Objectives

To evaluate whether 12 weeks of nocturnal CPAP use decreased the concentration of methacholine necessary to reduce FEV₁ by 20% (PC₂₀) in asthma patients.

Background

Asthma is characterized by an increase in airways smooth muscle constriction to non-specific agonists and hyper-responsiveness to stimulation of airway constriction. Current therapies, such as inhaled corticosteroids (ICS) and long-acting bronchodilators (beta-agonists), address inflammation and increased airway tone. Limitation of current therapies are cost, adherence, and concerns about long-term use.

Airway smooth muscle tissue requires intermittent stretching-dilation and constriction. In the absence of dilation, airways smooth muscle tissue may alter its contractile properties to continue to perform its role. This is supported by the maintenance of elevated end-expiratory lung volume (FRC) through tonic contraction of respiratory muscles in asthmatics. FRC is reduced during sleep resulting in decreased dilation of airways from lack of deep inspiration. Low FRC may account for some unexplained characteristics of asthma, notably the worsening of symptoms in the morning, and the inability of deep inspiration to dilate airways and reverse bronchoconstriction.

Providing a conceptual basis for a novel treatment of asthma that does not rely on pharmacologic modulation of inflammation or bronchoconstriction was the focus of this trial. Continuous Positive Airway Pressure (CPAP) increases stretching of the airways during sleep and prevents a fall in FRC that could lead to closure of airways in dependent regions of the lung. CPAP has been widely and safely used for the treatment of sleep apnea and demonstrated to be effective in reducing airway activity in previous trials on animals and humans. Therefore an imperative of the trial was to determine whether the effect of CPAP could be reproduced and sustained for a longer time.

Participants

194 participants were included in the primary outcome assessment. Of these, 66 participants were randomized into the sham treatment arm (<1m H₂O), 69 participants were randomized into the 5cm H₂O arm, and 59 participants were randomized into the 10cm H₂O arm.

Eligible subjects for this study were men and women aged 15 to 60 years old at baseline. Subjects were included if they had stable, physician-diagnosed asthma, and were prescribed asthma medication for at least the past 12 months. Women who were pregnant or lactating were not eligible for the study, and those of child-bearing age agreed to practice birth control methods for the duration of the study. Participants were required to have the following results at the baseline visit: a pre-bronchodilator FEV₁ ≥ 75% and methacholine bronchial challenge with PC₂₀ ≤ 8 mg/mL for FEV₁.

Subjects with a BMI ≥ 35 or those weighing less than 66 lbs. at baseline were excluded. Chronic diseases, sleep apnea and/or disorders, prior use of CPAP, and subjects with acute respiratory illness or those who received systemic corticosteroid therapy were excluded. Subjects with an intolerance to, or with contraindication(s) to methacholine were excluded. Members from the same household were not eligible to participate in the study at the same time.

Design

CPAP was a phase 2, multi-center, 3-parallel arm, randomized, sham-controlled trial to assess the effect of positive airway pressure on reducing airway reactivity in patients with asthma. Subjects who met the eligibility criteria were randomly assigned in a 1:1:1 ratio to one of three treatment arms two weeks after the baseline visit. The provided CPAP device delivered either <1 cm H₂O (sham), 5 cm H₂O, or 10 cm H₂O via a nasal mask fitted by a trained research coordinator. Factory calibration was performed to insure that all delivered CPAP devices were within tolerance (±1 cm). Sham devices received a modified mask to leak more H₂O, and had a similar flow rate and noise level to that of the non-sham devices. All CPAP devices were programmed to deliver warm, humid, and filtered air. Participants were allowed to adjust the air temperature only.

The treatment period was 12 weeks. Participants were instructed to use the machine nightly and to continue their routine asthma care, including drug therapy and environmental interventions. Participants’ airways reactivity to methacholine was assessed at baseline, 6 and 12 weeks of treatment and after a 2 week washout. CPAP devices monitored the number of hours that CPAP was actually being used by measuring respiratory pressure fluctuations. A SD card collected at 1, 6 and 12 weeks of treatment, participant diary cards, and machine run-time, were used to counsel and record participants’ adherence to CPAP usage.

Participants were instructed to hold their inhaled asthma controller medications for 12-48 hours prior to study visits that included a methacholine challenge test so as to obtain valid results However, they were permitted to use their rescue bronchodilator for relieve of symptoms up to six hours prior to methacholine challenge testing.

Conclusions

Adherence to nocturnal CPAP was low for all groups, with the sham group having the best adherence. All treatment arms experienced significant improvement in the primary endpoint, however the improvements between the active and sham treatment arms were not found to be statistically significant. Therefore there was no evidence to support positive pressure as being effective for reducing airway reactivity in people with well-controlled asthma.

Holbrook JT, Sugar EA, Brown RH, Drye LT, Irvin CG, Schwartz AR, Tepper RS, Wise RA, Yasin RZ, Busk MF; American Lung Association Airways Clinical Research Centers. Effect of continuous positive airway pressure on airway reactivity in asthma: a randomized, sham-controlled clinical trial. Ann Am Thorac Soc 2016;13:1940–1950.

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