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

脊髓损伤(SCI)在第6胸椎以上的个体经历严重的自主神经 功能障碍。这些人在有害或无害的情况下失去了控制血压(BP)的能力 损伤以下刺激(自主神经反射障碍[AD])和体位改变(直立位) 低血压[OH])。下行自主神经控制的丧失和随后的BP控制的丧失是非常严重的 常见于脊髓损伤患者。更重要的是，许多人没有意识到BP控制权的丧失 大多数人仍然没有症状。众所周知，英国石油公司的这些潜在威胁生命的振荡 导致进一步的损害；造成持续的自主神经和心血管功能障碍的恶性循环 解释了心血管相关死亡率的增加。不幸的是，预防措施对 这些人的自主神经功能障碍。此外，睡眠呼吸障碍(SDB)的流行率是 脊髓损伤患者(四肢瘫痪患者可以超过90%)很高，目前还没有最好的临床治疗方法。 脊髓损伤患者治疗SDB的实践指南。在患有和患有脊髓损伤的个体中，主要的 治疗采用持续气道正压通气(CPAP)。不幸的是，治疗依从性仍然存在 可怜。此外，已知SDB对糖尿病患者的自主神经、心血管和微血管功能有负面影响。 无脊髓损伤的个体。在没有脊髓损伤的个体中，对CPAP的坚持已显示出改善 微血管功能。尽管没有直接证据可用，但患有脊髓损伤的人已经显示出有 当依附于CPAP时AD的发生率降低，这表明微血管系统可能是一种主动的 AD和OH的治疗靶点。自主神经功能障碍和SDB都受到缺乏 脊髓损伤后的运动功能导致去条件性、肌肉和血管萎缩、胰岛素 抵抗力强，代谢率降低。此外，还建议在入院时较高的CPAP压力。 家庭治疗加上上呼吸道阻力增加是CPAP的主要生理障碍 治疗。因此，治疗方案直接改善血压对交感神经的反应 激活(图3)、上呼吸道功能(表2、图6、图7)以及改善微血管功能 (图8)对于有脊髓损伤的人来说是势在必行的。本提案的总体目标是调查是否每天 暴露于轻度间歇性低氧(MIH)也可以改善脊髓损伤患者的自主神经功能障碍 AS可改善线粒体和微血管功能。我们将招募有脊髓损伤的人，同时患有SDB， 和自主神经功能障碍的体征将被随机分配到两组之一(组1=MIH，组 2=对照[正常血氧])。治疗将在两周内进行8天。两个小组都将是 在8天内每晚在家中接受CPAP治疗。最后，个人将在MIH之前和之后接受测试 并在4周后返回实验室接受MIH术后自主神经、心血管和外周血管检查 肌肉功能测试(表3)。阳性患者将接受诊断性夜间多导睡眠监测 治疗前、后进行气道压治疗及24小时臂动脉血压监测。自主的 功能障碍的测量将在实验室中进行，在大腿时进行逐次血压和心电图检查。 压缩(AD)和位置变化(OH)。超声心动图和24小时血压监测将 在MIH治疗前后进行测量。CPAP遵守情况将在整个过程中受到监控。安全性和有效性 作为一种治疗，我们将在治疗前、治疗第4天采集血样进行监测 治疗后监测代谢和炎症生物标志物。参与者将在4周后返回 研究治疗性MIH对自主神经功能和SDB是否有持续影响。这个 这些结果的传播可能会改变治疗自主神经功能障碍和SDB的方法 患有脊髓损伤的个体。因此，本项目将决定MIH和CPAP是否可以作为 脊髓损伤和自主神经功能障碍患者的自主神经和心血管功能障碍的预防。

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.