Inhaled Fluticasone Effects on Upper Airway Patency in Obstructive Lung Disease

吸入氟替卡松对阻塞性肺疾病上呼吸道通畅的影响

• 批准号: 8698387
• 负责人: Mihaela Teodorescu
• 金额: --
• 依托单位: WM S. MIDDLETON MEMORIAL VETERANS HOSP
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8698387
• 关键词: Address; Adrenal Cortex Hormones; Affect; Asthma; Breathing; Caliber; Chairperson; Characteristics; Chronic Obstructive Airway Disease; Clinical; Clinical assessments; Data; Department of Defense; Deposition; Deterioration; Development; Diagnosis; Dilator; Disease Management; Dose; Fatty acid glycerol esters; Fluticasone propionate; Foundations; Functional disorder; Future; Goals; Guidelines; Hearing; High Prevalence; Hypoxia; Individual; Inflammatory; International; Investigation; Iowa; Isometric Exercise; Magnetic Resonance Imaging; Measurement; Measures; Mediator of activation protein; Muscle; Muscle function; Myopathy; Obesity; Obstructive Lung Diseases; Obstructive Sleep Apnea; Oral; Participant; Pathogenesis; Patients; Performance; Pharmaceutical Preparations; Polysomnography; Positioning Attribute; Predisposition; Prevalence; Process; Pulmonary Function Test/Forced Expiratory Volume 1; Randomized; Randomized Controlled Trials; Reporting; Research; Research Methodology; Risk; Risk Factors; Role; Running; Severities; Sleep; Sleep Apnea Syndromes; Steroids; Structure; Study Subject; Surveys; Symptoms; System; Testing; Tongue; Veterans; Wakefulness; Work; airway obstruction; base; design; disability; disorder control; evidence base; expectation; fluticasone; innovation; instrument; obesity risk; pharyngeal critical pressure; pressure; prevent; programs; response; risk benefit ratio

DESCRIPTION (provided by applicant): BACKGROUND/WORK ACCOMPLISHED: Growing data suggest that patients with obstructive lung disease (OLD) such as asthma and chronic obstructive pulmonary disease (COPD) have an increased predisposition for obstructive sleep apnea, but the mechanism(s) remain unknown. One characteristic these patients share is use of inhaled corticosteroid (ICS). We recently found a dose-dependent relationship of ICS use with high OSA risk. Furthermore, in a 16-week observational inhaled fluticasone (FP) treatment study, we observed increased upper airway (UAW) collapsibility during sleep, as measured by the critical closing pressure (Pcrit), parallelin the improvement in lower airways obstruction, with the largest Pcrit deterioration in the subject with most sleep-disordered breathing (SDB) at baseline. These findings suggest an effect of ICS on the "unified airway" of steroid responsive patients and of those with more collapsible upper airways at baseline. We also found a dose-dependent relationship of ICS with obesity. Based on their known effects, ICSs could deleteriously affect UAW collapsibility through inducing dilators' myopathy and fat deposition around the UAW. FP is the most potent and commonly used ICS. HYPOTHESIS/AIMS: The central hypothesis is that FP will increase UAW collapsibility (less negative Pcrit) and worsen SDB in steroid responsive patients with OLD and those with UAWs more susceptible to collapse at baseline, through alterations in tongue muscle function and fat accumulation in the UAW surrounding structures. To address this hypothesis, we propose to test the effects of inhaled FP on: 1) UAW collapsibility during sleep and SDB severity, assessed by Pcrit and polysomnographic (PSG) measures. Exploratory aims will test the role of steroid responsiveness and baseline collapsibility as determinants of FP effects on Pcrit and SDB; 2) tongue strength and fatigability, and fat accumulation (fraction and volume, measured on MRI) in the surrounding UAW structures. Exploratory aims will test whether these effects underlie the increase in UAW collapsibility and the role of steroid responsiveness status as a mediator of these FP effects. DESIGN: We propose a proof-of-concept and mechanistic, randomized-controlled, parallel groups study of high (220 mcg, 4 puffs twice a day) vs. low (44 mcg twice a day) dose inhaled FP, followed by an 8- week wash-out period, in 58 steroid-naive subjects with OLD. Following baseline Pcrit, PSG, MRI and tongue function (using the Iowa Oral Performance Instrument) measurements, subjects will enter a 2-week low-dose FP run-in, with subsequent randomization to either high- vs. low-dose FP, for 16 weeks. At mid-period, Pcrit, tongue function and steroid responsiveness status (defined as e5% improvement from baseline in FEV1%) will be determined. At the end of treatment, Pcrit, PSG, MRI and tongue measurements will be taken. Then, subjects will enter an 8-week wash-out that ends with repeat Pcrit and tongue function assessments. SIGNIFICANCE: Millions of people, including many Veterans, are treated with ICS for OLD, and among those with COPD, these numbers are likely to escalate. However, do these medications alter UAW collapsibility and predispose to OSA in some individuals, as our preliminary observations suggest? This research is innovative because it will directly evaluate the effects of ICS on the UAW structure and function during sleep and wakefulness. At the study completion, it is our expectation that we will have elucidated the effects and governing mechanisms of ICS on UAW patency and SDB severity. Data generated will form the foundation for future research aimed at expanding our understanding of ICS's effects on UAW and means to mitigate/prevent them. The clinical implication of our findings will be experimental-based verification of deleterious effects of ICS on UAW and risk for OSA, which will ultimately be of enormous financial benefit to the VA and OLD management programs.

描述（由申请人提供）： 背景/已完成的工作：越来越多的数据表明，哮喘和慢性阻塞性肺病（COPD）等阻塞性肺病（OLD）患者更容易患阻塞性睡眠呼吸暂停，但其机制仍不清楚。这些患者的共同特征之一是使用吸入性皮质类固醇（ICS）。我们最近发现 ICS 的使用与高 OSA 风险存在剂量依赖性关系。此外，在一项为期 16 周的观察性吸入氟替卡松 (FP) 治疗研究中，我们观察到睡眠期间上气道 (UAW) 塌陷性增加（通过临界闭合压 (Pcrit) 测量），同时下气道阻塞也得到改善，基线时睡眠呼吸障碍 (SDB) 最多的受试者中 Pcrit 恶化幅度最大。这些发现表明 ICS 对类固醇反应患者和基线时上呼吸道塌陷较多的患者的“统一气道”有影响。我们还发现 ICS 与肥胖存在剂量依赖性关系。根据其已知的影响，ICS 可能会通过诱发扩张器肌病和 UAW 周围的脂肪沉积，对 UAW 塌陷产生有害影响。 FP 是最有效且最常用的 ICS。 假设/目的：中心假设是，通过改变舌头肌肉功能和 UAW 周围结构中的脂肪积累，FP 将增加 UAW 塌陷性（负 Pcrit 较小），并恶化类固醇反应性 OLD 患者和 UAW 基线时更容易塌陷的患者的 SDB。为了解决这一假设，我们建议测试吸入 FP 对以下方面的影响：1) 睡眠期间 UAW 塌陷和 SDB 严重程度，通过 Pcrit 和多导睡眠图 (PSG) 测量进行评估。探索性目标将测试类固醇反应性和基线塌陷性作为 FP 对 Pcrit 和 SDB 影响的决定因素的作用； 2) 舌头力量和疲劳度，以及周围 UAW 结构中的脂肪积累（分数和体积，通过 MRI 测量）。探索性目标将测试这些影响是否是 UAW 塌陷性增加的基础，以及类固醇反应状态作为这些 FP 影响的中介者的作用。 设计：我们提出了一项概念验证和机制、随机对照、平行组研究，对 58 名未接受类固醇治疗的 OLD 受试者进行高剂量（220 微克，每天 4 口）与低剂量（44 微克，每天两次）吸入 FP 的研究，然后进行 8 周的清除期。在进行基线 Pcrit、PSG、MRI 和舌功能（使用爱荷华州口腔性能仪器）测量后，受试者将进入为期 2 周的低剂量 FP 磨合期，随后随机分为高剂量 FP 和低剂量 FP，为期 16 周。在中期，将确定 Pcrit、舌头功能和类固醇反应状态（定义为 FEV1% 较基线改善 e5%）。治疗结束时，将进行 Pcrit、PSG、MRI 和舌头测量。然后，受试者将进入为期 8 周的清除期，最后进行重复的 Pcrit 和舌头功能评估。 意义：包括许多退伍军人在内的数百万人接受 ICS 治疗老年疾病，而在慢性阻塞性肺病患者中，这一数字可能会上升。然而，这些药物是否会改变 UAW 塌陷性并导致某些个体易患 OSA，正如我们的初步观察结果所表明的那样？这项研究具有创新性，因为它将直接评估 ICS 对睡眠和清醒期间 UAW 结构和功能的影响。研究完成后，我们期望能够阐明 ICS 对 UAW 通畅性和 SDB 严重程度的影响和控制机制。生成的数据将为未来的研究奠定基础，旨在扩大我们对 ICS 对 UAW 的影响以及减轻/预防这些影响的方法的了解。我们的研究结果的临床意义将是基于实验验证 ICS 对 UAW 和 OSA 风险的有害影响，这最终将为 VA 和 OLD 管理计划带来巨大的经济效益。