Bronchodilators are medications that open the bronchi to help patients with COPD to breathe better. It is still not known exactly how this effect improves shortness of breath in people with COPD. The goal of this clinical trial is to determine whether bronchodilators lower resistance in the smallest airways in the lungs, and whether this will improve the feeling of breathlessness in these patients.

The main questions the investigators attempt to answer are:

• In patients with COPD, does treatment with a short-acting bronchodilator improve small airway resistance during exercise?
• In patients with COPD, does acute treatment with short-acting bronchodilator improve breathlessness and exercise endurance?

The investigators will compare short-acting bronchodilators to placebo (a substance that contains no drug) to see if the bronchodilator medications improve small airway resistance and breathlessness during exercise.

Participants will:

• Visit the research laboratory 3 visits to complete tests of lung function and exercise
• Complete 2 identical visits (Visit 2 and 3), one in which the participant receives bronchodilator and one in which the participant receives placebo.

Small airways disease is a major cause of increased airway resistance and obstruction in chronic obstructive pulmonary disease (COPD). Small airways are those airways beyond generation 8 that are <2 mm in diameter. Due to lung geometry and the mechanism of particle deposition, treatment of small airway disease is challenging and a major clinical concern. Recent advances in respiratory medication delivery devices have purported to improve delivery of medication to the small airways, thus providing better physiologic and symptomatic relief. One such example is Breztri™ Aerosphere©, is a pressurized metered-dose inhaler (pMDI) that delivers triple therapy (long-acting beta-2 agonist, long-acting muscarinic antagonist, and an inhaled corticosteroid), and is currently approved in Canada for patients with COPD. Preliminary evidence has suggested that this product reduced mortality risk and had beneficial effects on exertional dyspnea (shortness of breath), notably in symptomatic patients who have been treated with dry powder inhalers (DPIs). Modeling studies have shown better deposition of drug into the small airways with the pMDI than the DPI; however, it remains unclear whether improved deposition is sufficient to improve small airways function in patients with COPD, and whether these changes result in commensurate improvement in dyspnea and exercise tolerance. Uncovering the mechanisms of dyspnea improvement is a crucial step to provide evidence-based rationale for using pMDI to mitigate the burden of this key patient reported outcome.

Dyspnea during exercise (exertion) in COPD arises when the drive to breathe (neural) is not properly rewarded by the output of the lungs (respiratory mechanics), a phenomenon called "neuromechanical dissociation". In patients with moderate-to-severe COPD, this 'neuromechanical dissociation' is largely a result of impairment in the function of the small airways (airways that are <2mm in diameter) which conspire to induce pulmonary gas trapping and, consequently, increase lung volumes ("hyperinflation"). During exercise when ventilatory demands increase, the reduced time constant for lung emptying (i.e., impaired expiratory time due to increased breathing frequency) leads to acute-on-chronic lung hyperinflation which accelerates attainment of critical inspiratory constraints (i.e., tidal volume expansion is limited), and thus, patients have significantly greater dyspnea and earlier exercise termination. It is reasonable to assume that any inhaled medication for COPD with enhanced access to the small airways could reduce or delay dynamic hyperinflation during exercise and improve a patient's shortness of breath.

MAIN RESEARCH QUESTION In patients with COPD and significant resting lung hyperinflation, does acute treatment with a short-acting bronchodilator (salbutamol sulfate + ipratropium bromide) improve impulse oscillometry derived small airway resistance during cardiopulmonary exercise compared to placebo.

SECONDARY RESEARCH QUESTIONS In patients with COPD and significant resting lung hyperinflation, does acute treatment with short-acting bronchodilator (salbutamol sulfate + ipratropium bromide) improve exertional dyspnea and exercise tolerance during cardiopulmonary exercise compared to placebo. Are improvements in small airway resistance, associated with a reduction in inspiratory neural drive and improved lung mechanics, as measured by diaphragm electromyography (EMGdi).

RESEARCH METHODS Study design: This is a single center, investigator-initiated, prospective, cross over study being conducted over 2-3 weeks.

Study outline:

After giving written informed consent, all participants will be asked to complete 3 visits to the Respiratory Investigation Unit, Kingston General Hospital. Each visit will be conducted at the same time, in the morning, 2 to 7 days apart.

Visit 1 (eligibility assessment): Detailed medical history, physical examination and ECG will be performed. Participants will perform complete pulmonary function testing including spirometry, plethysmography, diffusing capacity for carbon monoxide (DLCO), small airway function assessment (impulse oscillometry (IOS), single-breath and multiple-breath nitrogen washout tests). Participants will complete a symptom-limited incremental cardiopulmonary exercise test (CPET) to determine maximum exercise capacity. PFT and CPET procedures will be conducted according to consensus recommendations.

Visit 2/3 (Constant Work Rate Cardiopulmonary Exercise Test with Placebo or Bronchodilator): Spirometry, body plethysmography, impulse oscillometery, and static and dynamic lung compliance measurements will be performed pre-intervention and 15 minutes post intervention (either dual short-acting bronchodilator (salbutamol sulphate (2.5 mg) + ipratropium bromide (0.5 mg) or a placebo (normal saline)). Participants will then perform a constant work rate tests at 75% peak exercise capacity (determined at V1). Participant will perform exercise on a stationary bicycle while breathing through a mouthpiece with nose clips on, which allows for the breath-by-breath recording of ventilatory and metabolic variables throughout exercise. After approximately 6 minutes of relaxed, baseline breathing, participants will be asked to pedal for 1 minute against no resistance to warm up. The load will then increase to constant work rate (determined at V1), participants will continue to pedal until symptom limitation. Every 2 minutes during exercise, the participant will perform an impulse oscillometery test for assessment of small airways function, followed by an inspiratory capacity maneuver to determine lung volumes. Respiratory discomfort (dyspnea) and leg fatigue will be assessed using the modified Borg 0-10 scale. Vital signs (BP, HR, SpO2) will be monitored throughout each exercise test and during recovery.

Diaphragm EMG and Respiratory Pressure Measurements: At the beginning of Visit 2 and 3, the investigators will apply a topical anesthetic spray to the nasal passages and throat of the participant. A thin catheter (diameter 2 mm) will be inserted by the investigator through the nose down the throat and into the esophagus and top part of stomach. This catheter measures the electric activity (EMG) of the diaphragm, which provides a surrogate measurement of the inspiratory neural drive to breathe. It also measures pressures in the esophagus within the chest as well as in the stomach, which gives useful information about the work of breathing and breathing mechanics.

Inclusion Criteria:

• Diagnosis of COPD
• Male or female ≥40-years-of-age
• Current or former smokers with ≥20 pack-year history
• Forced expiratory volume in 1 second (FEV1)/ forced vital capacity (FVC)\

Data will not be shared until completion of the trial and final analysis. Anonymized data may be made available upon reasonable request after appropriate ethical approval and institutional data sharing agreements

Data will not be released until study completion (anticipated January 2027).

Data will be released on reasonable request after appropriate ethical approval, anonymization, and data sharing agreements to ensure data integrity and participant privacy.