Measurement of Extravascular Lung Water to Detect and Predict Primary Graft Dysfunction Following Lung Transplant
Lung transplantation is a life-saving treatment for patients with advanced lung disease. A common complication following lung transplantation is injury to the new lungs as they receive the flow of blood from the recipient after a period of cold storage during transportation. This is known as primary graft dysfunction (PGD, poor functioning of the new lung). The treatment of PGD involves trying to protect the lung from further injury by careful use of the breathing machine, and in giving the minimal required amount of intravenous fluids to patients. In critically ill patients, however, it is often difficult to determine exactly how much fluid is needed. A new monitor allows us to determine how much fluid has leaked into the damaged lungs. This in turn may help determine if patients can tolerate more fluid administration in situations where they are in shock versus having their blood pressure supported by additional medications..
This study will determine if this new method of measuring the leakage of fluid into the lungs can predict the presence and severity of PGD and will determine if there is a certain threshold that can differentiate between those with and without PGD. The investigators will also compare this method to other traditional methods used to measure fluid leak into the lungs.
This method has never been properly evaluated in lung transplant patients. It may provide a useful clinical tool to monitor and hopefully eventually guide the treatment of lung transplant patients after surgery.
Primary Graft Dysfunction
|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|
- 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.
- 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.
|Study Start Date:||July 2012|
|Estimated Study Completion Date:||July 2014|
|Estimated Primary Completion Date:||July 2014 (Final data collection date for primary outcome measure)|
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.
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1.1 INTRODUCTION: Primary graft dysfunction (PGD) is the most common cause of early morbidity and mortality following lung transplant. PGD is characterized by acute lung injury and capillary leak leading to an increase in extravascular lung water (EVLW) and impaired graft function. PGD has many features in common with acute respiratory distress syndrome (ARDS) as they are both characterized by inflammation, pulmonary edema secondary to capillary leak and impaired lung compliance. This impaired graft function 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 EVLW that accumulates in the setting of PGD are lacking. Using transpulmonary thermodilution to estimate EVLW and the pulmonary permeability index 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, we first wish to establish whether these methods are able to predict the onset of clinical pulmonary edema earlier and whether they correlated with traditional markers and definitions of PGD.
1.2 AIMS and OBJECTIVES:
This study is designed with 3 primary objectives in mind:
Establish a cut-point of EVLW that can be used to discriminate between lung transplant recipients that have PGD and those that do not:
We hypothesize that a cut-point of EVLW can be used to discriminate between those with and without PGD. We further hypothesize that it may predict the later development or worsening severity of PGD.
Associations between EVLW and PGD:
We hypothesize that the threshold for edema, using transpulmonary thermodilution and EVLW in lung transplant, is similar to that described in ARDS. We aim to evaluate whether associations exist between the presence and severity of PGD and a range of EVLW measurements. We further wish to delineate whether abnormal EVLW and permeability measurements can precede the clinical and radiographic evidence of the presence of or severity of PGD. We will compare the EVLW threshold for non-cardiogenic pulmonary edema in PGD to those described in ARDS.
- Correlation between EVLW and other surrogates of pulmonary edema:
Current surrogates of volume status (fluid balance, chest radiography, central venous pressure) are used to guide fluid administration in PGD; however, they are fraught with subjectivity and error. We will evaluate if EVLW measurements correlate with current surrogate markers of pulmonary edema in lung transplant that we use to guide treatment for PGD (CXR demonstrating bilateral airspace disease, daily and cumulative fluid balance, elevated central venous pressure, daily weights).
The results of this study will be used to:
- Provide the rationale for routine monitoring of EVLW to detect PGD and
- Provide some of the groundwork for a clinical trial comparing the effects of an EVLW-driven protocol versus usual care on ICU outcomes of lung transplant recipients.
2.1 PRIMARY GRAFT DYSFUNCTION: Primary graft dysfunction (PGD) is a serious and common complication that typically occurs in the first 72 hours after lung transplantation. PGD is characterized by worsening acute lung injury with capillary leak leading to impaired graft function. PGD is the result of the accumulation of insults inflicted upon the lungs from the premortem time period of the donor to implantation into the recipient. Clinically, patients develop hypoxemia and lung infiltrates that require the use of more aggressive ventilatory strategies and occasionally extracorporeal support. In its most severe form, the resultant systemic inflammatory response can induce multisystem organ failure, vasodilatory shock and hypoxia induced pulmonary hypertension. PGD occurs in 10-25% of patients and is associated with significant morbidity and mortality. Despite improvements in the transplantation process, PGD remains the leading cause of prolonged mechanical ventilation and death following transplant. Heightened challenges exist in this population regarding the management of pulmonary edema given the severed lymphatic drainage following lung transplant. A vicious spiral may ensue as the presence of PGD can further precipitate ongoing capillary leak induced by the systemic inflammatory response worsening the severity of PGD. The potential multi-factorial etiologies of shock in this state can provide challenges to the intensive care and thoracic surgery teams in establishing the balance that must be achieved between minimizing pulmonary edema and ensuring adequate cardiac output.
2.2 FLUID STRATEGIES AND OUTCOMES FOR ARDS: Clinically and pathologically PGD is similar to ARDS. Multiple previous studies have evaluated the impact of fluid balance on outcomes in ARDS demonstrating that a restrictive fluid management strategy results in more favorable outcomes. A landmark trial further exploring this was an evaluation of the two fluid management strategies in acute lung injury by the ARDS Clinical Trials Network. One-thousand patients with acute lung injury were evaluated in a randomized study comparing explicit protocols applied for 7 days of a conservative compared to liberal fluid management strategy. This demonstrated improved oxygenation index, lung injury score and number of ventilator free days in the conservative group.
2.3 SHORTCOMINGS ON CURRENT METHODS OF EVALUATING FLUID STATUS: There is little data available on the optimal fluid management strategy for lung transplant patients, though current guidelines support maintaining a restrictive fluid management protocol. Hemodynamic management strategies after lung transplantation are currently routinely guided by a pulmonary artery catheter to determine the patient's volume status. However, there is, mounting evidence within the critical care literature that challenges the safety and reliability of the pulmonary artery catheter derived measurements of cardiac preload. In fact, it has been postulated that these methods are associated with an increase in mortality. Unfortunately, alternative surrogates of pulmonary edema including chest radiography, fluid balance and daily weights are neither sensitive nor specific in the critical care setting for detecting or managing pulmonary edema. In critically ill patients traditional methods to determine fluid balance have been shown to be poor. It would be ideal to have a method that allows for more reliable measurement of cardiac preload and lung water to minimize graft dysfunction. Other techniques currently available in critical care including pulse pressure variation would be limited in this population given the high incidence of arrhythmias, rendering the measurements unreliable and its failure to predict adequate fluid responsiveness in ARDS.Additionally, for those patients who develop PGD a more reliable method to guide fluid administration is needed.
2.4 EXTRAVASCULAR LUNG WATER AND TRANSPULMONARY THERMODILUTION: Single indicator transpulmonary thermodilution is a minimally invasive technique that monitors continuous cardiac output using systemic thermodilution. It also provides measurements including global end diastolic volume (a surrogate for cardiac preload), extravascular lung water, and pulmonary permeability indices (to differentiate between hydrostatic and permeability pulmonary edema). The method involves the intravenous injection of a known volume of cold saline that is subsequently thermally distributed within the cardiac and pulmonary volumes. A thermodilution decay curve is generated by a thermistor placed in an arterial vessel. Cardiac output is calculated mathematically (Stewart-Hamilton Equation) using the decay curve. The mean transit time of the temperature indicator to peak in combination with the cardiac output results in the intrathoracic thermal volume. Intrathoracic thermal volume is comprised of the blood in the cardiac chambers, intravascular pulmonary blood volume and extravascular lung water. The difference between the intrathoracic thermal volume and the intrathoracic (intravascular) blood volume is the EVLW. Intrathoracic blood volume can be derived using single indicator transpulmonary thermodilution by a constant linear relationship that has been established between intrathoracic blood volume and global end diastolic volume. This relationship has been validated in a series of studies.Global end diastolic volume represents cardiac preload and is the difference between intrathoracic thermal volume and pulmonary thermal volume. When a group of mixing chambers with a constant flow are in a series, the slowest thermodilution decay curve will be determined by the largest chamber (in this case, it would be the lungs). Therefore, pulmonary thermal volume is obtained from the exponential downslope of the decay curve of thermodilution. Once intrathoracic thermal volume and pulmonary thermal volume are determined by thermodilution, global end diastolic volume is converted to intrathoracic blood volume and EVLW can be calculated. These values can also be used to calculate the pulmonary permeability index.
2.5 EXTRAVASCULAR LUNG WATER AND PRIOR CLINICAL EXPERIENCE: Single indicator transpulmonary thermodilution and EVLW have been well validated in critical care in acute respiratory distress syndrome and sepsis. ELVW in combination with pulmonary permeability index, determined by the ratio between EVLW and pulmonary blood volume, has been validated as a means to differentiate between hydrostatic pulmonary edema and permeability pulmonary edema. Intrathoracic blood volume has been directly compared with the pulmonary artery catheter in multiple studies of patients with septic shock. In these studies it has been found to have superior accuracy in evaluating cardiac preload. A recent study in patients with sepsis and septic shock demonstrated that increased EVLW levels correlate with the development of multi organ dysfunction syndrome and mortality. Those with ARDS are found to have a higher peak in EVLW measurements compared to other critically ill patients. These measurements have been shown to be better estimates of cardiac preload compared to standard methods (pulmonary artery catheter, echocardiography), and are felt to be a more sensitive indicator of the development and type of pulmonary edema.
2.6 EXTRAVASCULAR LUNG WATER AND APPLICATION TO LUNG TRANSPLANT: Within the area of lung transplantation, only four small studies have evaluated its use with promising results. The reliability of intrathoracic blood volume as an index of preload during lung transplant surgery was evaluated in fifty patients using transpulmonary thermodilution and compared to the pulmonary artery catheter. Intrathoracic blood volume measurements not only correlated well with stroke volume but was felt to be superior compared to pulmonary artery occlusion pressure. EVLW measurements taken immediately post reperfusion of each lung were statistically significantly higher compared pre- transplant values.
Determining the reliability of EVLW to diagnose PGD was assessed in a pig model. In this study a left lung transplant was performed. Graft function and native lung function were assessed at the time of transplant and for the following 5 hours after reperfusion. In the setting of severe alveolar edema, a significant increase in EVLW was noted. Quantification of PGD was evaluated in a this model using the transpulmonary thermodilution technique concluding that EVLW measurements are a reliable and sensitive method to quantify lung allograft PGD and may be useful as an early assessment tool of PGD in the clinical setting.
In a study evaluating criteria for early extubation following lung transplant, transpulmonary thermodilution was used to determine intrathoracic blood volume. A particular intrathoracic blood volume threshold was part of the criteria that patients would have to fulfill to be streamlined into the immediate extubation group. In the 12 patients who fulfilled the criteria for early extubation, none required reintubation and EVLW measurements were statistically significantly lower compared to those who did not undergo extubation.
The potential superiority of EVLW measurement over traditional methods was illustrated in a study by Perrin et al. In this study, 30 patients had EVLW measurements for the first 72 hours following lung transplantation. Although intended to evaluate the effect of inhaled nitric oxide on EVLW, they demonstrated that there was a progressive reduction in EVLW over the 3 days of observation. Furthermore EVLW/ITBV (an indirect measure of permeability) decreased over time. While this study did not specifically evaluate the relationship between EVLW and other measurements of fluid status, there was poor agreement between EVLW and central venous pressure measurements.
The importance of attending to lung edema is supported in the treatment of ARDS. Positive fluid balance is associated with a worse outcome. These observations and preliminary data supports the need to systematically evaluate the potential utility of EVLW and transpulmonary thermodilution in the post operative management of lung transplantation. Global end diastolic volume and EVLW may be influenced by graft - recipient size mismatch, cardiopulmonary bypass during surgery, the severed lymphatic drainage, and lack of immediate bronchial circulation. It follows then that a study be conducted to evaluate its use following lung transplant. It is unclear whether the traditional thresholds for pulmonary edema determined by EVLW apply to the lung transplant population and whether it may be associated with the development of PGD.
3.0 STUDY DESIGN, METHODOLOGY AND ANALYSIS
3.1 METHODS: We will conduct a prospective observational study in patients undergoing bilateral lung transplant to evaluate associations between EVLW and higher grades of PGD, and to determine optimal cut-points of EVLW for identifying patients that have PGD. All patients will be managed according to our institution's standard protocol for bilateral lung transplant.
Following enrollment into the study, patients will be managed according to our institution's usual protocol using pulmonary artery catheter guided hemodynamic measurements intraoperatively. The PiCCO system (Pulsion Medical) which will be used to obtain post-operative EVLW measurements can use brachial, axillary or femoral (but not radial) arterial lines, as the thermistor catheter for transpulmonary thermodilution measurements. Given the nature of the operation (and after consultation with the transplant anaesthetists and surgeons about their current practice in our institution), we have elected to use the femoral arterial line site which will be inserted under sterile technique in the operating room by the anaesthetist. The femoral arterial catheter will also serve to record systemic arterial pressure to guide management. Lung transplantation will follow according to our institution's standard technique.
Patients will be managed according to the usual practices for lung transplantation, with all management decisions being directed by the clinical team. Briefly, on arrival in the ICU patients are placed on an FiO2 of 1.0 and a PEEP of 5 (in the absence of hypoxia necessitating higher support from the ventilator). Following this assessment, patients will be weaned from mechanical ventilation according to a standard protocol. Once hemodynamic stability and adequate end-organ perfusion are confirmed by the clinical team, infusions of vasoactive medications will be weaned off according to usual practice. The only change from usual practice will be that the PiCCO monitor will be attached, with periodic measurements recorded by the study team; these will not be given to the clinical team and will not be used to guide clinical management.
Determination of EVLW and other exposure variables:
While in the ICU, transpulmonary thermodilution and pulmonary artery catheter measurements will be recorded at admission to ICU and at predefined time points for the first 72 hours post lung transplant (upon admission to ICU, 4hrs, 8hrs, 12hrs, 24hrs then q12h until 72hrs or until the patient is extubated). After calibration, the nurses will be blinded to the measurements. The physicians will be blinded to all of the PiCCO data including the initial readings obtained by the nurse. A bedside nurse will press the data capture key at each protocol determined time point. These "readings of interest" will be stored in the PICCO system and saved for evaluation following completion of the study for that patient. The transpulmonary thermodilution data to be collected includes cardiac index, systemic vascular resistance, stroke volume, stroke volume variability, global end diastolic volume, extravascular lung water and pulmonary permeability index.
Pulmonary artery catheter measurements will be recorded in the case report forms and clinical flow sheets at the same time points.
According to study protocol, the pulmonary artery catheter and femoral arterial catheters will be removed 72hrs after arrival in the ICU (or 12hrs after the patient is extubated if this occurs prior to the 72hr time point). Beyond 72hrs, the decision to keep the pulmonary artery catheter will be left to clinical team's discretion. All measurements will be indexed to predicted body weight (EVLW) and total body surface area (global end diastolic volume).
Determination of Primary Graft Dysfunction (PGD):
We will use the standard definition of PGD as defined by the International Society of Heart and Lung Transplant using the following criteria:
- Presence of diffuse pulmonary infiltrates involving the lung allografts on post operative chest X ray AND
Pulmonary arterial oxygen and fraction of inspired oxygen ratios (P/F ratio) in mmHg
- Grade 1 PGD (PF ratio >300)
- Grade 2 PGD (PF ratio 200-300)
- Grade 3 PGD (PF ratio <200)
No other secondary cause of graft dysfunction readily identified such as:
- Cardiogenic pulmonary edema: defined as prior evidence of LV systolic function on preoperative echocardiogram or post operative echocardiogram and resolution of infiltrates with effective diuresis
- Pathologic evidence of rejection
- Pneumonia (evidence of presence of fever, leukocytosis, purulent secretions and positive culture on bronchoscopy)
- Pulmonary venous outflow obstruction as demonstrated on TEE, surgical reexploration or postmortem examination
- All patients on oxygen via nasal cannula with fraction of inspired oxygen estimated as less than 0.3 will be graded as 0 or 1 based upon CXR
- All subjects on extracorporeal life support are graded as grade 3
Daily chest radiographs, along with P/F ratios and oxygenation index ((FiO2/PaO2) x mean airway pressure x 100) at each time point in the first 72 hours will be collected, as well as variables to rule out confounders for PGD (see appendix 3).
The clinical diagnosis of PGD as judged by 2 independent reviewers, blinded to EVLW measurements will be used as the "gold standard". Each reviewer will evaluate the CXRs, P/F ratios and have access to all clinical data in the patient's medical record to allow them to determine the presence and grade of PGD and to rule out alternative diagnosis; they will not have access to the EVLW measurements.
Mechanical ventilation settings, hemodynamics, volume status, and end organ perfusion will be collected and recorded at the study specified intervals. Clinical indicators reflecting volume status, fluid administration (volume and type of fluid), risk factors for PGD, potential confounders for PGD, duration of mechanical ventilation and length of stay in the ICU and hospital will also be collected.
3.4 OUTCOMES AND ANALYSIS: AIM 1: Establish a cut-point of EVLW that can be used to discriminate between lung transplant recipients that have PGD and those that do not 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 specificity39. Secondary analyses will incorporate other clinical predictors into the diagnostic odds ratio models; evaluate the optimal cutpoints of EVLW for identifying PGD at other time points; evaluate the ability of EVLW to predict different grades of PGD; and account for repeated measurements of EVLW and PGD being performed in the same patients.
AIM 2: Associations between EVLW and PGD:
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). Following determination of the presence or absence of PGD (defined as grade 2 or higher), the range of values of EVLW will be analyzed and compared to the presence or absence of PGD across time. An exploratory analysis will be performed to evaluate the relationship between EVLW, global end diastolic volume and pulmonary permeability index and the presence and severity of PGD over time since transplant. Traditional thresholds of normal and abnormal values previously described in the ARDS literature will be compared to those discovered through our exploratory analysis.
AIM 3: Correlation between EVLW and other surrogates of pulmonary edema:
At each time point, the EVLW will be compared to the current surrogates of pulmonary edema used to guide current management of PGD including CXR evidence of bilateral airspace disease, central venous pressure, fluid balance, oxygenation index, P/F ratio and daily weights. These values will be compared to determine which best correlate with the presence of PGD.
|Contact: John Granton, MD, FRCPCemail@example.com|
|Contact: Laveena Munshi, MD, FRCPC||416-340-4800 ext firstname.lastname@example.org|
|Toronto General Hospital|
|Toronto, Ontario, Canada, M5G 2C4|
|Principal Investigator:||John Granton, MD, FRCPC||University Health Network, Toronto|