Inspiratory Muscle Training in Lung Transplant Candidates

Not Applicable

Recruiting

• Conditions: Inspiratory Muscle Training
• Interventions: Other: IMT and exercise training group

• Registration Number: NCT06370832
• Lead Sponsor: University Health Network, Toronto

Brief Summary

Recovery after lung transplantation (LTx) may be complicated by prolonged mechanical ventilation (MV) and protracted intensive care unit (ICU) stay leading to immobilization and impaired health-related quality of life (HRQoL). In the critical care setting, diaphragm atrophy and weakness have been associated with difficulty weaning from MV, increased risk for readmission to hospital or ICU, and increased mortality. Increasing respiratory muscle strength by inspiratory muscle training (IMT) as part of pre-rehabilitation mitigates respiratory muscle dysfunction peri-operatively and may reduce the risk of post-operative complications. However, IMT is not widely used prior to LTx and the benefits of pre-operative IMT on post-transplant outcomes in LTx candidates have not been studied. Objectives: 1) To evaluate the feasibility of a randomized clinical trial of IMT in LTx candidates in terms of recruitment rate, retention, program adherence, safety and outcome ascertainment. 2)To establish whether IMT improves pre-transplant dyspnea perception, diaphragm structure and function, HRQoL and post-transplant ICU, hospital and 3-month outcomes. 3)To characterize the effect of pre-transplant IMT on peri-transplant diaphragm myofibrillar cross-sectional area, oxidative capacity, inflammatory markers and diaphragm muscle thickness and function. Methods: Prospective study of 50 LTx candidates recruited from the pulmonary rehabilitation program at University Health Network (UHN). Participants will have baseline evaluations of maximal inspiratory pressure (MIP), dyspnea, respiratory muscle endurance, diaphragm thickness and thickening fractions, as well as health-related quality of life questionnaires. After baseline assessments, participants will be randomized to the two study groups: IMT or usual care. IMT will be progressed weekly (max of 70% total MIP) until transplant. Participants will have repeat assessments (from baseline) at 4,8 and 12 weeks and then every 3 months until transplant (final assessment 3 months post-LTx).

Detailed Description

Diaphragm atrophy at the time of initiating mechanical ventilation (MV) after solid organ transplantation and major surgery is associated with prolonged MV and higher hospital mortality. The incidence of diaphragm dysfunction after LTx is estimated to be up to 30%; post-transplant diaphragm dysfunction is associated with prolonged MV and hospitalization after LTx.

The American Thoracic Society/European Respiratory Society (2013) guidelines recommend further evaluation of inspiratory muscle training (IMT) combined with routine rehabilitation prior to major surgery. Pre-operative IMT in patients with even normal maximal inspiratory pressures (MIP) have been shown to decrease post-operative pulmonary complications and shorten hospitalization after cardio-thoracic surgery. However, pre-operative IMT is not commonly used for LTx candidates and its benefits are poorly researched. IMT may prove to be a simple pre-transplant intervention to prevent post-transplant morbidity and improve post-transplant functional status. The current focus is to investigate the impact of IMT on early post-lung transplant results while evaluating its effectiveness through a randomized controlled trial.

Objectives: 1) To evaluate the feasibility of a randomized clinical trial of IMT in LTx candidates in terms of recruitment rate, retention, program adherence, and outcome ascertainment with the use of self-reported questionnaires and data logs. 2) To establish whether IMT improves pre-transplant dyspnea perception, diaphragm structure and function, HRQoL and post-transplant ICU, hospital and 3-month clinical outcomes. 3) To characterize the effect of pre-transplant IMT on peri-transplant diaphragm myofibrillar cross-sectional area, oxidative capacity, inflammatory markers and post-transplant diaphragm muscle thickness and function.

Hypotheses: 1) It will be feasible to recruit LTx candidates into an IMT program randomized control trial with a consent rate ≥ 30 %, enrolment rate of ≥ 3 patients per month, adequate outcome ascertainment (≥ 80%), and acceptable adherence (≥ 80% compliance with IMT sessions). 2) IMT will increase respiratory muscle endurance duration by 20% and improve exertional dyspnea and HRQoL in comparison to usual care over the pre-transplant period. IMT will be associated with greater hospital free days at 90 days. 3) Pre-transplant IMT increases diaphragm myofibrillar cross-sectional area and post-LTx diaphragm thickness and maximal diaphragm thickening during inspiration in comparison to usual care. The improved mitochondrial respiration will occur concurrently with improvements in muscle fiber size, immune infiltration and oxidative stress.

The IMT and exercise training group (IMT group) will perform two daily IMT sessions of 30 breaths (\< 5 minutes/session) during the pre-LTx period. IMT will start at 30% of MIP with a 5-10% weekly increase in training intensity guided by weekly MIP as tolerated (median weekly Borg dyspnea score \< 7 during IMT until reaching 70% of MIP) and continued until LTx. In conjunction with their IMT program, IMT group participants will undergo exercise training at least three times per week as part of their usual care. The control group (exercise training group) will perform exercise training as part of their usual care three times per week for the duration of the waitlist period. The exercise regimen for both groups consists of aerobic, resistance, and flexibility training supervised by a physiotherapist three times a week. The training includes a combination of in-person visits and home-based sessions. Both groups will also receive a respiratory endurance device to evaluate respiratory endurance throughout the trial.

IMT can improve respiratory muscle strength and endurance, potentially helping those who are candidates for LTx. In addition, studying patients undergoing LTx affords unique opportunities to investigate the mechanistic effects of IMT on diaphragm structure and function.

Study Timeline

• Study First Submitted: 2024-03-04
• Study First Submitted QC: 2024-04-12
• Study First Posted: 2024-04-17
• Status Verified: 2024-08
• Study Start: 2024-08-06
• Last Update Submitted: 2024-08-07
• Last Update Posted: 2024-08-09
• Primary Completion: 2026-09-30
• Study Completion: 2027-09-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 50

Inclusion Criteria

• Adult participants (≥ 18 years of age)
• Lung Transplant Candidates
• Participating in outpatient pulmonary rehabilitation (standard of care)
• Diagnosis of Interstitial Lung Disease or Chronic Obstructive Pulmonary Disease

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Exclusion Criteria

• Respiratory exacerbation within the last 1 month
• Neurologic or musculoskeletal conditions that may interfere with IMT or functional assessments (i.e. history of stroke, severe arthritis of hands)
• Insufficient English fluency to provide informed consent or to follow study protocols
• Any evidence of pneumothorax on recent imaging (< 6 months)
• Present ruptures of eardrums or infections leading to fluid behind ear drum
• Marked left or right ventricular end-diastolic volume and pressure overload on right heart catheterization or echocardiogram
• Severe osteoporosis with history of rib fractures
• Cardiac pacemaker or other electronic or magnetic body implant
• Individuals listed as rapidly deteriorating or inpatient at the time of eligibility assessment
• Individuals awaiting a re-transplant
• Inability of the patient to connect to the internet

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
IMT and exercise training group	IMT and exercise training group	Participants in the IMT and exercise training group will perform twice daily 30-breath IMT sessions and exercise training sessions three times per week as part of their usual care during the pre-lung transplant phase. The exercise training is comprised of aerobic, resistance and flexibility training.

Primary Outcome Measures

Name	Time	Method
Self-Reported Adherence to Inspiratory Muscle Training According to Participant IMT Diary	Over intervention period (from randomization until time of transplantation, up to maximum of 24 weeks)	Adherence to inspiratory muscle training will be assessed via the IMT training diary completed by participants. Successful adherence will be defined as completion of ≥ 80% training sessions.
Study Recruitment According to Research Team Records	Over study recruitment period (approximately 2 years)	Recruitment-success percentage in the study will be assessed based on research team study records.
Participant Retention in the Study According to Research Team Records	Over the study data collection period (from enrolment until 3 months post-transplant)	Participant retention will be assessed by measuring participant follow-up throughout the study period, according to research team records. A retention rate of 80% or greater (in each group) has been established as the criteria to determine study feasibility.
Adverse Events and IMT Training Side Effects Reported by Participants	Over intervention period (from randomization until time of transplantation, up to maximum of 24 months)	Adverse events and training side-effects (e.g., muscle soreness) with inspiratory muscle training will be monitored through participant training diaries during the study intervention period. The research coordinator will review these diaries with participants on a weekly basis. Additionally, participants will be strongly encouraged to promptly inform the study team if they experience any challenges with IMT.
Inspiratory Muscle Training Satisfaction Questionnaire (IMT Group Only)	At 3 months post-transplant follow-up	Participant satisfaction and motivation with the IMT intervention will be determined using a satisfaction questionnaire.

Secondary Outcome Measures

Name	Time	Method
Respiratory Muscle Endurance Test	Change from baseline at 4 weeks, 8 weeks, 12 weeks, every 3 months until lung transplant (up to 24 months total), and 3 months post-transplant	Respiratory muscle endurance (measured in seconds) will be assessed at 30% of Maximum Inspiratory Pressure (MIP) using a manual threshold loading device (Powerbreathe Classic light resistance trainer)
Health-Related Quality of Life Assessed by St. George's Respiratory Questionnaire	Change from baseline at 4 weeks, 8 weeks, 12 weeks, every 3 months until lung transplant (up to 24 months total), and 3 months post-transplant	Health-related Quality of Life (HRQL) will be assessed through the St. George's Respiratory Questionnaire (SGRQ) and consists of three domains (symptoms, activity and impacts) and total score. The SGRQ has a range of scores from 0 to 100 with higher scores signifying worse HRQL.
Physical Activity and Exercise Behaviors Assessed by International Physical Activity Questionnaire	Change from baseline at 4 weeks, 8 weeks, 12 weeks, every 3 months until lung transplant (up to 24 months total), and 3 months post-transplant	The International Physical Activity Questionnaire - Short Form (IPAQ-SF) will be used to measure physical activity levels in study participants. The questionnaire consists of seven questions to capture average daily time spent sitting, walking, and engaging in moderate and vigorous physical activity over the last seven days. The IPAQ-SF provides an overall physical activity level of participants based on their Metabolic Equivalent Task minutes per week.
Physical Function Assessed by the Short Physical Performance Battery	Baseline, 4 weeks, 8 weeks, 12 weeks, every 3 months until lung transplant (up to 24 months total), and 3 months post-transplant	Clinical rehabilitation charts will be reviewed to document physical function as assessed by the Short-Physical Performance Battery, which evaluates balance, gait speed, and ability to rise from a chair 5 times.
Pre-Transplant Hospitalizations	From baseline up until the time of admission for the index transplant hospitalization (up to 24 months total)	Clinical charts will be reviewed to document any hospitalizations and ICU admissions before the time of transplantation.
WIND Weaning Classification	At the time of liberation from mechanical ventilation following transplant surgery (up to 3 months total).	The WIND weaning classification (short, difficult, or prolonged) will be ascertained by ICU staff at the time of liberation from mechanical ventilation based on the number of spontaneous breathing trials and weaning difficulty.
Post-Transplant Mortality	Up to 90 days (3 months) post-transplant	Clinical charts will be reviewed to document post-transplant mortality and etiology.
Dyspnea Severity Assessed by Medical Research Council Dyspnea Scale	Change from baseline at 4 weeks, 8 weeks, 12 weeks, every 3 months until lung transplant (up to 24 months total), and 3 months post-transplant	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 Measures of Dyspnea Assessed by Qualitative Dyspnea Scale	Change from baseline at 4 weeks, 8 weeks, 12 weeks, every 3 months until lung transplant (up to 24 months total), and 3 months post-transplant	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.
Mood Assessed by Depression, Anxiety, and Stress Scale	Change from baseline at 4 weeks, 8 weeks, 12 weeks, every 3 months until lung transplant (up to 24 months total), and 3 months post-transplant	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.
Respiratory Muscle Strength Assessed by Maximal Inspiratory Pressure	Change from baseline at 4 weeks, 8 weeks, 12 weeks, every 3 months until lung transplant (up to 24 months total), time of liberation from mechanical ventilation, and 3 months post-transplant	Respiratory muscle strength will be quantified as Maximal Inspiratory Pressure (MIP), evaluated using a respiratory muscle trainer (PowerBreathe KH2).
Days Alive and at Home at 90 Days (DAAH90)	Up to 90 days (3 months) post-transplant	Clinical charts will be reviewed to determine the number of days participants are alive and at home at 90 days post-transplant.
Pulmonary Function Testing (Spirometry)	Baseline, 4 weeks, 8 weeks, 12 weeks, every 3 months until lung transplant (up to 24 months total), and 3 months post-transplant	Clinical charts will be reviewed to obtain results from spirometry assessments including Forced Vital Capacity (FVC), and Forced Expiratory Volume in the first second (FEV1).
Aerobic Endurance Assessed by the Six-Minute Walk Test	Baseline, 4 weeks, 8 weeks, 12 weeks, every 3 months until lung transplant (up to 24 months total), and 3 months post-transplant	Clinical rehabilitation charts will be reviewed to document aerobic endurance as assessed by distance walked during the Six-Minute Walk Test.
Peri-Transplant Mechanical Ventilation Bridging	Peri-operative period, from time of index transplant hospital admission to time of transplant surgery (up to 24 months total)	Clinical charts will be reviewed to determine whether mechanical ventilation or extracorporeal membrane oxygenation (ECMO) were required as a bridge to transplantation.
Post-Transplant Duration of Mechanical Ventilation (Days)	From time of transplant surgery to the time of liberation from mechanical ventilation (up to 3 months total)	Clinical charts will be reviewed to determine the duration of mechanical ventilation required following transplantation surgery, measured in days.
Post-Transplant Hospital Length of Stay (Days)	From time of transplant surgery to the time of discharge from hospital (up to 3 months total).	Clinical charts will be reviewed to determine the length of stay in hospital following transplant surgery, measured in days.
Post-Transplant Discharge Disposition	Time of discharge from index transplant hospitalization (up to 3 months total).	Clinical charts will be reviewed to determine participants' discharge disposition from the index transplant hospitalization (e.g., home, inpatient rehabilitation, long-term care).
Primary Graft Dysfunction	Up to 72 hours post-transplant	Clinical charts will be reviewed to determine the presence and severity of primary graft dysfunction following transplant surgery.

Trial Locations

Locations (1)

University Health Network; 🇨🇦 Toronto, Ontario, Canada