Inspiratory Muscle Training in Lung Transplant Candidates

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.

• Respiratory Muscle Endurance Test [Срок оценки: 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]
• Dyspnea Severity Assessed by Medical Research Council Dyspnea Scale [Срок оценки: 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]
• Qualitative Measures of Dyspnea Assessed by Qualitative Dyspnea Scale [Срок оценки: 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]
• Mood Assessed by Depression, Anxiety, and Stress Scale [Срок оценки: 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 Assessed by St. George's Respiratory Questionnaire [Срок оценки: 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 Strength Assessed by Maximal Inspiratory Pressure [Срок оценки: 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]
• Physical Activity and Exercise Behaviors Assessed by International Physical Activity Questionnaire [Срок оценки: 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]
• Pulmonary Function Testing (Spirometry) [Срок оценки: Baseline, 4 weeks, 8 weeks, 12 weeks, every 3 months until lung transplant (up to 24 months total), and 3 months post-transplant]
• Aerobic Endurance Assessed by the Six-Minute Walk Test [Срок оценки: Baseline, 4 weeks, 8 weeks, 12 weeks, every 3 months until lung transplant (up to 24 months total), and 3 months post-transplant]
• Physical Function Assessed by the Short Physical Performance Battery [Срок оценки: Baseline, 4 weeks, 8 weeks, 12 weeks, every 3 months until lung transplant (up to 24 months total), and 3 months post-transplant]
• Pre-Transplant Hospitalizations [Срок оценки: From baseline up until the time of admission for the index transplant hospitalization (up to 24 months total)]
• Peri-Transplant Mechanical Ventilation Bridging [Срок оценки: Peri-operative period, from time of index transplant hospital admission to time of transplant surgery (up to 24 months total)]