Predicting response to non-PAP therapies in OSA using PSG-derived endotypes

使用 PSG 衍生的内型预测 OSA 对非 PAP 疗法的反应

基本信息

批准号：
10705062
负责人：
DAVID ANDREW WELLMAN
金额：
$ 79.65万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10705062
关键词：
Acetazolamide Address Algorithms Anterior Apnea Arousal Clinical Combined Modality Therapy Compensation Continuous Positive Airway Pressure Data Development Devices Disease Drug Targeting Effectiveness Electric Stimulation Epiglottis structure Failure Goals Grant Health Hypoglossal nerve structure Individual Intelligence Lateral Left Logistic Regressions Mandibular Advancement Measurement Measures Methods Mission Movement National Heart, Lung, and Blood Institute Obstruction Obstructive Sleep Apnea Outcome Palate Patient Selection Patients Persons Pharmaceutical Preparations Pharmacotherapy Pharyngeal structure Physiological Physiology Predisposition Public Health Research Residual state Severities Signal Transduction Site Sleep Sleep Disorders System Techniques Testing Therapeutic Tongue Trazodone United States National Institutes of Health Work alternative treatment atomoxetine common treatment effective therapy follow-up hyoepiglottic ligament improved novel outcome prediction oxybutynin pharmacologic pharynx muscle pilot test predicting response prevent respiratory response success trait treatment choice treatment response treatment strategy

项目摘要

ABSTRACT Obstructive Sleep Apnea (OSA) is a common disorder with serious health consequences that often remains undertreated due to few therapeutic options beyond continuous positive airway pressure (CPAP). Alternative treatments are available, such as mandibular advancement devices (MADs) and hypoglossal nerve stimulation (HGNS). However, these treatments are not always effective, and the predictors of success are poorly understood or difficult to obtain. Furthermore, patients who fail these therapies are often left untreated and therefore susceptible to the clinical consequences of OSA. In the previous grant period, we developed methods for estimating the pathophysiological endotypes of OSA (pharyngeal collapsibility, loop gain, pharyngeal muscle compensation, and arousal threshold), as well as the primary site of airway collapse (palate, tongue, lateral walls, epiglottis), from the clinical polysomnogram (PSG). The objective of this grant is to apply these methods to 1) find predictors of MAD and HGNS response and 2) test endotype-specific pharmacotherapies in MAD and HGNS non-responders. Our hypothesis is that these endotypes/sites of collapse, as determined from the PSG, are important predictors of MAD and HGNS response. We also hypothesize that the addition of a drug targeting an abnormal endotype, e.g., high loop gain, can be used to more effectively treat MAD and HGNS non-responders. In the first two aims, the physiological endotypes and sites of collapse will be determined from the clinical PSG using the methods developed in the previous grant cycle. Patients will then undergo MAD (Aim 1) or HGNS (Aim 2) therapy. A follow-up PSG will be performed to evaluate the success of treatment. Using multivariable logistic regression, the significant physiological predictors of success will be determined. In Aim 3, the patients who fail MAD or HGNS in the previous aims, approximately one-third of individuals, will be treated with a drug targeting the most abnormal endotype (acetazolamide for high loop gain, atomoxetine-plus-oxybutynin for poor pharyngeal muscle compensation, or trazodone for low arousal threshold). Recent evidence suggests that these drugs can manipulate the endotypes. The drug will be administered concurrently with MAD or HGNS treatment (combination therapy). Aims 1 and 2 are expected to find the important physiological predictors of MAD and HGNS response, respectively, using novel metrics derived from the clinical PSG. Aim 3 is expected to provide proof-of-principle for a pharmacologic approach to treating MAD and HGNS failures, patients who otherwise have limited treatment options. Ultimately, these studies have the potential to improve patient selection for non-CPAP alternatives and broaden the treatment options for OSA.

抽象的阻塞性睡眠呼吸暂停 (OSA) 是一种常见疾病，通常会造成严重的健康后果由于除了持续气道正压通气 (CPAP) 之外的治疗选择很少，该疾病的治疗仍然不足。可以使用替代治疗，例如下颌前移装置 (MAD) 和舌下神经刺激（HGNS）。然而，这些治疗并不总是有效，成功的预测因素是知之甚少或难以获得。此外，这些疗法失败的患者往往得不到治疗因此容易受到 OSA 临床后果的影响。在上一个资助期间，我们开发了估计病理生理内型的方法 OSA（咽塌陷、环增益、咽肌代偿和唤醒阈值）以及临床多导睡眠图显示气道塌陷的主要部位（腭、舌、侧壁、会厌）（巴黎圣日尔曼）。此项资助的目标是将这些方法应用于 1) 寻找 MAD 和 HGNS 响应的预测因子 2) 在 MAD 和 HGNS 无反应者中测试内型特异性药物疗法。我们的假设是根据 PSG 确定的这些内型/塌陷位点是 MAD 和 HGNS 的重要预测因子回复。我们还假设添加针对异常内型的药物，例如高环增益，可用于更有效地治疗 MAD 和 HGNS 无反应者。在前两个目标中，生理内型和崩溃部位将由使用上一个资助周期开发的方法进行临床 PSG。然后患者将接受 MAD（目标 1）或 HGNS（目标 2）治疗。将进行后续 PSG 以评估治疗的成功。使用多变量逻辑回归，将确定成功的重要生理预测因素。在目标 3 中，在先前目标中未通过 MAD 或 HGNS 的患者中，大约有三分之一个体，将接受针对最异常内型的药物治疗（乙酰唑酰胺用于高环增益，托莫西汀加奥昔布宁治疗咽肌代偿不良，或曲唑酮治疗低唤醒临界点）。最近的证据表明这些药物可以操纵内型。该药物将是与 MAD 或 HGNS 治疗同时进行（联合治疗）。目标 1 和 2 有望找到 MAD 和 HGNS 反应的重要生理预测因子，分别使用源自临床 PSG 的新指标。目标 3 预计将提供原理验证对于治疗 MAD 和 HGNS 失败的药理学方法，其他情况有限的患者治疗方案。最终，这些研究有可能改善非 CPAP 患者的选择替代方案并扩大 OSA 的治疗选择。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Loop gain in REM versus non-REM sleep using CPAP manipulation: A pilot study.

使用 CPAP 操作在 REM 睡眠与非 REM 睡眠中的环路增益：一项试点研究。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Messineo, Ludovico;Taranto;Azarbarzin, Ali;Marques, Melania;Calianese, Nicole;White, David P;Wellman, Andrew;Sands, Scott A
通讯作者：
Sands, Scott A

Daytime loop gain is elevated in obstructive sleep apnea but not reduced by CPAP treatment.

阻塞性睡眠呼吸暂停患者的日间循环增益会升高，但 CPAP 治疗不会降低白天循环增益。

DOI：
发表时间：
2018
期刊：
影响因子：
0
作者：
Deacon;Sands, Scott A;McEvoy, R Doug;Catcheside, Peter G
通讯作者：
Catcheside, Peter G

The Effect of Body Position on Physiological Factors that Contribute to Obstructive Sleep Apnea.

身体姿势对导致阻塞性睡眠呼吸暂停的生理因素的影响。

DOI：
发表时间：
2015-09-01
期刊：
影响因子：
5.6
作者：
Joosten, Simon A;Edwards, Bradley A;Wellman, Andrew;Turton, Anthony;Skuza, Elizabeth M;Berger, Philip J;Hamilton, Garun S
通讯作者：
Hamilton, Garun S

PSGs: more than just the AHI.

PSG：不仅仅是 AHI。

DOI：
发表时间：
2013-06-15
期刊：
影响因子：
0
作者：
Edwards, Bradley A;Wellman, Andrew;Owens, Robert L
通讯作者：
Owens, Robert L

Breath-holding as a means to estimate the loop gain contribution to obstructive sleep apnoea.

屏气作为估计环路增益对阻塞性睡眠呼吸暂停的影响的一种方法。

DOI：
发表时间：
2018-09
期刊：
影响因子：
0
作者：
Messineo, Ludovico;Taranto;Azarbarzin, Ali;Oliveira Marques, Melania D;Calianese, Nicole;White, David P;Wellman, Andrew;Sands, Scott A
通讯作者：
Sands, Scott A