Intermittent hypoxia has generally been perceived as a high-risk stimulus, particularly in the field of sleep medicine, because it is thought to initiate detrimental cardiovascular, respiratory, cognitive, and metabolic outcomes. In contrast, the link between intermittent hypoxia and beneficial outcomes has received less attention, perhaps because it is not universally understood that outcome measures following exposure to intermittent hypoxia may be linked to the administered dose. The present review is designed to emphasize the less recognized beneficial outcomes associated with intermittent hypoxia. The review will consider the role intermittent hypoxia has in cardiovascular and autonomic adaptations, respiratory motor plasticity, and cognitive function. Each section will highlight the literature that contributed to the belief that intermittent hypoxia leads primarily to detrimental outcomes. The second segment of each section will consider the possible risks associated with experimentally rather than naturally induced intermittent hypoxia. Finally, the body of literature indicating that intermittent hypoxia initiates primarily beneficial outcomes will be considered. The overarching theme of the review is that the use of intermittent hypoxia in research investigations, coupled with reasonable safeguards, should be encouraged because of the potential benefits linked to the administration of a variety of low-risk intermittent hypoxia protocols.

Our purpose was to determine whether exposure to mild intermittent hypoxia leads to a reduction in the therapeutic continuous positive airway pressure required to eliminate breathing events. Ten male participants were treated with twelve 2-min episodes of hypoxia ([Formula: see text] ≈50 mmHg) separated by 2-min intervals of normoxia in the presence of [Formula: see text] that was sustained 3 mmHg above baseline. During recovery from the last episode, the positive airway pressure was reduced in a stepwise fashion until flow limitation was evident. The participants also completed a sham protocol under normocapnic conditions, which mimicked the time frame of the intermittent hypoxia protocol. After exposure to intermittent hypoxia, the therapeutic pressure was significantly reduced (i.e., 5 cmHO) without evidence of flow limitation (103.4 ± 6.3% of baseline, = 0.5) or increases in upper airway resistance (95.6 ± 15.0% of baseline, = 0.6). In contrast, a similar decrease in pressure was accompanied by flow limitation (77.0 ± 1.8% of baseline, = 0.001) and an increase in upper airway resistance (167.2 ± 17.5% of baseline, = 0.01) after the sham protocol. Consistent with the initiation of long-term facilitation of upper airway muscle activity, exposure to intermittent hypoxia reduced the therapeutic pressure required to eliminate apneic events that could improve treatment compliance. This possibility, coupled with the potentially beneficial effects of intermittent hypoxia on comorbidities linked to sleep apnea, suggests that mild intermittent hypoxia may have a multipronged therapeutic effect on sleep apnea. Our new finding is that exposure to mild intermittent hypoxia reduced the therapeutic pressure required to treat sleep apnea. These findings are consistent with previous results, which have shown that long-term facilitation of upper muscle activity can be initiated following exposure to intermittent hypoxia in humans.

Our investigation was designed to determine whether the time of day affects the carbon dioxide reserve and chemoreflex sensitivity during non-rapid eye movement (NREM) sleep. Ten healthy men with obstructive sleep apnea completed a constant routine protocol that consisted of sleep sessions in the evening (10 PM to 1 AM), morning (6 AM to 9 AM), and afternoon (2 PM to 5 PM). Between sleep sessions, the participants were awake. During each sleep session, core body temperature, baseline levels of carbon dioxide (PET(CO2)) and minute ventilation, as well as the PET(CO2) that demarcated the apneic threshold and hypocapnic ventilatory response, were measured. The nadir of core body temperature during sleep occurred in the morning and was accompanied by reductions in minute ventilation and PetCO2 compared with the evening and afternoon (minute ventilation: 5.3 ± 0.3 vs. 6.2 ± 0.2 vs. 6.1 ± 0.2 l/min, P < 0.02; PET(CO2): 39.7 ± 0.4 vs. 41.4 ± 0.6 vs. 40.4 ± 0.6 Torr, P < 0.02). The carbon dioxide reserve was reduced, and the hypocapnic ventilatory response increased in the morning compared with the evening and afternoon (carbon dioxide reserve: 2.1 ± 0.3 vs. 3.6 ± 0.5 vs. 3.5 ± 0.3 Torr, P < 0.002; hypocapnic ventilatory response: 2.3 ± 0.3 vs. 1.6 ± 0.2 vs. 1.8 ± 0.2 l·min(-1)·mmHg(-1), P < 0.001). We conclude that time of day affects chemoreflex properties during sleep, which may contribute to increases in breathing instability in the morning compared with other periods throughout the day/night cycle in individuals with sleep apnea.

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We investigated if the number and duration of breathing events coupled to upper airway collapsibility were affected by the time of day. Male participants with obstructive sleep apnea completed a constant routine protocol that consisted of sleep sessions in the evening (10 PM to 1 AM), morning (6 AM to 9 AM), and afternoon (2 PM to 5 PM). On one occasion the number and duration of breathing events was ascertained for each sleep session. On a second occasion the critical closing pressure that demarcated upper airway collapsibility was determined. The duration of breathing events was consistently greater in the morning compared with the evening and afternoon during N1 and N2, while an increase in event frequency was evident during N1. The critical closing pressure was increased in the morning (2.68 ± 0.98 cmH2O) compared with the evening (1.29 ± 0.91 cmH2O; P ≤ 0.02) and afternoon (1.25 ± 0.79; P ≤ 0.01). The increase in the critical closing pressure was correlated to the decrease in the baseline partial pressure of carbon dioxide in the morning compared with the afternoon and evening ( r = −0.73, P ≤ 0.005). Our findings indicate that time of day affects the duration and frequency of events, coupled with alterations in upper airway collapsibility. We propose that increases in airway collapsibility in the morning may be linked to an endogenous modulation of baseline carbon dioxide levels and chemoreflex sensitivity (12), which are independent of the consequences of sleep apnea.

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We investigated if time of day affects loop gain and the arousal threshold during non-rapid eye movement (NREM) sleep. Eleven males with obstructive sleep apnea completed a constant routine protocol comprised of sessions in the evening [10 PM (1) to 1 AM], morning (6 AM to 9 AM), afternoon (2 PM to 5 PM) and subsequent evening [10 PM (2) to 1 AM]. During each sleep session loop gain and the arousal threshold was measured during NREM sleep using a model-based approach. Loop gain and the arousal threshold were greater in the morning compared to both evening sessions [Loop gain: 10 PM (1) p = 0.01; 10 PM (2) p < 0.001] [Arousal threshold: 10 PM (1) p = 0.02; 10 PM (2) p = 0.001]. Moreover, no difference in loop gain and the arousal threshold existed between 10 PM (1) and 10 PM (2) (Loop gain: p = 0.27; Arousal threshold: p = 0.24). Loop gain was correlated to previously published measures of chemoreflex sensitivity (r = 0.72 & p = 0.045) and airway collapsibility (r = 0.77 & p = 0.02). We conclude that time of day modulates loop gain and the arousal threshold during NREM sleep. These modifications may contribute to increases in breathing instability in the morning compared to other periods in the day/night cycle. In addition, efficaciousness of treatments for obstructive sleep apnea that target loop gain and the arousal threshold may be modified by a rhythmicity of these variables.

Acute intermittent hypoxia (AIH) elicits a form of spinal, respiratory motor plasticity known as phrenic long‐term facilitation (pLTF). Preconditioning with a single day of chronic intermittent hypoxia (8 hours, 2 min hypoxic episodes with 2 min intervals) abolishes AIH‐induced pLTF through a mechanism that requires systemic inflammation and spinal p38 MAP kinase activation (Huxtable et al., 2015). pLTF is restored by high‐dose, systemic administration of the non‐steroidal anti‐inflammatory drug, ketoprofen, or spinal p38 MAP kinase inhibition. Similarly, preconditioning with 7 days of CIH (8 hours per day, 2 min episodes, 2 min intervals) abolishes pLTF, but we observed that phospho‐p38 within phrenic motor neurons is unchanged from control rats (Gonzalez‐Rothi and colleagues, unpublished). Thus, mechanisms whereby 7 days of CIH undermines AIH‐induced pLTF are unclear. Since CIH induces time‐dependent spinal inflammatory gene expression profiles over time (Smith et al., 2013), we hypothesize that prolonged CIH (versus a single day) blunts LTF through an inflammation‐dependent mechanism independent of p‐38MAP kinase. In ongoing experiments, we are evaluating whether anti‐inflammatory drugs restore AIH‐induced pLTF in rats preconditioned with prolonged CIH (7–28 days). Preliminary analyses in rats preconditioned with CIH for 7 days indicate that pLTF is expressed when ketoprofen is given on each day of the CIH exposure (67% baseline), but not when a single ketoprofen dose is given 3 hours prior to assessment of pLTF (−6% baseline). These experiments are the first to explore shifting mechanisms whereby prolonged CIH and associated inflammation undermine phrenic motor plasticity. Such experiments are essential since CIH is a hallmark of sleep apnea, a condition highly prevalent in individuals living with neurological disorders (spinal cord injury, ALS, etc.). It is therefore important to identify and mitigate factors which may undermine the potential for therapeutic interventions (i.e. repetitive AIH) to harness endogenous plasticity and ultimately improve breathing. Support or Funding Information Supported by: Department of Defense: SCI160123 and NIH R01 HL147554