Mild Intermittent Hypoxia: A Prophylactic for Autonomic Dysfunction in Individuals with Spinal Cord Injuries

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Individuals with a spinal cord injury (SCI) above the 6th thoracic vertebrae experience severe autonomic dysfunction. These individuals lose the ability to control blood pressure (BP) during a noxious or non-noxious stimulus below the injury (Autonomic Dysreflexia [AD]) and during positional changes (Orthostatic Hypotension [OH]). The loss of descending autonomic control and subsequent loss of BP control are highly prevalent in individuals with SCI. More importantly, many individuals are unaware of the loss of BP control as most individuals remain asymptomatic. These potentially life-threatening oscillations in BP are known to induce further damage; creating a vicious cycle of continued autonomic and cardiovascular dysfunction which explains the increased cardiovascular related mortality. Unfortunately, there is no effect prophylaxis for autonomic dysfunction in these individuals. Furthermore, the prevalence of sleep disordered breathing (SDB) is high in individuals with SCI (Individuals with tetraplegia can exceed 90%), and there is no current best clinical practice guidelines for treating SDB in individuals with SCI. In both individuals with and with SCI, the primary treatment is with continuous positive airway pressure (CPAP). Unfortunately, treatment adherence remains poor. Moreover, SDB is known to negatively impact autonomic, cardiovascular, and microvascular function in individuals without SCI. In individuals without an SCI, adherence to CPAP has shown to improve microvascular function. Although no direct evidence is available, individuals with SCI have shown to have a reduction in the frequency of AD when adherent to CPAP suggesting the microvasculature may be a pro-active therapeutic target for AD and OH. Both autonomic dysfunction and SDB are negatively impacted by the lack of motor function following SCI resulting in deconditioning, atrophy of the muscles and vessels, insulin resistance, and reduced metabolic rate. Additionally, it has been suggested higher CPAP pressure during in- home treatment coupled with increased upper airway resistances are primary physiological barriers to CPAP treatment. Therefore, treatment options that directly improve the blood pressure response to sympathetic activation (Figure 3), upper airway function (Table 2, Figure 6, 7) as well as improve microvascular function (Figure 8) are imperative for those with a SCI. The overall goal of the present proposal is to investigate if daily exposure to mild intermittent hypoxia (MIH) can ameliorate autonomic dysfunction in persons with SCI as well as improve mitochondrial and microvascular function. We will recruit individuals with SCI, concurrent SDB, and signs of autonomic dysfunction who will be randomly assign to one of two groups (Group 1 = MIH, Group 2 = Control [Normoxia]). Treatment will be administered for 8 days over a 2-week period. Both groups will be treated with nightly in-home CPAP over the 8 days. Lastly, individuals will be tested before, and after MIH as well as return to the laboratory 4 weeks later to undergo post-MIH autonomic, cardiovascular, and peripheral muscle function tests (Table 3). Individuals will undergo diagnostic split-night polysomnography with positive airway pressure treatment and 24-hour brachial BP monitoring before and after therapy. Autonomic dysfunction will be measured in-lab with beat-to-beat blood pressure and electrocardiograms during thigh compression (AD) and positional changes (OH). Echocardiograms and 24-hour blood pressure monitoring will be measured before and after MIH-therapy. CPAP adherence will be monitored throughout. Safety and efficacy of MIH as a treatment we will be monitored with blood samples collected on before, on day 4 of therapy, and post-therapy to monitor metabolic and inflammatory biomarkers. Participants will return 4-weeks later to investigate if there is a sustained impact of therapeutic MIH on autonomic function and SDB. The dissemination of these outcomes could transform the approach to treating autonomic dysfunction and SDB in individuals with SCI. Therefore, this project will determine if MIH combined with CPAP can be used as prophylaxis for autonomic and cardiovascular dysfunction in patients with SCI and autonomic dysfunction.