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.

A major cause of mortality after spinal cord injury is respiratory failure. In normal rats, acute intermittent hypoxia (AIH) induces respiratory motor plasticity, expressed as diaphragm (Dia) and second external intercostal (T2 EIC) long-term facilitation (LTF). Dia (not T2 EIC) LTF is enhanced by systemic adenosine 2A (A2a) receptor inhibition in normal rats. We investigated the respective contributions of Dia and T2 EIC to daily AIH-induced functional recovery of breathing capacity with/without A2a receptor antagonist (KW6002, i.p.) following C2 hemisection (C2HS). Rats received daily AIH (dAIH: 10, 5-min episodes, 10.5% O2; 5-min normoxic intervals; 7 successive days beginning 7 days post-C2HS) or daily normoxia (dNx) with/without KW6002, followed by weekly (reminder) presentations for 8 weeks. Ventilation and EMGs from bilateral diaphragm and T2 EIC muscles were measured with room air breathing (21% O2) and maximum chemoreceptor stimulation (MCS: 7% CO2, 10.5% O2). dAIH increased tidal volume (Vt) in C2HS rats breathing room air (dAIH + vehicle: 0.47 ± 0.02, dNx + vehicle: 0.40 ± 0.01ml/100 g; p<0.05) and MCS (dAIH + vehicle: 0.83 ± 0.01, dNx + vehicle: 0.73 ± 0.01ml/100g; p<0.001); KW6002 had no significant effect. dAIH enhanced contralateral (uninjured) diaphragm EMG activity, an effect attenuated by KW6002, during room air breathing and MCS (p<0.05). Although dAIH enhanced contralateral T2 EIC EMG activity during room air breathing, KW6002 had no effect. dAIH had no statistically significant effects on diaphragm or T2 EIC EMG activity ipsilateral to injury. Thus, two weeks post-C2HS: 1) dAIH enhances breathing capacity by effects on contralateral diaphragm and T2 EIC activity; and 2) dAIH-induced recovery is A2a dependent in diaphragm, but not T2 EIC. Daily AIH may be a useful in promoting functional recovery of breathing capacity after cervical spinal injury, but A2a receptor antagonists (eg. caffeine) may undermine its effectiveness shortly after injury.

Incomplete spinal cord injuries (iSCI) leave spared synaptic pathways below the level of injury. Intermittent hypoxia (IH) elicits plasticity in the spinal cord and strengthens spared synaptic pathways, expressed as respiratory and somatic functional recovery in experimental animals and humans with iSCI. This study is a randomized, triple-blind, two-arm parallel clinical trial performed in Santiago, Chile. We compared the effects of a 4-week protocol of IH combined with body weight-supported treadmill training (BWSTT), with continuous normoxia (Nx) and BWSTT on 10-meter walk test (10MWT), 6-minute walk test (6MWT), and timed up and go (TUG) test in American Spinal Injury Association C and D individuals with iSCI. Subjects received daily IH (cycling 9%/21% O every 1.5 min, 15 cycles/day) or continuous Nx (21% O) combined with 45 min BWSTT for 5 consecutive days, followed by IH/Nx 3 × per week (3 × wIH/Nx) for 3 additional weeks. Subjects were assessed at day 5, weekly from weeks 2-4, and at a 2-week follow-up. Daily IH plus BWSTT enhanced walking speed, expressed as decreased 10MWT time at day 5 versus baseline (IH: -10.2 ± 3.0 vs. Nx: -1.7 ± 1.7 sec, p = 0.006), and walking endurance expressed as increased 6MWT distance at day 5 versus baseline (IH: 43.0 ± 10.7 vs. Nx: 6.1 ± 3.4 m, p = 0.012), but not TUG time. Further, 3 × wIH maintained the daily IH-induced walking speed, and enhanced the daily IH-induced walking endurance, which is maintained up to the 2-week follow-up. We conclude that daily IH enhances walking recovery in subjects with iSCI, confirming previous findings. Moreover, 3 × wIH prolonged or enhanced daily IH-induced walking speed and endurance improvements, respectively, up to 5 weeks post-daily IH. Repetitive IH may be a safe and effective therapeutic alternative for persons with iSCI.

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Purpose The vast majority of rare diseases (RDs) are complex, disabling, and life-threatening conditions with a genetic origin. RD patients face significant health challenges and limited treatments, yet the extent of their impact within health care is not well known. One direct method to gauge the disease burden of RDs is their overall cost and utilization within health-care systems. Methods The 2016 Healthcare Cost and Utilization Project (HCUP) databases were used to extract health-care utilization data using International Classification of Diseases, Tenth Revision (ICD-10) codes. Results Of 35.6 million national hospital weighted discharges in the HCUP Nationwide Inpatient Sample, 32% corresponded to RD-associated ICD-10 codes. Total charges were nearly equal between RDs ($768 billion) compared to common conditions (CCs) ($880 billion) (p < 0.0001). These charges were a result of higher charges per discharge and longer length of stay (LOS) for RD patients compared to those with CCs (p < 0.0001). Health-care cost and utilization was similarly higher for RDs with pediatric inpatient stays, readmissions, and emergency visits. Conclusion Pediatric and adult discharges with RDs show substantially higher health-care utilization compared to discharges with CCs diagnoses, accounting for nearly half of the US national bill.

Daily acute intermittent hypoxia (dAIH) improves breathing capacity after C2 spinal hemisection (C2HS) in rats. Since C2HS disrupts spinal serotonergic innervation below the injury, adenosine-dependent mechanisms underlie dAIH-induced functional recovery 2 weeks post-injury. We hypothesized that dAIH-induced functional recovery converts from an adenosine-dependent to a serotonin-dependent, adenosine-constrained mechanism with chronic injury. Eight weeks post-C2HS, rats began dAIH (10, 5-min episodes, 10.5% O2; 5-min intervals; 7 days) followed by AIH 3× per week (3×wAIH) for 8 additional weeks with/without systemic A2A receptor inhibition (KW6002) on each AIH exposure day. Tidal volume (VT) and bilateral diaphragm (Dia) and T2 external intercostal motor activity were assessed in unanesthetized rats breathing air and during maximum chemoreflex stimulation (MCS: 7% CO2, 10.5% O2). Nine weeks post-C2HS, dAIH increased VT versus time controls (p < 0.05), an effect enhanced by KW6002 (p < 0.05). dAIH increased bilateral Dia activity (p < 0.05), and KW6002 enhanced this effect in contralateral (p < 0.05) and ipsilateral Dia activity (p < 0.001), but not T2 inspiratory activity. Functional benefits of combined AIH plus systemic A2A receptor inhibition were maintained for 4 weeks. Thus, in rats with chronic injuries: 1) dAIH improves VT and bilateral diaphragm activity; 2) VT recovery is enhanced by A2A receptor inhibition; and 3) functional recovery with A2A receptor inhibition and AIH “reminders” last 4 weeks. Combined dAIH and A2A receptor inhibition may be a simple, safe, and effective strategy to accelerate/enhance functional recovery of breathing capacity in patients with respiratory impairment from chronic spinal injury.

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Acute intermittent hypoxia (AIH) elicits diaphragm (Dia) and second external intercostal (T2 EIC) long-term facilitation (LTF) in normal unanesthetized rats. Although AIH-induced phrenic LTF is serotonin dependent, adenosine constrained in anesthetized rats, this has not been tested in unanesthetized animals. Cervical (C2) spinal hemisection (C2HS) abolishes phrenic LTF because of loss of serotonergic inputs 2 weeks post-injury, but LTF returns 8 weeks post-injury. We tested three hypotheses in unanesthetized rats: (1) systemic adenosine 2aA (A2A) receptor inhibition with intraperitoneal (IP) KW6002 enhances Dia and T2 EIC LTF in normal rats; (2) Dia and T2 EIC LTF are expressed after chronic (8 weeks), but not acute (1 week) C2HS; and (3) KW6002 enhances Dia and T2 EIC LTF after chronic (not acute) C2HS. Electromyography radiotelemetry was used to record Dia and T2 EIC activity during normoxia (21% O 2 ), before and after AIH (10, 5-min 10.5% O 2 , 5-min intervals). In normal rats, KW6002 enhanced DiaLTF versus AIH alone (33.1 -4.6% vs. 22.1 -6.4% baseline, respectively; p < 0.001), but had no effect on T2 EIC LTF ( p > 0.05). Although Dia and T2 EIC LTF were not observed 2 weeks post-C2HS, LTF was observed in contralateral (uninjured) Dia and T2 EIC 8 weeks post-C2HS (18.7 -2.7% and 34.9 -4.9% baseline, respectively; p < 0.05), with variable ipsilateral expression. KW6002 had no significant effects on contralateral Dia ( p = 0.447) or T2 EIC LTF ( p = 0.796). We conclude that moderate AIH induces Dia and T2 EIC LTF after chronic, but not acute cervical spinal injuries. A single A2A receptor antagonist dose enhances AIH-induced Dia LTF in normal rats, but this effect is not significant in chronic (8 weeks) C2HS unanesthetized rats.