Therapeutic potential of intermittent hypoxia: a matter of dose

Abstract

Intermittent hypoxia (IH) has been the subject of considerable research in recent years, and triggers a bewildering array of both detrimental and beneficial effects in multiple physiological systems. Here, we review the extensive literature concerning IH and its impact on the respiratory, cardiovascular, immune, metabolic, bone, and nervous systems. One major goal is to define relevant IH characteristics leading to safe, protective, and/or therapeutic effects vs. pathogenesis. To understand the impact of IH, it is essential to define critical characteristics of the IH protocol under investigation, including potentially the severity of hypoxia within episodes, the duration of hypoxic episodes, the number of hypoxic episodes per day, the pattern of presentation across time (e.g., within vs. consecutive vs. alternating days), and the cumulative time of exposure. Not surprisingly, severe/chronic IH protocols tend to be pathogenic, whereas any beneficial effects are more likely to arise from modest/acute IH exposures. Features of the IH protocol most highly associated with beneficial vs. pathogenic outcomes include the level of hypoxemia within episodes and the number of episodes per day. Modest hypoxia (9-16% inspired O2) and low cycle numbers (3-15 episodes per day) most often lead to beneficial effects without pathology, whereas severe hypoxia (2-8% inspired O2) and more episodes per day (48-2,400 episodes/day) elicit progressively greater pathology. Accumulating evidence suggests that "low dose" IH (modest hypoxia, few episodes) may be a simple, safe, and effective treatment with considerable therapeutic potential for multiple clinical disorders.

Keywords: dose; intermittent hypoxia; pathogenic; review; therapeutic.

Fig. 1.

Schematic summarizing factors most influential in determining the balance of beneficial vs. pathogenic intermittent hypoxia (IH) effects. IH protocols consisting of severe hypoxia (2–8% inspired O₂) and between 48–2,400 cycles/day are prone to pathology; citations demonstrating pathogenic effects of IH are listed in the upper left quadrant (i.e., high cycle numbers per day with relatively severe hypoxemia within episodes, as indicated by orange/red shading). In contrast, IH protocols consisting of moderate IH (>9% inspired O₂; <15 cycles/day) appear to elicit beneficial (potentially “therapeutic”) effects with minimal pathology; citations demonstrating beneficial effects of IH are listed in the lower right quadrant (indicated by blue shading). There is unlikely to be a clear division between protocols giving rise to pathogenic/beneficial effects since there is most likely a gradual transition (39); further, details of this transition may differ in detail among physiological systems. Representative literature concerning the range of IH protocols investigated are summarized in Figs. 2 (pathogenic) and 3 (beneficial).

Fig. 2.

Selected IH protocols reported to elicit pathology. Each protocol depicts the effective IH “dose,” including the severity of hypoxia during each episode (inspired O₂), the duration of hypoxic episodes (6 s to 12 h), the number of cycles per day (c/day), and the total time of exposure. Severe protocols (2–8% inspired O₂, 48–2,400 c/day) have been shown to elicit detrimental effects in multiple physiological systems (see orange-to-red shading in Fig. 1).

Fig. 3.

Selected IH protocols reported to elicit beneficial (potentially) therapeutic effects. Each protocol depicts the effective IH “dose,” including the severity of hypoxia during each episode (inspired O₂), the duration of hypoxic episodes (6 s to 12 h), the number of cycles per day (c/day), and the total time of exposure. Moderate IH protocols consisting of 9–16% O₂ and up to 15 cycles per day elicit beneficial effects in multiple physiological systems (blue shading in Fig. 1).