Reversible Effect of Falling Ventilatory Drive in Drive-dependent OSA
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 36
- 试验地点
- 2
- 主要终点
- Reduction in odds of respiratory event
研究概览
简要总结
Obstructive sleep apnea (OSA) is a highly prevalent disorder that has major consequences for cardiovascular health, neurocognitive function, risk of traffic accidents, daytime sleepiness, and quality of life. For years, a "classic" model of OSA has been used to describe the disorder, which fails to capture it's complexity. Recently, a model for OSA called drive-dependent OSA was discovered be more prevalent in the OSA population. The drive-dependent subgroup benefits exclusively from increased ventilation, increased dilator muscle activity, and reduced event risk when drive spontaneously rises. This study seeks to provide direct evidence that reducing the loss of drive prevents the loss of ventilation, pharyngeal muscle activity, and thus the onset of OSA respiratory events, specifically in "drive-dependent" but not "classic" OSA. This will be achieved using CO2 delivered at precise times during breaths in sleep to prevent loss of overall ventilatory drive.
详细描述
This is a detailed physiological study, with gold-standard measurements of ventilatory drive and dilator muscle activity, we aim to mitigate falling drive with carefully-timed inspired CO2 administration in patients with (N=18) and without (N=18) drive-dependent OSA. We will test the hypothesis that OSA events are preventable by mitigating falling drive exclusively in drive-dependent OSA.
Subjects will attend a virtual Screening and Consent visit to assess eligibility for enrollment. Participants will take part in a video call with the consenting doctor to obtain consent (Zoom). After consent, patients will first attend a baseline routine sleep study to confirm eligibility and establish baseline characteristics. Patients will subsequently attend an overnight physiology study with gold standard instrumentation (ventilation and ventilatory drive, see below) to establish OSA phenotype (presence/absence of drive-dependent OSA).
Finally, an overnight physiological intervention study dedicated to mitigating ventilatory drive decline with carefully-timed inspired CO2 stimulation will be performed.
At the Dynamic CO2 Study, we will also record upper airway dilator muscle activity (multiunit genioglossus electromyography, EMG). Once respiratory events begin, an investigator will switch the 4-way tap to deliver 2% inspired CO2 during the first 3-4 recovery breaths following a respiratory event. Consequently, end-tidal CO2 will no longer drop as abruptly to lower levels, and thus on the return to sleep, ventilatory drive will not decline as seen during the prior event. Sham interventions (medical air) will also be performed (1:1) to ensure that event risk is not lowered trivially due to spontaneous event resolution or deepening sleep with time. If necessary to precisely control end-tidal CO2 and ventilatory drive, we will 1) raise the magnitude to a maximum of 6%CO2 (in 14% O2) for a single breath intervention, or 2) lower the magnitude to 1.0% or 1.5% via dilution. The first 30 mins of each study will be dedicated to identifying the optimal dose, before formal interventions with alternating shams proceed.
Data analysis
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Outcomes Assessor)
入排标准
- 年龄范围
- 21 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosed OSA (AHI≥15 events/h reported in a PSG performed within 1 year) or Suspected OSA (snoring, sleepiness, witnessed apneas, other clinical symptoms)
- •Use of CPAP or other therapies is acceptable; individuals will be asked to withhold treatment for 3 days before each study visit. Individuals who are occupational drivers or operate heavy machinery will not be asked to withhold treatment.
排除标准
- •Any unstable medical conditions
- •Conditions that could meaningfully raise the cardiovascular risks of brief low-dose hypercapnic-hypoxic inspired gas mixture: heart failure (LVEF<45% if known), recent cardiovascular event (<12 mo), recent cerebrovascular event (<12 mo)*
- •Medications known to depress ventilatory drive (e.g. opioids, barbiturates)
- •Conditions likely to increase arousability from sleep: insomnia
- •Other sleep disorders that may complicate establishment of sleep: periodic limb movements (periodic limb movement arousal index > 10/hr), narcolepsy, or parasomnias
- •For intramuscular electrodes and catheter: allergy to lidocaine
- •Highly-sensitive gag reflex. Patients with a self-reported 'highly-sensitive gag reflex', including an affirmative response to 'Do you sometimes gag when brushing your teeth?', will not take part in the physiology studies given the placement of an esophageal catheter
- •For intramuscular electrodes: use of aspirin or other oral anti-platelets / anti-coagulants
- •For oronasal mask: severe claustrophobia
- •Pregnancy or nursing
- •We do not intend to exclude patients with controlled cardiovascular disease (hypertension of any severity, arrhythmias, stents) common in the OSA patient population. The transient gas mixture interventions are mild, short-lived, and act to slow the spontaneous recovery of blood gas levels to prevent cyclic upper airway obstruction as opposed to exacerbating them. Control of breathing studies commonly increase inspired CO2/reduce inspired oxygen (using higher concentrations via rebreathing tests for longer durations) in patients with a range of comorbidities including heart failure. The level of hypercapnic-hypoxia used is equivalent to taking slightly smaller breaths (by about a third, for the standard dose gas mixture 2%CO2/18.5%O2) for several breaths, or skipping a breath (for the highest dose gas mixture 6%CO2/14%O2), physiological changes that typically cause no noticeable oxygen desaturation, and are minimal compared with the effects of the larger ventilation reduction that accompanies OSA.
结局指标
主要结局
Reduction in odds of respiratory event
时间窗: 1 night
Active versus sham ventilatory drive intervention, difference between drive-dependent OSA and classic OSA subgroups
次要结局
- Increase in peak genioglossus muscle activity(1 night)
- Increase in ventilation per unit increase in ventilatory drive(1 night)
- Increase in peak genioglossus muscle activity per unit increase in ventilatory drive(1 night)
- Reduction in odds of respiratory event per unit increase in ventilatory drive(1 night)
- Increase in ventilation(1 night)
研究者
Scott Aaron Sands
Assistant Professor
Brigham and Women's Hospital