Mild Intermittent Hypoxia and Its Multipronged Effect on Obstructive Sleep Apnea
Authors: Panza Gino Severio , Puri Shipra , Rimar Caroline , Lin Ho-Sheng , Mateika Jason 
Published: April 2020

Study ObjectiveMild intermittent hypoxia (MIH) may induce beneficial cardiovascular (CV), autonomic nervous system (ANS), metabolic and neurocognitive (NC) outcomes. In addition, we have shown that MIH decreases continuous positive airway pressure (CPAP) and improves CPAP adherence in participants with obstructive sleep apnea (OSA). Thus, we hypothesized that MIH coupled with CPAP improves CV, metabolic, NC function.MethodsNine hypertensive participants with OSA were exposed to twelve 2‐minute episodes of hypoxia (PETO2 ≈ 50 mmHg) separated by 2‐minute normoxic intervals for 15 days over 3 weeks. PETCO2 was sustained at 2 mmHg above baseline during MIH administration. Five participants were exposed to a sham protocol comprised of 2‐minute episodes of room air. Both groups were treated with in‐home CPAP on a nightly basis. Before and after the 3‐week protocol, blood pressure was measured over 24 hours. On the initial and final day of the protocol, blood biomarkers, and NC tests were measured before MIH. Moreover, heart rate and beat‐to‐beat blood pressure were measured throughout the protocol to obtain non‐invasive measures of parasympathetic and sympathetic nervous system activity (PNSA and SNSA) via heart rate and blood pressure variability analysis.ResultsMIH combined with CPAP therapy led to a significant decrease in 24‐hour systolic (SBP) (142.43 ± 2.8 vs 132.0 ± 3.8 mmHg, p ≤ 0.01), diastolic blood pressure (DBP) (88.7 ± 3.4 vs 80.2 ± 3.8 mmHg, p ≤ 0.01) and mean arterial pressure (MAP) (106.4 ± 3.2 vs 97.5 ± 3.7 mmHg, p ≤ 0.01). CPAP therapy in the sham group did not result in changes in SBP (151.9 ± 3.8 vs 151.3 ± 5.3 mmHg, p = 0.8), DBP (90.3 ± 3.5 vs 89.3 ± 3.4 mmHg, p = 0.6), or MAP (111.8 ± 2.6 vs 109.9 ± 3.6 mmHg, p = 0.3). SNSA decreased (75.4 ± 3.6 vs 64.6 ± 4.0 normalized units, p ≤ 0.01) and PNSA increased (21.4 ± 3.5 vs 31.9 ± 3.9 normalized units, p ≤ 0.02) following MIH. No change in PNSA and SNSA were found in the sham group. The MIH group had significantly higher PNSA and lower SNSA when compared to the sham group (p ≤ 0.01). Total (9.1 ± 0.7 vs. 2.3 ± 0.6 number of trials, p ≤ 0.01), short‐term (2.3 ± 0.5 vs. 0.3 ± 0.2 number of items recalled in initial trial, p ≤ 0.01) and long‐term recall (6.2 ± 0.8 vs. 16.9 ± 1.1 number of items recalled in initial trial, p ≤ 0.001) determined from the Buschke selective reminding test showed improvements following MIH. Changes in NC function were not evident in the sham group. Following MIH, HbA1C was lower compared to the sham group (5.0 ± 0.1 vs 5.9 ± 0.1, p ≤ 0.05), while prior to the protocol this was not the case (5.3 ± 0.1 vs 5.6 ± 0.1 percent, p = 0.2).ConclusionsWe propose that the improved outcomes we observed are consequence of the direct effect of MIH and indirect effects of improved adherence to CPAP (data not included). Moreover, negative metabolic outcomes were not found in our MIH group. Thus, exposure to MIH may serve as a multipronged therapy to treat OSA and its overlapping co‐morbidities.Support or Funding InformationFunding: Department of Veterans Affairs (I01CX000125 & 15SRCS003 JHM, 1IK1RX002945GSP), and National Institutes of Health (R56HL142757 & R01HL142757 JHM).