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

在脊髓完整的退伍军人中，阻塞性睡眠呼吸暂停（OSA）的患病率很高99， 四肢瘫痪患者的患病率甚至更高（即74%）19。不完全性脊髓损伤（SCI）， 并发的OSA伴有自主神经、心血管和神经认知共病，以及， 呼吸和肢体运动功能障碍。治疗方案，以减轻这些合并症，同时促进 呼吸运动功能的恢复范围从有限到不存在96.当前的总体目标 一项研究建议是研究每天暴露于轻度间歇性缺氧（MIH）是否会增加上呼吸道 持续气道正压通气（CPAP）的使用 （小时/夜）。MIH与改进的夜间家庭CPAP结合的直接效果可以作为 减轻自主神经、心血管和神经认知共病的多管齐下的治疗方法 同时促进患有SCI和并发OSA的个体的呼吸运动功能的恢复。 我们认为，每天暴露于MIH可以减少治疗睡眠呼吸暂停所需的正压， 因此可以提高家庭治疗依从性。提高依从性有助于 减轻上述并发症。此外，MIH也可能直接影响这些合并症， 促进呼吸神经肌肉功能的恢复。为了实现我们的目标，我们将招募个人 并将他们随机分配到两组中的一组。[The参与者将被 对分组设盲]。一组将在3周内每天接受MIH治疗，持续15天 一组暴露于环境空气（即对照组），另一组暴露于环境空气（即对照组）。此外，本发明还提供了一种方法， 两组都将在整个方案期间用[每晚在家] CPAP治疗。一开始， 在方案的中间和结束时，将获得一些测量值，以评估MIH暴露是否可以 有效缓解上述合并症，[以及降低治疗压力， 治疗] OSA。血压是主要结局，将在24小时内测量， 在方案前后使用动态自动血压监测装置。此外，自动和手动 将在MIH治疗期之前、期间和之后获得血压测量值。神经认知功能. 方案的开始和结束将使用侧重于警惕性、记忆力和 执行功能在治疗期间，将通过心率每天评估自主神经功能， BP变异性分析。治疗CPAP压力，以及主动和被动的临界关闭压力， 将在方案开始、中间和结束时测量上气道。[此外，二氧化碳 在每次访视的前10分钟内，通过监测潮气末CO2，每天测量尿潴留。]到 为了监测MIH作为SCI和OSA治疗的安全性和有效性， 从在15天方案开始、中间和结束时收集的血液样品测量。血液 测试将确定潜在的代谢（即血脂，血红蛋白A1 C），炎症（即高敏感性C- 反应蛋白、TNF-α、白细胞介素1、6、8和CCL 3 -887）和血管生成/血管生成（缺氧诱导 因子1α和血管内皮生长因子）。最后，将测量红细胞计数（红细胞压积）， 监测红细胞增多症通过传播这一项目和未来项目所报告的成果， 为那些脊髓损伤[和医疗后遗症， 阻塞性睡眠呼吸暂停综合征[obstructive sleep apnea]在退伍军人人群中。因此，本项目将确定MIH是否与 CPAP可作为一种治疗方法，在促进康复的同时减轻多种合并症 脊髓损伤合并阻塞性睡眠呼吸暂停综合征退伍军人的神经肌肉功能。

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.