Laveena Munshi, MD, MSc
November 2018
Interdepartmental Division of Critical Care MedicineMount Sinai Hospital/University Health NetworkUniversity of Toronto
Toronto, Canada
The Utility of
Extravascular Lung Water Measurements
Following
Bilateral Lung Transplant
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
• Transpulmonary thermodilution and extravascular lung water
• Evolution of evidence surrounding extravascular lung water
• The utility of extravascular lung water following bilateral lung transplant
Objectives
Transpulmonary
Thermodilution:
Extravascular Lung Water
Mean Transit Time
Down slope timeCardiac Output
Extravascular Lung Water
Global End Diastolic Volume
Pulmonary Vascular Permeability Index
7
EVLW ≥ 10 cc/kg Associated with Clinically Significant
Pulmonary Edema
The Evidence: Validation
8
9
The Evidence: EVLW Distinguishes Between Causes of
Acute Respiratory Failure
10
Acute Respiratory Failure Following Lung Transplant is Not
Uncommon
11
PRIMARY
GRAFT
DYSFUNCTION
Severed Lymphatics
During Transplant
Diffuse Pulmonary Infiltrates in 72 hours Post Lung Transplant:
Primary Graft Dysfunction (PGD)
12
Diamond et al The Journal of Heart and Lung Transplant 2017
Diffuse pulmonary infiltrates in first 72 hours following transplant
• Grade 1 PGD (PaO2/FiO2 ratio >300)
• Grade 2 PGD (PaO2/FiO2 200-300)
• Grade 3 PGD (PaO2/FiO2 <200)
Evaluated at time 0, 24 hours, 48 hours, 72 hours following transplant
Incidence of grade 3 PGD at any time point after transplant ~30%
Associated with increased LOS, mortality and BOS – with later scores correlating better with outcomes
Utility of PGD
classification
Lack precise
methods to predict
development and
prognosticate
outcome
Emerging Utility of
EVLW
Pulmonary edema
may be more
challenging to
manage post LTx
PGD classification
issues and inability
to predict PGD
13
The Utility of Extravascular Lung Water
Following Bilateral Lung Transplant
14
OBJECTIVES
AIM 1: Evaluate the associationbetween EVLW and PGD
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
PGD 1
PGD 2
PGD 3
EVL
WT
XPGD PGD PGD
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) 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
0 6 12
24 36 48 60 72
Goal:
56 patients
30% incidence of higher
grade PGD/3cc/kg EVLW
difference
229 Patients
Approached
87 Called for
Transplant
56 Patients
Included
31 patients
excluded
36 No
56
Maybe
268 TPTD
measurements
220 PGD
determinations
137 Consented
Patient and Donor Details
Age 55 (SD 11)
Sex 58% Male
Transplant
indication
35% IPF
31% COPD/Emphysema
11% CF
24% Other
Donor 82% NDD
Donor Age 48 (SD 19)
Donor
Smoking
44% Yes
54% No
2% Unknown
Donor
Duration of
MV
2 (IQR 1-3)
EVLP 25%
OR and ICU Details
IntraOR
Support
44% ECLS
4% CPB
Blood
Transfusion
47%
Total
Ischemic
Time (min)
1215 (SD 430)
APACHE II 17 (SD 4)
Pa02/FiO2 355 (240-445)
iNO 42%
Duration of
MV
2 (1-5) days
MV >48hrs 44%
Low Incidence of Grade 3 PGD
25% had a deterioration in PGD grade over this
time period
0
1
2
3
4
5
6
7
8
PGD 1 PGD 2 PGD 3
Median Duration of Mechanical Ventilation (days)
Grade 1 PGD
at admission
Grade2 PGD at
admission
Grade 3 PGD
at admission
DurMV 2 days (1-3) 2 day (1-9) 8 days (3-24)
Grade 3 PGD Associated with Longer Duration of
Mechanical Ventilation
9 9 9
11
15
0
2
4
6
8
10
12
14
16
18
P/F>400 P/F 300-400 P/F 200-300 P/F 100-200 P/F <100
ELWI LCI UCI
Worsening Severity of Graft Dysfunction
PaO2/FiO2 <200 strong correlation with increase in
EVLW
Correlation between
EVLW and PF <200
Spearman’s Rho -0.64,
p=0.001
EVLW but not PVPI was associated with PGD Grade
0
2
4
6
8
10
12
14
PGD 1 PGD 2 PGD 3
Median EVLW across PGD (cc/kg) Median PVPI across PGD
1
1.2
1.4
1.6
1.8
2
2.2
2.4
2.6
2.8
3
PGD 1 PGD 2 PGD 3
Grade 1 PGD Grade2 PGD Grade 3 PGD
EVLW 9 (8-11) 10 (8-12) 12 (9-15)
Grade 1 PGD Grade2 PGD Grade 3 PGD
PVPI 1.7 (1.5-
2.4)
1.8 (1.3-
2.0)
2.1 (1.9-2.7)
p <0.001 p=0.067
PGD 1
PaO2/FiO2 >300
PGD 2
PaO2/FiO2 200-300
PGD 3
PaO2/FiO2 <200
EVLW low
(≤8)
EVLW high
(>8)
EVLW low
(≤9)
EVLW high
(>9)
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
Within strata of higher grade PGD at 24 hours
high/low EVLW yielded different durations of MV
Time 0 EVLW
Time 6 EVLW
Prediction of PGD at 24 hours based upon early EVLW
Time 12 EVLW
EVLW TIME 0
9.5 (8-12)
10 (8-13)
14 (13-15)
PGD 24 HOURS
GRADE 1 PGD
GRADE 2 PGD
GRADE 3 PGD
EVLW TIME 6
9 (8-10)
11 (8-17)
12 (9-17)
EVLW TIME 12
8 (8-12)
9 (8-12)
13 (9-17)
p=0.25
*p=0.02
*p=0.03
Unclear if early EVLW added
value beyond other early
factors associated with PGD
at 24 hours
PaO2/FiO2 time
0
PGD time 0
405
(298-452)
72% - grade 1
21% - grade 2
6% - grade 3
262
(232-408)
38% - grade 1
50% - grade 2
13% - grade 3
89
(66-154)
20% - grade 1
20% - grade 2
60% - grade 3
Factors Associated with PGD at 24 hoursAdjusted 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
SPECIFICITY SENSITIVITY ROC
EVLW time 0
>=15cc/kg
89% 40% 0.81
ELWI time 6 >=14cc/kg 88% 50% 0.67
ELWI time 12
>=15cc/kg
93% 50% 0.70
High Specificity, Low Sensitivity of Early EVLW ≥ 15cc/kg in Predicting Grade 3 PGD at 24 hours
Factors Independently Associated with Duration of MVAdjusted 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
0.47
0.50
0.22-1.01
0.11-2.10
0.06
0.34
PGD at 24 hours*
PGD grade 2
PGD grade 3
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
SPECIFICITY SENSITIVITY ROC
EVLW time 0 >=15
cc/kg
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)
32
Intrathoracic Thermal Volume = ITTV
Intrathoracic Blood Volume = ITBV
EVLW = ITTV-ITBV
ELWI =
EVLW
indexed to
PBW
Double Indicator
Dilution
Technique
cold
indocyanine
green dye
Cumbersome
Expensive
Time consuming
Technically
challenging
33
Intrathoracic Thermal Volume
=
CO x MTT
Pulmonary Thermal Volume
=
CO x DST
Global End Diastolic Volume
=
ITTV - PTV
ITBV related to GEDV
1.25 x GEDI-28.4
PB
V
ITBV
34Pulmonary Vascular Permeability Index: EVLW/PBV
Lots of leak = HIGH
Minimal leak = LOW
3-7 cc/kg normal
10 cc/kg pulmonary
edema
Limitations….
35
• Vascular Obstruction
• Hypoxic Vasoconstriction
• Positive End Expiratory Pressure
• Pleural Effusions
• Lung resection
• Low Cardiac Output States
• Mgt algorithms
