Dyspnea in Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorder

Study Overview
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Brief Summary
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Individuals with hypermobile Ehlers-Danlos Syndrome (hEDS) and Hypermobility Spectrum Disorders (HSD) often experience dyspnea. Inspiratory Muscle Training (IMT) has been shown to improve dyspnea and respiratory muscle function; however, the impact of IMT in combination with whole-body exercise training on respiratory muscle strength, dyspnea, and daily function remains unknown. The objectives of this research are i) to evaluate dyspnea, respiratory muscle strength and function, ventilatory parameters, and health-related quality of life (HRQL) in individuals with hEDS and HSD compared to healthy age and sex-matched controls, ii) to explore the contributors to dyspnea during exercise with a specific focus on respiratory muscle structure and function in hEDS and HSD patients and healthy controls, and iii) to assess whether the combination of IMT and whole-body exercise training will be more effective than whole-body exercise training alone in improving participant outcomes in hEDS and HSD participants. It is hypothesized that i) hEDS and HSD participants will have lower respiratory muscle strength, higher peripheral airway resistance, lower HRQL, and higher anxiety and depression levels compared to healthy controls, ii) the contributors to increased exercise induced dyspnea will include decreased respiratory muscle strength, increased airway resistance, and greater prefrontal cortical neural activity, and iii) the combination of IMT and whole-body exercise training will be superior to whole-body training alone for improving dyspnea, respiratory muscle strength and endurance, aerobic capacity, HRQL, anxiety, and depression.

Detailed Description
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Thirty-four hEDS and HSD participants will be recruited from the University Health Network (Toronto, Canada). Participants will have baseline evaluations of dyspnea, pulmonary function tests (i.e., oscillometry, spirometry, and lung volumes), respiratory muscle structure and function (i.e., diaphragm ultrasound and respiratory muscle strength), HRQL, anxiety and depression. Symptom limited cardiopulmonary exercise testing will be utilized to quantify exertional dyspnea using the 10-item Borg dyspnea scale, 18-point qualitative dyspnea assessment scale, peak oxygen uptake (peak VO2), and assessment of dynamic ventilatory parameters. Neural activity in the pre-frontal cortex will be measured during cardiopulmonary exercise testing via functional near-infrared spectroscopy. These baseline measures will be compared to 17 age and sex-matched healthy controls. After baseline assessments, hEDS and HSD participants will be randomized to one of the following groups: i) Usual Care plus IMT: 8 weeks of whole-body exercises (standard care provided to hEDS and HSD patients at the University Health Network) plus a concurrent IMT intervention 5 times per week); ii) Usual Care: 8 weeks of whole-body exercises (as outlined above). After four and eight weeks, participants will have repeat assessments as described below. Exertional dyspnea is a prevalent and troublesome symptom experienced by individuals living with hEDS and HSD. This study will provide a better understanding of the underlying contributors of dyspnea in hEDS and HSD patients, with a focus on respiratory muscle structure and function, prefrontal cortical neural activity, and ventilatory parameters, both at rest and with exertion.

Official Title
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Evaluation and Management of Dyspnea in Hypermobile Ehlers-Danlos Syndrome (hEDS) and Hypermobility Spectrum Disorder (HSD)

Conditions
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Hypermobile EDS (hEDS), Hypermobility Syndrome

Intervention / Treatment
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* Behavioral: Usual Care plus Inspiratory Muscle Training (IMT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult participants (≥ 18 years of age) New referral to the GoodHope Exercise and Rehabilitation (GEAR) Program at the University Health Network Diagnosis of hEDS based on the 2017 diagnostic criteria or diagnosis of HSD (defined as generalized joint hypermobility, chronic pain, and systemic findings to suspect connective tissue underpinnings) with clinical verification by the EDS medical team Exclusion Criteria: Genetic testing confirming the diagnosis of another type of EDS (i.e., vascular EDS, classical EDS) Any contraindication to exercise testing (i.e., unstable cardiac disease). Presence of cardiac pacemaker/implantable defibrillator or structural cardiac abnormalities on echocardiogram Recent respiratory infection (< 1 month) or known diagnosis of obstructive (i.e., asthma, chronic obstructive pulmonary disease) or restrictive parenchymal lung disease History of pneumothorax, otitis media (fluid behind the ear drum), or rupture of tympanic membranes given risk with IMT Recent participation in formal exercise training or IMT program (within the last 3 months) Persistent symptoms or difficulty tolerating IMT (i.e., breathing difficulties and/or chest pain) Diagnosis of severe autonomic dysfunction or postural orthostatic tachycardia syndrome limiting daily physical activity or exercise Neuromuscular disease (i.e., myositis, diaphragm paralysis) that may interfere with IMT Insufficient English fluency to provide informed consent or ability to follow study protocols Self-reported pregnancy Inability to connect to the internet

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Hypermobile EDS and HSD participants will be randomized to an inspiratory muscle training group versus usual care. Baseline measures will be compared to 17 age and sex-matched healthy controls.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Usual Care plus Inspiratory Muscle Training (IMT)<br>Participants will attend the standard of care rehabilitation program offered to hEDS and HSD patients at the University Health Network. The program consists of i) an individualized home-based rehabilitation and exercise program (twelve weeks of aerobic, neuromotor, and resistance-based exercises), ii) a self-management education intervention, and iii) a community resource engagement plan. Furthermore, patients attend four on-site sessions (a baseline assessment and three follow-up visits). Participants in this group will also be provided with a personalized prescription for an IMT program for eight weeks to be performed in the home environment (two daily IMT sessions of 30 breaths, five days per week). Participants will be virtually supervised by the study team weekly with any adverse events closely monitored. Participants will receive instructions and feedback on how to optimize their home training efforts with direct observation of their IMT practice. | Behavioral: Usual Care plus Inspiratory Muscle Training (IMT)<br>* Participants will receive usual care and will also be provided with a personalized prescription for an IMT program for 8 weeks. Participants will perform two daily IMT sessions of 30 breaths (< 5 minutes/session), 5 days per week in their home environment. IMT intensity will be progressed weekly by 5-10% of the baseline maximal inspiratory pressure if the Borg Dyspnea score is < 7.<br>|
| No Intervention: Usual Care<br>Participants will participate in the standard of care rehabilitation program offered to hEDS and HSD patients at the University Health Network. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal Inspiratory Pressure | Maximal inspiratory pressure will be evaluated using standard methods in the pulmonary function laboratory, with the highest value (cm H2O) taken within 10 percent of the other readings as per American Thoracic Society recommendations. | Change from baseline at 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal Expiratory Pressure | Maximal expiratory pressure will be evaluated using standard methods in the pulmonary function laboratory, with the highest value (cm H2O) taken within 10 percent of the other readings as per American Thoracic Society recommendations. | Change from baseline at 8 weeks | 
| Respiratory Muscle Endurance | Respiratory muscle endurance (endurance time measured in seconds) will be assessed using a manual threshold loading device (Philips Threshold trainer). | Change from baseline at 4 weeks and 8 weeks | 
| Inspiratory Muscle Training Workload | Total IMT workload per session (product of inspiratory muscle force and inhaled volume expressed in Joules) will be extracted from the IMT device in the experimental group. | Through study completion, an average of 8 weeks | 
| Inspiratory Muscle Training Load | Inspiratory muscle training Load (cm H2O) will be abstracted from the IMT device in the experimental group. | Through study completion, an average of 8 weeks | 
| Inspiratory Muscle Training Mean Power | Inspiratory muscle training mean power per breath (Watts) will be abstracted from the IMT device in the experimental group. | Through study completion, an average of 8 weeks | 
| Inspiratory Muscle Training Mean Volume | Inspiratory muscle training mean volume per breath (Litres) will be abstracted from the IMT device in the experimental group. | Through study completion, an average of 8 weeks | 
| Medical Research Council Dyspnea Scale | The Medical Research Council Dyspnea Scale will be used to assess the effect of breathlessness on daily activities. The scale comprises five statements that describe the range of respiratory dyspnea from none (Grade 1) to severe with difficulties performing self-care (Grade 5). | Change from baseline at 8 weeks | 
| Borg Dyspnea Scale | The 10-point Borg Dyspnea Scale will be used throughout the study to adjust the intensity of inspiratory muscle training sessions The lowest score (0) corresponds to the sensation of normal breathing (absence of dyspnea) and the highest score (10) corresponds to the maximum possible sensation of dyspnea. | Through study completion, an average of 8 weeks | 
| Borg Dyspnea Scale | The 10-point Borg Dyspnea Scale will be used during cardiopulmonary exercise testing to characterize degree of dyspnea. The lowest score (0) corresponds to the sensation of normal breathing (absence of dyspnea) and the highest score (10) corresponds to the maximum possible sensation of dyspnea. | Change from baseline at 8 weeks | 
| Qualitative Assessment of Dyspnea | The 18-point Qualitative Dyspnea Scale will be ascertained at the end of cardiopulmonary exercise testing. Participants will be presented with a list of 18 descriptors characterizing their dyspnea and will be asked to rank the top three. | Change from baseline at 8 weeks | 
| Qualitative Assessment of Dyspnea | The 18-point Qualitative Dyspnea Scale will be ascertained at the end of respiratory muscle endurance testing. Participants will be presented with a list of 18 descriptors characterizing their dyspnea and will be asked to rank the top three. | Change from baseline at 4 weeks and 8 weeks | 
| Oscillometry | Oscillometry will be performed in the pulmonary function laboratory following the protocol from the European Respiratory Society. | Change from baseline at 8 weeks | 
| Spirometry (Forced Vital Capacity) | Spirometry (forced vital capacity) will be measured in the pulmonary function laboratory following the American Thoracic Society Guidelines. | Change from baseline at 8 weeks | 
| Spirometry (Forced Expiratory Volume in 1 Second) | Spirometry (forced expiratory volume in 1 second) will be measured in the pulmonary function laboratory following the American Thoracic Society Guidelines. | Change from baseline at 8 weeks | 
| Lung Volumes (Total Lung Capacity) | Lung volumes (i.e., Total Lung Capacity) will be measured in the pulmonary function laboratory following the American Thoracic Society Guidelines. | Change from baseline at 8 weeks | 
| Lung Volumes (Inspiratory Capacity) | Lung volumes (i.e., inspiratory capacity) will be measured in the pulmonary function laboratory following the American Thoracic Society Guidelines. | Change from baseline at 8 weeks | 
| Lung Volumes (Residual Volume) | Lung volumes (i.e., Residual Volume) will be measured in the pulmonary function laboratory following the American Thoracic Society Guidelines. | Change from baseline at 8 weeks | 
| Diaphragm Thickness | The right hemi-diaphragm thickness will be measured using a 13 megahertz ultrasound transducer. | Change from baseline at 8 weeks | 
| Diaphragm Thickening Fraction | The right hemi-diaphragm thickening fraction will be measured using a 13 megahertz ultrasound transducer. | Change from baseline at 8 weeks | 
| Peak Oxygen Uptake During Cardiopulmonary Exercise Testing | Cardiopulmonary exercise test-based assessment of peak oxygen uptake (VO2 peak) will be performed on a cycle ergometer. | Change from baseline at 8 weeks | 
| Ventilatory Response During Cardiopulmonary Exercise Testing | Ventilatory response will be assessed during cardiopulmonary exercise testing (on a cycle ergometer) with exhaled gas measurements captured breath by breath. | Change from baseline at 8 weeks | 
| Heart Rate Response During Cardiopulmonary Exercise Testing | Heart rate response will be assessed during cardiopulmonary exercise testing on a cycle ergometer. | Change from baseline at 8 weeks | 
| Pre-frontal Cortical Neural Activity During Cardiopulmonary Exercise Testing | Oxygenated and total hemoglobin of the prefrontal cortex will be measured with Functional Near Infrared Spectroscopy during cardiopulmonary exercise testing. | Change from baseline at 8 weeks | 
| Physical Activity Levels | Physical activity (daily steps) will be measured via a tracking device (Fitbit, San Francisco, USA) for a 7-day period. | Change from baseline at 4 weeks and 8 weeks | 
| Leisure-Time Exercise | Leisure-time exercise will be measured via the 3-item Godin Leisure-Time Exercise Questionnaire - Leisure Score Index. The Leisure Score Index is used to rank individuals from the lowest to highest exercise levels: sedentary (score less than 14 units); moderately active (score of 14-23 units); and active (24 units or more). | Baseline | 
| Health-Related Quality of Life | The Short-Form 36 Health Survey (SF-36) will be used to assess general health-related quality of life. The SF-36 consists of eight scaled scores (total score ranging from 0 to 100), with lower scores representing lower health-related quality of life. | Change from baseline at 8 weeks | 
| Depression, Anxiety and Stress Scale | The Depression, Anxiety and Stress Scale (DASS-21) questionnaire has 21 items to assess mood (anxiety, depression, and stress). Each statement for the three domains is given a score of 0 (not applicable) to 3 (applicable most of the time) with scores categorized as follows: Normal, Mild, Moderate, Severe, and Extremely Severe. | Change from baseline at 8 weeks | 
| Participant Study Recruitment | Recruitment-success percentage and reasons for participation/non-participation in the study will be collected. | Over the study period (8 weeks) | 
| Participant Retention in the Study | Participant retention will be assessed by measuring participant follow-up with testing throughout the study period. | Over the study period (8 weeks) | 
| Adherence to Inspiratory Muscle Training Load | Adherence to the IMT intervention will be tracked electronically via the IMT device (i.e., percentage of the maximal inspiratory pressure prescribed). | Over the intervention period (8 weeks) | 
| Adherence to Inspiratory Muscle Training Days | Adherence to the IMT intervention will be tracked using a participant log to record the number of training days completed each week. | Over the intervention period (8 weeks) | 
| Adverse Events During Inspiratory Muscle Training Practice (Safety and Tolerability) | Any adverse events (i.e. prolonged muscle soreness, pneumothorax) with IMT will be assessed throughout the study period. | Over the intervention period (8 weeks) | 
| Participant Satisfaction with the IMT Intervention | A multiple-choice and free-form questionnaire assessing the participants' satisfaction with the IMT intervention will be completed by study participants. | Change from baseline at weeks 1, 4 and 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypermobile Ehlers Danlos Syndrome, Hypermobility Spectrum Disorder, Dyspnea, Inspiratory Muscle Training, Exercise