Continuous Versus High Intensity Interval Exercise in Chronic Obstructive Pulmonary Disease

This is a single-centre, prospective, randomized, cross-over clinical trial that will be conducted at "G. Papanikolaou Hospital, Thessaloniki, Greece. For the purposes of this study, COPD patients that fulfil the inclusion/exclusion criteria will be recruited from Pulmonary Outpatient Clinics of "G. Papanikolaou" General Hospital of Thessaloniki and included after signing a written informed consent form. The study protocol was approved by the Ethics Committee of the School of Medicine, Aristotle University of Thessaloniki. All procedures and evaluations will be performed according to the Declaration of Helsinki 2013 Amendment.

The study will be conducted in a total of 4 visits including baseline assessment. At baseline assessment (visit 1), all subjects will provide a detailed medical history including smoking history, comorbidities, history of acute COPD exacerbations and severity of dyspnea (based on the modified Medical Research Council dyspnea scale). Then, they will undergo a post-bronchodilation spirometry, assessment of diffusion capacity (DLCO), measurement of lung volumes and blood pressure measurements after 10min of rest. Arterial blood gases sampling (breathing room air) will be collected, to confirm lack of resting hypoxemia. Moreover, data regarding physical activity will be collected, using the short form of International Physical Activity Questionnaire (IPAQ). The eligible patients that will be recruited will be advised to refrain from food for 4h and from caffeine, alcohol, or tobacco for 12 h and receive any standard medication before their morning appointment in the research laboratory to perform the assessments described below.

Visit 2 will be conducted with a week of baseline visit. and visits 3 and 4 will take place at least 72h after visit 2. During visit 2, all recruited patients will undergo a cardiopulmonary exercise test (CPET) on a cycle ergometer using an incremental exercise RAMP protocol to exhaustion to establish peak work rate (WRpeak). For visits 3 and 4, all patients will perform in random order on different visits (separated by one week) two exercise protocols on the same cycle ergometer, a high-intensity interval aerobic exercise (HIIE) protocol and a moderate-intensity continuous aerobic exercise (MICE) protocol. The HIIE protocol will consist of 60 seconds work at 85% WRpeak followed by 60 seconds of rest and the MICE protocol will include 20 minutes of cycling at 50% WRpeak. Exercise protocols will be matched for total workload. All parameters will be recorded at rest (3 minutes), during unloaded warm-up (3 minutes), during the exercise and during 3-min recovery following the completion of exercise bouts. The rate of perceived exertion (1-10 Borg scale), legs' perceived exertion (1-10 Borg scale), dyspnea (0-10 scale), and will be assessed every 3 min and at exercise termination.

During the CPET and the protocols, respiratory gas exchange will be recorded using a metabolic cart (Ultima CPX™, MGC Diagnostics). Breath-by-breath values for minute ventilation (VE), respiratory rate (RR), tidal volume (Vt), oxygen uptake (VO2), and end-expiratory pressure of carbon dioxide (PETCO2) will be recorded, along with derived variables. Maximum Minute Ventilation (MVV) will be calculated using the formula "Forced Expiratory Volume in 1 s (FEV1) x 40". A 12-lead electrocardiogram and oxygen saturation (SpO2, finger pulse oximetry) will be continuously monitored.

For cerebral oxygenation assessment, near-infrared spectroscopy (NIRS, OxyMon, Artinis Medical Systems, Elst, the Netherlands) will continuously monitor, non-invasively, changes in cerebral oxygenation, by measuring the micromolar (μΜ) relative changes from (resting conditions for oxygenated hemoglobin (O2Hb), deoxygenated hemoglobin (HHb), total hemoglobin (tHb), and Hb-difference. The NIRS probes will be placed over the patients' left prefrontal lobe between Fp1 and F3, according to the modified international EEG 10-20 system, with the receiving sensor fixed laterally to the emitter at a distance of 4.5 cm.

Hemodynamic parameters will be continuously and non-invasively assed using a photoplethysmography apparatus (Finometer, Finapres Medical Systems, Amsterdam, The Netherlands) connected to the participants' finger. This device allows beat-to-beat tracing of systolic and diastolic blood pressure (SBP and DBP relatively, mmHg), mean arterial pressure (MAO, mmHg) and heart rate (HR). Beat-by-beat HR and stroke volume (SV, ml) will be computed using the Modelflow method, an arterial pressure wave analysis which has been shown to be a reliable alternative to invasive thermodilution techniques at rest and during exercise. Cardiac output (CO, L/min), systemic vascular resistance (SVR, mmHg.s/mL) and ejection time (EJT, s) will be estimated using the BeatScope software (Beatscope version 1a, Finometer, Finapres Medical Systems). Autonomic responses will be assessed using the non-linear components of Heart Rate Variability (HRV) with Kubios software (Kubios, version 3.3.1, Kubios Oy, 2019). The root mean square of successive differences (RMSSD), an index of parasympathetic system activity, will be calculated. The standard deviation perpendicular to the line-of-identity SD1 (an index of parasympathetic system activity), the standard deviation along the line-of-identity (SD2) and their ratio (SD1/SD2) (an index of vagal/sympathetic function) will be analysed, since these measures are not affected by changes in respiration patterns. Baroreflex sensitivity (BRS, ms/mmHg) will be assessed by examining the spontaneous fluctuations in the blood pressure as assessed by a cross-correlation method, using the same software, as described previously.