Mechanisms for Dyspnea on Exertion in Children With Obesity and Asthma: Distinct Physiological Phenotypes

Sponsor

Ohio State University (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT04184609

Collaborator

Nationwide Children's Hospital (Other)

200

Enrollment

Location

Arm

Anticipated Duration (Months)

3.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The overall objective of this study is to better understand the respiratory mechanisms provoking DOE in obese asthmatic children.

Condition or Disease	Intervention/Treatment	Phase
Asthma in Children Dyspnea; Asthmatic Obesity, Childhood	Other: Control Drug: Albuterol Drug: Ipratropium Bromide	Phase 4

Detailed Description

Obesity and asthma are the most common diseases of childhood, causing activity limitation and impaired quality of life. Most obese asthmatic children report dyspnea on exertion (DOE) as their primary asthma symptom. Fear of dyspnea promotes sedentariness and reduces exercise capacity and quality of life. DOE in asthmatic children is typically attributed to bronchoconstriction but it is also possible that obesity is an equal or even major contributor to dyspnea. Our supportive data show that excess chest and abdominal weight in obese children results in low lung volumes, which increases the risk of mechanical ventilatory constraints such as expiratory flow limitation, dynamic hyperinflation, and airway closure, all of which can provoke DOE. Unnecessary use of corticosteroids and other asthmatic medication in obese asthmatic children cannot treat obesity-specific mechanical ventilatory constraints and could have unintended deleterious effects. Therefore, there is an urgent need to better understand the mechanisms involved in DOE to provide evidence-based symptom management for obese asthmatic children that will promote regular physical activity and lessen DOE.

The overall objective of this study is to better understand the respiratory mechanisms provoking DOE in obese asthmatic children. We hypothesize that low lung volume breathing in obesity leads to mechanical ventilatory constraints in the presence or absence of bronchoconstriction during exercise. Whereas DOE attributable to bronchoconstriction should respond to bronchodilators, DOE attributable to obesity-specific mechanical ventilatory constraints will not respond to bronchodilators. We propose a comprehensive physiological pulmonary function and exercise-testing based approach in 9-17-year-old obese and nonobese asthmatic children with DOE who do (N=45) and do not (N=60) bronchoconstrict during exercise to uncover the respiratory mechanisms for DOE. The presence/absence of bronchoconstriction will be determined by a comprehensive measure of exercise-induced central and peripheral airway reactivity using spirometry and impulse oscillometry (i.e., greater than or equal to 10% reduction in forced expiratory volume in 1s, FEV1, greater than or equal to 35% increase in total airway resistance, R5, or greater than or equal to 40% increase in peripheral airway resistance, R5-20, will be indicative of bronchoconstriction). Since bronchodilators are a standard-of-care pre-exercise prescription to prevent asthma-related bronchoconstriction, we will also determine the extent to which bronchodilators like albuterol and ipratropium are effective in reducing DOE, bronchoconstriction, amd mechanical ventilatory constraints in asthmatic children with and without obesity.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

200 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

3 repeated measures (within factor): Albuterol, Ipratropium, and Control3 repeated measures (within factor): Albuterol, Ipratropium, and Control

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

Mechanisms for Dyspnea on Exertion in Children With Obesity and Asthma: Distinct Physiological Phenotypes

Anticipated Study Start Date :

Dec 1, 2023

Anticipated Primary Completion Date :

Nov 30, 2027

Anticipated Study Completion Date :

Nov 30, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Exercise test All participants will undergo a moderate-intensity exercise test under three conditions in a repeated measures study design: Control Albuterol Ipratropium Bromide	Other: Control In this condition, the participants will not receive any medications or drugs before exercise Other Names: No-treatment Drug: Albuterol 180 mcg of Albuterol will be administered before exercise Other Names: Ventolin Drug: Ipratropium Bromide 34 mcg of Ipratropium Bromide will be administered before exercise Other Names: Atrovent

Arm

Intervention/Treatment

Experimental: Exercise test

All participants will undergo a moderate-intensity exercise test under three conditions in a repeated measures study design: Control Albuterol Ipratropium Bromide

Other: Control

In this condition, the participants will not receive any medications or drugs before exercise

Other Names:

No-treatment

Drug: Albuterol

180 mcg of Albuterol will be administered before exercise

Other Names:

Ventolin

Drug: Ipratropium Bromide

34 mcg of Ipratropium Bromide will be administered before exercise

Other Names:

Atrovent

Outcome Measures

Primary Outcome Measures

Expiratory flow limitation [During the intervention (exercise)]
Units: % of tidal volume, measured as overlap between exercise tidal flow volume loop and maximal expiratory flow volume loop
Dynamic hyperinflation [During the intervention (exercise)]
Units: % of total lung capacity, measured as change in end-expiratory lung volume from rest to exercise
Closing capacity [During the intervention (exercise)]
Units: % of total lung capacity, measured using single breath nitrogen washout
Forced expiratory volume in 1 s [During the intervention (exercise)]
Units: Litres, measured with spirometry

Secondary Outcome Measures

Rating of perceived breathlessness [During the intervention (exercise)]
Borg 0 - 10 scale

Eligibility Criteria

Criteria

Ages Eligible for Study:

9 Years to 17 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

General inclusion criteria:

Age range: 9-17 years of age
Participants with physician diagnosed asthma and on regular asthma controller therapy for at least 8 weeks prior to enrollment will be recruited for this study.
Objectively Confirmed Asthma Diagnosis: Asthma diagnosis will be confirmed objectively using spirometry (FEV1 < 80% predicted or FEV1/FVC < lower limit of normal), bronchodilator reversibility testing (post-bronchodilator improvement of ≥ 12% and 200mL in FEV1 or FVC; or a decrease in lung hyperinflation of at least 150 mL; ATS guidelines on lung function test interpretation), or a methacholine challenge test. Patients in whom asthma cannot be confirmed objectively will be excluded from the study.
Experience dyspnea on exertion as assessed by answering "yes" to one of the following two questions on the screening questionnaire: 1) Do you get short of breath with exertion? 2) Do you feel that your asthma is limiting you from participating in exercise?
Ability to communicate in English

Body mass index criteria (BMI): We will study two discrete groups of asthmatic children based on their BMI percentile:

Nonobese: BMI 5th-84th percentile based on norms from the Centers for Disease Control (CDC)
Obese: BMI ≥95th percentile and less than 170% of the 95th BMI percentile based on norms from the CDC

Exclusion criteria:

Criteria for pulmonary function: We will exclude asthmatic children with:

Severe asthma: Forced expiratory volume in 1s (FEV1) < 50% predicted
Restrictive pulmonary disease: Forced vital capacity (FVC) and total lung capacity (TLC) < 80% predicted
Diffusion limitation: Diffusing capacity relative to alveolar volume (DLCO/VA) < 80% predicted

Daily activity levels: Children participating in regular vigorous conditioning exercise such as running, jogging, aerobics, cycling, or swimming for ≥60min/session and ≥five times per week will be excluded to ensure similarity in physical activity levels between subjects and to avoid enrolling a potential high-fit, extremely active child. Children who participate in daily, unorganized physical activity (i.e., majority of children), will not be excluded. Children who are sedentary or only participate in school physical education classes will not be excluded.

The following exclusion criteria will be used in this study:

History of oral steroid medications for 4 weeks prior to enrollment
History of being admitted to an intensive care unit or being intubated because of their asthma in the past five years
History of allergy or hypersensitivity to albuterol or ipratropium or history of narrow-angle glaucoma that could get worse with ipratropium
History of vocal cord dysfunction
History of obesity hypoventilation syndrome
History of untreated sleep apnea
History of heart disease, metabolic disease, or renal disease that, in the opinion of the PI (or co-I's), would increase the risks of exercise testing or alter the physiological responses to exercise
History of significant mental illness that in the opinion of the PI (or co-I's) would interfere with study participation or increase risks to the participant
History of musculoskeletal abnormality that would preclude cycling exercise
Pregnant or become pregnant during their participation in the study
History of other significant illnesses that, in the opinion of the PI (or co-I's), either increase risks of participation or alter the physiological responses to exercise
Inability to successfully complete pulmonary function or exercise testing measurements or difficulty with following instructions during testing
Inability to tolerate testing procedures or complications related to testing
If a participant develops hypoxemia or meets indications for terminating exercise, the exercise test will be terminated, and the participant will be referred for further evaluation In general, all participants will be encouraged to follow up with their asthma care provider or pediatrician for any health concerns that are discovered during their participation.