Respiratory Muscles in End-stage Lung Disease: Pathophysiological Processes & Clinical Consequences

NCT06935825 | Not Yet Recruiting

• 1 other identifier: PaNaMaID: 22059
• Study Type: observational
• Target: 60
• Locations: 1 country
• Sites: 4

Brief Summary

Rationale: In patients with chronic lung diseases, the role of respiratory muscle dysfunction has been underestimated. Also, current treatment options, like chronic NIV and lung transplantation (LTx), might also have deleterious effects on the respiratory muscles, and the mechanisms are poorly understood. Therefore in this exploratory study the objectives are to:

1. 1.Determine in vivo respiratory muscle function and progression of respiratory muscle dys-function in end-stage COPD patients
2. 2.Establish the correlation between changes in the structure and contractility of respiratory myofibers and in vivo respiratory muscle function.
3. 3.Establish the effect of chronic NIV on structure and contractility of respiratory muscle fi-bers
4. 4.Determine whether the structure and contractility of respiratory muscles cells at the time of LTx predicts clinical recovery post-LTx.

Conditions

COPD

Keywords

COPD; NIV; Lung transplantation; Respiratory muscles; diaphragm; ultrasound; sEMG; MIP

Outcome Measures

Primary Outcomes (8)

• Respiratory neural drive

  With surface EMg (sEMG) a measure of respiratory neural drive is obtained, which could be used as stand alone parameter to estimate effort and, when combined with output parameters as diaphragm movement or MIP/MEP, might be useful to estimate neuro-ventilatory efficiency.

  3-6 monthly before LTx, directly before and after LTx, 3-6 monthly after LTx

• Respriatory muscle output - contraction and movement

  With ultrasound, we will measure diaphragm and intercostal thickening fraction (DF-TF) thereby investigating the amount of muscle contraction. Diaphragm excursion will be measured from subcostally.

  3-6 monthly before LTx, directly before and after LTx, 3-6 monthly after LTx

• Respriatory muscle output - strength

  Maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) will be measured at the lung function department according to ERS guidelines or by using a handheld device when patients are at the ward. Patients are asked to inhale and exhale deeply against a resistance and then measuring airway pressure produced.

  3-6 monthly before LTx, directly before and after LTx, 3-6 monthly after LTx

• Myofiber mechanics

  The maximum force generating capacity, the force response to a range of submaximal \[Ca2+\], active stiffness (reflecting the number of attached and non-attached myosin heads) is determined of individual myofibers.

  Biopsies are obtained during LTx

• Low angle X-ray diffraction

  Measure the position of myosin heads in relaxed and in activated myofibers

  Biopsies are obtained during LTx

• Mant-ATP chase experiments

  To biochemically assess the percentage of myosin heads in the SRX state

  Biopsies are obtained during LTx

• Myofiber and extra-cellular matrix structure

  We will assess myofiber size by immunohistochemistry using antibodies that label the sarcolemma and myosin heavy chain isoforms

  Biopsies are obtained during LTx

• Transcriptomic and proteomic analyses of muscle biopsies

  To study the activation of fibrosis pathways we will apply RNAseq and proteomics on the biopsies

  Biopsies are obtained during LTx

Study Arms (3)

NIV+

Group of patients on nocturnal NIV prior to LTx

NIV-/hypercapnic

Group of patients who are chronic hypercapnic but not on NIV prior to LTx

normocapnic

Group of normocapnic patients prior to LTx

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

COPD patients on the lung transplantation waiting list

In order to be eligible to participate in this study, a participant must meet all of the following criteria: * Age \> 18 years old * Severe COPD defined as COPD GOLD stage III or IV (FEV1 \< 50% of predicted; FEV1/FVC ratio \< 70%, no significant reversibility, smoking history of at least 10 pack-years). * Being on the lung transplant waiting list * Being able to understand the patient information and provide written informed consent for participation in the study A potential participant who meets any of the following criteria will be excluded from participation in this study: * Patients suffering from acute conditions at the time of inclusion or LTx * Patients using more than 20 mg of morphine, or an equivalent, or more than 20 mg oxazepam, or an equivalent, at the time of inclusion or LTx

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• University Medical Center Groningen: lead
• Erasmus Medical Center: collaborator
• Amsterdam UMC, location VUmc: collaborator
• Radboud University Medical Center: collaborator
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator

Study Sites (4)

Amsterdam University Medical Center

Amsterdam, Netherlands

Location

University Medical Center Groningen

Groningen, Netherlands

Location

Radboud University Medical Center

Nijmegen, Netherlands

Location

Erasmus Medical Center

Rotterdam, Netherlands

Location

Biospecimen

Retention: SAMPLES WITH DNA

To study the respiratory myofibers, we will obtain muscle biopsies of diaphragm and intercostal muscles during LTx. From the biopsies individual myofibers will be isolated and their structure and contractility will be assessed. After the isolation of individual myofibers, the remaining muscle tissue will be used for immunohistochemical staining and gene expression analyses to study the molecular mechanisms underlying respiratory muscle dysfunction.

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Central Study Contacts

Marieke L Duiverman, MD PhD

CONTACT

+31503616161; m.l.duiverman@umcg.nl

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 3, 2025
• First Posted: April 20, 2025
• Study Start: September 1, 2025
• Primary Completion (Estimated): April 1, 2029
• Study Completion (Estimated): September 1, 2029
• Last Updated: April 20, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

NL (4)