Clinical trial NCT06370832: Inspiratory Muscle Training in Lung Transplant Candidates
Official title: Inspiratory Muscle Training in Lung Transplant Candidates and Implications on Early Post-Transplant Outcomes: A Pilot and Feasibility Multicenter Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Inspiratory Muscle Training
Keywords: Lung transplant candidates
Exercise training
Prehabilitation
Chronic Obstructive Pulmonary Disease
Interstitial Lung Disease
Lead sponsor: University Health Network, Toronto
Sponsor class: OTHER
Collaborators: name: Canadian National Transplant Research Program
name: Canadian Institutes of Health Research (CIHR)
name: Ozmosis Research Inc.
name: Centre hospitalier de l'Université de Montréal (CHUM)
name: Vancouver General Hospital
First posted: 2024-04-17
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Pre-lung transplant candidates will be randomized to one of two groups: (1) IMT + exercise training; or (2) exercise training alone.
Primary purpose: TREATMENT

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 multicenter randomized clinical trial of IMT in LTx candidates in terms of recruitment rate, retention, program adherence, and outcome ascertainment; (2) To establish the change in pre-transplant dyspnea perception, diaphragm structure and function, health related quality of life (HRQoL) and post-transplant intensive care unit (ICU), hospital and post-transplant 3-month outcomes with IMT relative to usual care group; and (3) To characterize the effect of pre-transplant IMT on peri-transplant diaphragm myofibrillar cross-sectional area (CSA), oxidative capacity, inflammatory markers and post-transplant diaphragm muscle thickness and function (UHN TGH site).

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 pilot multicenter randomized controlled trial.

Objectives: 1) To evaluate the feasibility of a multicenter randomized clinical trial of IMT in LTx candidates in terms of recruitment rate, retention, program adherence, and outcome ascertainment.

2) To establish the change in pre-transplant dyspnea perception, diaphragm structure and function, health related quality of life (HRQoL) and post-transplant intensive care unit (ICU), hospital and post-transplant 3-month outcomes with IMT relative to usual care group.

3) To characterize the effect of pre-transplant IMT on peri-transplant diaphragm myofibrillar cross-sectional area (CSA), oxidative capacity, inflammatory markers and post-transplant diaphragm muscle thickness and function (UHN TGH site).

Hypotheses: 1) It will be feasible to recruit LTx candidates into an IMT program RCT with a consent rate ≥ 30 %, enrolment rate of 2-3 patients per month at UHN and 1 patient per month at each other participating site, adequate outcome ascertainment (≥ 80%), and acceptable adherence (≥ 80% compliance with IMT sessions). 2) IMT will increase respiratory muscle endurance 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 CSA 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 approximately 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.

Eligibility criteria: 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

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

Primary outcomes:
measure: Study Recruitment According to Research Team Records
timeFrame: Over study recruitment period (approximately 2 years)
measure: Participant Retention in the Study According to Research Team Records
timeFrame: Over the study data collection period (from enrolment until 3 months post-transplant)
measure: Self-Reported Adherence to Inspiratory Muscle Training According to Participant IMT Diary
timeFrame: Over intervention period (from randomization until time of transplantation, up to maximum of 24 months)
measure: Adverse Events and IMT Training Side Effects Reported by Participants
timeFrame: Over intervention period (from randomization until time of transplantation, up to maximum of 24 months)
measure: Inspiratory Muscle Training Satisfaction Questionnaire (IMT Group Only)
timeFrame: At 3 months post-transplant follow-up
Secondary outcomes:
measure: Respiratory Muscle Endurance Test
timeFrame: 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
measure: Dyspnea Severity Assessed by Medical Research Council Dyspnea Scale
timeFrame: 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
measure: Qualitative Measures of Dyspnea Assessed by Qualitative Dyspnea Scale
timeFrame: 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
measure: Mood Assessed by Depression, Anxiety, and Stress Scale
timeFrame: 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
measure: Health-Related Quality of Life Assessed by St. George's Respiratory Questionnaire
timeFrame: 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
measure: Respiratory Muscle Strength Assessed by Maximal Inspiratory Pressure
timeFrame: 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
measure: Physical Activity and Exercise Behaviors Assessed by International Physical Activity Questionnaire
timeFrame: 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
measure: Pulmonary Function Testing (Spirometry)
timeFrame: Baseline, 4 weeks, 8 weeks, 12 weeks, every 3 months until lung transplant (up to 24 months total), and 3 months post-transplant
measure: Aerobic Endurance Assessed by the Six-Minute Walk Test
timeFrame: Baseline, 4 weeks, 8 weeks, 12 weeks, every 3 months until lung transplant (up to 24 months total), and 3 months post-transplant
measure: Physical Function Assessed by the Short Physical Performance Battery
timeFrame: Baseline, 4 weeks, 8 weeks, 12 weeks, every 3 months until lung transplant (up to 24 months total), and 3 months post-transplant
measure: Pre-Transplant Hospitalizations
timeFrame: From baseline up until the time of admission for the index transplant hospitalization (up to 24 months total)
measure: Peri-Transplant Mechanical Ventilation Bridging
timeFrame: Peri-operative period, from time of index transplant hospital admission to time of transplant surgery (up to 24 months total)
measure: Post-Transplant Duration of Mechanical Ventilation (Days)
timeFrame: From time of transplant surgery to the time of liberation from mechanical ventilation (up to 3 months total)
measure: WIND Weaning Classification
timeFrame: At the time of liberation from mechanical ventilation following transplant surgery (up to 3 months total).
measure: Post-Transplant Hospital Length of Stay (Days)
timeFrame: From time of transplant surgery to the time of discharge from hospital (up to 3 months total).
measure: Post-Transplant Discharge Disposition
timeFrame: Time of discharge from index transplant hospitalization (up to 3 months total).
measure: Primary Graft Dysfunction
timeFrame: Up to 72 hours post-transplant
measure: Post-Transplant Mortality
timeFrame: Up to 90 days (3 months) post-transplant
measure: Days Alive and at Home at 90 Days (DAAH90)
timeFrame: Up to 90 days (3 months) post-transplant
Other outcomes:
measure: Diaphragm Thickness and Thickening Fraction Assessed by Ultrasound
timeFrame: Change from baseline to all on-site visits at 4 weeks, 8 weeks, 12 weeks, every 3 months until lung transplant (up to 24 months total), time of liberation from MV, and 3 months post-transplant
measure: Histopathology Analyses of Diaphragm Biopsies (Optional)
timeFrame: At the time of lung transplantation, up to maximum of 24 months after randomization
measure: Biochemical Analyses of Diaphragm Biopsies (Optional)
timeFrame: At the time of lung transplantation, up to maximum of 24 months after randomization
measure: Mitochondrial Respirometry Analyses of Diaphragm Biopsies (Optional)
timeFrame: At the time of lung transplantation, up to maximum of 24 months after randomization
Locations:
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
city: Montréal
country: Canada
facility: Centre hospitalier de l'Université de Montréal (CHUM)
state: Quebec
Study officials:
affiliation: University Health Network/University of Toronto
name: Dmitry Rozenberg, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Christie JD, Kotloff RM, Ahya VN, Tino G, Pochettino A, Gaughan C, DeMissie E, Kimmel SE. The effect of primary graft dysfunction on survival after lung transplantation. Am J Respir Crit Care Med. 2005 Jun 1;171(11):1312-6. doi: 10.1164/rccm.200409-1243OC. Epub 2005 Mar 11.
citation: Adler D, Dupuis-Lozeron E, Richard JC, Janssens JP, Brochard L. Does inspiratory muscle dysfunction predict readmission after intensive care unit discharge? Am J Respir Crit Care Med. 2014 Aug 1;190(3):347-50. doi: 10.1164/rccm.201404-0655LE. No abstract available.
citation: Sklar MC, Dres M, Fan E, Rubenfeld GD, Scales DC, Herridge MS, Rittayamai N, Harhay MO, Reid WD, Tomlinson G, Rozenberg D, McClelland W, Riegler S, Slutsky AS, Brochard L, Ferguson ND, Goligher EC. Association of Low Baseline Diaphragm Muscle Mass With Prolonged Mechanical Ventilation and Mortality Among Critically Ill Adults. JAMA Netw Open. 2020 Feb 5;3(2):e1921520. doi: 10.1001/jamanetworkopen.2019.21520.