Measurement of Extravascular Lung Water to Detect and Predict Primary Graft Dysfunction Following Lung Transplant

Study Overview
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Brief Summary
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Primary graft dysfunction (PGD) is the most common cause of early morbidity and mortality following lung transplant and is characterized by acute lung injury and capillary leak leading to an increase in extravascular lung water index (ELWI) and impaired graft function. PGD has many features in common with acute respiratory distress syndrome (ARDS). PGD may be life-threatening and can also lead to impaired long term lung function. In ARDS, a restrictive fluid strategy has been associated with an improvement in lung function and outcomes. Accurate methods of evaluating, quantifying and guiding the hemodynamic / fluid management and limiting the extent of ELWI that accumulates in the setting of PGD are lacking. Using transpulmonary thermodilution to estimate ELWI and the pulmonary permeability index (PPI) represents a novel approach to fluid management, which has been used in patients with ARDS, but to date not in the transplant setting. To determine if these measurements may better guide the management of lung transplant patients, the investigators first wish to establish whether these methods are able to predict the onset of clinical pulmonary edema earlier, whether they correlated with traditional markers of PGD, and whether they may be useful for predicting outcomes. AIM 1: The investigators will evaluate the correlation between ELWI and current surrogates of pulmonary edema in lung transplant patients with and without Primary Graft Dysfunction (PGD) AIM 2: The investigators will correlate the use of ELWI and PPI to determine the presence and severity of PGD. AIM 3: a) The investigators will determine whether early measurements of ELWI and PPI can predict the onset of PGD. b) Across different strata of PGD, the investigators will determine whether ELWI and PPI have a differential effect on duration of mechanical ventilation. The results of the study will be used for the following: Provide the rationale for routine monitoring of ELWI to detect PGD if found to be more discriminatory and have a stronger association with outcome compared to the current gold standard. Provide the means of early identification of those as risk of developing PGD in order to guide management decisions or future therapeutic interventions aimed at preventing or treating PGD. Provide the requisite groundwork for a clinical trial comparing the effects of an ELWI-driven protocol versus usual care on ICU outcomes in lung transplant recipients.

Official Title
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Measurement of Extravascular Lung Water to Detect and Predict Primary Graft Dysfunction Following Lung Transplant

Conditions
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Primary Graft Dysfunction

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All consecutive bilateral lung transplant recipients Exclusion Criteria: Immediate need for extracorporeal life support following transplant (those requiring ECLS four hours after intensive care admission can be included as the investigators would have obtained some ELWI measurements) Contraindications to femoral artery catheterization (eg, abdominal aortic aneurysm)

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 |
| --- | --- |
| Bilateral Lung Transplant<br>All patients undergoing bilateral lung transplant for any indication will be considered for enrollment in the study. The characteristics of measurements of extravascular lung water will be compared following surgery in those who develop primary graft dysfunction compared to those who do not. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AIM 1: The presence of pulmonary edema on chest X ray (CXR) at 24 hours determined by blinded CXR reviewers | On post operative day 1 (24 hours following lung transplant), the investigators will evaluate whether extravascular lung water measured at 24 hours correlates with pulmonary edema determined by reviewers of the CXR blinded to the extravascular lung water measurement. The investigators will use Pearson's correlation for normally distributed and Spearman's correlation for non-normally distributed values. A correlation coefficient of >0.8 will be considered a strong correlation | 24 hours following lung transplant | 
| AIM 2: The presence of primary graft dysfunction at 24 hours determined by CXR evidence of bilateral airspace disease and Pa02/FiO2 ratio threshold by reviewers blinded to the extravascular lung water and pulmonary permeability measurements at 24 | 24 hours following lung transplant, the investigators will evaluate whether the combination of extravascular lung water and pulmonary permeability measurements at 24 hours correlate with the presence and severity of primary graft dysfunction (PGD) at 24 hours. The median extravascular lung water and pulmonary permeability measurements will be calculated. The combinations of above/below median extravascular lung water with above/below median pulmonary permeability will be correlated to the presence of PGD. (eg. high ELWI + high PPI, high ELWI + low PPI, low ELWI + high PPI, low ELWI + low PPI) using Pearson's and Spearman's correlation where appropriate. Grade 0 PGD - Normal CXR AND a PaO2/FiO2 >300mmHg Grade 1 PGD - Bilateral airspace disease on CXR with AND a PaO2/FiO2 >300mmHg Grade 2 PGD - Bilateral airspace disease on CXR with AND a PaO2/FiO2 200-300mmHg Grade 3 PGD - Bilateral airspace disease on CXR with AND a PaO2/FiO2 <200mmHg. | 24 hours | 
| AIM 3: The presence of primary graft dysfunction at 24 hours determined by CXR and Pa02/FiO2 ratio by reviewers blinded to early (time 0) extravascular lung water and pulmonary permeability measurements | The investigators will compare whether immediate (time 0) post operative measurements of the combination of extravascular lung water and pulmonary permeability can predict the later onset (24 hours) of primary graft dysfunction. The combinations of above/below median extravascular lung water with above/below median pulmonary permeability will be correlated to the presence of PGD. (eg. high ELWI + high PPI, high ELWI + low PPI, low ELWI + high PPI, low ELWI + low PPI) using logistic regression. Grade 0 PGD - Normal CXR AND a PaO2/FiO2 >300mmHg Grade 1 PGD - Bilateral airspace disease on CXR with AND a PaO2/FiO2 >300mmHg Grade 2 PGD - Bilateral airspace disease on CXR with AND a PaO2/FiO2 200-300mmHg Grade 3 PGD - Bilateral airspace disease on CXR with AND a PaO2/FiO2 <200mmHg. | Time 0 extravascular lung water and pulmonary permeability measurements and primary graft dysfunction at 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AIM 1: The presence of pulmonary edema on chest X ray at 48 and 72 hours evaluated by CXR reviewers blinded to the extravascular lung water measurements measured at 48 and 72 hours | On post operative day 2 and 3 (48 and 72 hours following lung transplant), the investigators will evaluate whether the extravascular lung water measurements taken at 48 and 72 hours correlate with pulmonary edema determined by CXR. The investigators will use Pearson's correlation for normally distributed and Spearman's correlation for non-normally distributed values. A correlation coefficient of >0.8 will be considered a strong correlation | 48 and 72 hours following lung transplant | 
| AIM 2: The presence of late primary graft dysfunction determined by CXR and PaO2/FiO2 ratio evaluated by reviewers blinded to the extravascular lung water and pulmonary permeability measurements evaluated at 48 and 72 hours | On post operative day 2 and 3 (48 and 72 hours following lung transplant), the investigators will evaluate whether the combination of of extravascular lung water and pulmonary permeability measurements taken at 48 and 72 hours correlate with the presence and severity of primary graft dysfunction (PGD). The combinations of above/below median extravascular lung water with above/below median pulmonary permeability will be correlated to the presence of PGD. (eg. high ELWI + high PPI, high ELWI + low PPI, low ELWI + high PPI, low ELWI + low PPI) using Pearson's and Spearman's correlation where appropriate. Grade 0 PGD - Normal CXR AND a PaO2/FiO2 >300mmHg Grade 1 PGD - Bilateral airspace disease on CXR with AND a PaO2/FiO2 >300mmHg Grade 2 PGD - Bilateral airspace disease on CXR with AND a PaO2/FiO2 200-300mmHg Grade 3 PGD - Bilateral airspace disease on CXR with AND a PaO2/FiO2 <200mmHg. | 48 and 72 hours following lung transplant | 
| AIM 3: The presence of late primary graft dysfunction (48 and 72 hours) determined by CXR and PaO2/FiO2 ratio evaluated by reviewers blinded to the extravascular lung water and pulmonary permeability measurements at time 0 | The investigators will evaluate whether the early (time 0 hours) measurements of the combination of extravascular lung water and pulmonary permeability index can predict the development of late primary graft dysfunction (PGD) at 48 hours or 72 hours. The combinations of above/below median extravascular lung water with above/below median pulmonary permeability will be correlated to the presence of PGD. (eg. high ELWI + high PPI, high ELWI + low PPI, low ELWI + high PPI, low ELWI + low PPI) using Pearson's and Spearman's correlation where appropriate. Grade 0 PGD - Normal CXR AND a PaO2/FiO2 >300mmHg Grade 1 PGD - Bilateral airspace disease on CXR with AND a PaO2/FiO2 >300mmHg Grade 2 PGD - Bilateral airspace disease on CXR with AND a PaO2/FiO2 200-300mmHg Grade 3 PGD - Bilateral airspace disease on CXR with AND a PaO2/FiO2 <200mmHg. | Extravascular lung water and pulmonary permeability measurements at time 0 hours, primary graft dysfunction determination at 48 or 72 hours | 
| AIM 3: The presence of any primary graft dysfunction determined by CXR and PaO2/FiO2 ratio (24, 48 or 72 hours) evaluated by reviewers blinded to the early extravascular lung water and pulmonary permeability measurements (6 hours and 12 hours) | The investigators will evaluate whether the early (time 6 hours and 12 hours) measurements of the combination of extravascular lung water and pulmonary permeability index can predict the development of primary graft dysfunction (PGD) at 24, 48 or 72 hours. The combinations of above/below median extravascular lung water with above/below median pulmonary permeability will be correlated to the presence of PGD. (eg. high ELWI + high PPI, high ELWI + low PPI, low ELWI + high PPI, low ELWI + low PPI) using logistic regression. Grade 0 PGD - Normal CXR AND a PaO2/FiO2 >300mmHg Grade 1 PGD - Bilateral airspace disease on CXR with AND a PaO2/FiO2 >300mmHg Grade 2 PGD - Bilateral airspace disease on CXR with AND a PaO2/FiO2 200-300mmHg Grade 3 PGD - Bilateral airspace disease on CXR with AND a PaO2/FiO2 <200mmHg. | Extravascular lung water and pulmonary permeability measurements at 6 hours and 12 hours, any primary graft dysfunction determined at 24, 48 or 72 hours | 
| AIM 3: Duration of mechanical ventilation | The investigators will evaluate whether extravascular lung water and pulmonary permeability measurements at 24 hours, regardless of primary graft dysfunction grade, correlates with duration of mechanical ventilation during the first intensive care unit stay following lung transplant using linear regression analysis | Extravascular lung water and pulmonary permeability measurements at 24 hours, Hospital admission following lung transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Extravascular Lung Water, Transpulmonary Thermodilution, Primary Graft Dysfunction, Ischemia Reperfusion Injury