Ventilator-associated Injury (VAI) in Chronic Home Mechanical Ventilation

Study Overview
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Brief Summary
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Rationale: The pathophysiological changes in respiratory muscle morphology and functioning in patients with end-stage pulmonary disease are not very well known. Furthermore, in COPD, long-term high-intensity NIV is applied without knowing the exact consequences on the lungs and respiratory muscles. Objective: The aims of the study are to get insight in: A. changes respiratory muscles in end-stage respiratory disease, comparing COPD with restrictive lung disease (RLD) due to pulmonary fibrosis B. the effects of long-term HI-NIV in severe COPD patients on the respiratory muscles and the lungs; by comparing COPD patients that had been treated with long-term NIV to COPD patients that were not treated with long-term NIV. Study design: In order to investigate this, the investigators will include in a small pilot cohort study patients being lung transplanted. In these patients there is lung tissue available and respiratory muscle biopsies will be performed during lung-transplant surgery. Study population: Patients that are listed for lung transplantation for an underlying diagnosis of COPD or RLD will be asked to participate. Three groups will be included: patients with a RLD due to pulmonary fibrosis, COPD patients that had been treated with long-term NIV prior to being lung transplanted and COPD patients that were not treated with long-term NIV. Patients will be included definitely once being lung transplanted. Main study parameters/endpoints: The study is an exploratory pilot study. Both contractile strength and the structure of single diaphragm and intercostal muscle fibres as well as lung injury; i.e. alveolar structure and damage and inflammation in the alveoli, will be investigated.

Detailed Description
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Rationale: Chronic Obstructive Pulmonary Disease (COPD) is a progressive inflammatory disease characterised by airway and lung parenchyma damage. At end-stage disease patients may develop chronic hypercapnic respiratory failure, a disease characteristic that is however not uniformly seen in other end-stage lung diseases, such as in patients with pulmonary fibrosis. The underlying process for the development of chronic hypercapnic respiratory failure is incompletely understood and the role of respiratory muscle alterations is unclear. Home noninvasive ventilation with high-intensity ventilatory settings (HI-NIV) has been shown to be effective in these severe COPD patients. However, in patients being mechanically ventilated on the intensive care unit for diverse reasons, high-intensity ventilation, especially high tidal volumes, has been shown to result in ventilator associated lung and diaphragm injury. Whether this occurs in home high-intensity NIV, is however completely unknown. Objective: The aims of the study are to get insight in: A. changes respiratory muscles in end-stage respiratory disease, comparing COPD with restrictive lung disease (RLD) due to pulmonary fibrosis B. the effects of long-term HI-NIV in severe COPD patients on the respiratory muscles; i.e. the contractile strength and the structure of single diaphragm and intercostal muscle fibres and the lungs; i.e. alveolar structure and damage and inflammation, by comparing COPD patients that had been treated with long-term NIV to COPD patients that were not treated with long-term NIV. Study design: In order to investigate this, the investigators will include in a small pilot cohort study patients being lung transplanted. In these patients there is lung tissue available and respiratory muscle biopsies will be performed during lung-transplant surgery. Study population: Patients that are listed for lung transplantation for an underlying diagnosis of COPD or RLD will be asked to participate. Three groups will be included: patients with a RLD due to pulmonary fibrosis, COPD patients that had been treated with long-term NIV prior to being lung transplanted and COPD patients that were not treated with long-term NIV. Patients will be included definitely once being lung transplanted. Main study parameters/endpoints: The study is an exploratory pilot study. The study aims to get data on respiratory muscle and lung and airway pathology in order to, if important results are observed, set up a larger prospective trial investigating both clinical outcomes and pathology of the respiratory muscles/lungs. Both contractile strength and the structure of single diaphragm and intercostal muscle fibres as well as lung injury; i.e. alveolar structure and damage and inflammation in the alveoli, will be investigated.

Official Title
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Ventilator-associated Injury (VAI) in Chronic Home Mechanical Ventilation: a Paradigm Switch in Order to Improve Ventilatory Support

Conditions
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Respiratory Failure, Long-term Non-invasive Ventilation

Intervention / Treatment
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* Other: No other than standard care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: RLD: probable or confirmed diagnosis of interstitial pulmonary fibrosis (IPF) or other fibrotic lung disease of unknown origin. COPD: GOLD stage III or IV Being listed for lung transplantation Exclusion Criteria: Concomitant neuromuscular or systemic/collagen-vascular disease Prior lung surgery (except for lung biopsies) or lung volume reduction treatment Being unable to understand the patient information and consent for the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Lung Fibrosis<br>probable or confirmed diagnosis of interstitial pulmonary fibrosis (IPF) or other fibrotic lung disease of unknown origin. being listed for lung transplantation | Other: No other than standard care<br>* No other than standard care.<br>|
| COPD standard therapy<br>COPD: GOLD stage III or IV being listed for lung transplantation did not underwent LVR surgery or endoscopic LVR not being treated with chronic NIV | Other: No other than standard care<br>* No other than standard care.<br>|
| COPD with long-term NIV<br>COPD: GOLD stage III or IV being listed for lung transplantation did not underwent LVR surgery or endoscopic LVR being treated with chronic NIV before lung transplantation (at least 1 months, at least 4 hours per day). | Other: No other than standard care<br>* No other than standard care.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Respiratory muscle morphology and functioning | Biopsies of the diaphragm and intercostal muscles will be taken during surgery | during surgery | 
| Ventilator-associated lung injury serum TNF-alfa | serum TNF-alfa | during surgery | 
| Ventilator-associated lung injury serum IL-6 | serum IL-6 | during surgery | 
| Ventilator-associated lung injury serum IL-1beta | serum IL-1beta | during surgery | 
| Ventilator-associated lung injury serum IL-8 | serum IL-8 | during surgery | 
| Ventilator-associated lung injury serum MIP-2 | serum MIP-2 | during surgery | 
| Ventilator-associated lung injury serum sRAGE | serum sRAGE | during surgery | 
| Ventilator-associated lung injury BAL TNF-alfa | BAL TNF-alfa | during surgery | 
| Ventilator-associated lung injury BAL IL-6 | BAL IL-6 | during surgery | 
| Ventilator-associated lung injury BAL IL-1beta | BAL IL-1beta | during surgery | 
| Ventilator-associated lung injury BAL IL-8 | BAL IL-8 | during surgery | 
| Ventilator-associated lung injury BAL MIP-2 | BAL MIP-2 | during surgery | 
| Ventilator-associated lung injury BAL sRAGE | BAL sRAGE | during surgery | 
| Ventilator-associated lung injury basal membrane | histopathological changes to the basal membrane | during surgery | 
| Ventilator-associated lung injury alveolar cells | histopathological changes to type I alveolar cells | during surgery | 
| Ventilator-associated lung injury edema | edema in the alveoli and interstitium | during surgery | 
| Ventilator-associated lung injury fibrin | interstitial fibrin | during surgery | 
| Ventilator-associated lung injury inflammatory cells | Inflammatory cells influx in the alveoli | during surgery | 
| Ventilator-associated lung injury gene-expression | Gene-expression profiling of epithelial cells with regard to inflammatory factors | during surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ventilatory use | Duration of usage (longitudinally and use per day) | during surgery | 
| Ventilatory settings | Settings of the NIV | during surgery | 
| Demographics_age | age | during surgery | 
| Demographics_gender | gender | during surgery | 
| Demographics_BMI | BMI | during surgery | 
| Lung Function_FEV1 | FEV1 | during surgery | 
| Lung Function_FVC | FVC | during surgery | 
| Blood gasses_PaCO2 | PaCO2 | during surgery | 
| Blood gasses_HCO3- | HCO3- | during surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COPD, Lung fibrosis, non-invasive ventilation, respiratory muscles, diaphragm, lung inflammation, ventilator-induced lung injury