Mild intermittent hypoxia: A therapeutic modality to mitigate co-morbidities and promote recovery of respiratory motor function in spinal cord injured patients with sleep apnea

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The prevalence of obstructive sleep apnea (OSA) is high in Veterans with an intact spinal cord99 and the prevalence is even greater (i.e.74%) in patients with tetraplegia19. Incomplete spinal cord injury (SCI) with concurrent OSA is accompanied by autonomic, cardiovascular and neurocognitive co-morbidities, as well as, respiratory and limb motor dysfunction. Treatment options to mitigate these co-morbidities while promoting recovery of respiratory motor function range from limited to non-existent96. The overall goal of the present proposal is to investigate if daily exposure to mild intermittent hypoxia (MIH) [can increase upper airway muscle activity leading to increased nightly in-home] continuous positive airway pressure [(CPAP) usage (Hours/night). The direct effects of MIH in combination with the improved nightly in-home CPAP] can serve as a multipronged therapeutic approach to mitigate autonomic, cardiovascular and neurocognitive co-morbidities while promoting recovery of respiratory motor function in individuals suffering from SCI and concurrent OSA. We believe that exposure to daily MIH could reduce the positive pressure required to treat sleep apnea at home and as a result could improve in-home treatment adherence. Improved adherence could contribute to mitigating the co-morbidities listed above. In addition, MIH might also directly impact these co-morbidities while promoting recovery of respiratory neuromuscular function. To accomplish our goal we will recruit individuals with SCI and concurrent OSA, and randomly assign them to one of two groups. [The participants will be blinded to group assignment]. One group will be treated daily with MIH for a period of 15 days over a 3 week period (i.e. 5 days/week) and the other group will be exposed to ambient air (i.e. control group). In addition, both groups will be treated with [nightly in-home] CPAP over the length of the protocol. At the beginning, middle and end of the protocol a number of measures will be obtained to assess if exposure to MIH can effectively mitigate the co-morbidities listed above, [as well as reduce the therapeutic pressure required to treat] OSA. Blood pressure is a primary outcome and will be measured over a 24 hour period with an ambulatory automated BP monitoring device before and after the protocol. Additionally, automated and manual measures of BP will be obtained before, during, and after MIH treatment sessions. Neurocognitive function at the beginning and end of the protocol will be assessed using tests that focus on vigilance, memory and executive function. Autonomic function will be assessed on a day to day basis during therapy via heart rate and BP variability analysis. The therapeutic CPAP pressure, and active and passive critical closing pressure of the upper airway will be measured at the beginning, middle and end of the protocol. [Additionally, carbon dioxide retention will be measured daily during the first 10 minutes of each visit by monitoring end tidal CO2.]To monitor the safety and efficacy of MIH as a treatment for SCI and OSA, numerous biomarkers will be measured from blood samples collected at the beginning, middle and end of the 15 day protocol. The blood tests will identify potential metabolic (i.e. lipid profile, hemoglobin A1C), inflammatory (i.e. high sensitivity C‐ reactive protein, TNF-alpha, Interleukin 1, 6, 8 and CCL3-887) and angiogenic/vasculogenic (hypoxia inducible factor 1α and vascular endothelial growth factor). Lastly, red blood cell count (hematocrit) will be measured to monitor for polycythemia. The dissemination of the outcomes reported from this, and future projects, could lead to more advanced and timely treatments for those with spinal cord injuries [and medical sequela due to obstructive sleep apnea] in the Veteran population. Therefore, this project will determine if MIH combined with CPAP can be used as a treatment to mitigate numerous co-morbidities while promoting recovery neuromuscular function in Veterans with SCI and concurrent OSA.