Diaphragm Structure and Pathobiology in Patients Being Bridged to Lung Transplant

Study Overview
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Brief Summary
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This study is designed to characterize the changes in diaphragm structure, function and biology during bridging to lung transplant by mechanical ventilation or extracorporeal life support.

Detailed Description
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Mechanical ventilation has been linked to diaphragm injury and dysfunction. During mechanical ventilation, the amount of breathing work done by the diaphragm is unpredictable: the diaphragm could be completely rested, or it could be overworked. Either of these possibilities may cause injury to the diaphragm. Patients with an injured and dysfunctional diaphragm have greater difficulty weaning from mechanical ventilation - they become too weak to breathe. However, little is known about the relationship between changes in the diaphragm and the histological (structure of cells and tissue) basis of these changes. The investigators have developed a new technique employing beside ultrasound to measure diaphragm thickness. This allows them to observe changes in diaphragm muscle structure and function. The goal of the study is to determine whether different forms of respiratory support (mechanical ventilation vs extracorporeal life support) lead to different degrees of diaphragm injury and to compare changes in the diaphragm seen on ultrasound to changes in the diaphragm tissues under a microscope. This will help the investigators to confirm the best way to avoid diaphragm injury and to understanding the meaning of diaphragm ultrasound images.

Official Title
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Diaphragm Structure and Pathobiology in Patients Being Bridged to Lung Transplant

Conditions
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Diaphragm Injury, Respiratory Failure, Mechanical Ventilation Complication

Intervention / Treatment
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* Device: Respiratory support


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (Cases): Receiving a respiratory support modality as a bridge to lung transplantation Formally listed for transplantation Inclusion Criteria (Control Group 1): - Undergoing lung transplantation for either obstructive or restrictive lung disease Inclusion Criteria (Control Group 2): - Undergoing elective thoracic surgery without any prior history of chronic pulmonary parenchymal disease Exclusion Criteria (Cases and Controls): Previously diagnosed with neuromuscular disorder Received invasive mechanical ventilation for >48 hours in the preceding four weeks Thoracic cage deformity

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients undergoing LTx with respiratory failure (cases)<br>Patients are receiving a respiratory support modality (mechanical ventilation and/or extracorporeal life support) as a bridge to lung transplantation (LTx). | Device: Respiratory support<br>* Mechanical ventilation or extracorporeal life support<br>|
| Patients undergoing LTx without prior respiratory support<br>Patients undergoing lung transplantation but do not require prior bridging respiratory support. | |
| Elective thoracic surgical patients<br>Patients undergoing elective thoracic surgery for planned lung or esophageal resection. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in diaphragm thickness and thickening fraction in patients using MV and patients using ECLS | Diaphragm thickness and injury score will be tested for an interaction between the bridging modality (MV vs. ECLS) and the duration of exposure to the modality on the degree of diaphragm injury and atrophy | Change from baseline diaphragm thickness and thickening fraction at 7 days after lung transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlate changes in diaphragm thickness and histological features of diaphragm dysfunction | Histological features to be assessed are: myofibril cross-sectional area, muscle fiber type, presence of cellular infiltrates, myofiber necrosis and regeneration, autophagy and fibro-fatty infiltration | Assessed immediately after transplantation | 
| Biomarkers for diaphragm dysfunction | Biomarkers to be assessed are: skeletal troponin-I and markers of systemic inflammation (IL-1, IL-6, Tumor Necrosis Factor (TNF)-alpha) | Assessed immediately before transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diaphragm Dysfunction, Acute Respiratory Failure, Mechanical Ventilation