Hypoxia Boosts Walking Ability in Spinal Cord Patients

Pauline Anderson

November 27, 2013

A novel strategy that incorporates hypoxia therapy and walking training results in improved walking speed and endurance in patients with an incomplete spinal cord injury, a new study has shown.

Dr. Randy Trumbower

The results suggest that combining low-oxygen therapy with traditional rehabilitation exercises is better than either treatment approach alone, said study author Randy D. Trumbower, PhD, assistant professor, Division of Physical Therapy, Emory University School of Medicine, Atlanta, Georgia.

"Scientists, researchers, and clinicians in the field of spinal cord injury rehabilitation have all championed a need for combination therapeutic approaches," said Dr. Trumbower. "What we're showing here is that a very simple breathing intervention may be an effective pretreatment for traditional locomotor training, with the combined treatment being more powerful than either treatment alone."

The study was published online November 27 in Neurology.

Combined Therapy

The study enrolled 22 adults with an incomplete spinal cord injury (between C2 and T12) of more than 1 year duration who had no joint contracture but some voluntary ankle, knee, and hip movements and who were able to ambulate at least 1 step without human assistance. Three participants later dropped out of the study for various reasons.

Participants were comparable in terms of impairment score, need for assistive devices, baseline strength scores, and male–female ratio.

The study involved 2 parts, each with a randomized, blinded crossover design. The first part randomly assigned 11 patients to receive either daily acute intermittent hypoxia (dAIH) or a daily sham treatment (dSHAM) delivered through a mask, switching to the alternate treatment at least 2 weeks later.

The hypoxia treatment involved fifteen 90-second periods of hypoxia alternating with 60 seconds of breathing normal air, for a total of 37.5 minutes for 5 consecutive days. Participants were blinded and could not distinguish between this hypoxia treatment or sham treatment, said Dr. Trumbower.

This part of the study showed that the hypoxia treatment alone improved walking speed, as measured by the 10-Meter Walk Test. Compared with the sham treatment, walking time improved after 1 day by a mean difference of 3.8 seconds (95% confidence interval [CI], 1.1 - 6.5 seconds; P = .006). The same mean time difference was observed at 2 weeks (95% CI, 0.9 - 6.7 seconds; P = .010).

But "what was really provocative" were the results of combining the hypoxia therapy with a walking exercise in the second part of the study, said Dr. Trumbower, This part randomly assigned 11 patients to first receive either dAIH plus walking overground or dSHAM plus walking, with participants then switching to the alternate treatment.

The walking exercise was initiated within an hour of the breathing protocol and was at maximal sustainable exertion for 30 minutes (resting time was not included in the 30 minutes). The researchers measured walking endurance with the 6-Minute Walk Test.

This part of the study showed that the walking distance increased with combined dAIH plus walking compared with dSHAM plus walking after 5 days by a mean difference of 94.4 m (95% CI, 17.5 - 171.3 m; P = .017) and by a mean difference of 97.0 m at 1 week (95% CI, 20.1 - 173.9 m; P = .014).

Overall, the combination of hypoxia with walking training resulted in clinically meaningful changes in walking speed among 30% of participants and in endurance among more than 70% of participants.

The changes were at least comparable to those of traditional approaches to rehabilitation, commented Dr. Trumbower, who is a physical therapist whose PhD is in engineering. "What was really dramatic in the exercise protocol was that just a single week of breathing with intermittent hypoxia and walking had an effect size that was comparable to, if not in many cases greater than, that shown in previous studies of locomotor training for 4 to 6 weeks."

Such results demonstrate that the nervous system can still be manipulated even more than a year after a spinal cord injury in patients who, were considered to have "plateaued," said Dr. Trumbower, The intermittent hypoxia treatment may act as "a primer" to improve walking ability, he added.

Experimental models demonstrating that hypoxia therapy induces cellular and physiological changes in the nervous system that translate into beneficial plasticity and strength laid the groundwork for this new work, said Dr. Trumbower.

No Gunshot Approach

"This is not a gunshot approach — trying to combine all sorts of therapies to see what works. Our research is based on translating fantastic animal model discoveries to humans with the ultimate goal of improving motor recovery in persons with spinal cord injury."

The hypoxia treatment was well-tolerated by all participants, with no adverse events reported or observed. None of the patients reported any discomfort before, during, or after treatments.

Low-oxygen therapy is easy to administer, requiring only a mask and a generator tabulated to deliver oxygen at desired concentrations and intervals. Already, athletes who want alterations of "altitudes" for training purposes use commercially available hypoxia "kits," said Dr. Trumbower.

He stressed that although the kits are available, the safety and efficacy of repetitive exposure to intermittent hypoxia is still being studied, and untrained patients should not administer it themselves.

Dr. Trumbower also pointed out that the therapy has not yet been tested on "fragile populations" such as patients with serious sleep apnea or other chronic respiratory or cardiovascular problems. "Intermittent hypoxia can trigger changes in heart rate and respiratory rate; it's a mild stress on the body — in some ways, it's like exercise," he said.

However, because it is simple, safe, noninvasive, and now proven to be effective, hypoxia therapy could eventually become a standard approach to rehabilitation in some populations, said Dr. Trumbower. It is important, though, to first understand individual effects of hypoxia exposure over time. Clinical trials are now under way to test the potential benefits of longer-term exposure to this therapy in patients with spinal injury, he said.

Hypoxia Safety?

Asked to comment, Michael G. Fehlings, MD, PhD, professor, neurosurgery, University of Toronto, and medical director, Krembil Neuroscience Centre, Toronto Western Hospital, Ontario, Canada, said it was "a very nicely done" study that in some respects had some "surprising" results.

In an interview with Medscape Medical News, Dr. Fehlings outlined some of the concerns he raised with Ela B. Plow, PhD, from the Department of Biomedical Engineering and the Department of Physical Medicine and Rehabilitation, and the Center for Neurological Restoration, Cleveland Clinic, Ohio, in an accompanying editorial they wrote.

One issue is safety of hypoxia therapy. "Certainly in this small case series it did appear to be safe, but that needs to be confirmed in a larger patient population," said Dr. Fehlings. "The potential downside is in whether there are some issues with this vulnerable patient population that frequently has cardiorespiratory impairment."

Another issue is whether this treatment approach could be applied to a broader range of patients. "The investigators appropriately selected the subjects most likely to benefit, and these are patients with the least severe type of spinal cord injury," who typically already have some ability to walk and significant muscle strength in their lower limbs, said Dr. Fehlings.

"One of questions is, could this be applicable to individuals who do not have the ability to walk, or could it actually help them recover that ability to walk?"

As for what could explain the study results, Dr. Fehlings said there are several mechanistic possibilities. One is that hypoxia-induced release of spinal serotonin sets off a cellular cascade leading to respiratory and motor plasticity. Another possibility is the induction of hypoxia-inducible factors–vascular endothelial growth factor signaling cascade, which influences posttraumatic neural repair and plasticity.

Although on the one hand it might not matter how the therapy works, as long as it is effective and safe, on the other hand, understanding the mechanism may allow for a more targeted approach, according to Dr. Fehlings. For example, he said, there may eventually be a drug therapy that offers "a more elegant and simpler way to have the same effect."

Dr. Trumbower received research support from the Craig H. Neilsen Foundation, the Department of Defense, and the National Institutes of Health. Dr. Fehlings is supported by the Gerald and Tootsie Halbert Chair in Neural Repair and Regeneration and receives grant support from the Canadian Institutes of Health Research, the Christopher and Dana Reeve Foundation, AOSpine, and the Wings for Life Foundation. Dr. Plow is supported by the Department of Defense/US Army's Medical Research and Materiel Command, American Heart Association, and National Institutes of Health.

Neurology. Published online November 27, 2013.

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