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“Portable Normothermic Ex Vivo Lung Perfusion to Reduce Warm Ischemia Time
and Increase Graft Usage "
Gabriel Loor, MD Baylor St. Luke’s Medical CenterSurgical Director Lung TransplantationCo-chief Section of Adult Cardiac Surgery
Disclosures
• Grant support from Transmedics for involvement in EVLP clinical and
translational trials
• Travel reimbursement for study related travel
• United Therapeutics grant support for translational research
• Receive grant support from Maquet for an ECMO in lung transplantation
registry
End stage lung disease
4
15-30% of patients die on the waitlist
Critical organ shortage
5
Donor lungswastedDonor lungsused
20%
80%
Critical organ shortage
Primary Graft Dysfunction
Ex Vivo Lung Perfusion
XPS –Novel Trial
Static Perfusion Systems
Vivo Line –Develop UK Trial
Portable Ex-vivo Lung Perfusion (EVLP)“Breathing Lung Transplantation”
§ Organ Care System Lung (OCS Lung)
§ Portable EVLP platform
§ Normothermic, blood based perfusion, ventilation, monitoring and recruitment
§ Additives – steroids, antibiotics, glucose, multivitamins, insulin
Critical Trends
Pump Flow
VR (Vascular Resistance)
SaO2 & SvO2
Tidal Volume
PAP (Pulmonary Artery Pressure)
PAWP (Peak Airway Pressure)PEEP (Positive End Expiratory Pressure)
Monitoring
12
13
INSPIRE trial
§ Standard Criteria Donors§ PaO2:FiO2 >300mmHg§Age < 65§Organ suitable for either cold storage or OCS§No active pulmonary disease§Non DCD
14
INSPIRE trial
Physiologic parameters on portable EVLP
Total ischemic time and total cross clamp time
Donor lung splitting
• Reduces ischemic exposure even further
• Increases options for size reduction and single lungs to expand the donor pool
18
PGD3 within 72 hours
Resource utilization
20
Survival
21
Summary of portable EVLP in standard donors
• Safe, FDA approved • Mean clamp times of 8 hours, despite lower ischemic
times• Less PGD 3 – better graft function• Trends towards decreased resource utilization• Costs include modules and stationary console • Survival at 12 months and 24 months are similar to ice
storage• CLAD data is not yet available
Can we extrapolate this to extended criteria lungs?
23
Donor lungswastedDonor lungsused
20%
80%
Critical organ shortage
24
The OCS Lung EXPANDI International Trial Results
G. Loor, G. Warnecke, M. Villavicencio, M. Smith, J. Kukreja, J. Moradiellos, A. Varela, J. Madsen, A. Haverich, M. Hertz, A. Ardehali, D. Van Raemdonck
U. Minnesota, Minneapolis, USA; Hannover Medical School, Germany; Massachusetts General Hospital, Boston, USA; St. Joseph’s Medical Center, Phoenix, USA; University of California San
Francisco, USA; University Hospital Puerta de Hierro, Madrid, Spain; Ronald Reagan UCLA Medical Center, Los Angeles, USA; University Hospital Leuven, Leuven, Belgium
• Objective: To evaluate the safety and effectiveness of the OCS™
Lung System to recruit, preserve and assess non-standard donor lungs that may not meet current standard donor lung acceptance criteria for transplantation
• Trial Design: Prospective single arm multi-center international pivotal trial focusing on improving utilization of non-ideal donor lungs for double lung transplantation
OCS Lung EXPANDI Trial
EXPAND Lung Donor Eligibility
Inclusion ExclusionDonor PaO2/FiO2 ≤ 300 mmHg
Expected Ischemic time > 6 hours
DCD Donors
Donor Age ≥ 55 years
Moderate/Severe Lung Injury
Presence of Active Pneumonia
History of Active Lung Disease
Blood Transfusion >10 pRBCs
ABO Incompatibility
Tobacco history >20 pack years
EXPAND I Trial
Did Not Meet Tx Criteria on OCS N=12
Recipient Txed. with OCS Lungs N= 79
Met Transplant Criteria on OCS N=81
OCS Perfused Donor Lungs N=93
Not TransplantedN=1 Recipient dx. lung CaN=1 No surgeon available
87% Yield Rate
30
DCD + other (N=6, 50%)
Age > 55 yo(N=4, 33%)
DCD isolated (N=1, 8%)Anticipated ischemic time > 6 hrs(N=1, 8%)
Lungs screened out on OCS
31
Donor lung inclusion characteristic(s)
Percentage of donor entries
PF < 300 25%DCD 33%Anticipated ischemic time > 6 hours
32%
Age > 55 yo 39%> 1 inclusion 27%
52 U.S. Transplanted Donors in EXPAND had an Avg. of 39
Declines by other U.S. Centers in UNOS Match Run
Donor lung inclusion characteristics
32
Transplanted Recipients with OCS LungsN=79
Age (years) (Mean ± SD) 55.6 ± 10.6 (32 – 74)Female Gender 33 (42%)Male Gender 46 (58%)LAS Score (Range) 42 ± 13 (31 – 93)Primary Diagnosis
COPD 31 (39%)IPF 23 (29%)CF 12 (15%)Sarcoidosis 2 (2%)Other 11 (14%)
Secondary Pulmonary Hypertension 22 (28%)Transplanted on CPB 38 (48%)
Recipient characteristics
Reduced Cold Ischemic Times Despite Extended Total Clamp Times
8.510.1
2.63.9
0
2
4
6
8
10
12
14
1st Lung 2nd Lung
Total Out of Body Time Total Ischemic Time
Mean Time(Hours)
EXPAND Lung Trial – EVLP Physiology
351
320
100
150
200
250
300
350
400
Initial OCS Assessment
Final OCS Assessment
1211
0
2
4
6
8
10
12
14
Initial OCS Assessment
Final OCS Assessment
378409
100
150
200
250
300
350
400
450
Donor Assessment
Final OCS Assessment
Vascular Resistance (dyn·s/cm5 ) Peak Airway Pressures (CmH2O) PaO2/FiO2 Ratio
EXPAND I Trial
Post-Transplant Patient Survival
Patient Survival 1, 6 and 12 months98.7%
93.7% 91.1%
0%
20%
40%
60%
80%
100%
Proportion (%)
1 month 6 months 12 months
Patient Survival EXPANDI vs INSPIRE Cohorts98.7
93.7 91.199.5
90.887
0
10
20
30
40
50
60
70
80
90
100
30 Days 6 Months 12 Months
EXPAND Trial (Extended Criteria Donors) INSPIRE Trial Control (Standard Criteria Donors)
37
Proportion (%)
EXPAND Patient Survival vs Standard of Care98.7
93.7 91.199.5
90.8 90.296.2
90.285
0
10
20
30
40
50
60
70
80
90
100
30 Days 6 Months 12 Months
EXPAND Trial (Extended Criteria) INSPIRE Trial Control (Standard Criteria) US National UNOS Data
Proportion (%)
EXPAND I Trial
Primary Graft Dysfunction Grade 3
EXPAND I Trial PGD3 Rates
40.5%
16.5%
9.0%6.4%
0%
10%
20%
30%
40%
50%
Proportion (%)
T0 T24 T48 T72
44.30%
0%
10%
20%
30%
40%
50%
PGD3 Within Initial 72 Hours
PGD3 Rates EXPAND (ECD) vs INSPIRE (SOC)
40.5
16.5
96.4
20.7
10.9
6.6 5.5
0
10
20
30
40
50
T0 T24 T48 T72
EXPAND I Trial INSPIRE Trial Control
Proportion (%)
44.3%
28.8%
0%
10%
20%
30%
40%
50%
PGD3 Within Initial 72 Hours
EXPAND Trial INSPIRE Trial Control
Incidence of PGD3 Within 72 hours Incidence of PGD3 At Each Timepoint
PGD3 in EXPAND (OCS) and DEVLOP UK Trial (Static)
42
Proportion (%) 40.5%
16.5%9.0% 6.4%
88.9%
44.4%38.9%
27.8%
0%
20%
40%
60%
80%
100%
T0 T24 T48 T72
EXPAND Trial DEVELOP UK TrialFisher A, et al.; An observational study of donor ex-vivo lung perfusion in UK lung transplantation: DEVELOP-UK
HTA 2016 Vol20, No. 85
PGD3 Stratified by Donor Inclusion Criteria
40% 41%48%
61%
0%
20%
40%
60%
80%
100%
PF Ratio <300mmHg
Age > 55 YO Ischemic Time >6hours
DCD Donors
Proportion (%)
PGD3 Rates in EXPAND (OCS) and NOVEL Extension (XPS) by Donor Inclusion
15.4%
7.7% 7.7%
50.0%
29.2%25.0%
0%
20%
40%
60%
T24 T48 T72
EXPAND Trial NOVEL Extension
17.0%
9.6%5.8%
21.1%
12.7%8.5%
0%
20%
40%
60%
T24 T48 T72EXPAND Trial NOVEL Extension
44
Proportion (%)
Whitson, B.A., et al. Ex-Vivo Lung Perfusion in Donation after Circulatory Death Lung Transplantation Increases Donor Utilization: Analysis of the NOVEL Extension Trial, No. 355, ISHLT 2018 Annual Meeting, Nice, France.
Incidence of PGD3 DCD Donor Population Incidence of PGD3 DBD Donor Population
Portable EVLP in Extended Criteria Donors
• Excellent survival with Extended Criteria Donors (EXPAND)
• But still have a burden of PGD with Extended Criteria Donors
• Static platform also FDA approved – need to further understand options.
4 8 12 16 20 24
Perfusion Time (hrs)
StandardDonor run (INSPIRE)
Extended criteriaDonor run (EXPAND)
Ris
k of
PG
D
Effects of time on portable EVLP on incidence of PGD remain unknown
Does this curve change if the parameters are excellent on EVLP??
THANK YOU!JLH Foundation grantMcDonald GrantUniversity of Minnesota Lillehei InstituteUnited TherapeuticsRobert and Sonja Steinberg FoundationUniversity of Minnesota CollaboratorsVisible Heart Lab OCS Investigators collaborators