Dyspnea in Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorder

Not Applicable

Recruiting

• Conditions: Hypermobility Syndrome; Hypermobile EDS (hEDS)
• Interventions: Behavioral: Usual Care plus Inspiratory Muscle Training (IMT)

• Registration Number: NCT04972565
• Lead Sponsor: University Health Network, Toronto

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2021-06-25
• Study First Submitted QC: 2021-07-12
• Study First Posted: 2021-07-22
• Study Start: 2021-08-16
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-27
• Last Update Posted: 2024-05-29
• Primary Completion: 2024-12-31
• Study Completion: 2024-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 34

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Usual Care plus Inspiratory Muscle Training (IMT)	Usual Care plus Inspiratory Muscle Training (IMT)	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.

Primary Outcome Measures

Name	Time	Method
Maximal Inspiratory Pressure	Change from baseline at 8 weeks	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.

Secondary Outcome Measures

Name	Time	Method
Inspiratory Muscle Training Mean Volume	Through study completion, an average of 8 weeks	Inspiratory muscle training mean volume per breath (Litres) will be abstracted from the IMT device in the experimental group.
Lung Volumes (Inspiratory Capacity)	Change from baseline at 8 weeks	Lung volumes (i.e., inspiratory capacity) will be measured in the pulmonary function laboratory following the American Thoracic Society Guidelines.
Diaphragm Thickness	Change from baseline at 8 weeks	The right hemi-diaphragm thickness will be measured using a 13 megahertz ultrasound transducer.
Participant Study Recruitment	Over the study period (8 weeks)	Recruitment-success percentage and reasons for participation/non-participation in the study will be collected.
Inspiratory Muscle Training Load	Through study completion, an average of 8 weeks	Inspiratory muscle training Load (cm H2O) will be abstracted from the IMT device in the experimental group.
Inspiratory Muscle Training Mean Power	Through study completion, an average of 8 weeks	Inspiratory muscle training mean power per breath (Watts) will be abstracted from the IMT device in the experimental group.
Health-Related Quality of Life	Change from baseline at 8 weeks	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.
Respiratory Muscle Endurance	Change from baseline at 4 weeks and 8 weeks	Respiratory muscle endurance (endurance time measured in seconds) will be assessed using a manual threshold loading device (Philips Threshold trainer).
Lung Volumes (Residual Volume)	Change from baseline at 8 weeks	Lung volumes (i.e., Residual Volume) will be measured in the pulmonary function laboratory following the American Thoracic Society Guidelines.
Maximal Expiratory Pressure	Change from baseline at 8 weeks	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.
Borg Dyspnea Scale	Change from baseline at 8 weeks	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.
Oscillometry	Change from baseline at 8 weeks	Oscillometry will be performed in the pulmonary function laboratory following the protocol from the European Respiratory Society.
Spirometry (Forced Vital Capacity)	Change from baseline at 8 weeks	Spirometry (forced vital capacity) will be measured in the pulmonary function laboratory following the American Thoracic Society Guidelines.
Spirometry (Forced Expiratory Volume in 1 Second)	Change from baseline at 8 weeks	Spirometry (forced expiratory volume in 1 second) will be measured in the pulmonary function laboratory following the American Thoracic Society Guidelines.
Lung Volumes (Total Lung Capacity)	Change from baseline at 8 weeks	Lung volumes (i.e., Total Lung Capacity) will be measured in the pulmonary function laboratory following the American Thoracic Society Guidelines.
Diaphragm Thickening Fraction	Change from baseline at 8 weeks	The right hemi-diaphragm thickening fraction will be measured using a 13 megahertz ultrasound transducer.
Peak Oxygen Uptake During Cardiopulmonary Exercise Testing	Change from baseline at 8 weeks	Cardiopulmonary exercise test-based assessment of peak oxygen uptake (VO2 peak) will be performed on a cycle ergometer.
Ventilatory Response During Cardiopulmonary Exercise Testing	Change from baseline at 8 weeks	Ventilatory response will be assessed during cardiopulmonary exercise testing (on a cycle ergometer) with exhaled gas measurements captured breath by breath.
Pre-frontal Cortical Neural Activity During Cardiopulmonary Exercise Testing	Change from baseline at 8 weeks	Oxygenated and total hemoglobin of the prefrontal cortex will be measured with Functional Near Infrared Spectroscopy during cardiopulmonary exercise testing.
Inspiratory Muscle Training Workload	Through study completion, an average of 8 weeks	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.
Medical Research Council Dyspnea Scale	Change from baseline at 8 weeks	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).
Qualitative Assessment of Dyspnea	Change from baseline at 4 weeks and 8 weeks	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.
Heart Rate Response During Cardiopulmonary Exercise Testing	Change from baseline at 8 weeks	Heart rate response will be assessed during cardiopulmonary exercise testing on a cycle ergometer.
Physical Activity Levels	Change from baseline at 4 weeks and 8 weeks	Physical activity (daily steps) will be measured via a tracking device (Fitbit, San Francisco, USA) for a 7-day period.
Participant Retention in the Study	Over the study period (8 weeks)	Participant retention will be assessed by measuring participant follow-up with testing throughout the study period.
Leisure-Time Exercise	Baseline	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).
Depression, Anxiety and Stress Scale	Change from baseline at 8 weeks	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.
Adherence to Inspiratory Muscle Training Days	Over the intervention period (8 weeks)	Adherence to the IMT intervention will be tracked using a participant log to record the number of training days completed each week.
Adverse Events During Inspiratory Muscle Training Practice (Safety and Tolerability)	Over the intervention period (8 weeks)	Any adverse events (i.e. prolonged muscle soreness, pneumothorax) with IMT will be assessed throughout the study period.
Adherence to Inspiratory Muscle Training Load	Over the intervention period (8 weeks)	Adherence to the IMT intervention will be tracked electronically via the IMT device (i.e., percentage of the maximal inspiratory pressure prescribed).
Participant Satisfaction with the IMT Intervention	Change from baseline at weeks 1, 4 and 8	A multiple-choice and free-form questionnaire assessing the participants' satisfaction with the IMT intervention will be completed by study participants.

Trial Locations

Locations (1)

University Health Network; 🇨🇦 Toronto, Ontario, Canada