Inspiratory Muscle Training in Lung Transplant Candidates

Inspiratory Muscle Training Clinical Trial

Official title:

Inspiratory Muscle Training in Lung Transplant Candidates and Implications on Early Post-Transplant Outcomes: A Pilot and Feasibility Randomized Clinical Trial

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06370832
• Other study ID #: 22-5171
• Status: Not yet recruiting
• Phase: N/A
• Start date: June 15, 2024
• Est. completion date: September 30, 2027

Study information

• Verified date: May 2024
• Source: University Health Network, Toronto
• Contact: Dmitry Rozenberg, MD, PhD
• Phone: 416-340-4800
• Email: Dmitry.Rozenberg[@]uhn.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 50
• Est. completion date: September 30, 2027
• Est. primary completion date: September 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Inspiratory Muscle Training
• Respiratory Aspiration

Intervention

Other:
• IMT and exercise training group
Participants will perform supervised exercise training per usual care and will be provided with a personalized prescription for an IMT program during the pre-transplant phase. Participants will perform two daily IMT sessions of 30 breaths (< 5 minutes/session) 5 days per week in their home environment or in-person visits. IMT intensity will be progressed weekly by 5-10% of the baseline maximal inspiratory pressure if the Borg Dyspnea score is < 7.

Locations

Country	Name	City	State
Canada	University Health Network	Toronto	Ontario

Sponsors (4)

Lead Sponsor	Collaborator
University Health Network, Toronto	Canadian Institutes of Health Research (CIHR), Canadian National Transplant Research Program, Ozmosis Research Inc.

Country where clinical trial is conducted

Canada, 

References & Publications (6)

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. — View 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. — View Citation

Fuehner T, Kuehn C, Welte T, Gottlieb J. ICU Care Before and After Lung Transplantation. Chest. 2016 Aug;150(2):442-50. doi: 10.1016/j.chest.2016.02.656. Epub 2016 Mar 4. — View Citation

Hook JL, Lederer DJ. Selecting lung transplant candidates: where do current guidelines fall short? Expert Rev Respir Med. 2012 Feb;6(1):51-61. doi: 10.1586/ers.11.83. — View 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. — View Citation

Weill D, Benden C, Corris PA, Dark JH, Davis RD, Keshavjee S, Lederer DJ, Mulligan MJ, Patterson GA, Singer LG, Snell GI, Verleden GM, Zamora MR, Glanville AR. A consensus document for the selection of lung transplant candidates: 2014--an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2015 Jan;34(1):1-15. doi: 10.1016/j.healun.2014.06.014. Epub 2014 Jun 26. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Diaphragm Thickness and Thickening Fraction Assessed by Ultrasound	The right hemi-diaphragm thickness and thickening fraction will be measured using a 13 Megahertz ultrasound transducer. Bright-mode (B-mode) ultrasound will be used to visualize the diaphragm and motion-mode (M-mode) will be utilized to assess the amplitude of the cranio-caudal diaphragmatic excursion during quiet and deep breathing. Diaphragm thickness will be measured in M-mode with a 5-13 MHz linear transducer over the apposition zone, near the costophrenic angle, from the most superficial hyperechoic line (pleural line) to the deepest hyperechoic line (peritoneal line).	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
Other	Histopathology Analyses of Diaphragm Biopsies (Optional)	Participants will have the option of consenting to diaphragm collected during the transplant surgery. Biopsies (50 mg) will be procured from the anterolateral and posterolateral regions of the right costal hemi-diaphragm midway between the origin and insertion. A portion of the tissue sample (20mg) will be fixed in formalin for histopathology analyses including assessing fibre type distribution, fibre type-specific cross-sectional area, immune infiltration, oxidative capacity, and fibrosis using light microscopy.	At the time of lung transplantation, up to maximum of 24 months after randomization
Other	Biochemical Analyses of Diaphragm Biopsies (Optional)	A second tissue portion (20mg) will be flash frozen in liquid nitrogen to assess mitochondrial content (via western blotting) and signaling cascades to examine atrophic signaling cascades using polymerase chain reactions.	At the time of lung transplantation, up to maximum of 24 months after randomization
Other	Mitochondrial Respirometry Analyses of Diaphragm Biopsies (Optional)	The final tissue portion (10 mg) will be used for live assessments of mitochondrial function using the Oroboros O2K High Resolution Respiratory system on the day of transplantation, as quickly after biopsy collection as possible.	At the time of lung transplantation, up to maximum of 24 months after randomization
Primary	Study Recruitment According to Research Team Records	Recruitment-success percentage in the study will be assessed based on research team study records.	Over study recruitment period (approximately 2 years)
Primary	Participant Retention in the Study According to Research Team Records	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.	Over the study data collection period (from enrolment until 3 months post-transplant)
Primary	Self-Reported Adherence to Inspiratory Muscle Training According to Participant IMT Diary	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.	Over intervention period (from randomization until time of transplantation, up to maximum of 24 weeks)
Primary	Adverse Events and IMT Training Side Effects Reported by Participants	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.	Over intervention period (from randomization until time of transplantation, up to maximum of 24 months)
Primary	Inspiratory Muscle Training Satisfaction Questionnaire (IMT Group Only)	Participant satisfaction and motivation with the IMT intervention will be determined using a satisfaction questionnaire.	At 3 months post-transplant follow-up
Secondary	Respiratory Muscle Endurance Test	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)	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
Secondary	Dyspnea Severity Assessed by 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 4 weeks, 8 weeks, 12 weeks, every 3 months until lung transplant (up to 24 months total), and 3 months post-transplant
Secondary	Qualitative Measures of Dyspnea Assessed by Qualitative Dyspnea Scale	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, 8 weeks, 12 weeks, every 3 months until lung transplant (up to 24 months total), and 3 months post-transplant
Secondary	Mood Assessed by 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 4 weeks, 8 weeks, 12 weeks, every 3 months until lung transplant (up to 24 months total), and 3 months post-transplant
Secondary	Health-Related Quality of Life Assessed by St. George's Respiratory Questionnaire	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.	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
Secondary	Respiratory Muscle Strength Assessed by Maximal Inspiratory Pressure	Respiratory muscle strength will be quantified as Maximal Inspiratory Pressure (MIP), evaluated using a respiratory muscle trainer (PowerBreathe KH2).	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
Secondary	Physical Activity and Exercise Behaviors Assessed by International Physical Activity Questionnaire	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.	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
Secondary	Pulmonary Function Testing (Spirometry)	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).	Baseline, 4 weeks, 8 weeks, 12 weeks, every 3 months until lung transplant (up to 24 months total), and 3 months post-transplant
Secondary	Aerobic Endurance Assessed by the Six-Minute Walk Test	Clinical rehabilitation charts will be reviewed to document aerobic endurance as assessed by distance walked during 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
Secondary	Physical Function Assessed by the Short Physical Performance Battery	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.	Baseline, 4 weeks, 8 weeks, 12 weeks, every 3 months until lung transplant (up to 24 months total), and 3 months post-transplant
Secondary	Pre-Transplant Hospitalizations	Clinical charts will be reviewed to document any hospitalizations and ICU admissions before the time of transplantation.	From baseline up until the time of admission for the index transplant hospitalization (up to 24 months total)
Secondary	Peri-Transplant Mechanical Ventilation Bridging	Clinical charts will be reviewed to determine whether mechanical ventilation or extracorporeal membrane oxygenation (ECMO) were required as a bridge to transplantation.	Peri-operative period, from time of index transplant hospital admission to time of transplant surgery (up to 24 months total)
Secondary	Post-Transplant Duration of Mechanical Ventilation (Days)	Clinical charts will be reviewed to determine the duration of mechanical ventilation required following transplantation surgery, measured in days.	From time of transplant surgery to the time of liberation from mechanical ventilation (up to 3 months total)
Secondary	WIND Weaning Classification	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.	At the time of liberation from mechanical ventilation following transplant surgery (up to 3 months total).
Secondary	Post-Transplant Hospital Length of Stay (Days)	Clinical charts will be reviewed to determine the length of stay in hospital following transplant surgery, measured in days.	From time of transplant surgery to the time of discharge from hospital (up to 3 months total).
Secondary	Post-Transplant Discharge Disposition	Clinical charts will be reviewed to determine participants' discharge disposition from the index transplant hospitalization (e.g., home, inpatient rehabilitation, long-term care).	Time of discharge from index transplant hospitalization (up to 3 months total).
Secondary	Primary Graft Dysfunction	Clinical charts will be reviewed to determine the presence and severity of primary graft dysfunction following transplant surgery.	Up to 72 hours post-transplant
Secondary	Post-Transplant Mortality	Clinical charts will be reviewed to document post-transplant mortality and etiology.	Up to 90 days (3 months) post-transplant
Secondary	Days Alive and at Home at 90 Days (DAAH90)	Clinical charts will be reviewed to determine the number of days participants are alive and at home at 90 days post-transplant.	Up to 90 days (3 months) post-transplant