Background Dyspnea is a prevalent symptom in individuals with hypermobile Ehlers-Danlos Syndrome (hEDS) and generalized hypermobility spectrum disorder (G-HSD), yet its contributors have not been identified. One known contributor to dyspnea is respiratory muscle weakness. The feasibility and effectiveness of inspiratory muscle training (IMT) in combination with standard-of-care rehabilitation (aerobic, resistance, neuromuscular stabilization, and balance and proprioception exercises) in improving respiratory muscle strength and patient-reported outcomes in patients with hEDS or G-HSD have not been evaluated. Objective This study aims to evaluate dyspnea, respiratory muscle strength, and patient-reported outcome measures (PROMs) in hEDS or G-HSD compared with healthy controls and to assess the feasibility of a randomized controlled trial of IMT and standard-of-care rehabilitation for improving respiratory muscle strength, exercise capacity, and PROMs compared with standard-of-care rehabilitation in hEDS and G-HSD. Methods The study will include 34 participants with hEDS or G-HSD and 17 healthy, age- and sex-matched controls to compare respiratory muscle structure and function and PROMs. After baseline assessments, participants with hEDS or G-HSD will be randomized into the intervention group and provided IMT combined with Ehlers-Danlos Syndrome standard-of-care rehabilitation or into the usual care group, and provided only standard-of-care rehabilitation for 8 weeks. The intervention group will be prescribed IMT in their home environment using the POWERbreathe K5 IMT device (POWERbreathe International Ltd). IMT will comprise 2 daily sessions of 30 breaths for 5 days per week, with IMT progressing from 20% to 60% of the baseline maximal inspiratory pressure (MIP) over an 8-week period. Feasibility will be assessed through rates of recruitment, attrition, adherence, adverse events, and participant satisfaction. The primary pilot outcome is MIP change over an 8-week period in hEDS or G-HSD. Secondary outcomes will include the evaluation of dyspnea using Medical Research Council Scale and 18-point qualitative dyspnea descriptors; diaphragmatic thickening fraction using ultrasound; respiratory muscle endurance; pulmonary function; prefrontal cortical activity using functional near-infrared spectroscopy; aerobic capacity during cardiopulmonary exercise testing; quality of life using Short Form-36; and scores from the Depression, Anxiety, and Stress scale-21. These measures will also be performed once in healthy controls to compare normative values. Multivariable regression will be used to assess the contributors to dyspnea. Paired 2-tailed t tests will be used to assess the changes in MIP and secondary measures after 8 weeks of IMT. Results Study recruitment began in August 2021 and, with several disruptions owing to COVID-19, is expected to be completed by December 2023. Conclusions This study will provide a better understanding of the factors associated with dyspnea and the feasibility and effectiveness of IMT combined with standard-of-care rehabilitation. IMT may be a novel therapeutic strategy for improving respiratory muscle function and patient-reported outcomes in individuals with hEDS or G-HSD. Trial Registration ClinicalTrials.gov NCT04972565; https://clinicaltrials.gov/ct2/show/NCT04972565 International Registered Report Identifier (IRRID) DERR1-10.2196/44832

BACKGROUND Introduction: Dyspnea is a prevalent symptom for individuals with hypermobile Ehlers-Danlos Syndrome (hEDS) and generalized hypermobility spectrum disorder (G-HSD). The characteristics and contributors to dyspnea in hEDS/G-HSD have not been well elucidated. One known contributor to dyspnea is respiratory muscle weakness. The feasibility and effectiveness of inspiratory muscle training (IMT) in combination with standard of care rehabilitation (aerobic, resistance, neuromuscular stabilization, and balance and proprioception exercises) to improve respiratory muscle strength and related patient-reported outcomes in hEDS/G-HSD patients have not been evaluated. OBJECTIVE Objectives: 1) To evaluate dyspnea, respiratory muscle strength, and patient-reported outcome measures (PROMs) in hEDS/G-HSD compared to healthy controls, and 2) to assess the feasibility of a randomized control trial of IMT and standard of care rehabilitation to improve respiratory muscle strength, exercise capacity and PROMs compared to standard of care rehabilitation in hEDS/G-HSD. METHODS Methods: The study will include 34 hEDS/G-HSD participants from the EDS rehabilitation program at Toronto General Hospital and 17 healthy, age-sex matched controls for comparison of respiratory muscle structure and function and PROMs. After baseline assessments, hEDS/G-HSD participants will be randomized into IMT combined with EDS standard of care rehabilitation (intervention group) versus standard of care rehabilitation (usual care) for 8 weeks. The intervention group will be prescribed IMT in the home environment using the POWERbreathe®K5 IMT device. IMT will comprise of 2 daily sessions, 5 days per week of 30 breaths, with IMT progressing from 20% to 60% of baseline maximal inspiratory pressure (MIP) over an 8-week period. Feasibility will be assessed through rates of recruitment, attrition, adherence, and adverse events, as well as participant satisfaction. The primary pilot outcome will be MIP change over an 8-week period in hEDS/G-HSD. Secondary outcomes will include evaluation of dyspnea (Medical Research Council Scale and 18-point Qualitative Dyspnea Descriptors), diaphragmatic thickening fraction with ultrasound, respiratory muscle endurance, pulmonary function including oscillometry, pre-frontal cortical activity using functional near-infrared spectroscopy and aerobic capacity during cardiopulmonary exercise testing, quality of life (Short Form-36), and scores from the depression, anxiety and stress scale (DASS-21). These measures will also be performed once in healthy controls for comparison of normative values. Multivariable regression will be used to assess the contributors to dyspnea. Paired-t-tests will be utilized to assess the change in MIP and secondary measures with 8 weeks of IMT. RESULTS Results: Study recruitment began in August 2021, with several disruptions due to COVID-19, and is expected to be completed by December 2023. CONCLUSIONS Conclusion: This study will provide a better understanding of the factors associated with dyspnea and the feasibility and effectiveness of IMT combined with standard of care rehabilitation. IMT may be a novel therapeutic strategy to improve respiratory muscle function and patient reported outcomes in individuals with hEDS/G-HSD. CLINICALTRIAL ClinicalTrials.gov (NCT04972565)