Effects of Blood Flow Restriction Aerobic Exercise on Inflammation, Hypoxia, Exercise Capacity, and Lung Function in COPD

1. RATIONALE AND AIM OF THE STUDY Chronic Obstructive Pulmonary Disease (COPD) is a progressive respiratory condition characterized by airflow limitation, systemic inflammation, impaired gas exchange, and significant skeletal muscle dysfunction. Individuals with COPD frequently experience reduced exercise capacity, peripheral muscle weakness, chronic hypoxemia, fatigue, sleep disturbances, and decreased quality of life. These systemic features contribute to increased symptom burden and diminished functional independence. Pulmonary rehabilitation (PR) is an established intervention that improves exercise tolerance, reduces dyspnea, and enhances quality of life. However, many patients are unable to sustain high-intensity exercise because of ventilatory limitations, early muscle fatigue, or oxygen desaturation. This creates a need for alternative exercise strategies that provide an adequate physiological stimulus while remaining tolerable for individuals with limited exercise reserve. Blood Flow Restriction (BFR) exercise is a low-intensity training method that induces localized hypoxic and metabolic stress, promoting physiological adaptations such as increased muscle activation and improved functional performance. Although early findings suggest potential benefits of BFR, its effects when integrated into a PR program-particularly on systemic inflammation, oxygenation, respiratory muscle function, and exercise capacity-have not been comprehensively investigated. This study aims to compare conventional PR with PR combined with low-intensity aerobic exercise performed under BFR in individuals with stable COPD. The study will evaluate systemic inflammatory markers, oxygenation and hypoxemia responses, exercise capacity, spirometric measurements, respiratory muscle strength, arterial blood gases, and patient-reported symptoms. By assessing physiological, functional, and subjective outcomes together, the study seeks to determine the potential added value of BFR-assisted aerobic training within pulmonary rehabilitation. The findings are expected to clarify whether BFR can enhance the effectiveness of PR, provide a more tolerable training option for individuals with limited exercise capacity, and support the development of individualized rehabilitation strategies for people with COPD. 2. DESIGN For this study, the sample will consist of patients aged 40-80 years with a diagnosis of COPD who are referred to the Pulmonary Rehabilitation Unit of the Department of Pulmonology at Sultan Abdülhamid Han Training and Research Hospital, University of Health Sciences, by a pulmonology specialist. Participants will be randomly assigned into two groups using a computerized randomization method: a routine pulmonary rehabilitation group (control group) and a group receiving blood flow restriction (BFR) during aerobic exercise, which is one of the parameters of pulmonary rehabilitation (intervention group). Pulmonary rehabilitation programs for both groups will be administered by an experienced physiotherapist under the supervision of a pulmonology specialist. Before initiating the rehabilitation program, the cardiovascular suitability of the patients for pulmonary rehabilitation will be determined by a cardiologist. The program will begin once medical approval indicating "suitable for pulmonary rehabilitation" has been obtained. The study has a multidisciplinary and multidimensional structure. Both groups will participate in a total of 16 pulmonary rehabilitation sessions conducted twice weekly for 8 weeks within the hospital. Each session will last 60 minutes. 2.1. Intervention Group In the intervention group, the pulmonary rehabilitation program will include the active cycle of breathing techniques, diaphragmatic breathing, pursed-lip breathing, and respiratory muscle training. In addition, a bilateral resistance exercise program will be given to target the shoulder flexors, elbow flexors, and quadriceps muscle groups. Furthermore, aerobic exercise with blood flow restriction (BFR) will be performed on a cycle ergometer. Active Cycle of Breathing Techniques (ACBT) ACBT consists of a series of techniques applied to improve ventilation efficiency. These techniques strengthen respiratory muscles and enhance respiratory function. In this cycle, various breathing strategies are applied consecutively to increase ventilatory capacity. In COPD patients, these techniques help open the airways and optimize ventilation. Techniques include deep breathing, breath-holding, and controlled exhalation strategies. Diaphragmatic Breathing Diaphragmatic breathing is a method of inhalation performed using the diaphragm instead of the accessory muscles. This technique increases ventilation of the lower lungs, enhances oxygen uptake, and reduces respiratory muscle fatigue. In COPD patients, diaphragmatic breathing reduces the work of breathing and allows patients to breathe more efficiently. Pursed-Lip Breathing Pursed-lip breathing is a technique that helps keep the airways open during exhalation. The patient exhales slowly through lightly pursed lips during breathing. This technique facilitates overcoming airway resistance, regulates airflow in COPD patients, and enables more effective breathing. It also helps correct ventilation-perfusion imbalances and reduces dyspnea. Respiratory Muscle Training In this study, inspiratory muscle training will be performed using the Powerbreathe Medic Plus (gray) device twice a week for 8 weeks. The initial load will be set at 30% of the patient's measured maximal inspiratory pressure (MIP). Progression will be made according to the perceived difficulty level reported during exercise based on the Modified Borg Scale (0-10), keeping the perceived exertion (RPE) between 3-4 and increasing the load by 5-10% each week. The goal will be to reach 60% of the MIP. The training will follow a protocol of 5 breaths × 6 sets, with rest intervals adjusted based on patient tolerance. Peripheral Muscle Training Resistance training will be applied as 2 sets × 8 repetitions at an RPE of 3-4 on the Modified Borg Scale. Targeted muscle groups will include the quadriceps femoris, shoulder flexors, and elbow flexors. BFR + Aerobic Exercise Program BFR will be applied using a wireless AirBands cuff placed proximally on the thigh at the level of the femoral artery at 45% of the individual limb occlusion pressure (LOP). Aerobic exercise will be performed on a cycle ergometer at 40-60% of the target heart rate (low-moderate intensity). The target heart rate will be determined using the Karvonen formula \[THR=HRmax-HRrest)×%intensite\]+HRrest\]. Each session will consist of 3 minutes of warm-up, 15 minutes of exercise, and 3 minutes of cool-down (21 minutes total). BFR will begin after warm-up and remain inflated throughout the exercise. At the end of the session, the cuff will be released, followed by a 5-minute reactive hyperemia period. Exercise progression will be individualized according to the MBS RPE scores recorded during each session; the target perceived effort will be kept between 2-3 (light-moderate), and workload (watts) will be increased by 5-10% weekly as tolerated. 2.2. Control Group In the control group, the pulmonary rehabilitation program will include the active cycle of breathing techniques, diaphragmatic breathing, pursed-lip breathing, and respiratory muscle training. In addition, a bilateral resistance training program targeting the shoulder flexors, elbow flexors, and quadriceps muscle groups will be implemented. Aerobic exercise training will be performed on a cycle ergometer without the use of BFR. Active Cycle of Breathing Techniques (ACBT) ACBT consists of techniques applied to improve the efficiency of breathing. These techniques strengthen the respiratory muscles and enhance respiratory function. Various breathing strategies are applied consecutively to increase ventilatory capacity. In COPD patients, these strategies open the airways, optimize ventilation, and improve airflow. The cycle includes techniques such as deep breathing, breath-holding, and controlled exhalation. Diaphragmatic Breathing Diaphragmatic breathing is a method of breathing performed by effectively using the diaphragm rather than the abdominal or accessory muscles. This technique improves ventilation of the lower lungs, increases oxygen intake, and reduces respiratory muscle fatigue. In COPD patients, diaphragmatic breathing decreases the work of breathing and helps patients breathe more efficiently. Pursed-Lip Breathing Pursed-lip breathing is a technique that helps maintain airway patency during exhalation. The patient exhales slowly through lightly pursed lips. This technique facilitates overcoming airway resistance, regulates airflow in COPD patients, and makes breathing more efficient. It also corrects ventilation imbalances and reduces dyspnea. Respiratory Muscle Training Inspiratory muscle training will be performed using the Powerbreathe Medic Plus (gray) device, twice a week for 8 weeks. The initial training load will be set at 30% of the patient's measured maximal inspiratory pressure (MIP). Progression will be based on perceived exertion reported during exercise according to the Modified Borg Scale (0-10), maintaining an RPE of 3-4, with weekly increases of 5-10% in resistance. The goal is to reach 60% of the MIP. Training will follow the "5 breaths × 6 sets" format with individualized rest intervals according to patient tolerance. Peripheral Muscle Training Resistance training will be applied as 2 sets of 8 repetitions at an RPE of 3-4. Targeted muscle groups will include the quadriceps femoris, shoulder flexors, and elbow flexors. Aerobic Exercise Program The aerobic exercise protocol on the cycle ergometer will be performed at 60-80% of the target heart rate. The target heart rate will be calculated using the Karvonen formula, which incorporates the heart rate reserve (HRR):\[THR=(HRmax-HRrest)×%intensite\]+HRrest\] This formula provides a more accurate estimation of the training heart rate, especially in clinical populations. Aerobic training will be performed twice weekly for 8 weeks, with each session consisting of 3 minutes of warm-up, 15 minutes of target aerobic exercise, and 3 minutes of cool-down (21 minutes total). Pedal resistance and pedaling speed will be adjusted according to the Borg RPE scores reported during the session. The target RPE during exercise will be kept at 3-4, with weekly increases of 5-10% in workload. 3. Sample Size Calculation The primary outcome of the study is the change in 6MWT distance. Based on previously reported clinically meaningful differences in 6MWT distance in individuals with COPD and assuming a medium effect size, a power analysis was performed using a significance level of 0.05 and a power of 80%. The calculation indicated that 17 participants per group (34 in total) would be sufficient to detect clinically relevant between-group differences in 6MWT distance. 4. Statistical Analysis All data will be analyzed using a statistical software package. The normality of distribution for continuous variables will be assessed using appropriate tests. Parametric variables will be presented as mean ± standard deviation, and non-parametric variables as median with interquartile range. Baseline differences between groups will be analyzed using independent samples t-tests or Mann-Whitney U tests, as appropriate. Categorical variables will be compared using the chi-square test. Within-group changes from pre- to post-intervention will be evaluated using paired samples t-tests or Wilcoxon signed-rank tests, depending on data distribution. Group × time interactions will be examined using two-way repeated measures ANOVA or linear mixed models. Correlations between changes in inflammatory markers and changes in 6MWT distance will be analyzed using appropriate correlation coefficients. A p-value of \<0.05 will be considered statistically significant for all analyses, and effect sizes will be reported to aid interpretation of clinical relevance.