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

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2015 by University Health Network, Toronto
Sponsor:
Collaborator:
Toronto General Hospital
Information provided by (Responsible Party):
John Granton, University Health Network, Toronto
ClinicalTrials.gov Identifier:
NCT01605214
First received: May 22, 2012
Last updated: November 13, 2015
Last verified: November 2015
  Purpose

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:

  1. 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.
  2. 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.
  3. 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.

Condition
Primary Graft Dysfunction

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Measurement of Extravascular Lung Water to Detect and Predict Primary Graft Dysfunction Following Lung Transplant

Resource links provided by NLM:


Further study details as provided by University Health Network, Toronto:

Primary Outcome Measures:
  • AIM 1: The presence of pulmonary edema on chest X ray (CXR) at 24 hours determined by blinded CXR reviewers [ Time Frame: 24 hours following lung transplant ] [ Designated as safety issue: No ]
    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

  • 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 [ Time Frame: 24 hours ] [ Designated as safety issue: No ]

    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.


  • 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 [ Time Frame: Time 0 extravascular lung water and pulmonary permeability measurements and primary graft dysfunction at 24 hours ] [ Designated as safety issue: No ]

    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.



Secondary Outcome Measures:
  • 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 [ Time Frame: 48 and 72 hours following lung transplant ] [ Designated as safety issue: No ]
    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

  • 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 [ Time Frame: 48 and 72 hours following lung transplant ] [ Designated as safety issue: No ]

    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.


  • 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 [ Time Frame: Extravascular lung water and pulmonary permeability measurements at time 0 hours, primary graft dysfunction determination at 48 or 72 hours ] [ Designated as safety issue: No ]

    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.


  • 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) [ Time Frame: Extravascular lung water and pulmonary permeability measurements at 6 hours and 12 hours, any primary graft dysfunction determined at 24, 48 or 72 hours ] [ Designated as safety issue: No ]

    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.


  • AIM 3: Duration of mechanical ventilation [ Time Frame: Extravascular lung water and pulmonary permeability measurements at 24 hours, Hospital admission following lung transplant ] [ Designated as safety issue: No ]
    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


Estimated Enrollment: 60
Study Start Date: October 2015
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: November 2016 (Final data collection date for primary outcome measure)
Groups/Cohorts
Bilateral Lung Transplant
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.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
All patients undergoing bilateral lung transplant for any indication will be considered to be enrolled in this study.
Criteria

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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01605214

Contacts
Contact: John Granton, MD, FRCPC 416-340-4485 john.granton@uhn.ca
Contact: Laveena Munshi, MD, FRCPC 416-586-4800 laveena.munshi@utoronto.ca

Locations
Canada, Ontario
Toronto General Hospital Recruiting
Toronto, Ontario, Canada, M5G 2C4
Contact: John Granton, MD    4163404800 ext 4485    john.granton@uhn.ca   
Contact: Laveena Munshi, MD    4165864800 ext 6571    laveena.munshi@uhn.ca   
Principal Investigator: John Granton, MD, FRCPC         
Sponsors and Collaborators
University Health Network, Toronto
Toronto General Hospital
Investigators
Principal Investigator: John Granton, MD, FRCPC University Health Network, Toronto
  More Information

Publications:

Responsible Party: John Granton, Dr. John T. Granton, Professor, Division Head of Respirology, University Health Network, Toronto
ClinicalTrials.gov Identifier: NCT01605214     History of Changes
Other Study ID Numbers: UHNEVLW-1 
Study First Received: May 22, 2012
Last Updated: November 13, 2015
Health Authority: Canada: Ministry of Health & Long Term Care, Ontario

Keywords provided by University Health Network, Toronto:
Extravascular Lung Water
Transpulmonary Thermodilution
Primary Graft Dysfunction
Ischemia Reperfusion Injury

Additional relevant MeSH terms:
Primary Graft Dysfunction
Reperfusion Injury
Vascular Diseases
Cardiovascular Diseases
Postoperative Complications
Pathologic Processes

ClinicalTrials.gov processed this record on August 30, 2016