Article In Brief
A new study found that hyperbaric oxygen therapy alleviated symptoms of post-concussive syndrome in children. Independent experts pointed to several limitations in the current study and a need for more research before drawing any conclusions about the therapy.
The medical community has had mixed response to the use of hyperbaric oxygen therapy (HBOT) to treat concussion over the years, with studies showing inconsistent or inconclusive results.
But now, a randomized, sham-control trial aims to bring clarity to the evidence for the protocol, which involves breathing 100 percent pure oxygen inside a pressurized chamber.
Shai Efrati, MD, medical director of the Sagol Center for Hyperbaric Medicine and Research at Shamir Medical Center in Be'er Ya'akov, Israel, and chair of Aviv Scientific's Medical Advisory Board, and colleagues set out to evaluate the effects of HBOT in children experiencing persistent post-concussion syndrome (PPCS) for at least six months after a traumatic brain injury (TBI).
Published online Sept. 23 in Scientific Reports, this study is the first to examine the protocol in pediatric patients.
Dr. Efrati and coauthors suggested the treatment works because of “the combined action of hyperoxia and hyperbaric pressure, [which] leads to significant improvements in tissue oxygenation, while targeting both oxygen and pressure sensitive genes.” Although their sample size was limited, the authors reported a significant improvement in function, symptoms, and quality of life in children with PPCS who underwent HBOT.
“For the first time, we have demonstrated an effective treatment for pediatric PPCS, whether the injury occurred six months to 10 years ago. This discovery offers hope to the thousands of families watching their children suffer from unrelenting symptoms,” Dr. Efrati said in a news release from Aviv Clinics.
The double-blind trial, conducted from December 2017 to November 2021 at Shamir Medical Center, included 25 children ages 8 to 15 who had experienced mild-moderate traumatic brain injury six months to 10 years prior to the study and reported at least two symptoms from the post-concussion symptom inventory for at least three months.
Fifteen children were randomized to the intervention, and 10 received the control sham therapy. Eighty percent of the participants were male with a mean age of 11.6 ± 2.32 at enrollment and of 6.7 ± 3.18 at the time of injury. The researchers found no significant differences in injury characteristics, demographics, time from injury, or PPCS symptoms between the two groups.
The interventional group received 60 daily oxygen sessions five days per week within a three-month period. The investigators found a significant increase in cognitive function after HBOT, including improvements in the general cognitive score (d = 0.598, p = 0.01), executive function (d = 0.739, p = 0.003), memory (d = 0.480, p = 0.02), PPCS symptoms including emotional score (d = – 0.676, p = 0.04), behavioral symptoms including hyperactivity (d = 0.244, p = 0.03), global executive composite score (d = 0.528, p = 0.001), and the planning/organizing score (d = 1.09, p = 0.007). Using MRI scans, the authors also reported a correlation between the trial's clinical outcomes and significant improvements in microstructural changes in the insula, lingual, supramarginal, inferior frontal, and fusiform gyri.
The number of side effects, however, was high, which the authors said was to be expected when treating children; 90 percent of the patients in the sham group (9/10) and 86.7 percent (13/15) of patients undergoing HBOT reported instances of otalgia, mild-moderate barotrauma, and/or headaches.
Overall, the study suggests that the oxygen therapy improves cognitive and behavioral function and quality of life in children experiencing PPCS even years after injury, the authors wrote. They acknowledged, however, that the trial's sample size was considerably limited and underpowered. In the future, Dr. Efrati and coinvestigators said they will need additional data to optimize the protocol and to improve the selection criteria for children who would benefit most from HBOT.
Independent Experts Weigh In
Pediatric neurologists said PPCS is a substantial concern, particularly in pediatric populations, so they welcomed new advances and treatment approaches for the field. However, they pointed to several limitations in the current study and a need for more research before drawing any conclusions about the therapy.
To date, very few randomized control trials in pediatric concussion patients have shown effective treatment, and many of those that have were focused on post-concussive headache—both acute and chronic—with limited efficacy, said Meeryo Choe, MD, FAAN, associate clinical professor and residency program director of the division of pediatric neurology at University of California, Los Angeles (UCLA), and associate director of the UCLA Steve Tisch BrainSPORT Program.
The current study adds to the existing literature on HBOT, “which has shown some improvement in physiologic markers in pre-clinical and clinical studies mostly in the more severe TBI, because it is the first to look at the use of hyperbaric oxygen therapy in a pediatric population with persistent symptoms after concussion,” she said.
“This study shows improvements in the subjects receiving the therapy in cognitive functioning, symptoms, and quality of life, and the authors suggest that this was associated with microstructural changes in specific areas utilizing diffusion tensor imaging,” Dr. Choe continued.
The sample size of 25,however, was very small, she said, noting that the investigators attributed this to resistance from parents who did not want to risk randomization to a sham therapy.
“This may be particularly true when their children may have been suffering with symptoms for years prior to participation in the study. In our experience, families whose kids have PPCS often seek out any treatment possible, including those without good evidence of efficacy. Some parents do ask us about HBOT, even though prior to this study there was only evidence in [adult] patients who had suffered a more severe TBI,” she added
“The current trial is ultimately underpowered to draw statistically solid conclusions as the authors acknowledge,” said Bethany Johnson-Kerner, MD, PhD, assistant professor of neurology and pediatrics program director of Brain Recovery Education in the division of child neurology at University of California, San Francisco Benioff Children's Hospital.
She also emphasized the low enrollment rate in the study and hesitation from parents, noting that this was “certainly a risk of prematurely publicizing the benefits of an intervention before there is sound evidence.”
Feasibility and safety were additional concerns in this trial because of the “intense protocol” of 60 daily sessions and the high side effect rate for participants—even if mild, Dr. Johnson-Kerner said. Importantly, the mechanism or mechanisms of this therapy are still unknown, she told Neurology Today. A 2017 Cochrane Review on this topic includes several previous studies for treating PPCS in adults, but the findings are inconsistent, she said.
Dr. Choe also pointed out that many of the participants in the current trial were years out from injury “with noted means of 11.6 years at inclusion and 6.7 years at injury.”
In the future, she suggested it would be interesting to see if this duration has an effect on the efficacy of HBOT depending on time since injury.
“Furthermore, preventing the development of PPCS with an intervention would be the ultimate goal for concussion therapy,” she added. “This heterogeneous patient population likely requires more individualized treatments based on symptoms as well as potential biomarkers that identify the specific endophenotype of concussion to guide the management.”
“PPCS is a very important pediatric medicine topic, and more research into sustainable treatments is needed,” Dr. Johnson-Kerner said, “including early recognition of patients at risk and connection to appropriate resources based on symptoms.”
It is important to identify those at risk for PPCS whether in primary care, trauma centers, or school settings, she said, and “to educate providers and educators that concussion symptoms, while generally transient, may last for longer than they think, and that children may need symptoms validated and assistance provided.”
Drs. Choe and Johnson-Kerner had no disclosures to report.