Therapeutic potential of intermittent hypoxia: Lessons from respiratory motor plasticity

Abstract

Intermittent hypoxia (IH) is a subject of considerable interest since it has both beneficial and adverse effects. Unfortunately, a lack of consistency in the use of the term intermittent hypoxia has led to considerable confusion in the field. In reviewing available literature, the physiological and pathological impact of IH appears to be highly associated with the effective IH dose. IH consisting of modest hypoxic episodes (≥9 % inspired O 2) and lesser numbers of hypoxia/reoxygenation events per day (≤15 cycles/day) is generally associated with beneficial effects in multiple body systems. In contrast, severe hypoxic episodes (<9 % inspired oxygen) and more frequent hypoxic episodes per day (40-2,400 cycles/day) shift the balance towards morbidity. In accordance, the impact of IH on the neural system controlling breathing is critically dependent on variables including the pattern of hypoxia (intermittent versus sustained), the severity of hypoxia within episodes, and the overall duration of IH exposure (minutes to years). A low IH dose (few episodes, moderate hypoxia) elicits serotonin-dependent spinal, respiratory motor plasticity that may be harnessed as a therapeutic approach to improve respiratory function in clinical conditions that impair breathing, such as cervical spinal injury. With a similar protocol but more severe hypoxic episodes, a distinct adenosine-dependent mechanism of spinal respiratory motor plasticity is observed. The cumulative effectives of repeated, low-dose IH (metaplasticity) suggest that repetitive, acute IH may represent a simple, safe, and effective treatment to promote meaningful therapeutic benefit in a range of clinical conditions that compromise respiratory (and nonrespiratory) somatic motor function.