Mar 16 2009

Hyperbaric Oxygen for Autism

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Comments: 24

A new study looks at the effectiveness of hyperbaric oxygen therapy in autism. The study is the first double-blind placebo controlled study of such therapy in autism and found a significant improvement in those children in the treatment group.

However, the treatment is very controversial and remains so, even after this study.

Hyperbaric oxygen therapy involves placing patients in a chamber with pressure increased above atmospheric pressure with an enriched oxygen content.  It has many legitimate medical applications, such as treating certain kinds of infection, but also has become popular among some as an unscientific treatment. It is offered by practitioners and chambers are even sometimes purchased by private individuals for their own family’s use.

The problem, of course, is that some claims for hyperbaric oxygen go way past the evidence, or exist in the utter absence of evidence. This includes autism – there are no compelling studies showing any benefit from hyperbaric oxygen therapy in autism. The few studies that do exist are uncontrolled, which means they are mostly worthless.

This current study is at least a double-blind controlled trial. But it still has significant weaknesses. The primary weakness, in my opinion, is that the parents of the children being studied were allowed in the chamber with their children. The two groups in the study either received 24% oxygen in 1.3 atmospheres, or 21% oxygen in 1.03 atmospheres. It’s probable that many of the parents knew if they were getting increased pressure or not, and this therefore could have unblinded the study.

Tight blinding is critical for these type of studies because the assessment of the effect on the autistic children is highly subjective. For example, the assessment includes how much eye contact the children make.

The study is also on the small side, with 62 children total. However, the clinical effects were very robust.

Some have pointed out that the study leader, Daniel Rossignol, has a potential conflict of interest in that he offers hyperbaric oxygen therapy in his practice. He therefore stands to gain personally if its effectiveness is proven. While such conflicts are important to expose, I think they are trumped by a well-enough controlled study. The whole point of a well-designed study is to eliminate the effects of bias. But given that this study was poorly blinded, and bias was present, it certainly diminishes its impact.

Everyone agrees, even Rossignol, that this study will not end the controversy over hyperbaric oxygen in autism. It needs to be replicated. This is generically true of any new treatment – the first few smallish studies are never enough to establish its effectiveness. The strength of clinical trials rests primarily in replication. Only when various researchers with different biases come to the same conclusion from well-designed studies can we confidently come to a conclusion. The history of medicine is littered with treatments that initially seemed promising but just did not pan out.

Another weakness of the study is that it was short term, only four weeks. It therefore did not test if the effect of hyperbaric treatment survives much beyond the treatment itself. Even if the effect in this study is real, it may represent only a temporary symptomatic benefit – not altering the course of autism itself. Therefore longer followup studies are needed as well.

It is not impossible that hyperbaric oxygen may have some benefit in some children with autism. Although there is no established mechanism at this time, and proposed mechanisms (like the notion that hyperbaric O2 decreases inflammation) are largely speculative. But a physiological effect is not implausible. The treatment is also fairly safe. Therefore it is reasonable to study it further.

The biggest risk of the treatment now is that it is expensive – costing 150-900 dollars per treatment or 14-17 thousand dollars for a chamber. It also diverts energy and emotions away from possibly more productive treatments.

Because of this, this is one treatment where I think high quality research may have an actual impact. If it works, of course, than more people can benefit from it. If high quality studies show it does not work I think there are families who will save themselves from the expense of an ineffective treatment. It will likely not go away completely, but would be significantly marginalized.

But one thing is clear – any future studies should be very tightly controlled, or they will be counterproductive.

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24 responses so far

24 Responses to “Hyperbaric Oxygen for Autism”

  1. Jivlainon 16 Mar 2009 at 9:16 am

    According to the paper, although the parents were allowed in the chamber, they tested the pressures with adults first (granted, on only 6!) and found that they could not reliably differentiate between the pressures, covered the control switches, simulated pressure changes, and blinded everyone but the hyperbaric technician. It’s not immediately clear to me how, then, the parents would have been able to tell (low sample size aside) – though this is obviously a major concern if they could.

    Also, I have no idea of the technical details of how to operate a hyperbaric chamber, so there could be something I’m missing.

    I think the long-term efficacy of the treatment is an important issue, especially after the final test was administered “immediately” after the course of treatment and does not seem to have been followed up by one, say, a year down the road – which would be important to consider for a $6000+ course of treatment.

    But it’s an interesting initial study nonetheless, and if those results can be replicated in larger and better blinded trials – well, hoorah!

  2. medmonkeyon 16 Mar 2009 at 9:48 am

    Another important use for hyperbaric chambers with global implications … American football!

    http://www.hbotreatment.com/sportsinjury.htm

    But all kidding aside, what is the consensus on HBO therapy increasing muscle cell mitochondria and improving performance? It seems to me that oxygen depletion, rather than saturation, could cause an upregulation of mitochondria, improving endurance. It’s my understanding that this is how the anaerobic threshold increases in well-trained athletes – they chronically expose their tissue to hypoxic states & there is increased generation of mitochondria as compensation.

    Sorry to get off the topic of autism. The applications of any therapy for autism patients is very exciting!

  3. leoneton 16 Mar 2009 at 10:36 am

    Assuming the effect is real, I wonder whether it’s the result of so-called oxygen euphoria that people report after inhaling concentrated O2. A mild euphoria in the parent or the child could certainly look like a transient improvement in the autism.

  4. Enzoon 16 Mar 2009 at 10:58 am

    A big problem here, as Dr. Novella mentions, is a certain level of subjectivity in the diagnostic or treatment efficacy testing. I am not very familiar with what warrants an autism diagnosis or how treatment is monitored, but I am always highly skeptical of testing that involves inherently difficult to quantify measures.

    I have not had a chance to read the study as of yet, but it brings to mind an Alzheimer’s study that came out last year claiming that anti-TNF treatment improved Alzheimer’s related dementia almost immediately after treatment administration:

    Tobinick, E., Gross, H. Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer’s disease. BMC Neurology, July 21, 2008

    Seems to me that we need more studies that will enable us to refine diagnostic criteria to allow more stringent, less subjective measures. I especially don’t like doctor administered patient response tests that are repeated several times to monitor treatment, as several spaces open up for bias to influence what is recorded (like patient familiarity with the test).

  5. _Arthuron 16 Mar 2009 at 12:40 pm

    I seem to recall that the kind of hyperbaric enclosures Rossignol uses are inflated tents (that’s why they top at 1.3 atmospheres).

    If would still be possible to an observer to see if the module is fully inflated, as opposed to a metal enclosure.

    Having the parents with the kid during the “treatments” seems a good idea. Some autistic kids (or mere hyperactive kids) would possibly have to be restrained/sedated if they were forced to spend hours inside a tent or similar small enclosure

  6. titmouseon 16 Mar 2009 at 1:04 pm

    If hyperbaric oxygen helps autism, I’m very happy about that.

    Unfortunately for these researchers, the autism pseudoscience community and its mavericks have done much to damage the trust doctors might normally place in controlled research regarding novel autism therapies. The “we heart Wakefield” crew and anyone associated with them, such as these DAN! people, have lost all scientific credibility.

    Inviting someone like James Randi or Phil Plaitt to observe their methods would be a little strange, but would help their cause. Inviting skeptical MDs who understand autism probably wouldn’t be as good as having Randi there, but it would be better than no outsiders at all.

    Their pre-and post-treatment graphs don’t look so impressive when the raw scores are plotted, verses the “percent change” values. See here.

  7. titmouseon 16 Mar 2009 at 1:07 pm

    Fail! Delete bad post above if you can.

    http://www.flickr.com/photos/tuff_titmouse/3360453076/sizes/o

  8. isleson 16 Mar 2009 at 2:26 pm

    The Autism Street blog has examined Rossignol’s claims.

    http://www.autismstreet.org/weblog/?p=36
    http://www.autismstreet.org/weblog/?p=40
    http://www.autismstreet.org/weblog/?p=60
    http://www.autismstreet.org/weblog/?p=150

  9. Josephon 16 Mar 2009 at 2:29 pm

    Interestingly, if you look at the ABC and ATEC assessments by themselves, they took 9 measures total. Of these, only 1 (in ATEC) had a statistically significant between-groups difference.

    By mere chance, you’d expect 0.45 of the 9 measures to give a false positive, i.e. roughly 50% chance they’d find at least one false positive among the 9.

    Now, they did obtain statistically significant effects in “global impressions.” These are more subjective, and blinding would be very important here. It’s not clear if the parents were naive to the way HBOT works.

    Another thing that I found a little interesting was the difference in some of the intake variables between treatment and control groups.

    90.9% vs. 75.9% male.
    48.5% vs. 34.5% on meds.
    45.5% vs. 37.9% on ABA.

    None of these were statistically significant in themselves, but may be enough for a trend. (Male:female ratio in autism has come up as a confound in non-randomized autism trials.)

    The methodology of the study was better than I expected, though, for a treatment generally associated with DAN! A replication attempt is probably warranted.

  10. HHCon 16 Mar 2009 at 3:46 pm

    The fact that the study was effective in getting the parents to sit quietly and participate with the autistic child in the chamber over a prolonged period of time was beneficial. Some parents have increased anxieties when around their kids. For example, a father of an autistic teen knocked out his kid’s front teeth when he was left alone by staff on a unit at which I worked. The parents refused psychological evaluations of their child too.

    I wonder whether these autistic children had any medical injuries which increased their problem behaviors. If real injuries were addressed by this hyberbaric chamber, increased positive signs were measured.

  11. Gary Goldwateron 16 Mar 2009 at 3:59 pm

    Is there any connection between hyperbaria & another technique for kids with autism. I’m thinking of the bear-hugs, or other forms of pressure on the body such as being rolled-up in a rug?

  12. titmouseon 16 Mar 2009 at 4:38 pm

    Question for the statisticians: What happens to the error bars on the raw scores when those scores are translated into a “percent change” value? How does that translation impact tests of significance?

    Example:

    ABC Speech subscores:

    Pre-Rx: 3.4 +/- 3.1;
    Post-Rx: 2.6 +/- 2.5; % change = 23.2, p-value = 0.0155
    Pre-Ctl: 3.6 +/- 3.6
    Post-Ctl: 3.3 +/- 3.2; % change = 07.5, p-value = 0.4263

    The gestalt I feel from these noisy low numbers is, “meh.” So it surpises me that there’s any significance here.

  13. _Arthuron 16 Mar 2009 at 10:22 pm

    At the Autism Omnimbus trial, Dr. Mumper testified that the purpose of hyperbaric chambers (1.3 Athm) for autistic children, was to “increase profusion to the brain” “sometimes dramatically”. (P. 1346)

  14. Mueroon 17 Mar 2009 at 1:23 am

    @_Arthur

    That should be “perfusion” not “profusion”.

    From a support site for parents with autism (with some quackery): “In autistic children, it is believed that HBOT helps to reduce inflammation, increase perfusion to the brain, and may alleviate oxidative stress in some cases.”

  15. Mueroon 17 Mar 2009 at 1:27 am

    Whoops, I meant “parents with autistic children.”

  16. sonicon 17 Mar 2009 at 2:03 am

    It would be nice if a therapy for autism worked well.
    One possible difficulty- what happens if the parents being with the child is an important part of the therapy, yet the parents can tell the presure of the chamber? This might make the experiment impossible to blind, yet would not rule out the effectiveness of the therapy.
    The discussion of that problem (if it exists) would be most interesting to me.

  17. wertyson 17 Mar 2009 at 5:58 am

    i see immediately a few reasons to be very skeptical of this study.

    Firstly, hyperbaric O2 has been a therapy looking for a disease for quite a while now, and the business demands of keeping them running in between getting legitimate cases of bent divers and pilots, and severe anaerobic infected wounds are such as to constitute a profound bias.

    Secondly, there is no defined hypothesis as far as I can tell by which the hyperbaric O2 could reasonably be expected to alter a complex genetic and developmental disorder. That is, the hypothesis that HBO alters the natural history of ASD is not really consistent with existing understanding of the disorder, and does not explain it any better than what we already know. Therefore the biological plausibility is low.

    Thirdly, as has been pointed out already, there are a number of concerning, but not completely show-stopping methodological shortcomings of the actual study conducted.

    I am left asking…is this a study that really needed to be done ??

  18. daedalus2uon 17 Mar 2009 at 7:22 am

    From what is known of physiology, the only known possible and/or plausible mechanism is through an increased partial pressure of O2. That does not require a hyperbaric chamber to achieve. The partial pressure of O2 is equal to the percent O2 (molar or volumetric basis) times the total pressure. 24% times 1.3 atm is physiologically equivalent to breathing 31.2% O2 at 1 atm. Why they didn’t compare that intervention (which is much less invasive and much safer) isn’t at all clear (unless it had to do with the funding being from a hyperbaric chamber manufacturer). Unless they wouldn’t get as much placebo effect because a parent wouldn’t need to sit with the child for an hour during the twice a day treatments.

    O2 enriched atmospheres will greatly accelerate combustion. The Apollo 1 fire that killed all 3 astronauts was 100% O2 at only 1.09 atm. The major problem there was the use of flammable materials that easily caught on fire and then burned explosively. Velcro was possibly implicated.

    It is my understanding that the hyperbaric chambers used in this study are inflatable cloth chambers approved by the FDA for treating mountain sickness and then only when inflated with air. It is my understanding that there has been no determination that they are safe for use with an enriched O2 atmosphere from a combustion standpoint. I think that such a determination is unlikely unless special materials of construction are used, and special clothing worn during treatment. Essentially all clothing is quite flammable in an enriched O2 environment (other than fiberglass and that old standby asbestos).

    The normal mechanisms by which hypoxia generates oxidative stress are adaptive. By generating oxidative stress, NO local to mitochondria is destroyed, that disinhibits cytochrome c oxidase and allows consumption of O2 to a lower partial pressure, so that more O2 can diffuse to the site of consumption (by increasing the O2 concentration gradient). A relief of oxidative stress due to hypoxia by a non-physiological mechanism (increased O2 in breathing air) may exacerbate that oxidative stress in the long term by preventing the normal compensatory pathways from working (increasing mitochondria number, capillary density, and hematocrit).

    Hyperbaric O2 would more likely increase oxidative stress and so increase production of H2O2 which is a mitogen and can accelerate healing (sometimes). Many of the phase II detoxification pathways are triggered by oxidative stress and that might be the mechanism for the observed reduction in oxidative stress which is actually hard to measure. It could have been that it was increased at first and then there was a compensatory response. If so, then there is likely to be compensation and whether it appears to be good or bad depends on the timing of the endpoint testing. The cited paper on oxidative stress uses the very flawed plasma glutathione level. The important glutathione level is inside cells where it is 3 orders of magnitude higher than in plasma. Measuring plasma levels is not a standard test recognized by anyone.

  19. Calli Arcaleon 17 Mar 2009 at 11:00 am

    O2 enriched atmospheres will greatly accelerate combustion. The Apollo 1 fire that killed all 3 astronauts was 100% O2 at only 1.09 atm. The major problem there was the use of flammable materials that easily caught on fire and then burned explosively. Velcro was possibly implicated.

    Nothing burned explosively on Apollo 1. It burned very quickly, but there was no explosion. And in a 100% O2 environment at close to sea-level pressure, almost everything is flammable. (Just ask people whose nose-hair caught on fire while breathing oxygen in the hospital.) It wasn’t just Velcro. The major problem wasn’t the use of flammable materials; it was the use of a pure oxygen environment at 14 PSI, compounded by some unwise wiring designs and inadequate inspection procedures (which led to the fateful spark), and a hatch designed mostly to maintain the pressure vessel in space rather than to allow rapid emergency egress (which kept them trapped inside until the fire had burned itself out).

    As far as increased pressure goes, the idea isn’t to increase the amount of oxygen available in the air (as you can do that just by sticking oxygen tubes in a person’s nose) but to increase the blood’s carrying capacity, and that *is* dependent on the air pressure. Under normal circumstances, the hemoglobin in the blood is saturated. Increasing oxygen supply won’t increase the amount of oxygen actually being carried unless you’re having some particular difficulty getting enough oxygen to the blood in the first place. Assuming the person’s cardiovascular and respiratory systems are working nominally, then, you really don’t gain much by putting them on oxygen.

    But if you increase the air pressure, you can increase the amount of oxygen that will be dissolved in the blood plasma, over and above what the hemoglobin is carrying. Actually, you’d be increasing the amount of all atmospheric gases which get dissolved in the plasma, so really it ought to be done using pure oxygen, not just an enriched atmosphere. (Boosting nitrogen isn’t going to help with oxygen perfusion, for instance.)

    The best study I’ve seen regarding cerebral palsy and HBOT had mildly positive results but did have a much better blinding mechanism. Both study and control groups “dove” to the same pressure. One was breathing air, the other was breathing pure O2. There really would be no way for the parents to know whether they were getting air or O2. Both groups showed improvement, which the authors suggested could be simply a result of parents and patients getting in touch with others and forming support groups via participation in the same study. Unfortunately, the group was too small to make any real conclusions, and both groups showed improvement which was considerably greater than the difference in improvement between the groups, so the results were unimpressive. But it did demonstrate that it is possible to adequately blind the participants.

  20. daedalus2uon 17 Mar 2009 at 12:01 pm

    That is not correct. The amount of O2 disolved in fluid only depends on the O2 partial pressure, not the total pressure. In this study they were not breathing any where close to pure O2, it was 24% max. They could get the same amount of O2 dissolved in fluids by using 31% O2 at 1 atmosphere.

    The O2 carried by hemoglobin does saturate at close to the O2 level in air. Increasing the O2 partial pressure doesn’t increase that. Increasing the O2 partial pressure does increase the O2 dissolved in the fluid outside of the red blood cells.

    In CO, HCN and H2S poisoning, the goal is to increase the chemical potential of O2 at the mitochondria, so that O2 can displace CO from the hemes in the mitochondria.

    The discussion on AutismStreet is pretty good.

  21. HHCon 18 Mar 2009 at 5:34 pm

    Now that everyone has had some breathing room for St. Patrick’s Day, I think its time to discuss factors in autism.
    According to Floyd,et al,2007, alcohol use during pregnancy is a leading cause and a preventable cause of birth defects and developmental disabilities. The Centers for Disease Control and Prevention report that 500,000 U.S. pregnant women recently used alcohol and 80,000 reported binge drinking. At least, 40,000 babies are born with fetal alcohol spectrum disorders, a result of maternal drinking. And then there are the affects of paternal drinking…

  22. Calli Arcaleon 18 Mar 2009 at 5:35 pm

    I didn’t express myself well, probably because I had a bad headache yesterday and was probably leaving stuff out. I agree that this version of HBOT, using mildly oxygen-enriched air, isn’t increasing the partial pressure of O2 very much. My point was that real HBOT for real medical applications (like burn victims) uses pure O2, and in that case the partial pressure of O2 is much higher, resulting in an actual increase in the amount of oxygen dissolved in the blood plasma.

    As I said in my reply above, increasing pressure will increase the amount of all atmospheric gases dissolved in the person’s blood. In a normal atmosphere, that’s mostly nitrogen, which isn’t particularly useful.

  23. [...] Dr. Novella’s entry, “Hyperbaric Oxygen for Autism“; [...]

  24. [...] While a potential methodological weakness, this is probably a fairly small problem in light of potential issues with blinding and interpretation of the results as quantitatively and objectively meaningful with respect to [...]

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