Oxygen therapy may alter inflammatory mediators in IBD

The past decade has seen the emergence of novel therapies for inflammatory bowel disease (IBD) as well as new applications of existing drugs. Unfortunately, none is curative, some patients remain refractory to these medications and many who do respond lose their response over time. Even anti-tumor necrosis factor agents, arguably the most effective class of medications for IBD, have only a 70 to 80 percent response rate. IBD drugs are also associated with potentially serious side effects, adding further urgency to the search for safer and more effective treatments.

One centuries-old approach currently generating renewed interest is hyperbaric oxygen therapy (HBOT), which involves breathing 100 percent oxygen at an atmospheric pressure two to three times greater than normal air pressure (2.0-3.0 ATA).

The idea dates back at least to Aristotle, who first described the diving bell, an air-filled shell that allowed divers to remain underwater for extended periods. In the 1930s, it became clear that pressurized air could also play a role in medicine — breathing pure oxygen was found to aid healing by altering signaling pathways involved in wound repair. Since then, HBOT has been used primarily in wound healing and ischemic tissue injury, where it promotes angiogenesis, growth factor synthesis and mobilization of stem cells from bone marrow.

More recently, HBOT has also been used as an adjunct to standard medical therapy in patients with refractory IBD, especially perianal Crohn's disease (CD) and acute ulcerative colitis (UC).

A systematic literature review undertaken by researchers at Dartmouth-Hitchcock Medical Center found an overall response rate to HBOT of 86 percent — 85 percent for CD patients and 88 percent for those with UC. The overall response rate for perianal CD was 84 percent, with 18 of 42 patients showing complete healing. For patients with endoscopic follow-up, the response rate was 100 percent for UC. The findings appeared online in the April 16, 2014, issue of Alimentary Pharmacology and Therapeutics.

Laura E. Raffals, M.D., a gastroenterologist specializing in IBD at Mayo Clinic's campus in Rochester, Minnesota, says HBOT appears to have several mechanisms of action in inflammatory bowel disease, including alteration of the hypoxia inducible factor and heme oxygenase pathways and suppression of pro-inflammatory cytokines, such as IL-1, IL-6 and TNF-alpha, along with the simultaneous release of anti-cytokines.

Still, she says the data suggesting positive outcomes for IBD patients isn't robust. "Of the 17 studies — involving more than 600 patients — in the Dartmouth review, most were case series or case reports and only one was a randomized controlled trial," she says. "The trial wasn't conducted in a rigorous manner and carried a significant risk of bias. Furthermore, treatment protocols weren't consistent across the various studies. Despite these limitations, though, there was enough to warrant looking at HBOT further."

Study recruits participants

With that in mind, the Dartmouth group, in collaboration with Mayo Clinic and the University of Pittsburgh, is recruiting participants for a double-blind, sham-controlled trial investigating the feasibility and clinical effect of HBOT in patients hospitalized with acute UC flares. Participants will be randomized to receive either 10 90-minute real HBOT treatments (using 100 percent oxygen at 2.4 APA — a standard protocol) or 10 sham treatments.

"HBOT has proved very effective for perianal Crohn's disease, but it may be more beneficial overall for UC and is easier to study in those patients, with more robust outcomes," Dr. Raffals explains.

The trial's primary outcome is clinical response to therapy or remission by day five, with remission defined as a partial Mayo score less than or equal to 2. (The Mayo scoring system for assessing disease activity in UC ranges from 0 to 12, with higher scores indicating more severe disease).

"We'll be looking at improved symptoms but also endoscopic evaluation of mucosal healing, inflammatory markers — even the microbiome," Dr. Raffals says. "There are many ways of assessing clinical improvement."

Patients will also be monitored for reported adverse events such as trauma to the eardrum, temporary blurred vision and claustrophobia. Mayo plans to recruit five patients into the study's pilot phase as quickly as possible.

"We are very excited to be part of this study," Dr. Raffals says. "If HBOT does prove to be a safe and effective therapy for IBD, it may have fairly broad applications. Right now, it is best as an adjunct therapy — the effects of HBOT are temporary, although the hope is that those effects lead to changes in the inflammatory cascade that are longer lasting. Even more important, hospitalized UC patients are at high risk of colectomy, and it would be wonderful if HBOT could prevent surgical interventions."

For more information

Dulai PS, et al. Systematic review: The safety and efficacy of hyperbaric oxygen therapy for inflammatory bowel disease. Alimentary Pharmacology and Therapeutics. 2014;39:1266.

Dartmouth-Hitchcock Medical Center. Hyperbaric Oxygen for Ulcerative Colitis. ClinicalTrials.gov