Comments on the report by the scientific advisory committee
''Hyperbaric oxygen therapy for children with cerebral palsy:
A multicenter randomised clinical trial''
Prepared by Pierre Marois, physiatre
In this document, we will make comments on the report of the scientific advisory committee (1), bringing another perspective on some elements that, in our view, appear to be vague or inaccurate. We feel it it is important to situate the context in which this advisory scientific committee has acted to possibly produce a such report.
Far from wanting to denigrate the work of the professionals of this Committee that have invested themselves, with their knowledge and their beliefs, this document will present another angle to look at THE REALITY and certainly justify the dispute initiated by some researchers and the families who were implicated in this research.
Let's therefore recap some elements that will situate the context in which the scientific Committee has been put in place. First of all, it is necessary to remember the commitment of Minister Rochon, that was released in a communique on July 16 1999 that tells this: "being sensitive to the hope aroused by this treatment for children affected by this illness, the Minister has indicated that the best scientific resources from the province of Quebec will be mobilized ". The following was also added in this communique, "it therefore appears important to us, concluded the Minister, that we undertake to clarify the question of the efficacy of this treatment''.
We certainly believe that the best scientific resources in Quebec having the expertise in the studied area, have been involved, like the Minister wanted. However, it is intriguing that their contribution has been dismissed at the most important stage of all this research, that is to say, at the time of the analysis and interpretation of the results. It is at this phase that clinicians, epidemiologists and researchers who had the expertise had to put to contribution all their knowledge and experience to clearly interpret the results of this study, which has not been the case. What renders this situation even more odious is the fact that it concerned a clinical research and that the contribution of the clinicians in this
project has been rejected at the most critical moment.
(1) This committee was not planned in the protocol, and created at the last minute by the Q.H.R.F. - Quebec Health Research Fund (F.R.S.Q. Fond de Recherche en Santé du Québec) against the approval of the researchers that were never met, except through the president of the Committee, to transmit their own conclusions.
To illustrate the process by which the analysis and the interpretation of results of the research has been achieved, here are some facts.
The treatment of the last children has been made on the week of January 9, 2000, but the analysis of the results has already been started at this time by Dr. Collet's team at the Center of clinical epidemiology and public health research of the Jewish General Hospital.
In a letter sent by Dr. Collet on January 24 to all the researchers, (document 1) the billbook of all the analysis and the evaluation of the results is anticipated and Dr. Collet forms an advisory Committee for the interpretation of these results. On January 28, 2000, Dr. Marois wrote a letter to Dr. Collet (document 2) reminding him this: ''you know just as I do, that the way to analyze the datas and to interpret the results can have a major influence on the conclusion of this research. On this point, I can only approve your procedure, to select all persons that will be able to shed light for you on the best manners to see and intervene. I am however surprised that you do not request at the same time the expertise and experience of your co researchers and collaborators in this research.''
Dr. Collet quickly replies in a letter dated February 3rd in which the following line can be read:
''... do not believe that I want to shunt anyone in regard to the analysis of the datas''. '' I know by experience that clinicians are not comfortable with these questions. (Is this true? Was the question ever presented to them ?). This is why the meeting of February 23rd with the advisory Committee is reserved to the methodologists researchers''. ''However, before this meeting, results will be discussed with the clinicians of the project - you especially, considering your experience - with the aim to prepare the results to be presented to the advisory Committee''.
There has been no follow-up to this letter, Dr. Marois has never been invited to meet Dr. Collet and to review the results before they were presented to the Advisory Committee, that has effectively assembled on 23rd February. No clinicians has ever been able to see the datas before this meeting.
End of February, during a breakfast, Doctors Jean-Paul Collet and Pierre Boyle, announced to Doctor Michel Vanasse, that the analysis is completed and that the research demonstrates that there is no significant difference between the two groups which means that the hyperbaric treatment is ineffective. These results have been announced to the Ministry of Research during a meeting with the Doctor Jean Rochon. Already, it has been suggested to eventually explore only the psychological aspects by offering more support to families and by looking at which forms of stimulation could beneficial for the children. Conclusions were already drawned and the eventual exploration ways already chosen but excluding the possibility of the physiological effect of the treatment. No one among the main researchers besides Dr. Collet has had the opportunity to look at the results and none of the clinician researchers had ever been able to emit the slighest comment since they received no information in their hands.
It's only a month later, March 31 2000, that Dr. Collet sent to the different researchers, an invitation (document 4) for a meeting so that they could examine the results ~ internally ~. It was the first meeting of the group of researchers and the Director Committee since the month of September. It has to be noted that the executive Committee, the follow-up Committee, or the security Committee, which were all committees scheduled into the research protocol, were never called for a meeting during the course of the study.
On April 6, 2000, Dr. Collet presents all the results mentioning furthermore, that a meeting with Doctor Jean Rochon (Minister of Health) occurred and that recommendations were already made, suggesting to eventually explore various ways to further stimulate the children because it was the stimulations that these children have received during the course of the study, that emerge as being the main cause for the improvements observed.
During this meeting, the totality of results are presented and what appears very evident is the great improvement observed in the two groups of children that have participated in this research. Dr. Collet presents the article that he had already written, that proposes that the stimulation or also the psychological effects, such as the placebo effect or the Hawthorne effect, are responsible for the improvements observed during the research. The group of researchers opposes to this abusive interpretation and demand to Dr. Collet to modify its conclusions to reflect the more nuanced consensus of the researchers. Dr. Collet has committed to modify the discussion and conclusion of the article before submiting it for publication.
Unfortunately, a few days later, the article is sent and submitted for publication without the modifications requested by the researchers and this, despite Dr. Jean Paul Collet's commitment. Several letters have followed this meeting of April 06 (documents 5, 6, 7, 8). Each of these letters aimed at bringing more light on the interpretation of the datas. As the commitments made by Dr. Collet with respect to the requested modifications were not respected, they were asking for an urgency meeting of the Committee of researchers so as to make the point on the situation. Letters have also been sent to Doctor Pierre Boyle, general director of the Q.H.R.F.. They have remained unanswered despite a letter signed by four researchers.
¢ It's finally only on May 5 2000 that the totality of researchers has been united again after a convocation by Dr. Pierre Boyle of the Q.H.R.F.. Dr. Pierre Boyle has directed this meeting. He first tried to exclude the participation of the parents representative that had to sit on this Director Committee as outlined into the protocol. Furthermore, he has not respected the order of the day submitted to the researchers since a discussion had been planned to evaluate the next steps to be initiated after the study on hyperbaric oxygen therapy.
During this meeting, four hypothesis have been submitted to the researchers and only two of these hypothesis have been accepted as to be possibly retained for subsequent analysis. From the start, the hypothesis of the natural evolution has been excluded after a very clear demonstration of its impossibility and the other hypothesis of the effect of the training to the test, in light of the results of the three month post-treatment evaluation, was equally rejected. The group of researchers has retained only two hypothesis which are the psychological effects and the physiological effects. When the time came to approach the discussion on the continuation follow-up to give to this research, Dr. Boyle has rapidly ended the meeting after having asked the group of researchers if they accepted that an independent expert group would be hired to revise the research datas. This has been objected by the group of researchers that wished, to first assemble to further push the reflection on the results of the research and the following steps to initiate from there.
It's only on May 24 2000, that the researchers have been again called for a meeting, not to continue the discussion on this research, but to transmit the recommendations and conclusions of the scientific advisory committee that was created against the researchers approval by the Quebec Health Research Fund who met the same morning. The president of this committee, the Dr. Aurore Côté was present to the May 24th meeting with the researchers and has transmitted her conclusions and recommendations. Several researchers have demonstrated their opposition to this report that recognized the four hypothesis as being plausible and that gave more importance to some hypothesis as over the others. Physiological effects were relayed to the last plan while the psychological effects or the placebo effect were recognized as the most plausible hypothesis while there was no scientific justification behind this notice. When Dr. Côté has been asked on what foundation they arrived at such conclusions, she replied that the members of the Committee believed more in the psychological effects than the physiological effects in the context of this research. And it is therefore on beliefs rather than on scientific evidences that the conclusions of the Scientific advisory committee have been based.
It is surprising that this Scientific advisory committee has emitted these hypothesis without justifying them scientifically and without ever meeting the main researchers implied in this research. It is equally surprising that none of the Committees that were planned into the protocol has ever been met previously and that none of these Committees has ever ratified the conclusions of the Scientific advisory committee.
It was anticipated to make a presentation to the parents on May 26 2000 at Ste-Justine Hospital, to inform them about the results of this study along with the conclusions of the researchers. During the meeting at the Q.H.R.F. on May 24th 2000, several researchers have shared their desire to be present during the presentation made by Dr. Collet to the parents. Doctor Pierre Boyle has refused that the researchers who did participate in this study could assist to this meeting, pretexting that the researchers had their meeting on May 24 and that the parents had their meeting on May 26. Doctor Aurore Côté, president of the Scientific advisory committee was however invited to come to present the results, but she declined it on the spot in front of the team of researchers.
The same day on the the evening of May 24 2000, representatives from the Q.H.R.F., Doctor Jean-Paul Collet, representatives of the College of Physicians and Doctor Aurore Côté did procede to some meetings at Hospital Sainte-Justine with the chiefs of pediatrics departments of Hospital Sainte-Justine and Children Hospital of Montreal and with chiefs of physiatry and neurology of the same hospitals. They tried to convince them to come to present the results to families and to support their conclusions. This meeting in force did not produced the expected effects, because the different departments and service chiefs refused to come and present the results and proposed them instead to invite the researchers to do the presentation themselves and suggest tracks of research to explore eventually.
On May 26 2000, there has been a presentation of the result to the parents by some representatives from the Quebec Health Research Fund, like the president Doctor Bureau, and Doctor Boyle, general manager. Were equally present, doctors Jean-Paul Collet and Aurore Côté, this last being president of the Scientific advisory committee.
The parents have expressed their surprise to Dr. Collet about the fact that none of the known researchers who were involved in this project since the beginning were present. They have replied that the researchers were invited, which was totally false. Furthermore, during this meeting, on several occasions, they have lied to the parents by trying to persuade them that the treatment at 1,3 atmosphere was the equivalent of taking a syrup "with nothing more than sugar" asserting that the treatment at 1,3 atmosphere was not an hyperbaric treatment (which is equally false). They have also said that the recommendations of the Scientific advisory committee were only preliminary recommendations without effect, while official press release, emitted the same day, by the Q.H.R.F. and the Ministry of the Research were closing all the doors regarding the exploration of this treatment. They have mentioned to the parents that only thirty one children out of one hundred and ten had made progress while the reality is that thirty one children out of one hundred and ten have made progress of more than 5% on the GMFM (which is spectacular) and that there are more than twice that number that have made real progress.
During this same meeting held on May 26th 2000, the general manager and the President of the Q.H.R.F. have attempted to discredit several researchers and this in two ways. They have asserted that some researchers were in conflict of interest while this was totally false and already recongized by several ethics committees. They have also tried to demonstrate that the opinion of the researcher clinicians of the project had few weight, because it concerned the Monday morning or Friday afternoon researchers, while others researchers truly made full time research(2).
(2) Parents have recorded all the meeting and the recording is available for consultation.
It is clear that the manner by which all the analysis process, interpretation and presentation of the results, etc., has been managed does certainly not respect the deontology and ethics codes surrounding any research process. It is surprising that ''the best scientific resources in Quebec'' have been excluded from the analysis process, the presentation to the parents, and all discussions concerning following steps for this research. It is surprising that the Fund of the Research in Health of Quebec only considers the conclusions of people that have never been approached to make this research, since the Q.H.R.F. had the mandate to regroup the best resources in the province of Quebec. It is equally surprising that they have given all authority to this Committee that has been able to contradict and counterfeit, during a two hours meeting, the work of more than a year accomplished by the whole team of researchers that has been initially designated by the Ministry, and this, without ever having allowed them to confront their ideas by meeting with them.
It is incredible finally, that they had the audacity and the indecency to exclude the researchers from the presentation to parents and to lie about several elements in order to discredit several researchers like the clinicians of this clinic research.
Today is September 22nd 2000. There has been no new contact or meetings with the researchers. The future of this research and the steps to follow are between the hands of the Scientific advisory committee, the Quebec Health Research Fund of and the Ministry of Research that have emitted press release that very clearly claim the inefficacy of the
Hyperbaric treatment and which excludes the clinical exploration tracks of this treatment.
It is certainly not exaggerated to say that the scientific process has been short circuited and that it proved to be lacking neutrality, transparency and integrity. It is unfortunately under this context that the Scientific advisory committee work's has been achieved.
Finally, it is odious and scandalous that the Ministry of the Research, the Q.H.R.F. as well as Dr. Collet, are continuously announcing their conclusions as if they were those of the team of researchers. The recognition of the four hypothesis, the preponderance of the plausibility of the psychological hypothesis as well as the rejection of the physiological hypothesis are not the conclusions of the researchers, but only of the Scientific advisory committee.
On top of that, it is dishonest to lie to the population, the scientific community as well as the medias by relentlessly presenting the treatment at 1,3 atmosphere as an inert placebo, which is definitely not the case.
Comments on the document
Composition of the committee
Firstly, with regard to the composition of the Scientific advisory committee, the intent is not to discredit any members of this Committee. They all have a recognized expertise. It is nevertheless important to mention that even before this research was started, the majority of members of this committee had already pronounced themselves to be against this research on hyperbaric oxygen therapy for children affected by cerebral palsy, because they did not believe that there were scientific evidences to justify it. Four members of this committee also had seats on the committee that had the mandate to analyze the proposed research, at the request of the Ministry of Health in order to determine if the interest for this research was sufficiently important so that it would possibly be financed by the Ministry of Health and Research. The members have unanimously appeared closed to the financing of this research. Furthermore, other members of the Scientific advisory committee had already demonstrated their resistance in regard to the possibilities of hyperbaric treatment positive effect on children affected by cerebral palsy. Without questioning their integrity, several members of this committee were not in a position of impartiality having already demonstrated their negative position well before this research was initiated.
Was it really an objective and neutral committee, while the majority of members had not demonstrated any openmindedness towards this research or to the possibility of positive effect of the hyperbaric treatment.
Our comments will focus on the most important points, analysing each page of the document submitted by the Scientific advisory committee.
Validity of the study
On page 3 of the French text, the item ''validity of the study'', it is concluded that the hyperbaric oxygen therapy did not improve the condition of children affected by cerebral palsy in comparison to the administration of a placebo. It is surprising that they do not define this placebo in this sentence while everyone knows that it is not a true placebo. It was an active treatment, since children were submitted to a pressure of 1,3 atmosphere which had the effect of increasing by more than 50% the pressure in oxygen in their bodies. It was also an hyperbaric therapy.
On page 3, it is asserted that the four hypothesis have been presented by the team of researchers, which is totally false. Only two hypothesis had been retained by the team of researchers during the meeting at the beginning of the month of May. Additionally, the hypothesis have not been submitted by the team of researchers but rather by the Quebec Health Research Fund, since the team of researchers was opposed at the time to the constitution of the Scientific advisory committee preferring to continue its works before creating this committee.
The other comments will refer to the English document, which is more complete than the summary written in French.
Objectives of the study
On page 9, among the objectives of the study, they have forgot to mention that, besides the evaluation after 20 and 40 treatments, there was a 3 month post-treatment evaluation to verify if there had been a retention or an improvement of effects observed during the hyperbaric treatments. Therefore, it is an extremely important methodological element allowing to justify and to ponder some hypothesis.
To the methodology item, it would have been important to mention that all conventional therapies for these children, like physiotherapy, ergotherapy and orthophony have been stopped during hyperbaric treatments and that even medications aiming to decrease the spasticity have been equally abandoned during this period. These therapeutic approaches have been resumed immediately at the end of the hyperbaric treatments so that, during the three months that have followed hyperbaric treatment, children were submitted again to their usual treatment.
On page 9, it is surprising that the Scientific advisory committee makes no mention of the three month post-treatment results, results that has already been submitted to them previously. These results have had an extremely important impact on the analysis and the classification of the hypothesis, which rejected two of these hypothesis as non-plausible. We will shed more light on this later. At this stage, it is important to mention that on the GMFM scale, there has been 3% improvement in the ''placebo'' group during the two months of hyperbaric treatments and that this percentage of progress was increased by another 0,1% three months later, to reach 3.1%. In the group receiving the treatment at 1,75 atmosphere, there was a 0,5% improvement in the three months that followed the interruption of hyperbaric treatments being added to 2,9% reached in the course of the treatments for a total of 3,4%. It would have been equally important to mention that there was an initial 15% difference between the two groups : the group of children receiving the 1,75 atmosphere treatment being significantly more handicapped than the group receiving the ''placebo'' treatment. The relative progress percentage, that is to say, the percentage of progress as compared to the starting point in each groups is no longer identical if we are taking into account these initial differences. This can not change the conclusions of this study but could have be taken into consideration when we look at the steps to follow after this research.
Furthermore, when we look at the evolution of children in the three months that have followed the hyperbaric treatment, and that we observe that they have evolved an additionnal 0,1% in the ''placebo'' group and by another 0,5%, in the group at 1,75 atmosphere, it is easier to see the importance of effects observed in this research. Indeed, the two groups of children have evolved 10 times more (an average of 3%) during the 2 months of treatments in a hyperbaric chamber with either one of the treatments that they have received (while all therapies were stopped), than during the three months that have followed (an average of 0,3%), while they had resumed their usual therapies. It is strongly surprising as well to see that these datas are not mentioned by the Scientific advisory committee who already had them at their disposal.
Is this to say that the 1,75 atm. treatment has allowed a greater improvement or retention of the positive effects? This is strongly interesting, especially in light of what is known about the usual evolution of persons having a neurological condition while they are in recovery and readaptation phase.
Hypothesis 1: Physiological hypothesis
On page 11, hypothesis 1, it is presented that the ''placebo'' group that has received ambient air at a pressure of 1,3 atmosphere had an increase of approximately 50% in partial pressure of oxygen. This data proves that this was not an inert treatment or a placebo. It is equally important to remind a fact: the partial pressure calculation for ''in-vitro'' oxygen would effectively give an increase of 50%. Nevertheless, the real increase is by more than 50% because, besides the effect of the pressure increasing the partial pressure in oxygen, children were in a situation where they were hyperventilating. The temperature in a hyperbaric chamber is extremely high, often reaching more than 30 to 35 degrees centigrade and children were equally in a situation of ''stress'' increasing their respiratory rhythm. The real increase of the pressure in oxygen was certainly more in the order 60 to 70% when we take into account some of these "in-vivo" physical factors, what is once more backing up the affirmation that the ''placebo'' treatment was an active treatment.
I would like to make a comment here on the ''placebo'' treatment. It is true that the 1,3 atm. treatment has been retained at the beginning, as the placebo treatment, because it was commonly used as one, in research projects on hyperbaric oxygen therapy in others conditions. Nevertheless, even if the efficiency of hyperbaric oxygen therapy is demonstrated in the treatment of cerebral palsy, the mechanisms of actions would again be totally unknown. However, it could be certainly suspected that the mechanisms of actions are strongly different from those accepted in the treatment of carbon monoxyde intoxication or decompression incidents. We are far from being able to demonstrate that it was a valid placebo in the context of this research. Also, since the start-up, some researchers feared that the placebo used is not sufficiently inert in the current research. It is not because a given treatment is considered as a good placebo in a condition, that it is automatically the same thing in another condition. Aspirin at 80 mg/day doses could have been considered as an excellent placebo in a study on post-surgery severe pains, it would nevertheless be considered the worst placebo that could be used in a study about the prevention of thrombotic phenomenon.
Aside from that, to the question if there is a scientific evidence sustaining that oxygen at low doses (equivalent to the 1,3 atmosphere treatment) has a therapeutic effect, members of the scientific advisory committee confess that they have not been capable to find one single study exploring effects of oxygen to low doses. They have also noticed that several studies have been performed with oxygen at higher doses demonstrating the effects on cognitive performances, among others, studies made with 100%oxygen breathed for very brief periods.
Furthermore, several studies are currently under way in the U.S. or elsewhere in the world, on the utilization of small dose of oxygen. They seem to demonstrate some effects on cerebral lesions. Unfortunately manuscripts are available yet but, contacts with researchers such as Doctor Paul Harch in Louisiana confirm the interest of the research in this direction.
As there is no study that has explored the effects of oxygen at small doses on physiological functions, (''on subjects that had a normal oxygenation in the beginning ''), there is certainly no argument in favor or in disfavor of potential positive effects. It's not because there are no studies on a given treatment that it demonstrates the inefficiency of this treatment.
Also, the second study and the fourth study quoted by the Scientific advisory committee to analyze hypothesis 1-A, do not bring anything to the discussion on the current research. They relate to other clinical indications that have nothing to do with the cerebral physiology.
Study number 3, that has been made on rats, demonstrated the effects of hyperbaric treatment on cerebral lesions when the treatment was initiated early after the lesion occurred. No rigorous study has ever performed with hyperbaric treatment on chronic neurological lesions (such as cerebral palsy). Nevertheless, there are many anecdotes, testimonies, case studies, non-randomised studies and two pilot projects that seem to demonstrate effects on neurological lesions even after several months or years after the lesions.
In conclusion, the members of the Scientific advisory committee did signal that studies have demonstrated that, when there is an effect, it is at a pressure high in oxygen and not to at levels just above normal values, such as found in the placebo group of our study. Again, it is important to mention that no study has been made on low concentrations of oxygen, and that the non existence of studies does not allow to draw conclusions as to the efficacy or the inefficacy of oxygen at small dose. It goes similarly with the moment of the administration of oxygen where no systematic study has been made on chronic neurological lesions besides two pilot projects realized by researchers of Texas and Quebec demonstrating important evidences of change for several children.
The conclusion at the bottom of page 12, tells this: taken together, these published studies do not support an effect of oxygen to explain the changes in coarse motor functions of the placebo group. The contrary is also as true, because these studies do not contradict the possibility of an effect of oxygen to explain the observed changes. Also, if there has never been (as the committee said) any studies recreating the conditions of the ''placebo'' group, it would be therefore very surprising that these studies that do not exist could support or invalidate any one of the hypothesis.
Furthermore, the explanation that follows on page 13, where we see only two possibilities to explain the similar results in the two groups is extremely simplistic and applies difficultly to a situation infinitely more complex, that of children affected by cerebral palsy whose nature and the cause of lesions are often very different from one case to the other. On the other hand, a ''plateau'' effect is a well known effect and found in several studies contrarily to what has been affirmed by the members of the committee.
With regard to hypothesis 1-B, we agree with the conclusion, that there are no scientific evidences for an effect of oxygen or pressure at low doses to explain the changes observed in the child motor functions observed during the study. Once again, the contrary is also as true.
In front of the total ignorance of the effects of oxygen at low doses, on chronic lesions and even of the effects of the pressure, I hardly see how the Scientific advisory committee has been able to assert that this hypothesis 1.1 was unlikely and that hypothesis 1.2 very unlikely. It's not because we do not know something, that we do not understand something, and which has never been explored before, that allows someone to close the door on an hypothesis.
Furthermore, during international congress of the Undersea and Hyperbaric Medical Society in Stockholm, in July 2000, the results of the research have been presented by Doctor Stéphane Tremblay. Several international experts have suggested to him to continue the research on effects of the pressure or oxygen at small dose, raising and questioning the possibility of the physiological effect of the treatment at 1,3 atmosphere (cf. document 9). During the presentation in Toronto a couple of weeks ago, Doctor Michel Vanasse who served as a speaker recalls that the same comments and questions have been raised.
Hypothesis 2: Psychological effects
Hypothesis 2 is relative to effects of the participation in a clinic study. An article is quoted that presents a research on premature children. Effectively, in this study, children that have received a placebo have evolved better than children that have not participated in this study but the difference, if it is statistically acceptable, is very minimal. Days of hospitalization have slightly decrease and there was a bit less cerebral lesions in the group of ''placebo'' children as compared to the other group. But, in the actual study, we are in front of an incredible ''placebo'' effect since the children have evolved ten times more than in a normal situation (during the three months that have followed their hyperbaric therapy).
The placebo effect observed during the research, (and it is apparently the most plausible hypothesis according to members of the Scientific advisory committee) is certainly the most spectacular placebo effect ever demonstrated in Science, being more efficient than the recognized therapies that are paid by the State.
We recognize that the effects attributed to the selection, to the adherence, to a well definite protocol and to the placebo effect have certainly been able to contribute to the improvement observed in the state of the children that have participated in the research. However, once again, if we attribute the measured improvements in these children solely to these factors. this would be the most impressive result ever achieved. This must absolutely be considered to shade our discussion with respect to the plausibility of this hypothesis that, without being rejected, does certainly not deserve to be attributed a very high level of plausibility. I do not see on what scientific and logical basis the members of the Scientific advisory committee have arrived at this conclusion.
It is as important to take into account studies that have been made in the past, for this specific clientele. They have never been able to demonstrate any significant placebo effects. If furthermore, they attribute all the improvements observed during the research to the "placebo" effect or to the psychological effects, it would be necessary then to consider that therapeutic approaches such as intensive physiotherapy are totally useless since studies made among a population of children affected of cerebral palsy that received the intensive physiotherapy demonstrate less positive effects than these observed with the placebo treatment received by the children, in the course of our research.
Hypothesis 3: Effect of training to the test
Page 15. There is an evident contradiction in this paragraph. Members of the Scientific advisory committee recognize themselves the improbability of effects of the training to the test bestowed during this study, because the GMFM is recognized as a tool of observation of what the child is able to do. The scientific advisory committee writes ''it is thus unlikely that the training of children to the test has had a significant effect, particularly on the GMFM scale, even if a small effect is possible''. Nevertheless, when they summarize their position at the end of the paragraph, the term ''unlikely'' has become ''possible''. According to the members of this committee, this hypothesis even ranks in second place to the level of its plausibility to not only explain the small effects but the totality of the impressive effects !
(translation needs to be corrected from this point)
One of the important elements that allows to exclude the effect of training as plausible hypothesis is the fact that if this effect of training had proven an important factor, these children that have had a significant improvement during the two months of treatments should have equally had an improvement of their performance all as significant when they have been re-evaluated three month @@post - treatments. They made tests a time news! This has not been found and the factor of training to the test, if it has been in cause, has certainly been light and can not explain the evolution found at children, especially when one sees results a more precise bit, some children improving more of 10 or 15% drawn to scale ++GMFM during the two months of processing, what is a spectacular evolution.
The hypothesis 3, can not certainly be retained as a probable hypothesis, the less to explain the totality of results observed.
Hypothesis 4: natural evolution
@@ll concerns the mistletoe hypothesis proposes that the evolution of 3% drawn to scale ++GMFM represents a normal child evolution affected of cerebral palsy. Members of the committee claim that it is necessary to wait results of the study of the Doctor ++Rosenbaum to to be in measure to evaluate this hypothesis. This position leaves to glide a doubt on the plausibility of this hypothesis. Gold, researchers have made the demonstration that it was inadmissible and odd.
Firstly, the average of the starting point to the ++GMFM of children of the project, was approximately 60%. The average child age in this research was 7,2 years, that is to say 86 month. What means that the average of evolution (in term of percentage by month) since the birth at these children that have participated in the research has been 0,69% (60/86) (compared to 1,5 by month during the hyperbaric treatment). Gold, these that know the development of the child, and curves of the ++GMFM that measure it, know very although curves are the @@expotentielles inverted that flatten very rapidly after the age of a year, it doesn't matter the importance of the handicap (diagram #1). in other words, the slope of the evolution in the first year is raised and the percentage of evolutionas the child ages. To the average age of 7, 2 years, the curve is almost flat and it is elsewhere what one observes @@cliniquement. If the average child evolution during the research has been 0,69 by month since their birth, one can easily presume, without no risk to deceive, what was far more small to 7,2 years. It is a slope that would have far more to near 0,1 or 0,2% by month. Elsewhere, the steady three month @@post - processing of children that had resumed their usual therapies and their medications, demonstrates it clearly: children of the project during the three months that have followed, have evolved according to the rhythm of progression of 0,1% by month @@versus of 1,5% by month during the processing in bedroom @@hyperbare. The more elaborate analysis of the even child evolution that have participated in the research, since their birth, and followed it by these children in the three months @@post - processing demonstrates clearly that it can not concern a natural evolution and that, during the research, these children have evolved far more rapidly that in natural conditions.
Therefore, one has no null need the study of the Doctor Rosenbaum, study that, furthermore, can be extremely interesting, to conclude that the hypothesis 4 is inadmissible.
Nevertheless this demonstration has been made to members of the scientific advisory committee and I am surprised that it in has made no mention.
More, in the document, one makes mention a study that has been made on children affected of cerebral palsy where one has observed in the four space month, changes of 3,5% to the ++GMFM while children were submitted to the intensive physiotherapy twice by week. These results have been observed at a group of far more young children that these included in the current study. Then, how can - one to believe that 1,5% by month could be a natural evolution while the quoted study does not bring changes of 0.9% by month at the young children that have a potential of far more rapid evolution and that were submitted to intensive therapies. Thus, even arguments brought by members of the scientific advisory committee eliminate this hypothesis.
Summary of plausibility degrees
To the summary of plausibility degrees of each hypothesis, page 16, it is again difficult to understand how the degree of plausibility has been established. While it there has no mistletoe study has explored hypothesis 1.1, 1.2. the scientific advisory committee is capable to give them a degree of plausibility . One grants it even a little degree raised.
The hypothesis 2, although this is a @@''premièré' in favor the importance of an effect placebo (in this senses that observed effects are many times superior all recognized conventional therapies), receives the highest level of plausibility.
In the hypothesis 3, members of the scientific advisory committee have themselves written that it was unlikely that there has been an effect of training on drawn to scale result ++GMFM. Nevertheless, they classify this hypothesis as the second more plausible.
(It is difficult to understand the used scale while @@''possiblé' is more raised @@''qúimprobablé'. It is indeed possible that I could earn 1 million to lotto this evening, although that is well unlikely. According to what scale does one place the possible ahead the unlikely?)
We think that the most probable hypothesis is certainly a fifth hypothesis, that is to say, a combination of several factors. It is clear that these children have benefitted certain dune natural evolution during this research. It can not nevertheless explain the importance of results observed. On the other hand, it is strong probable that there has been a small due training effect to tests, even if the ++GMFM is not recognized as a test @@''sensiblé'' to effects of training. It is very possible that there has been an effect or psychological effects what that they are, on which have come to be added physiological effects what that they are. Unfortunately, the study does not allow from to separate or to identify what factor has played the most, and each is returned to its clean convictions, its clean beliefs, its clean experiences to define a degree of plausibility, what we would have never to make in science. We will return on this later.
Mechanisms of action
One can reproach to the hyperbaric treatment @+have no mechanism of clear action to explain its effects. However, this is true for several recognized treatments and approved in medicine. For example, one uses the @@corticostéroïdes at children affected of Muscular Dystrophy of ++Duchenne observing its beneficial effects and without nevertheless by knowing mechanisms of action.
It is furthermore surprising that the scientific advisory committee never makes mechanism mention proposed by researchers and extra to the protocol of research.
We can not claim to propose a mechanism of clear action but several tracks have to have envisaged, that it concerns the concept of the zone of darkness @@ischémique, metabolic effects, etc. This is not because we do not in understand mechanisms of action that we have to exclude effects of a processing given.
Recommendations of the scientific advisory committee:
++Ø Obviously, we are in agreement with the number recommendation 1, because the article has already been submitted for publication and signed by all researchers.
++Ø The number recommendation 2, appears inappropriate, because it is clear that it does not concern a natural evolution.
++Ø The number recommendation 3, appears based on personal member convictions of the scientific advisory committee and does not respect a scientific step that has to analyze all possible tracks. For researchers implied in the project, two alone track figure as being plausible, that is to say physiological tracks and psychological tracks. Before even to decide to does not explore manner more thorough than psychological tracks, it would be desirable to insure that it concerns the factor that has contributed the most to the improvement of children implied in the project. II there has currently no obviousness in this senses.
It is furthermore important to remind again the international expert proposal, aiming to push more the research on the possible effect exploration oxygen or the pressure to small dose to understand why the group @@''placebó' has as well evolved.
A new researches exploring the different possibilities is the alone avenue that allows us to be responsible and consequent with the scientific step already undertaken. We can not neglect open questions raised by this study. We can not, furthermore forget the context in which families are found after this study that has not certainly demonstrated negative results, the totality of children having improved impressive manner. This would be not to respect our commitments and our responsibility that to put a term to the exploration of possibilities that has made emerge this research.
We believe that results of this research do not allow to retain that two hypothesis to explain the evolution @@étonnante of children. On the one hand, physiological effects what that they are and on the other hand, psychological effects what that they are. The predominance of their plausibility is linked to the experience or to beliefs of each and a true scientist would have never to part a possibility. All possibilities have to be explored when this is achievable.
The scientific community as well as families had invested a lot hope on the under way research to what could bring replies to questions on the efficiency of the hyperbaric treatment. Unfortunately, to less to have a prejudice and to forget all scientific rigor, this research has not brought clear replies to this question, but has raised some many others on its passage.
To return to the commitment of the Minister Rochon @@''que one undertakes to clarify the question of the efficiency of this processing @@'', the alone reply, per hour current, is that the average and the majority of children that have participated in the study have received a very efficient processing but, one does not know truly what has acted.
The alone manner to reply to the question that remains opened, that is to say: what did produce improvements observed at these children ?, is to proceed to a more complex research with five groups. The first group of all obviousness, this time - here, would be a witness group that will allow once for all to exclude hypothesis of training to the test and natural evolution similarly that to verify ++I'importance ++I'effet placebo, if there some is a, because there will be a point of reference to demonstrate it.
The four other groups would have to be processed in a crate @@hyperbare and to have exactly the even approaches on the plan of procedures. Alone would have to vary the pressure and the concentration of oxygen used. The second group would have therefore to receive both pressure and oxygen, the third group solely of the pressure without oxygen. The fourth group would receive solely oxygen, to a dose that would produce the same level of increase of partial pressure in oxygen that the group that receives solely the pressure, and this, to well verify if it concerns an effect of the pressure or oxygen. The fifth group would have to receive neither pressure nor oxygen. II would be technically achievable to make believe in this group of patient that it is in hyperbaric treatment by beginning the processing with a small pressure, that would be decreased rapidly after some minuteing. II would be necessary to give a few pressure at the end of the processing during some instants. II is therefore possible to have a true placebo in a bedroom @@hyperbare, even if technically, this is a bit more complex than the placebo used in the last researches. II would concern this time - here from a true @@''placebo ''.
With a such research, we could have then, clear manner, to see if improvement are haveed to the effect placebo or to the psychological effect OR if improvements are secondary to the pressure, to oxygen, or to a combination of the two. One would eliminate rapidly effects of the training and the natural evolution as plausible hypothesis. II concerns dune researches relatively simple to realize but, that - considering of the current context -, will have certainly to imply several centers. II would be necessary to envisage a study @@pancanadienne to recruit a number sufficing children. Doubts on observed effect causes would be lifted although happened a physiological cause is recognized as the beneficial effect responsible, subsequent studies would be required to understand physiological mechanisms of this effect and to determine dosages, similarly that possible indications. II goes similarly if psychological effects were recognized as the cause of improvements observed.
We have to remind us that a scientist, is that that observes, that sees obviousness , draws the made and tent to integrate these elements in its paradigm, that is to say, in its beliefs and thought system. If it can not make it, it has to widen its thought, and to modify its vision to integrate the new fact. Unfortunately, one clings too often to our beliefs and when one sees some thing that jostles our paradigm, one parts it. The objective of a research is not to prove what one believes to know but well to make the light on questions that one puts. Rather than to play the ostrich, we believe that it is necessary to leave the open door on the pursuit of ++I'investigation and the exploration of these treatments in conditions @@sécuritaires, in a scientific context, until has what real replies could finally rise.
Since one recognizes that the processing placebo was not inert, one has to consider that the two groups of children of the project have received each a hyperbaric treatment to different doses. If these children have did significant manner in the two groups, how can one improve, in the absence of witness group, to conclude in the inefficiency of the hyperbaric treatment? It is exactly as if one made a research on preventive effects of the Aspirin in cases of @@thromboses @@coronariennes, by using two patient groups. One would receive for example 80 @@mg/@@jr. while the other would receive 2 g/@@jr. If in the two groups, effects are impressive (and more important than with any other known medicine), would one have the right to conclude, in the absence of witness group in the inefficiency of the aspirin in this condition?
Remind - we that during this research thirty and a children have made progress of more of 5% to the ++GMFM. Some have had a relative evolution (according to their starting point) of more of 20 to 30%. in other words, these children have made in two month, approximately the quarter of progress that they had realized during all their life.
These sometimes impressive improvements, have been measured without that not there having been worrisome adverse effects at none of the children that have participated in the research. Despite that we did not know the observed improvement cause - that has physiological or psychological causes -, we see badly how this processing could have be forbidden when it is given in conditions @@sécuritaires and in a context of evaluation. (@@cf proposal poured in annex)
Beyond our role of @@''scientifique @@'' that would have to push us to explore more the different results of this research, surety to interrogations raised by this last, we have also a role of @@''soignant @@''. The role of the physician is not - it to help, to heal, to ease, to guide ... If we have between hands a @@''approché' who, according to even results of the research, has did to improve impressive manner children, have we allowed truly the right to forbid some its access even if we do not understand again what has produced improvements observed ?
And even if it do of an effect placebo, is there a law who forbids to use a processing placebo if it is as much, otherwise more efficient than all treatments that we know and when undesirable effects linked to its utilization are minimal and less important than several other treatments @@offerts to these children? (++Radicellectomie, ++Botox, orthopaedic surgery, implantation of pump to ++Badofen, medications, etc.)
If it is necessary to put a helmet on the head of children and to give their a few pressure in order that they evolve more than with any other therapy that one offers them, following gymnastic what intellectual would forbid - one this approach ?
And do me honestly, to the results and improvement light observed during this research, if you had a child reaches cerebral palsy, that would make - you tell ??? Probably the same thing that make Quebecois family thousands that have hoped to find in the hyperbaric treatment a reply to their quest of an efficient approach for their child. Doubt several with reason, the neutrality and the rigor of the analysis and interpretation process of data of this research. Bad again, they question the integrity of the @@''système @@québécois''. Some have raw in the communicated official and have ceased to hope. But of hundred that have seen their eyes, progress at their children or at these of their neighbors of therapy, prefer to have faith some what they have seen rather than some what one tempts to make them believe. And continue them to fill clinics of Ottawa, ++Toronto or the twenty other open clinics to Canada since a year. These families begin to obtain bedrooms hyperbaric portable that they use to the house. All these treatments are bestowed currently in little conditions @@sécuritaires. Do we have a honest and responsible attitude towards these families ? Do we fill our roles @@''scientifiques @@'' and @@''soignants @@''? Can - we, honestly to look us in the mirror by telling us "we have made the good work, we have been to the end what we could make for these families ". We have a duty and a responsibility towards these last. Remind - we that we are to their service and that we are paid by the State to help them and to give their true replies, when one it can.
The report of the scientific advisory committee brings no definitive scientific argument convincing us the precision of their position. Conclusions of their document reflect only opinions of nobodies that them had already elsewhere well expressed before even that the study begins.
I recognize that my comments are also the reflection of my clean opinions and experiences. I have seen hundred to children improve significant manner in bedroom @@hyperbare, often more than with any other approach that I had proposed them . I have seen incredulous therapies to measure evolution @@étonnantes. I have seen three result researches (including the former) who me have not certainly convinced the inefficiency of this processing (on the contrary). Did I neutral? Whole depends on the manner that one has to define the neutrality. If ++Christophe ++Colomb was not neutral by advancing that the earth was round after having made some the tour, then I am not neutral. If the neutrality refers to a closed position, until proof of the contrary, by insuring to whole make to never prove the contrary, then I am not neutral. I remember without ceasing that the spirit is as a parachute, it makes a lot better its work when it is opened.
Despite my beliefs, I tempt to adopt a neutral position and strives me not to transmit what I believe, but to share the most rigorous viewpoint possible on observations make during this research.
Despite my beliefs, I have also my doubts as compared to what I believe. I do not claim to hold the truth and I can not indeed ++I'imposer by using my power. I defend in no case the preponderance of the physiological hypothesis, because there is no clear element that favors it. It is nevertheless similarly, for the psychological hypothesis.
We have no right to make tell to this research what it does not tell. We have not not more, the right to make reward our personal convictions on the rigor of the scientific analysis. We have nevertheless and finally, it to have to be responsible, consequent and honest towards families that wait a true reply and the international scientific community, that we have the power to influence but, before all , it to have to inform most neutral manner possible in order that it could be made its clean opinion.
And this is not by misusing its power or by making laws that forbid the access to this processing that one helps truly families of children affected of cerebral palsy. They go elsewhere, out of the province, to seek a processing some which they believe and bankrupt more. It is by insuring that this processing is given manner @@sécuritaire, it is by bringing scientific replies to an again whole scientific problem and by finding human replies to a human problem that one is in measure to help them the most and thus, well to fill our mandate.
(The remaining part of the document is composed of annex which are too heavy to to be reproduced here. It is however available upon request.)