Optimizing Outcomes
     Breakthrough to a Cure  
Welcome!   Make This My Homepage
Home | Donate |About Us | Discussion Group | Treatments and Research | Current Treatments | The Bright Project | Advocacy and Education | For the Professional | News | Case Studies | Contact Us | Advisory Panel | Search
The HBOT Debate
 

BRIGHT is very excited to have Pierre Marois, MD, FRCP(C) join BRIGHT's Scientific Advisory Board.  Dr. Marois has been an outspoken critic of the famed Collet study that drew the conclusion that HBOT has no more benefit for children with CP than the control group.

Below is a brief summary of the history of this debate.  Although it makes for colorful reading, BRIGHT feels that it has been an extremely unproductive chapter in the quest to find effective treatments for our children.  Work continues on HBOT and hopefully in the near future we will have a better understanding of this therapy.

 

The Opponents to HBOT:

Doubt Casted on Cerebral Palsy Treatment

By EMMA ROSS
.c The Associated Press

LONDON (Feb. 23, 2001) - Children with cerebral palsy get no benefit from expensive high-pressure oxygen treatment, a highly touted alternative therapy, new research has found.

A study published this week in The Lancet medical journal is the
first to properly investigate whether the technique improves the
lives of children with the incurable disability.

''This is one of a long succession of alleged treatments for cerebral
palsy that have come and gone, and this was by far the best
researched,'' said Dr. Peter Rosenbaum, a cerebral palsy expert who
was not involved in the study.

Children given slightly pressurized air improved just as much as
those treated in high-pressure oxygen chambers, the study found.

Though most experts said they thought the findings proved high-
pressure treatment was useless, proponents said the improvement in
the comparison group means even slightly pressurized air helps.

Cerebral palsy is a collection of diverse syndromes characterized by
movement disorders and is caused by brain damage before, during or
just after birth. It affects two in every 1,000 babies in the
industrialized world, and is sometimes caused when not enough oxygen
gets to the brain.

''The logic that we can repair brain impairment caused by oxygen
deprivation by supplying more oxygen after the damage has been done
is just crazy,'' said Rosenbaum, chair of the childhood research
center at McMaster University in Hamilton, Ontario.

''The underlying brain damage is permanent, and neither improves nor
worsens,'' Rosenbaum said.

Experts say that in the early years physiotherapy and drugs can help
children improve their motor function. As the child grows, the
acquisition of skills slows and therapy is geared toward preventing
deterioration, experts say.

High-pressure, or hyperbaric, oxygen is usually used to treat carbon
monoxide poisoning, some infectious diseases and to protect bones
before radiation therapy.

Its use in cerebral palsy has spread as testimonials of successful
treatment circulated among families of stricken children.

''It's hard to know the exact number, but there are many centers
doing it. It's a big business in the United States, and there are
also centers in the U.K. and Canada,'' said the study's leader, Dr.
Jean-Paul Collet, a professor of clinical research at McGill
University in Montreal. ''This is a classic situation of people in a
desperate situation. They are ready to try anything.''

Collet's study involved 111 children with cerebral palsy age 3 to 12.
Half were given high-pressure pure oxygen and half got air
pressurized to the lowest pressure that can be felt. Parents did not
know which treatment their children were getting.

The children got 40 daily sessions over eight weeks and were tested
after 20 sessions, after their last treatment and three months later.

The two groups' test scores improved by the same amount and the
changes persisted three months after the treatment. The greatest
improvements were seen in the children who started with low scores.

Even the slightly pressurized air increased the concentration of
oxygen in the blood. The normal level is 100 milliliters of mercury.
Slightly pressurized air pushed that up to 148 milliliters, while the
high-pressure oxygen increased it to 1,230 milliliters.

Collet said the findings don't mean extra oxygen goes to the brain,
but that it can't be ruled out.

''An increase to 148 may be enough to have an effect on motor
function, but we'd have to compare improvements with (unpressurized)
air to see if that's the case,'' he said.

Collet said he believes the children improved because their brains
were stimulated by the excitement of getting into a pressure chamber.

 

 

 

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 sant╚ 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 r╚adaptation en d╚ficience physique de Qu╚bec 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

 

 

Home | Donate |About Us | Discussion Group | Treatments and Research | Current Treatments | The Bright Project | Advocacy and Education | For the Professional | News | Case Studies | Contact Us | Advisory Panel | Search