The effects of hyperbaric oxygen therapy on oxidative stress, inflammation, and symptoms in children with autism: an open-label pilot study

Autism is a neurodevelopmental disorder currently affecting as many as 1 out of 150 individuals in the United States [1]. Autism is characterized by impairments in social interaction, difficulty with communication, and restrictive and repetitive behaviors [2]. Autism traditionally is considered a "static" neurological disorder [3] and improvements in core autistic features are not common [4, 5]. Furthermore, three rigorously performed epidemiological studies demonstrate that the prevalence of autism has increased in recent years [6‐8]. These facts might explain why parents of children with autism are more likely to seek alternative and off-label medical therapies than parents of children in the general population [9]. One off-label therapy that has recently increased in popularity as a treatment for autism is hyperbaric oxygen therapy (HBOT) [10, 11]. Traditionally, HBOT involves inhaling up to 100% oxygen at a pressure greater than one atmosphere (atm) in a pressurized chamber [12]. Most typical indications for HBOT involve the use of hyperbaric pressures above 2.0 atm. Higher atmospheric pressures are generally required to treat conditions such as carbon monoxide poisoning and to improve wound healing [12, 13].

In some studies, the use of oxygen appears to enhance neurological function. For instance, in a double-blind, placebo-controlled, cross-over study, oxygen administration in healthy young adults, when compared to room air, was demonstrated to enhance cognitive performance, including improved performance on attention, reaction times, and word recall [14]. Additionally, in elderly patients, HBOT at 2.5 atm and 100% oxygen, when compared to a control group, improved cognitive function, including memory [15]. Because of these outcomes, some investigators have used HBOT to treat certain neurological disorders, including chronic and traumatic brain injury [16‐22], as well as fetal alcohol syndrome [23], and clinical improvements in these patients have been observed. Furthermore, in a recent rat model of traumatic brain injury, treatment with HBOT at 1.5 atm and 100% oxygen, when compared to a sham-treated normobaric air group, improved spatial learning and memory [24]. Several studies, using HBOT at similar pressures, also demonstrated clinical improvements in some patients with cerebral palsy (CP) [25‐28] that in some cases was dramatic [29]; however, some researchers have questioned the results of these studies and have called for further controlled trials and a focus on defining the mechanism of action of HBOT in individuals with CP [30]. It is important to note that some of these studies [16, 21‐24, 26] used lower hyperbaric pressures (1.5 atm or less) than the pressures typically used for most clinical indications [13]. Given this background, some physicians have also applied similar lower hyperbaric pressures of 1.3 to 1.5 atm in autistic individuals, with oxygen concentrations ranging from 21% to 100% [10, 31].

HBOT for children is generally regarded as safe, even at pressures of 2.0 atm for 2 hours per day [32]. However, to our knowledge, the safety of HBOT for autistic children has not been previously studied; a review of MEDLINE indicates that there are no prospective studies on the use of HBOT for autism. Yet, there are anecdotal reports of clinical improvements in autistic children with hyperbaric therapy that have been reported by some physicians. For instance, Heuser et al. treated a four year old child with autism using hyperbaric therapy at 1.3 atm and 24% oxygen and reported "striking improvement in behavior including memory and cognitive functions" after only ten sessions. This child also had marked improvement of cerebral hypoperfusion as measured by pre-hyperbaric and post-hyperbaric Single Photon Emission Computed Tomography (SPECT) scans [31]. Another case series suggested that hyperbaric therapy at 1.3 atm led to clinical improvements in six autistic children [10].

Review of the pathophysiology found in some autistic individuals in conjunction with the mechanisms of action of HBOT lead to the speculation that HBOT might produce clinical improvements in autistic individuals [11]. Several studies indicate that some autistic individuals manifest cerebral hypoperfusion [33‐35], neuroinflammation [36‐38], and gastrointestinal inflammation [39, 40]. HBOT might ameliorate some of these problems by improving cerebral hypoperfusion [17, 21, 31, 41], and by decreasing neuroinflammation and gastrointestinal inflammation [42‐47]. However, no prospective studies have examined the role of HBOT on inflammation and cerebral hypoperfusion in autistic individuals.

Furthermore, concerns exist that HBOT might increase oxidative stress via the production of reactive oxygen species [48]. These concerns are especially relevant because some children with autism express evidence of increased oxidative stress [49] including lower serum glutathione levels [50, 51], and decreased activities of antioxidant enzymes including superoxide dismutase (SOD) [52], glutathione peroxidase [52], catalase [53], and paraoxonase, an enzyme that prevents lipid oxidation and also inactivates organophosphate toxins in humans [54]. Some autistic children also demonstrate evidence of increased lipid peroxidation [53, 55, 56]; this includes increased malondialdehyde which is a marker of oxidative stress and lipid peroxidation [57]. A review of the literature indicates that oxidative stress can occur with HBOT but appears to be less of a concern at hyperbaric pressures under 2.0 atm [58]. In fact, with long-term and repeated administration, HBOT below 2.0 atm can actually decrease oxidative stress [59‐61] by reducing lipid peroxidation [62], and by up-regulating the activity of antioxidant enzymes including SOD [60, 63], glutathione peroxidase [64], catalase [65], and paraoxonase [62, 66]. Furthermore, at the pressures examined in this current study (1.3 to 1.5 atm), a search of the literature failed to identify any studies indicating that oxidative stress worsened with HBOT.

Alternatively, some evidence suggests that HBOT could actually alleviate oxidative stress in children with autism. For example, halving oxygen concentrations in normal healthy volunteers results in relative hypoxia and actually increases oxidative stress [67]. There are several studies that demonstrate evidence of cerebral hypoxia, as measured by a reduction in brain Bcl-2 and an increase in brain p53, among some autistic individuals [68‐71]. Elevated p53 is induced by hypoxia [72] and a decrease in Bcl-2 is associated with increased apoptosis provoked by hypoxia [73]. Therefore, in theory, improving hypoxic areas in the autistic brain might decrease oxidative stress. However, the effects of HBOT on oxidative stress in autistic individuals are unknown. To our knowledge, there have been no studies performed which examine the role of HBOT on oxidative stress in autistic children.

This present study examined hyperbaric therapy at the low and the high ends of the ranges of atmospheric pressures and oxygen concentrations currently employed in individuals with autism: 1.3 atm and 24% oxygen [31], and 1.5 atm and 100% oxygen. This study had several objectives. First, since increased oxidative stress is found in some autistic children, the effects of HBOT on oxidative stress markers before and after 40 hyperbaric treatments were measured. Second, evidence of increased inflammation is found in many autistic individuals. HBOT is also known to have anti-inflammatory effects; therefore, the impact of HBOT on an inflammatory marker (C-reactive protein) was measured. Third, since the efficacy of HBOT in autism has not been previously evaluated, this current open-label pilot study (without a placebo-control group) examined the changes in clinical symptoms, as rated by parents or caregivers, after treatment with HBOT. Finally, the safety of HBOT, used at 1.3 and 1.5 atm, was evaluated in autistic children.

To our knowledge, this study represents the first prospective study on the use of HBOT for children with autism. In this study, lower hyperbaric pressures were used than those traditionally employed (typically pressures of 2.0 atm and above [13]) for the treatment of most clinical indications. However, significant increases in oxygen delivery were obtained during this study. The oxygen concentration in room air at sea level (1 atm) is about 160 mmHg. The two study sites were located at approximately 500 and 900 feet above sea level (0.97–0.98 atm). Therefore, the oxygen delivery in the 1.3 atm group was approximately 232 mmHg which is roughly 45% more than room air conditions. In the 1.5 atm group, the oxygen delivery was 1142 mmHg, or over 7 times more than room air conditions. The amount of oxygen delivered in the 1.3 atm group is similar to the amount used in a previous study on HBOT in children with CP that utilized 1.3 atm and room air pressure ("hyperbaric air") [26]. In that study, the authors commented that the amount of oxygen delivered at 1.3 atm was achievable with the use of "28% oxygen with a mask, without pressure"; however, this opinion did not account for the potential clinical effects of the increased atmospheric pressure delivered, because even low amounts of increased pressure may lead to significant clinical changes [44, 81]. Furthermore, the authors argued that hyperbaric air at 1.3 atm was unlikely to provide clinical benefit(s) because the mechanism of action of HBOT in CP is thought to be due to the "penumbra phenomenon" and that a clinical effect due to "a pure pressure effect" did "not correspond to the rationale behind the hyperbaric oxygen treatment" [26]. Since the mechanism of action of HBOT in autism may be different than in CP [11], including decreasing inflammation (as reviewed in the background section of this paper), it is entirely possible that clinical benefits may arise from purely increasing the atmosphere pressure delivered, because increased pressure delivery without additional oxygen appears to decrease inflammation (as measured by an inhibition of interferon-gamma release), and delivery of oxygen by mask without any increase in pressure may actually increase inflammation (as measured by an increase in interferon-gamma release) [44]. Since HBOT consists of 2 independent variables (pressure and inspired oxygen concentration), comparison studies are needed in individuals with autism before determining that the clinical effects of 1.3 atm and 24% oxygen are similar to those obtained by delivering oxygen by mask alone without additional pressure. In addition, further studies are needed that evaluate not only the clinical effects of hyperoxia delivered by HBOT, but also the effects of increased atmospheric pressure, because each of these effects may lead to different clinical outcomes depending on the underlying disease pathophysiology.

A primary goal of this study was to determine the effects of HBOT on oxidative stress markers in autistic children. Other objectives were to measure the effects of HBOT on CRP and changes in clinical symptoms. The final intention was to examine the safety of HBOT for use in autistic children. Of note, shorter duration hyperbaric treatment times (45 minutes) were used than what is traditional (60 minutes). This was due, in part, to scheduling constraints.

This prospective open-label pilot study in children with autism indicates, as measured by changes in plasma GSSG, that HBOT ranging from 1.3 to 1.5 atm and 24% to 100% oxygen was not significantly associated with increased intracellular oxidative stress. The use of therapies to raise glutathione levels and lower oxidative stress before beginning HBOT in individuals with autism appears prudent. Among children with high initial CRP, hyperbaric therapy led to a large improvement in CRP levels; this suggests that inflammation in these children improved with treatment. Improvements in clinical outcomes as measured by several scales were observed at both 1.3 atm and 1.5 atm. However, because this study was open-label, conclusions about the efficacy of HBOT as a treatment for autistic children cannot be drawn at this time. Definitive statements regarding the efficacy of HBOT for the treatment of children with autism must await results from future double-blind, controlled trials. Finally, HBOT was safely administered to autistic children in this study, and all participants were able to finish 40 HBOT sessions without any major adverse events.