Asthma, Sleep Apnea
Conditions
Keywords
Asthma, Nocturnal Asthma, Lung volumes, Deep inspiration, Obstructive sleep apnea
Brief summary
Asthma is an extremely common disorder, which is becoming more prevalent. The purpose of this study is to examine how nocturnal lung volumes contribute to asthma severity, which may explain part of the link between asthma and obesity. The investigators seek to test the hypothesis that raising lung volumes during the night will improve asthma symptoms. The investigators work may lead to new targets for therapy.
Detailed description
Asthma is a chronic respiratory disease characterized by airway inflammation and airway hyperresponsiveness, which causes airflow obstruction. It is extremely prevalent, affecting an estimated 22 million Americans, and costly with loss of productivity and direct healthcare costs in the billions of dollars. The incidence and prevalence of asthma are increasing, both in the US and around the world. This increase comes despite greater understanding of the inflammatory and allergic basis for asthma, and despite better antiinflammatory medications. One explanation for the increasing prevalence of asthma is the concomitant increase in obesity, with the majority of Americans now overweight or obese. Numerous studies have convincingly linked asthma and obesity, and demonstrated increased obstruction with weight gain and decreased obstruction with weight loss. However, the mechanisms that underlie this linkage are not known. We believe that low lung volumes contribute to the pathogenesis and severity of asthma. End-expiratory lung volume is decreased in obesity, and likely falls further during sleep, particularly in overweight and obese patients. Both upper and lower airway resistance increase with decreasing lung volumes, as airways become smaller. However, prior work has shown that lower airway resistance increases out of proportion to the decrease in lung volume that occurs during sleep in asthma patients. This difference between controls and people with asthma has not been further explored, yet may provide insight into asthma pathogenesis and provide potential targets for therapy. Therefore, we propose a series of experiments to define the impact of lung volumes during sleep on airway resistance. One of these experiments will be to to test the hypothesis that lung stretch can be used therapeutically by tonically and dynamically increasing lung volumes during sleep using bi-level positive airway pressure. This research can help delineate asthma pathogenesis and may help improve therapeutic options in this exceedingly common disease.
Interventions
DEVICEBilevel PAP (4 weeks)
Subjects will use bilevel PAP each night for 4 weeks. The pressure levels will be adjusted by the investigators to increase lung volumes during the night.
OTHERUsual Care (4 weeks)
Subjects will continue with their usual asthma care. Investigators will make no changes to their medications or other habits.
OTHERWashout Period (4 weeks)
Subjects will continue with their usual asthma care in between the Usual Care and Bilevel PAP periods. Investigators will make no changes to their medications or other habits.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* mild to moderate asthma, diagnosed by a physician, OR * mild to moderate asthma and CPAP treated OSA. Must be compliant with CPAP therapy (greater than 4 hours per night, at least 4 nights/week)
Exclusion criteria
* lung disease other than asthma or OSA * medications known to affect respiratory function (apart from asthma and rhinitis therapy) * abnormal nasal anatomy * current smokers and ex-smokers (quit within the last 3 months, or \>10 pack-years) * pregnant women - women of child bearing age will undergo a urine pregnancy test before enrollment and during the course of the study, as some of the study procedures cannot be performed during pregnancy and because pregnancy often changes asthma symptoms and severity. * severe asthma - defined as a recent exacerbation (doctor or ER visit for asthma, or oral steroid use, within the previous 4 weeks) or frequent exacerbations (\>4 exacerbations in the last year. * severe obstructive sleep apnea requiring supplemental oxygen in addition to CPAP therapy. * the regular use of prescription (e.g. zolpidem) or over-the-counter sleep aids (e.g. Benadryl). * Central sleep apnea
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Asthma Control Test | Every 4 weeks during the 12 week study (at the start and end of the Usual Care period, and at the start and end of the Bilevel PAP intervention period) | Well validated questionnaire of asthma symptoms which includes 5 written questions. Each question is answered on a scale of 1-5, which are summed to report a range of asthma control from 5 to 25 (higher score indicates better asthma control). |
| Airway Reactivity as Measured by Methacholine Challenge (PC20) | Every 4 weeks during the 12 week study (at the start and end of the usual care period, and at the start and end of the Bilevel PAP intervention period) | This is a physiological measurement derived from repeated breathing maneuvers which measures airway reactivity. Subjects are exposed to higher and higher concentrations of an airway irritant (in this case methacholine), and between each dose perform spirometry. The test is stopped after the forced expiratory volume in 1 second (FEV1) falls 20% below the baseline. The concentration of methacholine at which this occurs is called the PC20. Methacholine challenges are routinely used in the diagnosis of asthma, and in many asthma research studies to measure changes in airway reactivity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Epworth Sleepiness Scale (ESS) | Every 4 weeks during the 12 week study (at the start and end of the usual care period, and at the start and end of the Bilevel PAP intervention period) | 8 item questionnaire to measure daytime sleepiness, with total score reported 0 (less sleepy) to 24 (most sleepy). Scores greater than or equal to 10 are considered excessive daytime sleepiness. |
| Pittsburgh Sleep Quality Index (PSQI) | Every 4 weeks during the 12 week study (at the start and end of the usual care period, and at the start and end of the Bilevel PAP intervention period) | Well validated questionnaire used frequently to measure sleep quality over the prior 1 month. It consists of 19 individual items that combine to form 7 components summed to create one global score. The overall score is between 0 (better sleep) and 21 (worse sleep). |
| Short Form (SF-36) Health Survey | Every 4 weeks during the 12 week study (at the start and end of the usual care period, and at the start and end of the Bilevel PAP intervention period) | Well validated quality of life questionnaire that measures eight sub-sections, which are summed to yield a score from 0 (maximal disability) to 100 (no disability). The eight subsections are: vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, mental health. |
| FEV1 %Predicted | Every 4 weeks during the 12 week study (at the start and end of the usual care period, and at the start and end of the Bilevel PAP intervention period) | Performed as part of spirometry |
Countries
United States
Participant flow
Pre-assignment details
33 subjects were assessed for eligibility (20 asthma only, 13 asthma + OSA). 12 were excluded, with 11 not meeting inclusion criteria, and 1 declining to participate.
Participants by arm
| Arm | Count |
|---|---|
| Asthma Only Subjects meeting all inclusion criteria and no exclusion criteria with asthma only (no sleep apnea) | 13 |
| Asthma + OSA Subjects meeting all inclusion criteria and no exclusion criteria with asthma and obstructive sleep apnea on continuous positive airway pressure (CPAP) treatment | 8 |
| Total | 21 |
Baseline characteristics
| Characteristic | Asthma Only | Total | Asthma + OSA |
|---|---|---|---|
| Age, Continuous | 43.2 years STANDARD_DEVIATION 16.7 | 43.8 years STANDARD_DEVIATION 14.4 | 44.75 years STANDARD_DEVIATION 10.5 |
| AHI (events/hour) | 2.5 events per hour STANDARD_DEVIATION 2.3 | 11.6 events per hour STANDARD_DEVIATION 3.4 | 40.0 events per hour STANDARD_DEVIATION 30.1 |
| Body Mass Index (kg/m2) | 30.5 kg/m2 STANDARD_DEVIATION 7.4 | 32.7 kg/m2 STANDARD_DEVIATION 7.2 | 36.4 kg/m2 STANDARD_DEVIATION 5.2 |
| CPAP Pressure | — | 11.6 cm of water STANDARD_DEVIATION 3.4 | 11.6 cm of water STANDARD_DEVIATION 3.4 |
| CPAP Usage | — | 264 minutes STANDARD_DEVIATION 96 | 264 minutes STANDARD_DEVIATION 96 |
| FEV1/FVC | 0.75 ratio STANDARD_DEVIATION 0.09 | 0.75 ratio STANDARD_DEVIATION 0.07 | 0.75 ratio STANDARD_DEVIATION 0.06 |
| FEV1% predicted | 90.2 % STANDARD_DEVIATION 21.3 | 89.9 % STANDARD_DEVIATION 20.7 | 89.4 % STANDARD_DEVIATION 21 |
| PC20 (mg/mL) | 1.5 mg/mL STANDARD_DEVIATION 0.5 | 1.6 mg/mL STANDARD_DEVIATION 0.3 | 1.8 mg/mL STANDARD_DEVIATION 1.4 |
| Region of Enrollment United States | 13 participants | 21 participants | 8 participants |
| Sex: Female, Male Female | 9 Participants | 14 Participants | 5 Participants |
| Sex: Female, Male Male | 4 Participants | 7 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 13 | 0 / 8 |
| serious Total, serious adverse events | 0 / 13 | 0 / 8 |
Outcome results
Primary
Airway Reactivity as Measured by Methacholine Challenge (PC20)
This is a physiological measurement derived from repeated breathing maneuvers which measures airway reactivity. Subjects are exposed to higher and higher concentrations of an airway irritant (in this case methacholine), and between each dose perform spirometry. The test is stopped after the forced expiratory volume in 1 second (FEV1) falls 20% below the baseline. The concentration of methacholine at which this occurs is called the PC20. Methacholine challenges are routinely used in the diagnosis of asthma, and in many asthma research studies to measure changes in airway reactivity.
Time frame: Every 4 weeks during the 12 week study (at the start and end of the usual care period, and at the start and end of the Bilevel PAP intervention period)
Population: All subjects completed the crossover study design
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Usual Care | Airway Reactivity as Measured by Methacholine Challenge (PC20) | Pre | 1.3 mg/mL | Standard Error 0.31 |
| Usual Care | Airway Reactivity as Measured by Methacholine Challenge (PC20) | Post | 0.88 mg/mL | Standard Error 2.41 |
| Bilevel PAP | Airway Reactivity as Measured by Methacholine Challenge (PC20) | Pre | 1.24 mg/mL | Standard Error 1.97 |
| Bilevel PAP | Airway Reactivity as Measured by Methacholine Challenge (PC20) | Post | 1.36 mg/mL | Standard Error 2.13 |
Comparison: Change in PC20 between the two armsp-value: 0.2t-test, 2 sided
Primary
Asthma Control Test
Well validated questionnaire of asthma symptoms which includes 5 written questions. Each question is answered on a scale of 1-5, which are summed to report a range of asthma control from 5 to 25 (higher score indicates better asthma control).
Time frame: Every 4 weeks during the 12 week study (at the start and end of the Usual Care period, and at the start and end of the Bilevel PAP intervention period)
Population: All 21 patients went through usual care and bilevel PAP therapy
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Usual Care | Asthma Control Test | Pre | 19.3 units on a scale | Standard Deviation 5.1 |
| Usual Care | Asthma Control Test | Post | 19.1 units on a scale | Standard Deviation 4.6 |
| Bilevel PAP | Asthma Control Test | Pre | 19.8 units on a scale | Standard Deviation 3.4 |
| Bilevel PAP | Asthma Control Test | Post | 19.6 units on a scale | Standard Deviation 4.2 |
Comparison: The difference in the change in asthma control during the Usual care and the Bilevel PAP period were compared.p-value: 0.8t-test, 2 sided
Secondary
Epworth Sleepiness Scale (ESS)
8 item questionnaire to measure daytime sleepiness, with total score reported 0 (less sleepy) to 24 (most sleepy). Scores greater than or equal to 10 are considered excessive daytime sleepiness.
Time frame: Every 4 weeks during the 12 week study (at the start and end of the usual care period, and at the start and end of the Bilevel PAP intervention period)
Population: All subjects completed both arms of this crossover study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Usual Care | Epworth Sleepiness Scale (ESS) | Pre | 9.1 units on a scale | Standard Deviation 5.4 |
| Usual Care | Epworth Sleepiness Scale (ESS) | Post | 9.7 units on a scale | Standard Deviation 4.6 |
| Bilevel PAP | Epworth Sleepiness Scale (ESS) | Pre | 9.8 units on a scale | Standard Deviation 5 |
| Bilevel PAP | Epworth Sleepiness Scale (ESS) | Post | 9.1 units on a scale | Standard Deviation 5.2 |
p-value: 0.78t-test, 2 sided
Secondary
FEV1 %Predicted
Performed as part of spirometry
Time frame: Every 4 weeks during the 12 week study (at the start and end of the usual care period, and at the start and end of the Bilevel PAP intervention period)
Population: All subjects completed both arms of this crossover study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Usual Care | FEV1 %Predicted | pre | 89.9 percentage of predicted FEV1 | Standard Deviation 20.7 |
| Usual Care | FEV1 %Predicted | post | 88.1 percentage of predicted FEV1 | Standard Deviation 22.3 |
| Bilevel PAP | FEV1 %Predicted | pre | 87.1 percentage of predicted FEV1 | Standard Deviation 22.4 |
| Bilevel PAP | FEV1 %Predicted | post | 89.7 percentage of predicted FEV1 | Standard Deviation 20 |
p-value: 0.76t-test, 2 sided
Secondary
Pittsburgh Sleep Quality Index (PSQI)
Well validated questionnaire used frequently to measure sleep quality over the prior 1 month. It consists of 19 individual items that combine to form 7 components summed to create one global score. The overall score is between 0 (better sleep) and 21 (worse sleep).
Time frame: Every 4 weeks during the 12 week study (at the start and end of the usual care period, and at the start and end of the Bilevel PAP intervention period)
Population: All subjects completed both arms of this crossover study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Usual Care | Pittsburgh Sleep Quality Index (PSQI) | pre | 6.8 units on a scale | Standard Deviation 4 |
| Usual Care | Pittsburgh Sleep Quality Index (PSQI) | post | 6.1 units on a scale | Standard Deviation 3.4 |
| Bilevel PAP | Pittsburgh Sleep Quality Index (PSQI) | pre | 6.6 units on a scale | Standard Deviation 3.3 |
| Bilevel PAP | Pittsburgh Sleep Quality Index (PSQI) | post | 6.1 units on a scale | Standard Deviation 4.1 |
p-value: 0.61t-test, 2 sided
Secondary
Short Form (SF-36) Health Survey
Well validated quality of life questionnaire that measures eight sub-sections, which are summed to yield a score from 0 (maximal disability) to 100 (no disability). The eight subsections are: vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, mental health.
Time frame: Every 4 weeks during the 12 week study (at the start and end of the usual care period, and at the start and end of the Bilevel PAP intervention period)
Population: All subjects completed both arms of the study
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Usual Care | Short Form (SF-36) Health Survey | pre | 70.8 units on a scale | Standard Deviation 15.4 |
| Usual Care | Short Form (SF-36) Health Survey | post | 70.3 units on a scale | Standard Deviation 16.8 |
| Bilevel PAP | Short Form (SF-36) Health Survey | post | 73.5 units on a scale | Standard Deviation 16.6 |
| Bilevel PAP | Short Form (SF-36) Health Survey | pre | 74.0 units on a scale | Standard Deviation 14.5 |
p-value: 0.94t-test, 2 sided