists
possessing the competence
required to write the
original version of this
study, which was left
practically unchanged by
Dr. Collet. However
without prejudice, we feel
that our twenty years of
experience in paediatric
rehabilitation and our
involvement in numerous
research projects often
dealing with experimental
treatments gives us the
right to voice our
opinion. We invite the
readers to judge these
objective arguments on
their own merit.
A.HBO
Study: The uncontested
facts
The
consensus of the research
group was that the
randomized HBO study for
children with cerebral
palsy demonstrated that:
-Both groups of children
that participated in the
study showed improvements
in mobility as measured by
the Gross Motor Function
Measure (GMFM), in
language skills and in
auditory and visual
memory. -The results did
not show that the
treatment at 1.75 ATA and
100% O3⁄4 were
superior to the so-called
"placebo" at 1.3
atmospheres with ambient
air. As often pointed out
while the research
protocol was being
developed and in the
discussion of the results,
the "placebo"
was in fact not an inert
treatment. We had
recommended a true control
group that would not have
received any treatment.
Furthermore:
-The research group and
the scientific advisory
committee were of the
unanimous opinion that the
improvements observed were
clinically significant.
-The improvements in the
GMFM scores in both groups
were observed during the
retest three months
post-treatment. -There
were no serious side
effects in the course of
the 2,500 HBO treatments
administered during the
pilot-study and the double
blind study. -All who
evaluated this study
acknowledged its
scientific merit.
B.
The reasons for the
improvement During three
long plenary sessions and
several other meetings in
small groups, the
researchers debated the
possible explanations for
the improvements observed
in both groups of children
We feel it is appropriate
to convey the researcher's
conclusions with respect
to the possible reasons
for the observed
improvements. 1. A placebo
and/or participation
effect. According to many
researchers the apparent
cause of observed
improvements is the fact
that the individual
participated in a study.
Without being able to
clearly identify the
mechanism, studies have
shown that the involvement
in a research study
resulted in improvements
in the parameters being
evaluated. To explain the
observed changes, we have
made reference to the
placebo effect, the
Hawthorne effect, the
increased amount of time
the parents spent with
their children or the
increase in the social
interaction of the parents
and children. 2. The
effect of the HBO therapy.
As mentioned above, the
placebo referred to in
this study was not a true
placebo. It was a HBO
treatment at 1.3
atmospheres of pressure
with ambient air. This
treatment has an effect on
the partial pressure of
blood gases and perhaps
other physiological
effects. It is therefore
possible that this
treatment could have a
beneficial effect at the
cerebral level.
Hypotheses
not retained by the
research team The team of
researchers evaluated the
possibility that the
improvements were due to
the natural evolution in
the neurological condition
of the subjects or the
effect of learning in the
tests used. These
hypotheses were not
retained as the children's
development was stable or
had shown only slight
improvement. The
improvement was much
greater following the HBO
treatment. We also
consider that there was no
learning effect in the
tests used, especially
with the GMFM, which was
the principal variable.
C.
Our Position Our opinion
is based on the following
points that we will
elaborate: -The placebo
was not in fact inert and
it would be more
appropriate to claim that
these children received a
reduced dose of HBO, in
other words an exposure to
a pressure of 1.3
atmospheres of ambient
air. -Without denying the
existence of a placebo
effect, or the possibility
that the observed
improvements are due to
the placebo effect, we
maintain that there has
been no scientific proof
that: -a placebo can
significantly improve
mobility, language and
memory of children with
cerebral palsy clinically
or statistically. If the
results were due to a
placebo, then it was as
effective on motor
performance as the
conventional therapy
currently considered the
most effective treatment
(intensive physical
therapy) and in a shorter
amount of time. -a placebo
can produce long-lasting
effects. The improvements
were still observed three
months post-treatment in
the retest of the subjects
involved in this study.
Without being able to
scientifically confirm,
the impression of both
parents and health care
professionals following
these children is that the
improvements persisted,
(one year and more). -a
placebo can result in
reproducible improvements
from one study to another.
The mobility improvements
measured by the GMFM in
both groups involved in
the randomized study were
identical to the results
of three pilot studies and
one case study. We are in
agreement with the experts
on the scientific advisory
committee that there is no
irrefutable scientific
proof demonstrating any
therapeutic benefit of
low-pressure hyperbaric
therapy. This however does
not imply that a
beneficial effect does not
exist. Some clinical and
experimental data allows
us to defend this
hypothesis.
D.
The "placebo"
group received a reduced
hyperbaric treatment That
the placebo was not inert
was not only a concern
upon completion of the
study, but had been
pointed out and discussed
during the development of
the research protocol. The
initial versions of the
protocol (versions that
were submitted and
approved by the ethical
committees of Hopital St.
Justine, Centre
hospitalier regional de
Rimouski and Institut en rÈadaptation
en dÈficience physique de
QuÈbec in May 1999) read
as follows: "Since a
pressure of 1.3
atmospheres could
eventually produce an
effect (it is not an inert
placebo), we had proposed
the introduction of a
third group in the study
that would not receive any
treatment. The children in
the control group would be
evaluated, with the
awareness that they didn.t
receive the treatment,
initially, one month later
and at the end of the
study. This group of
subjects would allow us to
verify the natural
evolution of the condition
and the effect of
repeating the evaluation
on the measured
performance."
On
Dr. Collet's
recommendation (eventually
approved by the majority
of researchers) the
inclusion of this third
control group was
discarded in order to
include more subjects in
the other two groups thus
obtaining more significant
statistics.
We
were not the only ones to
have raised this
methodological problem.
The results of this study
were presented at the
Underwater and Hyperbaric
Medical Society Conference
by Dr. Stephane Tremblay
in June 2000. The report
of Dr. Tremblay's
presentation states:
"many individuals
recommend verifying in
future studies whether in
fact the placebo was inert
(28% O2=placebo) as well
as the effect of oxygen at
partial pressure, seeing
as the improvement in both
groups was clinically
significant." This
point was also raised
during the presentation of
the results of this study
at the American Academy of
Cerebral Palsy and
Developmental Medicine in
Toronto, September 2000,
given in part by Dr.
Michel Vanasse.
A
letter addressed to Dr.
Collet from Dr. Butcher,
the senior editor of the
journal The Lancet,
accepting the text of the
results of our study
stated: "I am very
pleased to be able to tell
you that The Lancet's
editorial team had decided
to accept your paper for
publication provided that
all references to
'placebo' are changed to
'slightly pressurized room
air (or something
similar)'."
Evidently
these comments do not
allow us to conclude that
the treatment was
responsible for
improvements observed in
the group that received
the attenuated hyperbaric
therapy. However, it does
indicate that many
scientists feel this
possibility cannot be
excluded and should be the
focus of further
investigation. It was the
conclusion in the resume
of the paper written by
Dr. Collet, on the results
of our study that has been
accepted for publication
in The Lancet: "The
important improvement
observed in both groups
for all three dimensions
tested deserves further
considerations."
E.
Comments regarding the
"placebo" effect
or the effect of
participation 1. Placebo
effect, effect of
participation (inclusion
benefit) and
"Hawthorne
effect" Without
intending to do a complete
analysis of the placebo
effect, we feel it is
important to comment on
the subject. During the
discussions pertaining to
the possible causes of the
improvements noted in both
groups of subjects, many
of the researchers
maintained that it was due
to a placebo effect,
inclusion benefit or
"Hawthorne
effect" or a
combination of the three.
The designated committee
of experts chosen by the
FRSQ concluded that this
was the most probable
explanation of the
reported improvements.
Some reproached us for
attempting to deny the
obvious, that these
effects are well known and
well documented. If this
is in fact the case, it is
surprising to report that
the paper reporting the
results of our study only
includes one very general
reference to this subject.
We do not in any way deny
the existence of the
placebo effect, however,
we have always maintained
that there is no
scientific proof that such
an effect could explain
the improvements reported
in the children that
received either the
complete or reduced
hyperbaric therapy. The
placebo effect is a
well-known phenomenon to
health care professionals
that has rarely been
studied. The titles of
certain papers cited by
the experts of the
scientific committee ref!
er to these studies:
"The Mysterious
Placebo Effect",
"The Uncontrollable
Placebo Effect".
The
effect of participating in
a study as possibly being
the sole factor resulting
in an improvement in the
subjects involved was also
postulated. It is a
fascinating hypothesis and
remains just that, a
hypothesis. The effect of
participating in a study,
also referred to as the
inclusion benefit, is not
well known. Remarks made
by Dr. Lantos suggesting
this phenomenon remains
hypothetical in an
editorial in the Journal
of Pediatrics 1999,
"The "inclusion
benefit" in clinical
trials": "As a
thought experiment, let us
suppose that it is really
true that participants in
randomized clinical trials
do have better outcomes
than similar patients with
similar diseases treated
in the same institution at
the same time". In
the same editorial he
adds: "The phenomenon
of inclusion benefit, if
real". The
"Hawthorne "
effect was also proposed
as a possible cause for
the reported improvements
of the subjects in our
study. This effect is
defined as: the effect of
being conscious of being
observed can cause a
modification in the
behavior of an individual.
In a recent study of the
"Hawthorne"
effect and the sensation
of feeling better after
anesthesia, De Amici et
al. (2000) concluded:
"Whereas this study
answers the question
concerning the importance
of the Hawthorne effect in
a field where subjective
perception is predominant,
the impact of this
phenomenon on more
"objective "
parameters remains open.
However, the improvements
reported in the children
treated were based on
objective data, not on a
sensation of feeling
better. These remarks can
explain our reluctance to
believe that the placebo,
the participation or
Hawthorne effects be the
cause of the reported
improvements.
Furthermore:
2. A placebo as effective
or even more so than
conventional treatment? We
have often mentioned that
there are few effective
treatments for children
with cerebral palsy, and
thus the importance of not
neglecting a treatment as
promising as hyperbaric
therapy. In the past few
years there have been
several papers
investigating therapeutic
modalities available for
children with cerebral
palsy, which have
concluded that there is no
scientific evidence to
support the effectiveness
of these treatments.
(Turnbull 1993, Graves
1995, Majnemer 1998). Dr.
Majnemer wrote in her
paper: "there is a
lack of evidence to
support the efficacy of
rehabilitation
interventions in children
with cerebral palsy".
Some
open or pilot studies have
reported that intensive
physical therapy (6 to 8
months, two times a week)
result in a functional
improvement measured by
the GMFM (Gross Motor
Function Measure, the
evaluation tool used in
our pilot and randomized
studies). However, for
comparable populations,
children with spastic
diplegia, we observed a
5.3% improvement on the
global score of the GMFM
in our pilot study (after
20 treatments, after one
month) compared to an
improvement of 4% reported
by Russell et al. ( after
6 months of intensive
therapy). Furthermore, in
the subjects involved in
the randomized study, a
generalized improvement
was reported, including
attention and
communication. We can
therefore establish that
the hyperbaric therapy
resulted in functional
improvements more rapidly
and more generalized than
conventional treatment. If
we accept that the
improvement observed in
the children having
received HBO therapy is
due to a placebo, must we
then conclude the
improvements resulting
from the 6-8 months of
intensive physical therapy
were also due to placebo
because the results were
identical?
3.A
reproducible and
persisting placebo effect?
Another interesting and,
in our opinion, very
important element that was
highlighted by our
research was that the
improvements persisted at
least three months post
treatment. The children
were systematically
re-evaluated three months
later and we were able to
document beyond doubt the
persistence of the gains
observed after 40
hyperbaric treatments (and
even a slight improvement
which was not
statistically
significant). In a pilot
study Dr. Maurine Packard
of Cornell University
evaluated 26 children that
had received 40 HBO
treatments (each lasting
one hour at 1.5 ATA). She
noted that the
improvements in the areas
of attention, language and
ability to play that were
observed immediately after
the treatments were still
present six months later.
Our
clinical experience leads
us to believe that the
improvements reported
persist even in the long
term, in other words for
at least one year after
the treatment. To our
knowledge, no scientific
proof exists confirming
the persistence of a
placebo for that period of
time. We are aware that
there does not exist,
other than our research
study, a randomized,
double blind study
conducted to analyze the
effect of this therapy.
However, there have been
some credible case studies
and pilot studies on
children with cerebral
palsy (Paleg 1998, Barrett
1999, Montgomery et al.
1999, Packard 2000),
published or presented at
conferences. We may have
reservations about the
conclusions of these
studies, but one thing
does remain unchanged,
they all showed similar
improvements. F. Is a
low-pressure hyperbaric
treatment effective?
We
would like to restate that
we are in agreement with
the report of scientific
advisory committee that
there is no irrefutable
proof illustrating that a
HBO treatment at low
pressure is effective on
humans. Equally, there is
no scientific proof
showing that it is
ineffective as there has
never been any research on
humans to evaluate this
hypothesis. In our
opinion, some of the
clinical and experimental
data deserve
consideration. -a recent
study evaluating
hyperbaric treatment with
and without oxygen therapy
in the treatment of
cerebral vascular
accidents in rats showed
that: " .Hyperbaric
oxygen and, to some
extent, hyperbaric
pressure reduced ischemic
brain damage and
behavioral
dysfunction."(Chang
et al. 2000)
-A
low-pressure hyperbaric
treatment ( without
oxygen) , the Gammow bag,
is effectively used to
treat cerebral edema
suffered by some
individuals when at high
altitude, a condition
known as "acute
mountain
sickness".(Austin
1998) It is estimated that
the pressure reached with
this bag is approximately
.2 ATA. Recently, Heuser
et al. reported a clinical
improvement after ten
hyperbaric treatments at a
pressure of 1.3 ATA and in
the cerebral SPECT scan in
six patients presenting a
toxic encephalopathy. -Two
double-blind studies were
conducted on humans to
evaluate the effectiveness
of HBO therapy in the
treatment of CVA in the
acute phase. (Anderson et
al. 1991, Nighoghossian
and Trouillas 1995) The
scientific advisory
committee did not cite
these studies. In both
studies, the experimental
group received a treatment
of hyperbaric oxygen
therapy at 1.5 ATA with
100% oxygen and the
placebo group 1.5 ATA
without oxygen. The study
by Nighoghossian and
Trouillas reported an
improvement in both groups
of subjects, with a
greater improvement
(however not statistically
significant) in the group
of patients that received
the hyperbaric treatment
with oxygen. In the study
conducted by Anderson et
al. improvement was
reported in both groups,
however the greater
improvement was noted in
the group that received
hyperbaric therapy without
oxygen (the difference was
not significant
statistically between the
two groups). These
patients were evaluated
with a quantified
neurological evaluation
and a measurement of the
volume of the cerebral
infarct using repeated
cerebral scans. The
patients in the
"placebo" group
experienced more favorable
results in these two
measurements, suggesting
that improbability of a
placebo effect.
It
is not up to us to
evaluate in hindsight the
results of these two
studies. However, it would
have been very interesting
to compare the evolution
of both groups with a
control group without
treatment. In our opinion,
the results of both of
these studies, especially
the one by Anderson et
al., support the
possibility that a
hyperbaric treatment at
low pressure (1.5 ATA in
that study) can have a
therapeutic effect.
Furthermore, the
physiological effects of
hyperbaric treatment are
certainly more complex
than solely the increase
in partial pressure of
oxygen (Buras 2000). It
would be interesting to
study the physiology of
hyperbaric therapy with
and without oxygen
therapy.
G.
Conclusion The conclusion
and the subsequent
proposals are taken
verbatim from what was
proposed in May 2000. Our
position remains unchanged
with regard to the
follow-up of our research
project.
We
are convinced that our
work on this therapeutic
approach must be pursued
in order to identify the
cause or causes of the
reported improvements. It
would be difficult to
accept shelving the
results of this study. We
base our convictions on
the fact that the
improvement in mobility
reported in these children
after two months of
hyperbaric treatment is
similar to that measured
after six months of
intensive physical therapy
(twice a week).
Furthermore the children
involved in this study
showed improvements in
language and
neuropsychological
evaluations as well as
mobility. Finally, the
improvements persisted for
at least three months
post-treatment (as
verified scientifically).
It
is our opinion that in
order to properly
investigate the different
hypotheses raised, a
double-blind study must be
conducted where a true
placebo would be compared
to different treatments
(oxygen alone, hyperbaric
treatment alone and
hyperbaric oxygen). It is
clear that we could not
recruit enough subjects
for such a thorough study
in Quebec. A multi-center
Canadian or international
study would have to be
considered . This study
would require many months
or years to plan, finance
and realize. Furthermore
it would require
hyperbaric chambers that
are not available at the
present time in the
Quebec's public health
care system. Finally, even
though we did not
definitively identify the
cause or causes of the
improvements, we are
convinced that these
results will encourage
parents to continue to
pursue hyperbaric
treatments for their
children. For these
reasons, we recommend that
at least one or more
hyperbaric treatment
centers remain open in
Quebec.
H.
Proposal to maintain one
or more hyperbaric
treatment centers in
operation For the above
mentioned reasons we
propose:
-to
maintain one or more
hyperbaric treatment
centers in operation
-to
make these centers readily
available to treat
patients presenting a
chronic, non-progressive
encephalopathy , at their
own expense
These
centers should assume, in
part, the responsibility
of systematically
evaluating the patients
undergoing hyperbaric
treatment with a validated
detailed questionnaire
such as the PEDI.
Depending on their means,
they should also evaluate
mobility, language and
cognition with as many
subjects as possible.
These centers should also
agree to participate with
any efforts to conduct a
multi-centre Canadian or
international study.
If
one or more centers
continue to operate and
administer treatments in
Quebec it would:
-avoid
the need for parents to
travel to Ontario or
elsewhere (with all of the
expenses and hardship it
entails) in order to
receive treatments often
administered without any
medical supervision nor
pre and post treatment
evaluation.
-allow
us to continue to study
the effects of this
treatment. Although we are
well aware that it would
not be a double-blind
study, it seems clear that
the systematic evaluation
process that we recommend
is better than no
evaluation at all.
-maintain
the centers best prepared
to participate in a multi-centre
study due to their
geographic location and
their ability to treat
many subjects at once.
Pierre
Marois, physiatrist
Michel Vanasse,
neurologist
Dr.
Philip James critques the
above commentary:
Unfortunately
Pierre Marois has not
referred to his previous
statement that the
children in the group
given oxygen at 1.75 ATA
were significantly more
disabled and yet improved
faster than the
compressed-air treated
group, but this is
probably being diplomatic.
The
central issues
1.
Were the improvements
found in BOTH groups a
placebo/participation
effect?
This is analysed
thoroughly by Marois and
Vanasse, but a critical
recent study must be
referenced. (Dev Med Child
Neurol 2002;45:4-15) Six
months of intensive
physiotherapy did not
produce evidence of
benefit. Note that for the
Canadian study all drugs
AND physiotherapy were
withdrawn.
2.
Is compressed-air at 1.3
ATA a placebo?
The
paper states that
physicians on BOTH sides
of the controversy in
Quebec agreed to the
statement that there is
'no irrefutable proof
illustrating that a HBO
treatment at low pressure
is effective in humans'.
This illustrates that the
fundamentals relating to
oxygen and barometric
pressure are NOT taught to
doctors in training and
not just in Quebec!
The
proof is IRREFUTABLE.
1.
Air at 1.3 ATA provides
the equivalent of 28%
oxygen at normal
atmospheric pressure. This
level of oxygen is
constantly used in every
hospital in the support of
patients with respiratory
and cardiac problems.
2.
Low pressure compressed
air treatment has been
standard practice for the
last 150 years for
thousands of
compressed-air workers and
divers.
3.
A small increase in the
partial pressure of oxygen
with a descent from high
altitude can reverse life
threatening cerebral
oedema. In Bolivia
recently, students who
developed severe mountain
sickness after ascending
to 5,400 metres (0.5 ATA)
from La Paz (3,600 metres,
0.65 ATA) had relief of
all symptoms on descent,
even before reaching La
Paz. This is a pressure
increase of less than 0.15
ATA. This improvement has
been experienced by
thousands of climbers over
the last hundred years.
The
CP story is a repeat of
the MS oxygen story.
Normally doctors research
a treatment because they
are convinced that it is
beneficial. They are often
then TOO enthusiastic
about their results,
especially when drug
company money is involved.
In both MS and CP the
doctors conducting the
oxygen trials have NOT
been enthusiastic about
the treatment and several
have denied a positive
result. Thankfully, Drs.
Marois and Vanasse have
the courage of their
convictions.
Dr
P B James MB ChB DIH PhD
FFOM
Wolfson Hyperbaric
Medicine Unit
University of Dundee
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