Cardiovascular Consequences of Inhaled Short-acting Beta-agonist Use

Session 1) The first visit is a screening visit where participants will be invited to our Clinical Sciences Building research lab to conduct pulmonary function testing and cardiopulmonary exercise testing. A small blood sample will be collected via finger prick to measure hemoglobin. The cardiopulmonary screening will ensure no underlining health problems are observed in the participant which would exclude them from the study. This visit will take ~2 hours.

Session 2) The second visit will occur within 1 week of the first visit. On the second visit, participants will arrive fasted (12 hours) and be asked not to consume caffeine or perform exercise 8 hours prior to arriving. These restrictions ensure accuracy in our measurement of vascular reactivity. Measurement of cardiovascular function using heart rate, blood pressure, flow-mediated dilation, and pulse wave velocity after 10 minutes of supine rest will occur. Participants will be randomized to one of three study arms: 1) salbutamol (2x200mcg), 2) budesonide-formoterol (1x400mcg), or 3) placebo (2x0mcg). Upon receiving their group allocation, an unblinded member of the research team will help the participant in taking the required dosage, and then the participant will return to 10 minutes of supine rest. Heart rate, blood pressure, flow-mediated dilation, and pulse wave velocity will then be re-evaluated by a blinded member of the research team. Session 2 should take approximate ~1.5 hours.

Session 2A) Participants will be asked to sign a second, optional, informed consent form outlining the additional measures, techniques, and risks that are associated with the protocol. Participants will rest in the supine position and have an intravenous line inserted into the cubital fossa of the forearm. A small amount of blood will be pulled for sex hormone analysis. A 3-lead electrocardiogram will be attached, and finger blood pressure will be monitored beat-by-beat. Cardiac output will be estimated using cardiac ultrasound, while brachial blood flow will be estimated using doppler ultrasound. Muscle sympathetic nervous activity will be measured in the peroneal nerve using microneurography. Lung diffusing capacity and its components will be evaluated by standardized breath-hold techniques. In short, participants inhale a very small amount of carbon monoxide and methane and hold their breath for 6 seconds before rapidly exhaling . This maneuver is completed three times using 21%, 40%, and 60% oxygen concentration to determine diffusing capacity and pulmonary vascular function. After obtaining baseline measures of all outcomes, a beta-agonist (isoproterenol) will be injected through the intravenous line at a starting dosage of 0.01 μg∙kg-1∙min-1 for 10 minutes and increase in a stepwise manner at a rate of 0.01 μg∙kg-1∙min-1 every 10 minutes to a maximal rate of 0.04 μg∙kg-1∙min-1. The incremental dosages creating a dose-response curve for the variables blood pressure, heart rate, cardiac output, and brachial blood flow with a reduced curve indicating less β-receptor sensitivity. All values will be obtained within the last two minutes of the 10-minute dosage. Lung diffusing capacity will be evaluated following the final dosage of isoproterenol. Upon completion of infusion and data acquisition, participants will remain resting until blood pressure and heart rate return to baseline values. This session will be completed within 2 weeks of session 1 and will take ~2 hours.

Intervention: Following either session 2 or 2A if the participant consented to the additional testing session, participants will then be sent home with their inhaler and dosage regimen and complete the intervention for 4-weeks, filling out questionnaires to monitor symptoms each week. Inhalers will be equipped with electronic trackers to calculate the number of doses the participants have received.

Session 3) Following the 4-week intervention, participants will then replicate session 1 with a pulmonary function test and exercise test spanning ~2 hours. As completed during the first session, a small blood sample will be collected via finger prick to measure hemoglobin. This session will occur within 1-2 days of completing the 4-week intervention.

Session 4) Participants will be asked to arrive fasted (12 hours) and be asked not to consume caffeine or perform exercise 8 hours prior to arriving. The session will consist of the same measurements (pulse wave velocity, blood pressure, heart rate, and flow-mediated dilation) and procedure as Session 2 and spanning ~1.5 hours. This session will occur between 2-4 days following the intervention.

Session 4A) Those partaking in the additional optional visits would also then complete visit 4A which would be the same protocol as visit 2A and take ~2 hours to complete. This session will occur 3-6 days following intervention.