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

May 22, 2012
November 13, 2015
October 2015
November 2016   (final data collection date for primary outcome measure)
  • 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.

Using Extravascular Lung Water (EVLW) to Discriminate Between Those With or Without Primary Graft Dysfunction (PGD) After 24 Hours. [ Time Frame: 24 hours following lung transplant ] [ Designated as safety issue: Yes ]
We will evaluate the optimal threshold of EVLW for discriminating between the presence versus absence of PGD. Our primary analysis will consider the measurements of EVLW obtained at 24 hours with simultaneous (blinded) determinations of PGD. The optimal threshold will be determined using diagnostic odds ratios that maximize sensitivity and specificity.
Complete list of historical versions of study NCT01605214 on ClinicalTrials.gov Archive Site
  • 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
  • Discriminating the Presence and Severity of PGD [ Time Frame: 72 hours following lung transplant ] [ Designated as safety issue: Yes ]
    We will evaluate the optimal cutpoints of EVLW for identifying PGD at multiple time points within the first 72 hours following surgery and we will evaluate the ability of EVLW to predict different grades of PGD.
  • Associations between EVLW and PGD [ Time Frame: 72 hours following lung transplant ] [ Designated as safety issue: Yes ]
    We will determine whether higher levels of EVLW across patients are predictive of greater degrees of PGD, and how these associations change over time. We will first establish the range and distribution of EVLW numbers across patients with and without PGD and over time. These ranges of EVLW will be compared to the previously described ranges of normal and abnormal values in previous populations that have been described in the literature (e.g. ARDS and sepsis).
  • Correlation Between EVLW and Other Surrogates of Pulmonary Edema [ Time Frame: 72 hours following lung transplant ] [ Designated as safety issue: No ]
    At each time point, the EVLW will be compared to the current surrogates of pulmonary edema used to guide current management of PGD including chest xray evidence of bilateral airspace disease, central venous pressure, fluid balance, oxygenation index, Partial pressure of oxygen:Fraction of inspired oxygen ratio and daily weights. These values will be compared to determine which best correlate with the presence of PGD.
Not Provided
Not Provided
 
Measurement of Extravascular Lung Water to Detect and Predict Primary Graft Dysfunction Following Lung Transplant
Measurement of Extravascular Lung Water to Detect and Predict Primary Graft Dysfunction Following Lung Transplant

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.
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Observational
Observational Model: Cohort
Time Perspective: Prospective
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Non-Probability Sample
All patients undergoing bilateral lung transplant for any indication will be considered to be enrolled in this study.
Primary Graft Dysfunction
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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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
60
December 2016
November 2016   (final data collection date for primary outcome measure)

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)
Both
18 Years and older   (Adult, Senior)
No
Contact: John Granton, MD, FRCPC 416-340-4485 john.granton@uhn.ca
Contact: Laveena Munshi, MD, FRCPC 416-586-4800 laveena.munshi@utoronto.ca
Canada
 
NCT01605214
UHNEVLW-1
No
Not Provided
Not Provided
John Granton, University Health Network, Toronto
University Health Network, Toronto
Toronto General Hospital
Principal Investigator: John Granton, MD, FRCPC University Health Network, Toronto
University Health Network, Toronto
November 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP