TITLE: Hyperbaric Oxygen Therapy for Autism: A Review of the Clinical and Cost- Effectiveness DATE: 19 November 2009 CONTEXT AND POLICY ISSUES: Autism is a pervasive developmental disorder characterized by impairments in social interaction and communication, and in unusual patterns of behaviour. It affects 1 in 150 children, with a male: female predominance of 4:1. Common co-morbidities include mental retardation and epilepsy. 1 Research has shown that some autistic children have decreased cerebral perfusion, evidence of neuroinflammation, and increased markers of oxidative stress. 2 Established therapies for autistic children are non-pharmacologic (behavioural and developmental interventions) and may include complimentary medicines and medication (e.g., risperidone for irritability), although autistic children are sensitive to medication and may experience serious adverse effects. 3 There is no known cure. Hyperbaric oxygen therapy (HBOT) involves inhaling up to 100% oxygen at a pressure greater than one atmosphere (atm) in a pressurized chamber. 2 HBOT may increase blood flow by increasing the oxygen content of plasma and body tissues, and may normalize oxygen levels in ischemic tissue. Animal studies have shown that HBOT has potent anti-inflammatory effects and reduces oxidative stress. For these reasons, it has been postulated that HBOT may improve symptoms of autistic children. 2 This report reviews the clinical and cost-effectiveness of HBOT in autistic children to inform decision-making. RESEARCH QUESTIONS: 1. What is the clinical effectiveness of hyperbaric oxygen therapy for the treatment of children with autism? 2. What is the cost-effectiveness of hyperbaric oxygen therapy for the treatment of children with autism? Disclaimer: The Health Technology Inquiry Service (HTIS) is an information service for those involved in planning and providing health care in Canada. HTIS responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources and a summary of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. HTIS responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material. It may be copied and used for non-commercial purposes, provided that attribution is given to CADTH. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.
METHODS: A limited literature search was conducted on key health technology assessment resources, including PubMed, The Cochrane Library (Issue 4, 2009), University of York Centre for Reviews and Dissemination (CRD) databases, ECRI, EuroScan, international health technology agencies, and a focused Internet search. The search was limited to English language articles published between 1999 and October 2009. For the first question, filters were applied to limit the retrieval to health technology assessments, systematic reviews, meta-analyses, randomized controlled trials (RCT), controlled clinical trials, and observational studies. For the second question, filters were applied to limit the retrieval to economic studies. SUMMARY OF FINDINGS: One health technology assessment report, one RCT, one non-randomized open-label trial, and two before and after studies were retrieved. There were no economic evaluations identified on the cost-effectiveness on the use of HBOT in autistic children. HTIS reports are organized so that the higher quality evidence is presented first. Therefore, health technology assessment reports are presented first. These are followed by randomized controlled trials (RCT), controlled clinical trials, and observational studies. Health technology assessment In 2007, the Quebec HTA unit (l Agence d évaluation des technologies et des modes d intervention en santé or AETMIS) published a report on the role of HBOT in the management of autism. 4 The authors found that, despite an extensive literature review, there was a lack of evidence to support the use of this technology in autism. This report pre-dates the 2009 publication of the RCT. Randomized controlled trial One prospective, randomized, double-blind, parallel, controlled trial involving 62 HBOT-naïve children with autism from six centres, was published in March 2009. 5 The children, aged two to seven years (mean, standard deviation: 4.92 years ± 1.21) were randomly allocated to 40 onehour sessions of either hyperbaric treatment at 1.3 atm and 24% oxygen (n=33 for the treatment group) or pressurized room air at 1.03 atm and 21% oxygen (n=29 for the control group). At the beginning of the trial, the use of medication, nutritional supplements, and applied behavioural analysis therapy were similar in both groups. The primary outcomes were changes compared to baseline measured using the Aberrant Behaviour Checklist-Community (ABC-C) administered by the parent at the beginning of study and after finishing 40 sessions, the Autism Treatment Evaluation Checklist (ATEC) administered by the parent at the beginning of study and after finishing 40 sessions, and the Clinical Global Impression-Improvement (CGI) scale for changes in overall functioning obtained immediately after 40 sessions by both the parent and the treating physician. A description of these instruments is available in Appendix 1. All those involved in the assessment of the outcomes were blinded to treatment. Two post-hoc analyses were conducted for age and for autism severity, but these analyses were not determined a priori and hence, will not be discussed. Hyperbaric Oxygen Therapy for Autism 2
ABC-C scores The HBOT group had an improved aggregate ABC-C score immediately after 40 sessions (p=0.0118) compared to baseline. Improvements were also noted in the subscale score for irritability (p=0.0147), stereotypy (p=0.0124), hyperactivity (p=0.0211), and speech (p=0.0155). Conversely, the control group did not improve its aggregate ABC-C and the subscale scores. When directly comparing the treatment group with the control group, post-treatment aggregate ABC-C and subscale scores were similar. 5 ATEC scores ATEC scores were not obtained for children attending one centre, and the analysis was based on 23 children for the treatment group, and 21 children in the control group. The HBOT group had an improved aggregate ATEC score (p=0.002) immediately after treatment compared with baseline. Also improved were the subscales of sociability (p=0.0009), sensory/ cognitive awareness (p=0.0017), and health/ physical/ behaviour (p=0.0446). The control group also had an improved aggregate ATEC score (p=0.0385) and an improved sociability subscale (p=0.0134) compared with baseline scores. When directly comparing the HBOT group with the control group, the HBOT group had an improved sensory/ cognitive awareness subscale (p=0.0367) compared with the control group. 5 CGI scores The mean physician CGI score for change in overall functioning compared to baseline improved by 1.13 points (p=0.0008) in the treatment group and by 0.38 points in the control group (p=ns) compared to baseline scores. More children improved in the treatment group compared to the control group in receptive language (p<0.0001), social interaction (p=0.0473), and eye contact (p=0.0102). The mean parental CGI score for change in overall functioning compared to baseline improved by 1.3 points (p=0.0336) in the treatment group and by 0.83 points in the control group (p=ns). More children improved in the treatment group compared to the control group in receptive language (p=0.0168), and eye contact (p=0.0322). Controlled clinical trial One prospective, non-randomized open-label study was retrieved. 6 It involved 18 children with autism ranging from 3 years of age to 16 years of age who underwent 40 HBOT sessions at 1.5 atm and 100% oxygen, or HBOT at 1.3 atm and 24% oxygen over a period of eight to nine weeks. Parents rated change by using three different instruments [ABC-C, ATEC, and the Social Responsiveness Scale (SRS)]. For the 1.5 atm group (n=6), aggregate mean scores were improved for SRS (15.4%, p=0.035) and ATEC (14.7%, p=0.02), but not ABC-C. Improvements were seen in the subscales of social withdrawal, motivation, speech/ language/ communication, and sensory and cognitive awareness. For the 1.3 atm group (n=12), aggregate mean scores were improved for SRS (16.5%, p=0.046) and ATEC (11.1%, p=0.007), but not ABC-C. There was improvement in motivation, mannerisms, speech/ language/ communication, sensory and cognitive awareness, and health/ physical behaviour. The results must be interpreted in light of the fact that parents were not blinded to treatment, the children Hyperbaric Oxygen Therapy for Autism 3
were not randomized to treatment group, the study did not include a control or placebo group, and it involved only 18 participants. There were many confounding variables including increased interaction between parents and their children, and increased motivation from the parents. The authors stated that, because the study was open-label, conclusion about the efficacy of HBOT as a treatment for autistic children cannot be drawn, and efficacy must be determined through RCTs. 6 Observational studies Two before and after studies were retrieved. The first study 2 involved six children with autism aged two to seven years. The participants were allowed to continue previous therapies and to add new ones. No one had received HBOT previously. All six children received 40 one-hour sessions of HBOT (1.3 atm) and 28-30% oxygen over a three-month period. Parents rated their children using three different scales [SRS, ATEC, and the Childhood Autism Rating Scale (CARS)] before and after treatment. Significant improvements were seen in all six children for all three scales. 2 The second study 7 was conducted in seven children with autism five to nine years old who received HBOT at 1.3 atm and 100% oxygen once a week for 10 weeks. 7 Five domains were assessed: social development, fine motor and eye-hand coordination, language development, gross motor development, and self-help skills. Significant improvements were noted in five of the seven children for all five domains. 7 Limitations The randomized controlled trial was a well-designed study. However, it was restricted to 62 children aged two to seven years. Assessments to determine efficacy were done immediately after 40 hourly sessions, with no follow-up to determine the long-term outcomes of HBOT and to determine if on-going treatments are required to maintain improvements. The other studies retrieved were subject to biases due to the fact that they were conducted in less than 20 patients, were not randomized, and were not blinded. Results must be used cautiously. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING: Prior to 2009, there was a lack of RCTs on the efficacy of HBOT in autism. The first RCT was recently published. ABC-C and ATEC aggregate mean scores were improved within the group of children treated with hyperbaric oxygen (but not within the control group). Specifically, improvements were noted in the subscales of irritability, stereotypy, hyperactivity, and speech with ABC-C, and sociability, sensory/ cognitive awareness, and health/ physical/ behaviour with ATEC, immediately at the end of the 40 sessions compared with baseline scores. No differences in post-treatment aggregate ABC-C mean score and aggregate ATEC mean score were obtained when directly comparing the treated group and the control group. According to CGI, overall functioning improved in the treated group and not the control group post-treatment, with subscale improvements in receptive language, social interaction, and eye contact. There was no information on the cost-effectiveness of HBOT as no economic evaluations were retrieved. Hyperbaric Oxygen Therapy for Autism 4
Hence, findings from the RCT suggest that improvements may be seen in some children with autism treated with HBOT, but when results are compared to a control group, no difference was found as measured by three clinical instruments. Further research is required to determine if HBOT is an effective and cost-effective treatment for autistic children. PREPARED BY: Christine Perras, BSc, MPH, Research Officer Jessie Cunningham, M.I.St., Information Specialist Health Technology Inquiry Service Email: htis@cadth.ca Tel: 1-866-898-8439 Hyperbaric Oxygen Therapy for Autism 5
REFERENCES: 1. Inglese MD, Elder JH. Caring for children with autism spectrum disorder. Part I: prevalence, etiology, and core features. J Pediatr Nurs. 2009 Feb;24(1):41-8. 2. Rossignol DA, Rossignol LW. Hyperbaric oxygen therapy may improve symptoms in autistic children. Med Hypotheses. 2006;67(2):216-28. 3. Brasic JR. Autism [Internet]. In: Pediatrics: developmental and behavioral. Omaha (NE): emedicine; 2009. [cited 2009 Oct 21]. Available from: http://emedicine.medscape.com/article/912781-overview. 4. Moqadem K, Pineau G. The role of hyperbaric oxygen therapy in the management of autism [summary] [Internet]. Montréal (PQ): Agence d'évaluation des technologies et des modes d'intervention en santé; 2007. [cited 2009 Oct 14]. Available from: http://www.aetmis.gouv.qc.ca/site/phpwcms_filestorage/6077c66c80233c08c799a9c4b4 e56e94.pdf 5. Rossignol DA, Rossignol LW, Smith S, Schneider C, Logerquist S, Usman A, et al. Hyperbaric treatment for children with autism: a multicenter, randomized, double-blind, controlled trial. BMC Pediatr. 2009;9:21. 6. Rossignol DA, Rossignol LW, James SJ, Melnyk S, Mumper E. The effects of hyperbaric oxygen therapy on oxidative stress, inflammation, and symptoms in children with autism: an open-label pilot study. BMC Pediatr. 2007;7:36. 7. Chungpaibulpatana J, Sumpatanarax T, Thadakul N, Chantharatreerat C, Konkaew M, Aroonlimsawas M. Hyperbaric oxygen therapy in Thai autistic children. J Med Assoc Thai. 2008 Aug;91(8):1232-8. Hyperbaric Oxygen Therapy for Autism 6
APPENDIX: Description of the Various Instruments Used in the Studies on Autism 5,6 Aberrant Behaviour Checklist-Community (ABC-C): A 58-item questionnaire that assesses communication, reciprocal social interaction, play, and stereotypical behaviours. It is scored from 0 (not at all a problem) to 3 (problem is severe in degree). A total score is calculated, in addition to scores in five subscales (irritability, social withdrawal, stereotypy, hyperactivity, and inappropriate speech). It is used to evaluate the effectiveness of medication and other therapeutic interventions. Autism Treatment Evaluation Checklist (ATEC): ATEC consists of four subscales: speech/ language/ communication, sociability, sensory/ cognition awareness, and health/ physical/ behaviour. The scores are weighted according to response and the corresponding subscale. A high level of impairment will yield a higher score. It is used to evaluate the treatment efficacy in individuals with autism. Childhood Autism Rating Scale (CARS): This scale is used for screening and diagnosing autism. Clinical Global Impression-Improvement (CGI): CGI gives an impression of the global changes in certain areas compared to baseline. A total score for change in overall functioning is obtained using the following ratings: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse. CGI subscales include: receptive language, expressive language, sleep pattern, attention span, activity level, bower movement pattern, self-stimulatory behaviour, social awareness/ alertness, social interaction, play skills, self-injurious behaviour, eye contact, mood, anxiety level, aggression, general health, gross motor skills, and fine motor skills. Social Responsiveness Scale (SRS): Test of interpersonal behaviour, communication, and stereotypical traits in autism. It consists of five subscales: social awareness, social cognition, social communication, social motivation, and autistic mannerisms. Hyperbaric Oxygen Therapy for Autism 7