The Utility of Extravascular Lung Water Measurements Following Bilateral Lung Transplant Laveena Munshi, MD, MSc November 2018 Interdepartmental Division of Critical Care Medicine Mount Sinai Hospital/University Health Network University of Toronto Toronto, Canada
Disclosures Ontario Thoracic Society Grant No Relevant Financial Disclosures
Pulmonary Edema Remains the Hallmark of ARDS The accurate detection and quantification of pulmonary edema has important clinical implications
Methods of estimating pulmonary edema and/or volume status are numerous but fraught with error Extravascular Lung Water Intravascular Volume Status
Objectives Transpulmonary thermodilution and extravascular lung water Evolution of evidence surrounding extravascular lung water The utility of extravascular lung water following bilateral lung transplant
Transpulmonary Thermodilution: Extravascular Lung Water Mean Transit Time Cardiac Output Down slope time Extravascular Lung Water Global End Diastolic Volume Pulmonary Vascular Permeability Index
EVLW 10 cc/kg Associated with Clinically Significant Pulmonary Edema 7
The Evidence: Validation 8
The Evidence: EVLW Distinguishes Between Causes of Acute Respiratory Failure 9
10
Acute Respiratory Failure Following Lung Transplant is Not Uncommon PRIMARY GRAFT DYSFUNCTION Severed Lymphatics During Transplant 11
Diffuse Pulmonary Infiltrates in 72 hours Post Lung Transplant: Primary Graft Dysfunction (PGD) Utility of PGD classification Lack precise methods to predict development and prognosticate outcome Diffuse pulmonary infiltrates in first 72 hours following Emerging transplant Utility of Grade 1 PGD (PaO 2 EVLW /FiO 2 ratio >300) Grade 2 PGD (PaO 2 /FiO 2 200-300) Grade 3 PGD (PaO 2 /FiO 2 <200) Pulmonary edema Evaluated at time 0, 24 hours, 48 hours, 72 hours following transplant may be more challenging to Incidence manage of grade post 3 PGD LTx at any time point after transplant ~30% Associated PGD with classification increased LOS, mortality and BOS issues with and later inability scores correlating better with to outcomes predict PGD 12 Diamond et al The Journal of Heart and Lung Transplant 2017
The Utility of Extravascular Lung Water Following Bilateral Lung Transplant 13
OBJECTIVES AIM 1: Evaluate the association between EVLW and PGD PGD 1 AIM 2: Evaluate whether early measurements of EVLW are associated with greater severities of PGD at later time points AIM 3: Evaluate whether early EVLW is associated with duration of mechanical ventilation independent of PGD T X EVL W PGD PGD PGD PGD 2 PGD 3 14
METHODS Prospective observational study of all adult consecutive bilateral lung transplant at TGH Exclusion Criteria: Immediate need for post operative ECMO, contraindication to femoral arterial catheterization, single lung transplant instead of double Transpulmonary Thermodilution (EVLW) 0 6 12 24 36 48 60 72 Goal: 56 patients 30% incidence of higher grade PGD/3cc/kg EVLW difference Outcomes PGD Determination 2 independent reviewers Evaluated at times 0, 24, 48, 72 hours Grades 0/1 classified as grade 1 All extubated patients classified as grade 1 Duration of Mechanical Ventilation
Patient and Donor Details Age 55 (SD 11) Sex Transplant indication Donor 36 No 58% Male 56 Maybe 35% IPF 31% COPD/Emphysema 11% CF 24% Other 82% NDD Donor Age 48 (SD 19) Donor Smoking Donor Duration of MV EVLP 25% 44% Yes 54% No 2% Unknown 2 (IQR 1-3) 31 patients excluded 229 Patients Approached 137 Consented 87 Called for Transplant 56 Patients Included 268 TPTD measurements 220 PGD determinations IntraOR Support Blood Transfusion Total Ischemic Time (min) OR and ICU Details 44% ECLS 4% CPB 47% 1215 (SD 430) APACHE II 17 (SD 4) Pa02/FiO2 355 (240-445) ino 42% Duration of MV MV >48hrs 44% 2 (1-5) days
Low Incidence of Grade 3 PGD 25% had a deterioration in PGD grade over this time period
Grade 3 PGD Associated with Longer Duration of Mechanical Ventilation Median Duration of Mechanical Ventilation (days) 8 7 6 5 4 3 2 1 0 PGD 1 PGD 2 PGD 3 Grade 1 PGD Grade2 PGD at Grade 3 PGD at admission admission at admission DurMV 2 days (1-3) 2 day (1-9) 8 days (3-24)
PaO 18 2 /FiO 2 <200 strong correlation with increase in EVLW 16 14 15 12 10 8 9 9 9 11 Correlation between EVLW and PF <200 Spearman s Rho -0.64, p=0.001 6 4 2 ELWI LCI UCI 0 P/F>400 P/F 300-400 P/F 200-300 P/F 100-200 P/F <100 Worsening Severity of Graft Dysfunction
EVLW but not PVPI was associated with PGD Grade Median EVLW across PGD (cc/kg) Median PVPI across PGD 14 12 10 8 6 4 2 0 PGD 1 PGD 2 PGD 3 3 2.8 2.6 2.4 2.2 2 1.8 1.6 1.4 1.2 1 PGD 1 PGD 2 PGD 3 Grade 1 PGD Grade2 PGD Grade 3 PGD EVLW 9 (8-11) 10 (8-12) 12 (9-15) p <0.001 PVPI 1.7 (1.5-2.4) Grade 1 PGD Grade2 PGD Grade 3 PGD 1.8 (1.3-2.0) p=0.067 2.1 (1.9-2.7)
Within strata of higher grade PGD at 24 hours high/low EVLW yielded different durations of MV PGD 1 PaO 2 /FiO 2 >300 EVLW low ( 8) EVLW high (>8) PGD 2 PaO 2 /FiO 2 200-300 EVLW low ( 9) EVLW high (>9) PGD 3 PaO 2 /FiO 2 <200 EVLW low ( 12) EVLW high (>12) PF 341 (333-360) PF 360 (320-400) PF 263 (225-273) PF 222 (214 226) PF 186 (180-193) PF 144 (99-190) Duration of Mechanical Ventilation 2 (1-3) days 1 (1-2) days 4 (3-11) days 14 (3-23) days 3 (3-33) days 30 (4-55) days
Prediction of PGD at 24 hours based upon early EVLW Time 0 EVLW Time 6 EVLW Time 12 EVLW EVLW TIME 0 p=0.25 9.5 (8-12) 10 (8-13) 14 (13-15) 405 EVLW TIME (298-452) 6 *p=0.02 9 (8-10) Unclear if early EVLW added value beyond other early factors associated with PGD at 24 hours PaO 2 /FiO 2 time 0 11 (8-17) 262 12 (9-17)(232-408) EVLW TIME 12 *p=0.03 8 89 (8-12) (66-154) 9 (8-12) 13 (9-17) PGD time 0 72% - grade 1 21% - grade 2 6% - grade 3 38% - grade 1 50% - grade 2 13% - grade 3 20% - grade 1 20% - grade 2 60% - grade 3 PGD 24 HOURS GRADE 1 PGD GRADE 2 PGD GRADE 3 PGD
Factors Associated with PGD at 24 hours Adjusted Analysis (patient, donor, intraoperative, ICU factors) EVLW measured at 6 hours was independently associated with PGD grade at 24 hours VARIABLE IRR 95% CI p EVLW at 6 hours 1.06 1.01-1.12 0.02 PGD at admission 1.06 0.85-1.31 0.58 Intraoperative Support: ECMO CPB 1.17 1.05 0.99-1.40 0.68-1.62 0.06 0.82 APACHEII 1.05 1.01-1.08 0.012 Ischemic time 0.99 0.99-1.00 0.17 Age 1.00 0.99 1.01 0.169 Donor smoking 1.09 0.96-1.24 0.175 PVPI at 6 hours 1.07 0.94-1.23 0.30
EVLW between 0-12 hours 15 cc/kg Had High Specificity to Detect Grade 3 PGD at 24 hours High Specificity, Low Sensitivity of Early EVLW 15cc/kg in Predicting Grade 3 PGD at 24 hours EVLW time 0 >=15cc/kg SPECIFICITY SENSITIVITY ROC 89% 40% 0.81 ELWI time 6 >=14cc/kg 88% 50% 0.67 ELWI time 12 >=15cc/kg 93% 50% 0.70
Factors Independently Associated with Duration of MV Adjusted Analysis (patient, donor, intraoperative, ICU factors) EVLW measured at 12 hours was independently associated with duration of mechanical ventilation VARIABLE IRR 95% CI p EVLW at admission 0.98 0.86-1.12 0.78 EVLW at 12 hours 1.12 1.03-1.24 0.012 PGD at admission* PGD grade 2 PGD grade 3 PGD at 24 hours* PGD grade 2 PGD grade 3 0.47 0.50 0.22-1.01 0.11-2.10 0.06 0.34 3.32 7.44 1.60-6.91 2.67-20.7 0.001 <0.001 APACHE II 1.06 0.99-1.14 0.090 INTRAOP SUPPORT ECMO CPB 2.12 1.69 1.25-3.59 0.78-3.65 0.005 0.18 Age 1.02 0.98-1.05 0.46
EVLW between 0-12 hours 15 cc/kg Had High Specificity to Detect Prolonged Mechanical Vent High Specificity, Low Sensitivity of Early EVLW 15cc/kg in Predicting MV >48 hours EVLW time 0 >=15 cc/kg SPECIFICITY SENSITIVITY ROC 93% 23% 0.67 ELWI time 6 >=14 cc/kg 92% 25% 0.67 ELWI time 12 >=15 cc/kg 96% 18% 0.61
Discussion and Limitations EVLW was associated with PGD grade Early measurements of EVLW (6 hrs) and (12 hrs) independently associated with PGD at 24 hours and duration of mechanical ventilation EVLW cutpoint of 15 cc/kg between 0-12 hours has high specificity for grade 3 PGD at 24 hours and MV >48 hours Single center, small prospective observational study Unclear if marker of severity of illness or whether manipulating EVLW can modify outcome
Implications for ARDS EVLW is associated with ARDS severity Potential future utility in ARDS: Predicting who may be at risk of developing ARDS which may guide early initiation of protective therapies or future therapeutic strategies More meticulously guide safe restrictive fluid management strategy determined by thresholds of EVLW during fluid administration in ARDS Identify subcategories of patients within ARDS severities who may benefit from specific interventions/evaluate response to therapies
Conclusions EVLW is a promising method to quantify pulmonary edema EVLW may have important implications in the setting of ARDS and PGD in predicting severity and prognosis More data is needed to further confirm these findings and evaluate whether an EVLW-goal-directed algorithm can improve outcomes
Thank you Acknowledgements: John Granton Marcelo Cypel Alaa Mohamed Alyaa Elhazmi Bruno Ferreyro Jussi Tikkanen Ontario Thoracic Society Lung Transplant Surgical Fellows TGH ICU attending and nursing teams Lorenzo Del Sorbo Damon Scales Gordon Rubenfeld Eddy Fan Lung Transplant team
In patients admitted with PGD 1 Median EVLW time 0 was HIGHER in those who went onto develop grade 3 PGD at 24 hours compared to grade 1 PGD 1 ADMISSION PGD 1 24 H PGD 1 ADMISSION PGD 2 24H PGD 1 ADMISSION PGD 3 24H EVLW0 9 (7-12) 10 (8-13) 12 (11-13) PF0 441 (396-499) 414 (404-465) 395 (152-636) CVP0 5.5 (3.5-8.5) 8 (5-9) 6.5 (3.5-8.5)
Intrathoracic Thermal Volume = ITTV Double Indicator Dilution Technique cold indocyanine green dye Intrathoracic Blood Volume = ITBV EVLW = ITTV-ITBV Cumbersome Expensive Time consuming Technically challenging ELWI = EVLW indexed to PBW 32
Intrathoracic Thermal Volume = CO x MTT Pulmonary Thermal Volume = CO x DST Global End Diastolic Volume = ITTV - PTV PB V ITBV ITBV related to GEDV 1.25 x GEDI-28.4 33
3-7 cc/kg normal 10 cc/kg pulmonary edema Pulmonary Vascular Permeability Index: EVLW/PBV Lots of leak = HIGH Minimal leak = LOW 34
Limitations. Vascular Obstruction Hypoxic Vasoconstriction Positive End Expiratory Pressure Pleural Effusions Lung resection Low Cardiac Output States Mgt algorithms 35