- Email: [email protected]
Donation after circulatory death in lung transplantation—five-year follow-up from ISHLT Registry
http://www.jhltonline.org
ISHLT REGISTRY ANALYSIS
Donation after circulatory death in lung transplantation—five-year follow-up from ISHLT Registry Dirk Van Raemdonck, MD, PhD,a Shaf Keshavjee, MD, MSc,b Bronwyn Levvey, RN,c Wida S. Cherikh, RN,d Greg Snell, MD,c Michiel Erasmus, MD,e Andre Simon, MD,f Allan R. Glanville, MD,g Stephen Clark, MD,h Frank D’Ovidio, MD,i Pedro Catarino, MD,j Kenneth McCurry, MD,k Marshall I. Hertz, MD,l Rajamiyer Venkateswaran, MD,m Peter Hopkins, MD,n Ilhan Inci, MD,o Rajat Walia, MD,p Daniel Kreisel, MD, PhD,q Jorge Mascaro, MD,r Daniel F. Dilling, MD,s Philip Camp, MD,t David Mason, MD,u Michael Musk, MD,v Michael Burch, MD,w Andrew Fisher, MD,h Roger D. Yusen, MD,q Josef Stehlik, MD,x and Marcelo Cypel, MDb, for the International Society for Heart and Lung Transplantation From the aUniversity Hospitals Leuven, Leuven, Belgium; bUniversity of Toronto, Toronto, Ontario, Canada; cAlfred Hospital, Melbourne, Victoria, Australia; dUnited Network for Organ Sharing, Richmond, Virginia; eUniversity Medical Center Groningen, Groningen, The Netherlands; fHarefield Hospital, London, United Kingdom; gSt Vincent’s Hospital, Sydney, New South Wales, Australia; hFreeman Hospital, Newcastle upon Tyne, United Kingdom; iColumbia University Presbyterian Hospital, New York, New York; jRoyal Papworth Hospital, Cambridge, United Kingdom; kCleveland Clinic, Cleveland, Ohio; lUniversity of Minnesota, Minneapolis, Minnesota; mWythenshawe Hospital, Manchester, United Kingdom; nThe Prince Charles Hospital, Brisbane, Australia; oUniversity Hospital Zurich, Zurich, Switzerland; pSt. Joseph’s Hospital & Medical Center, Phoenix, Arizona; qWashington University, St Louis, Missouri; rUniversity Hospitals Birmingham, Birmingham, United Kingdom; sLoyola University Medical Center, Chicago, Illinois; tBrigham and Womens Hospital, Boston, Massachusetts; uBaylor University Medical Center, Dallas, Texas; vFiona Stanley Hospital, Perth, Australia; w Great Ormond Street for Children, London, United Kingdom; and the xUniversity of Utah, Salt Lake City, Utah.
KEYWORDS: lung transplantation; donors after circulatory death; donor lung allograft; survival; mortality risk factors
BACKGROUND: This study aimed to examine intermediate-term outcomes of lung transplantation (LTx) recipients from donors after circulatory death (DCD). METHODS: We examined the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Transplant Registry data for patients transplanted between January 2003 and June 2017 at 22 centers in North America, Europe, and Australia participating in the DCD Registry. The distribution of continuous variables was summarized as median and interquartile range (IQR) values. Wilcoxon rank sum test was used to compare distribution of continuous variables and chi-square or Fisher’s exact test for categorical variables. Kaplan-Meier survival rates after LTx from January 2003 to June 2016 were compared between DCD-III (Maastricht category III withdrawal of life-sustaining therapy [WLST])
Reprint requests: Dirk Van Raemdonck, MD, PhD, Department of Thoracic Surgery, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium. Telephone: +32 16-346823. Fax: +32 16-346824. E-mail address: [email protected] 1053-2498/$ - see front matter Ó 2019 International Society for Heart and Lung Transplantation. All rights reserved. https://doi.org/10.1016/j.healun.2019.09.007
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The Journal of Heart and Lung Transplantation, Vol 38, No 12, December 2019 only and donors after brain death (DBD) using the log-rank test. Risk factors for 5-year mortality were investigated using Cox multivariate proportional-hazards model. RESULTS: The study cohort included 11,516 lung transplants, of which 1,090 (9.5%) were DCD lung transplants with complete data. DCD-III comprised 94.1% of the DCD cohort. Among the participating centers, the proportion of DCD-LTx performed each year increased from 0.6% in 2003 to 13.5% in 2016. DCD donor management included extubation in 91%, intravenous heparin in 53% and pre-transplant normothermic ex vivo donor lung perfusion in 15%. The median time interval from WLST to cardiac arrest was 15 minutes (IQR: 11-22 minutes) and to cold flush 32 minutes (IQR: 26-41minutes). Compared with DBD, donor age was higher in DCD-III donors (46 years [IQR: 34-55] vs 40 years [IQR: 24-52]), bilateral LTx was performed more often (88.3% vs 76.6%), and more recipients had chronic obstructive pulmonary disease and emphysema as their transplant indication. Five-year survival rates were comparable (63% vs 61%, p = 0.72). In multivariable analysis, recipient and donor ages, indication diagnosis, procedure type (single vs bilateral and double LTx), and transplant era (2003-2009 vs 2010-2016) were independently associated with survival (p < 0.001), but donor type was not (DCD-III vs DBD; hazard ratio, 1.04 [0.90-1.19], p = 0.61). CONCLUSION: This ISHLT DCD Registry report with 5-year follow-up demonstrated similar favorable long-term survival in DCD-III and DBD lung donor recipients at 22 experienced centers globally. These data indicate that more extensive use of DCD-LTx would increase donor organ availability and may reduce waiting list mortality. J Heart Lung Transplant 2019;38:1235−1245 Ó 2019 International Society for Heart and Lung Transplantation. All rights reserved.
The first successful use of donors after circulatory death (DCD) for lung transplantation (LTx) was reported in 1995 by Love et al1 from University of Wisconsin. It was another decade before the practice became more widespread in other LTx programs around the world. Several series from individual institutions and national organizations have reported comparable early- and medium-term recipient outcomes after LTx from controlled DCDs vs standard donors after brain death (DBD).2 Only a few reports have demonstrated worse outcomes for primary graft dysfunction (PGD)3 and bronchiolitis obliterans syndrome.4 A systematic review and recent meta-analysis of 11 observational cohort studies could not demonstrate any difference in 1year mortality, PGD, and acute rejection after LTx from DCD vs DBD.5 In 2011, a working group within the International Society for Heart and Lung Transplantation (ISHLT) initiated a DCD Registry with the help of the United Network for Organ Sharing. Programs contributing to the ISHLT Thoracic Transplant Registry with documented DCD LTx cases were invited to enroll and contribute data on preset DCD variables to the ISHLT database. A first DCD Registry report was published by Cypel et al6 in 2015 comparing early outcomes in 306 DCD vs 3,992 DBD transplants performed at 10 centers in North America, Europe, and Australia between January 2003 and June 2013. One-year survival after LTx did not differ between groups (89% vs 88%, respectively). Despite a significant growth in DCD multiorgan donation in many countries and the promising results previously reported, the percentage of LTx using DCDs remains substantially low in many centers with many donor lungs not being used.7 Concerns about the warm ischemic injury, lack of established protocols, uncertainty regarding the potential and actual donor conversion rate, and public scrutiny may be some factors involved.8
Following the decision in 2017 by the ISHLT Board Of Directors to incorporate relevant DCD variables into the main ISHLT Thoracic Transplant Registry for future transplants, data collection into the stand-alone ISHLT DCD Registry was concluded with transplants performed through June 30, 2017. This study aimed to provide a final report of the DCD Registry, examine the DCD transplant process, the donor and recipient characteristics, and to compare 5-year survival in LTx recipients from DCDs to those with DBDs.
Methods Study design This study was a retrospective DCD Registry cohort of all lung transplants performed between January 2003 and June 2017 by 22 participating institutions from North America including US (8) and Canada (1), Europe (9), and Australia. (4) The analysis included DCD data reported to the ISHLT DCD Registry through August 30, 2018. The control group was identified within the main ISHLT Transplant Registry as a cohort of lung recipients transplanted using DBDs during the same study period within the centers described above. Patients bridged to transplant with extracorporeal life support therapy and retransplantations were excluded.
Definitions DCD donors were classified into 5 categories. DCD-I to IV were defined according to the Maastricht classification reported by Kootstra et al in 1995.9 DCD-V was defined as donors after euthanasia as practiced in countries with existing legislation.10 Important time points of the DCD process and time intervals were captured as defined in the previous report.6 Three-time intervals (T1: from the withdrawal of life-sustaining therapy (WLST) till hypotension with systolic blood pressure <50 mm Hg; T2:
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from WLST till cessation of cardiac output; T3: from WLST till start of pulmonary flush) were then calculated and survival stratification was performed based on the length of these intervals.
Variables Several categorical variables were collected in order to establish current DCD practices. Donor characteristics included age, gender, mechanism of brain injury, and Maastricht category; use of heparin; use of steroids; use of fibrinolytics; extubation during WLST; use of nasogastric tube; use of bronchoscopy; and ex vivo lung perfusion (EVLP) for assessment. Recipient characteristics included age, medical diagnosis, and procedure type (single vs. bilateral and double). The primary endpoint was 5-year survival after lung transplantation.
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Compared with the first half, donors in the second half of the study period were older (47 years [IQR 35-56] vs 42 years [IQR 27-51] for DCD, p < 0.0001; and 42 years [IQR 26-53] vs 38 years [IQR 22-50] for DBD, p < 0.001; Supplementary Table S1 available online at www.jhltonline.org). The cause of fatal brain injury leading to DCD was anoxia (29%), cerebrovascular and stroke (42%), and head trauma (17%). Compared with the first half, donors of DBD recipients in the second half of the study period suffered less head trauma as cause of donor brain injury (16.5% vs 24.5% for DCD; not significant [NS] and 24.2% vs 27.5% for DBD, p < 0.001; Supplementary Table S1, available online).
Transplant process characteristics Statistical Analysis Distribution of continuous variables was summarized as median (interquartile range [IQR] values) by donor type (DCD vs DBD) and study period (first half: 2003-2009 vs. second half: 2010-June 2016). Wilcoxon rank sum test was used to compare distribution of continuous variables and chi-square or Fisher exact test for categorical variables presented as percentages. For survival analysis, DCDIII only and DBD transplants between January 2003 and June 2016 were included. Kaplan-Meier survival rates were compared between DCD-III and DBD transplants using the log-rank test. A multivariable Cox regression analysis was performed to identify risk factors associated with patient mortality within 5 years of DBD and Maastricht category III DCD transplants between January 2003 and June 2016. Categorical risk factors included recipient gender and diagnosis; donor type, gender, and mechanism of death; procedure type; and transplant era. Continuous risk factors included recipient age, donor age, and lung allograft ischemic time.
Results Donor characteristics During the study period, 11,516 LTx were performed by 22 institutions, including 1,167 (10.1%) from DCDs and the remaining from DBDs. A total of 1,090 DCD donor records (9.5%) were submitted in the DCD Registry indicating a submission rate of 93.4%. The total number of lung transplants by the individual participating centers are listed in Table 1. The proportion of DCD to total lung transplants in the 22 institutions gradually increased during the study period from 0.6% (3 of 530) in 2003 to 13.5% (146 of 1,081) in 2016 (Figure 1). Among the DCD transplants, 94.1% were from Maastricht category III, 3.9% category IV, and 1.3% category V controlled donors and 0.6% category II and 0.1% category I uncontrolled donors (Table 2). Practices related to DCD process before WLST were use of heparin (53%), corticosteroids (58%), and fibrinolytics (0.2%); and extubation (91%), presence of nasogastric tube (62%), and use of EVLP (15%) after graft retrieval. The use of EVLP for DCD-LTx has nearly doubled between 2009 and 2017 (Table 3). dPM Tage edian donor age among DCD-III transplants was 46 years (IQR: 34-55) compared with 40 (IQR: 24-52) in DBD (p < 0.0001). DCD-III male gender percentage was 57%.
The distribution of the pre-defined time intervals in the DCD process is shown in Figure 2. Among DCD-III transplants performed between 2003 and June 2016, no significant differences were noticed in survival within 12 months for different lengths (<10minutes vs. 10-20minutes vs > 20minutes) for interval 1 (p = 0.14) and interval 2 (p = 0.51). Similarly, no differences in survival were observed for total duration (<30minutes vs 30-45minutes vs > 45minutes) of interval 3 (p = 0.30). More bilateral and double lung transplants were performed in DCD-III compared with DBD (88.3% vs 76.6%, respectively, p < 0.0001; Table 4). Compared with the first half, DBD recipients in the second half of the study period had more double lung transplants (88.7% vs 83.6% for DCD; NS and 78.9% vs 73.0% for DBD, p < 0.001; Supplementary Table S1, available online). On average, ischemic times for DCD lung transplants were longer than DBD (6.0 hours (IQR: 5.0-7.4) vs 5.1 hours (IQR: 4.1-6.2 hours), p < 0.0001). Compared with the first half, DBD recipients in the second half of the study period had longer ischemic times (6.0 hours (IQR: 5.0-7.6) vs 6.0 hours (IQR: 4.6-7.4) for DCD; NS and 5.2 hours (IQR 4.2-6.4) vs 5.0 hours (IQR 4.1-6.0) for DBD, p < 0.001; Supplementary Table S1, available online).
Recipient characteristics The distribution of recipient age and transplant indication in the DCD and DBD groups are demonstrated in Figure 3. There was no significant difference in the age distribution (Figure 3a). Compared with the first half, recipients in the second half of the study period were older (55 years [IQR: 41-61] vs 53 years [IQR: 37-59] for DCD, p < 0.05; and 57 years [IQR: 46-63] vs 54 years [IQR: 39-60] for DBD, p < 0.001; Supplementary Table S1, available online). Diagnosis distribution was different between both study groups, with more emphysema and more cystic fibrosis recipients and fewer pulmonary fibrosis recipients in the DCD group (Figure 3b). Compared with the first half, recipients in the second half of the study period had more often pulmonary fibrosis as transplant diagnosis (19.1% vs 14.2% for DCD, p = 0.05; and 30.0% vs 21.4% for DBD, p < 0.001; Supplementary Table S1, available online).
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Table 1 Lung Transplant Centers Participating in the ISHLT DCD Registry with Transplants Performed between January 1, 2003 and June 30, 2017
Country
Transplant center
Australia
St Vincent’s Hospital The Prince Charles Hospital The Alfred Hospital Fiona Stanley Hospital University Hospital Gasthuisberg Leuven The Toronto General Hospital Universitair Medisch Centrum Groningen University Hospital Zurich St Joseph’s Hosp & Medical Center Loyola University Medical Center and Hines VA Hospital Brigham and Women’s Hospital University of Minnesota Medical Center, Fairview Barnes-Jewish Hospital/ Washington University The Presbyterian Hospital in New York City/Columbia Presbyterian Medical Center The Cleveland Clinic Foundation Baylor University Medical Center Great Ormond Street Hospital for Children The Freeman Hospital Harefield Hosp Wythenshawe Hospital Queen Elizabeth Hospital Papworth Hospital
Belgium Canada Netherlands Switzerland USA
United Kingdom
All
DCD transplants performed
Number of transplants with DCD donor data submitted
Percent of transplants with DCD donor data submitted
79 33
79 26
100.0 78.8
148 13 116
148 7 116
100.0 53.8 100.0
160
160
100.0
111
111
100.0
21 18
21 17
100.0 94.4
10
10
100.0
11
10
90.9
30
30
100.0
15
15
100.0
56
53
94.6
88
39
44.3
12
10
83.3
5
5
100.0
71 88 28 14 40 1,167
67 86 27 13 40 1,090
94.4 97.7 96.4 92.9 100.0 93.4
Abbreviations: DCD, donation after circulatory death; ISHLT, International Society for Heart and Lung Transplantation; VA, Veterans Affairs.
Post-transplant outcomes Thirty-day survival was 96% in the DCD group and 97% in the DBD group (p = 0.30), while 1- year survival was 89% in the DCD group and 88% in the DBD group (p = 0.44; Figure 4a). Five-year survival was 63% in the DCD-III group and 61% in the DBD group (p = 0.72; Figure 4b). In the DCD group, donor age did not influence recipient post-transplant survival within 1 year (p = 0.93; Figure 5a). The mechanism of brain injury within the DCD group also did not influence survival rates through 1 year (p = 0.82; Figure 5b). Bilateral and double lung transplantation, compared with single lung transplantation, resulted in significantly higher
5-year survival after DBD (p < 0.001; Figure 6a). In DCD, the survival of the bilateral and double lung transplantation at 5 years was numerically higher than single lung transplantation, but this difference did not reach statistical significance (p = 0.13; Figure 6b).
Risk factors for 5-year mortality The results of Cox multivariable model of 5-year posttransplant mortality with corresponding hazard ratios (HR) are shown in Figure 7 and Supplementary Table S2 (available online). On multivariable analysis, transplant diagnosis (bronchiectasis versus pulmonary fibrosis; HR: 1.48
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Figure 1 Annual number of DBD and DCD lung transplants at participating hospitals between January 1, 2003 and June 30, 2016. DBD, donors after brain death; DCD, donation after circulatory.
[1.21,1.80]; and other indications vs pulmonary fibrosis: HR 1.22 [1.09,1.37]), procedure type ([single lung versus bilateral and double lung]: HR 1.21 [1.11,1.32]), and transplant era (2003-2009 vs. 2010-June 2016: HR 1.18 [1.10,1.27]) were all independently associated with survival (p < 0.001). More importantly, donor type (DCD-III vs DBD) was not (HR 1.04 [0.90,1.19]; p = 0.61). Continuous risk factors for patient mortality within 5 years were recipient age (p < 0.001) and donor age (p < 0.001), but not allograft ischemic time (p = 0.236).
Discussion This report of the ISHLT DCD Registry presents intermediate-term results of DCD LTx. The total number of DCD cases reported to the Registry have more than tripled since its first publication in 2015.6 Six active lung transplant centers in the United Kingdom joined the Registry in 2018 transferring all their data on DCD lung transplants with the help of the United Kingdom National Health Service Blood and Transplant organization. The present multicenter, international study, thereby, is the largest report to date evaluating the survival of recipients receiving LTx from (controlled) DCD donors. Excellent post-transplant recipient outcome was demonstrated with this type of donor in 22 experienced and high-volume centers across North America, Europe, and Australia with 30-day, 1-year, and 5-year survival rates similar to those seen in DBD lung recipients. These data should reassure other centers to initiate DCD LTx as a safe donor source to expand their donor lung pool. DCD practice is still largely underutilized, even in some developed countries.7,11-14 Moreover, the conversion rate from potential to actual DCD donors varies widely between countries and may well be related to donor management and comfort therapy given at the time of WLST to limit the agonal phase.15 There is wide variability in practice, even between countries with high DCD rates.16
Maastricht category III comprised 94.1% of the DCD cohort in the ISHLT Registry. Very few LTx were reported from uncontrolled (Maastricht category I and II) DCDs. Despite the enthusiasm that uncontrolled donors are a potential valuable organ source,17,18 the conversion rate for LTx is reported to be frustratingly low.19 Current DCD-I and II practice remains anecdotal with only small series,20,21 and a few successful cases22,23 reported to date. After all, the lung allograft is exposed to a longer no-flow, warm ischemia phase and is, therefore, more at risk to develop PGD after LTx.20 In a more in-depth analysis of ISHLT DCD Registry data, Levvey et al24 studied the different time points and intervals during the DCD process that the investigators at the inception of data collection hypothesized may influence organ quality and thus recipient outcomes.24 Out of 465 cases, 84.5% of the DCD donors after WLST reached asystole in ≤30 minutes, 96.5% in ≤60 minutes with only 3.5% taking >60 minutes to reach asystole. Out of 301 cases with documented data to calculate the warm ischemic time
Table 2 Number of DCD Lung Transplants at Participating Hospitals by Category between January 1, 2003 and June 30, 2017 Maastricht category (I) Dead on arrival (uncontrolled) (II) Unsuccessful resuscitation (uncontrolled) (III) Awaiting cardiac arrest (controlled) (IV) Cardiac arrest in a brain dead donor (controlled) (V) Euthanasia (controlled) All
N
% 1 6
0.1 0.6
1,026 43
94.1 3.9
14 1,090
1.3 100.0
Abbreviations: DCD, donation after circulatory death Adapted from Kootstra et al9 and Detry et al.10
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The Journal of Heart and Lung Transplantation, Vol 38, No 12, December 2019 EVLP Use Reported by Transplant Year in DCD Lung Transplants at Participating Hospitals, January 1, 2003 and June 30, 2017 EVLP No
Transplant year 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 All
Yes
All
N
%
N
%
N
%
1 5 8 25 40 53 47 74 66 73 76 97 103 42 710
100.00 100.00 100.00 100.00 97.56 88.33 88.68 90.24 92.96 87.95 82.61 71.32 83.06 80.77 85.23
0 0 0 0 1 7 6 8 5 10 16 39 21 10 123
0 0 0 0 2.44 11.67 11.32 9.76 7.04 12.05 17.39 28.68 16.94 19.23 14.77
1 5 8 25 41 60 53 82 71 83 92 136 124 52 833
100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00
Abbreviations: DCD, donation after circulatory death; EVLP, ex vivo lung perfusion.
(WIT) interval, 90% of the DCD lungs suffered a WIT ≤30 minutes and 99% ≤75 minutes from WLST to cold pulmonary flush. No negative influence on 30-day and 1-year survival could be demonstrated when length of donor agonal and warm ischemic times were analyzed by 30-minute intervals and tertiles.24 In a multivariable model, donor agonal time and WIT were not associated with 1-year recipient mortality. Also in the present report with more significant numbers, we did not observe a difference in recipient survival with these pre-defined time intervals during the DCD process, confirming that even longer intervals (>30-60 minutes) from WLST to cold pulmonary flush can result in
favorable post-transplant outcomes. If adopted widely, this may further expand the current DCD donor pool. Additional findings of interest were observed in this study. First, we report that the majority of donors (91%) were extubated before WLST. Secondly, only half of the donors were pre-treated with heparin following countryspecific legislation. Thus, absence of anticoagulation does not seem to impact outcomes adversely. Thirdly, only 15% of DCD allografts underwent pre-transplant assessment by normothermic EVLP; the majority of such cases were done at one institution. This low percentage likely reflects the perception of each participating center of the real need or
Figure 2 The distribution of time intervals in the DCD process among DCD lung transplants between January 1, 2003 and June 30, 2017. Interval 1 = time from WLST to start of agonal phase (determined by systolic blood pressure < 50 mm Hg). Interval 2 = time from WLST to the cessation of cardiac output and asystole. Interval 3 = time from WLST to start cold flush perfusion. Horizontal line = median; vertical bars = 5th to 95th percentile. DBD, donors after brain death; DCD, donation after circulatory; WLST, withdrawal of life-sustaining therapy.
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Table 4 Distribution of Procedure Type for DBD and Maastricht category III DCD Lung Transplants Performed at Participating Hospitals between January 1, 2003 and June 30, 2017 Donor type DBD
Procedure type Bilateral or double lung Single lung All
DCD (category III)
Total
N
%
N
%
N
%
7,979 2,435 10,414
76.62 23.38 100.00
905 120 1,025
88.29 11.71 100.00
8,884 2,555 11,439
77.66 22.34 100.00
Abbreviations: DBD, donors after brain death; DCD, donation after circulatory.
benefit of EVLP in assessing lungs from DCD-III. The data provided here demonstrates the safety of standard-criteria controlled DCD LTx without EVLP. The exact role of EVLP for controlled DCD LTx could not be analyzed from this study and therefore remains unclear. Nevertheless, a form of in situ evaluation with normothermic regional perfusion25 or ex-situ assessment with machine perfusion before acceptance provides better safety margin when using donor lungs from uncontrolled DCDs26 and extended-criteria DCD-III lungs27,28 including the ones with long time from WLST to arrest, although successful
transplants have been reported without post-mortem EVLP evaluation.21 Survival analyses in DCD-III lung transplants showed some interesting findings. Firstly, no difference in 1- year survival was observed when stratified by donor age. Also, the mechanism of brain injury in the potential DCD-III, in contrast to the initial findings in the first report,6 no longer influenced recipient outcomes. Not surprisingly and following previous ISHLT annual reports,29 5-year survival in DBD recipients was significantly better after bilateral and double compared with single LTx. For DCD-III recipients,
Figure 3 Distribution of recipient age (a) and diagnosis (b) for DBD and Maastricht category III DCD lung transplants performed at participating hospitals between January 1, 2003 and June 30, 2017. CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; DBD, donors after brain death; DCD, donation after circulatory; PAH, pulmonary arterial hypertension.
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Figure 4 (a) One-year and (b) 5-year post-transplant survival in the DCD vs DBD groups. Transplants performed between January 2003 and June 2016 are used for survival calculations, and only Maastricht category III was included in the DCD group. DBD, donors after brain death; DCD, donation after circulatory.
this difference in 5-year survival did not reach statistical significance presumably as a result of lower number of cases in this group. In a multivariable model, transplant indication, procedure type, and transplant era were significant risk factors for mortality within 5 years for DBD and DCD-III lung recipients. In addition, recipient age, donor age, but not total lung allograft ischemic time were continuous risk factors for mortality within 5 years. These findings are also consistent with previously published ISHLT annual reports.29 Despite increased risk factors (older donor and recipient ages, more pulmonary
fibrosis, longer ischemic times) in the second half of the study period, the risk for 5-year mortality was lower (Figure 7), which may have been influenced by the higher number of double lung transplants in the second half of the study. Variables in the DCD process such as EVLP use were not included in the model, so no conclusions on the possible value of pretransplant EVLP can be drawn from this study. In addition, the impact of possible differences in DCD practice between continents was not analyzed. Although this cohort is the largest to date, our study has limitations. First, the centers reporting data to the ISHLT
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Figure 5 One-year survival for DCD transplants by (a) donor age and (b) mechanism of donor brain injury. Transplants performed between January 1, 2003 and June 30, 2016 are used for survival calculations, and only Maastricht category III was included in the DCD group. DBD, donors after brain death; DCD, donation after circulatory.
Figure 6 Survival within 5 years for (a) DBD and (b) DCD transplants by procedure type. Transplants performed between January 1, 2003 and June 30, 2016 are used for survival calculations, and only Maastricht category III was included in the DCD group. DBD, donors after brain death; DCD, donation after circulatory.
DCD Registry are highly committed to DCD LTx and have well-established DCD protocols, trained personnel, and overall outstanding outcomes. Thus, these excellent results may not be immediately generalizable if DCD LTx was expanded to less experienced centers. Secondly, some critical data that could reflect donor lung quality and be related to recipient outcomes may not be captured in the DCD Registry. For example, data on PGD in the first 72 hours after transplantation, length of mechanical ventilation, and chronic lung allograft dysfunction rates were not available for all participating institutions in the current registry. Thirdly, we acknowledge the limitation of not having sufficient data from DCD-I and DCD-II donors. As such, our DCD analyses were limited to the most widely used DCD-III donors. Finally, significant differences in donor and recipient characteristics may have played a role in the findings. DCD donors were older, and DCD lung recipients had more bilateral and double LTx and more often had a diagnosis of chronic obstructive pulmonary disease and emphysema. We had no control over the selection process of individual patients for DCD lung transplantation in the 22
participating institutions as this was a retrospective observational study. Some differences in acceptance of DCD vs DBD lungs as it relates to the recipient selection may therefore exist. The outcome may well have been influenced by a selection bias with less sick recipients receiving DCD lungs. However, participating centers in individual countries had to follow the allocation rules that are mostly patient-oriented. The fact that there has been a marked increase in DCD use over the study period examined (Figure 1) would suggest that the centers included in this cohort are getting increasingly comfortable with the use of DCD lungs and using them according to the allocation algorithm in recipients with a wide range of clinical characteristics. The multivariable analysis we present intended to correct for these baseline differences. Moreover, DCD lung selection criteria and the yield of capable DCD lung donors at each center were not collected and remain unknown. In summary, LTx using controlled DCD donation yielded excellent short and intermediate-term outcomes in 22 experienced centers with survival comparable to results achieved using DBD donors. The ISHLT Registry is the
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Figure 7 Risk factors for patient mortality within 5 years of transplant for DBD and Maastricht category III DCD lung transplants performed at participating hospitals between January 1, 2003 and June 30, 2016.Hazard ratios for continuous risk factors (recipient age, donor age, and ischemic time) are shown for third quartile compared with first quartile. The reference groups for categorical variables are listed after the colon (i.e., male recipient, pulmonary fibrosis diagnosis, DBD donor type, male donor, CVA and stroke mechanism of donor injury, double lung transplant, and 2010-June 2016 transplant era). COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular accident; DBD, donors after brain death; DCD, donation after circulatory death; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension;Tx, transplantation.
most extensive report on DCD LTx with an extended follow-up. We believe this report supports measures to implement and increase DCD lung donation and will promote wider use of DCD LTx, increase donor organ availability and potentially contribute to reduced waiting list mortality.
The DCD Registry has been funded by the International Society for Heart and Lung Transplantation, Dallas, TX. Paper was presented at the 2019 Annual Meeting and Scientific Sessions of the International Society for Heart and Lung Transplantation, Orlando, FL, April 3-6, 2019.
Disclosure statement
Supplementary data
S.K. and M.C. are founders and shareholders of XOR Labs Toronto and Perfusix Canada and are consultants for Lung Bioengineering, Inc, Silverspring, MD. D.V.R and M.I.H. are members of the OCS Lung advisory board of Transmedics, Andover, MA. D.F.D received clinical trial research support from Lung Bioengineering, Inc, Silverspring, MD. D.K. has a pending patent entitled “Compositions and methods for detecting CCR2 receptors.” None of the other authors have conflicts of interest to disclose. The authors would like to thank Aparna Sadavarte, MS from the United Network for Organ Sharing in Richmond, VA for preparing the analysis datasets for this manuscript. The authors acknowledge the contribution of all data coordinators at the 22 participating institutions. The authors are grateful to Sally Rushton for her tremendous help in transferring data from the National Health Service Blood and Transplant in the United Kingdom into the United Network for Organ Sharing database.
Supplementary data associated with this article can be found in the online version at www.jhltonline.org/.
Supplementary materials Supplementary material associated with this article can be found in the online version at https://doi.org/10.1016/j.hea lun.2019.09.007.
References 1. Love RB, Stringham JC, Chomiak PN, et al. Successful lung transplantation using a non-heart-beating donor. J Heart Lung Transplant 1995;14:S88. 2. Ceulemans LJ, Inci I, Van Raemdonck D. Lung donation after circulatory death. Curr Opin Organ Transplant 2019;24:288-96. 3. Puri V, Scavuzzo M, Guthrie T, et al. Lung transplantation and donation after cardiac death: a single center experience. Ann Thorac Surg 2009;88:1609-14; discussion 14-5.
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ISHLT DCD Lung Transplant Registry Final Report
4. Sabashnikov A, Patil NP, Popov AF, et al. Long-term results after lung transplantation using organs from circulatory death donors: a propensity score-matched analysisy. Eur J Cardiothorac Surg 2016;49:46-53. 5. Krutsinger D, Reed RM, Blevins A, et al. Lung transplantation from donation after cardiocirculatory death: a systematic review and metaanalysis. J Heart Lung Transplant 2015;34:675-84. 6. Cypel M, Levvey B, Van Raemdonck D, et al. International Society for Heart and Lung Transplantation donation after circulatory death registry report. J Heart Lung Transplant 2015;34:1278-82. 7. Villavicencio MA, Axtell AL, Spencer PJ, et al. Lung transplantation from donation after circulatory death: United States and single-center experience. Ann Thorac Surg 2018;106:1619-27. 8. Cypel M, Levvey B, Van Raemdonck D, et al. Lung transplantation using controlled donation after circulatory death donors: trials and tribulations. J Heart Lung Transplant 2016;35:146-7. 9. Kootstra G, Daemen JH, Oomen AP. Categories of non-heart-beating donors. Transplant Proc 1995;27:2893-4. 10. Detry O, Le Dinh H, Noterdaeme T, et al. Categories of donation after cardiocirculatory death. Transplant Proc 2012;44:1189-95. 11. Morrissey PE, Monaco AP. Donation after circulatory death: current practices, ongoing challenges, and potential improvements. Transplantation 2014;97:258-64. 12. Domınguez-Gil B, Haase-Kromwijk B, Van Leiden H, et al. Current situation of donation after circulatory death in European countries. Transpl Int 2011;24:676-86. 13. Mooney JJ, Hedlin H, Mohabir PK, et al. Lung quality and utilization in controlled donation after circulatory determination of death within the United States. Am J Transplant 2016;16:1207-15. 14. Rakhra SS, Opdam HI, Gladkis L, et al. Untapped potential in Australian hospitals for organ donation after circulatory death. Med J Aust 2017;207:294-301. 15. Snell GI, Levvey BJ, Levin K, Paraskeva M, Westall G. Donation after Brain Death versus Donation after Circulatory Death: lung Donor Management Issues. Semin Respir Crit Care Med 2018;39:138-47. 16. Gardiner D, Wind T, Cole B, et al. European vignettes in donation after circulatory death. Prog Transplant 2017;27:286-90. 17. Domınguez-Gil B, Duranteau J, Mateos A, et al. Uncontrolled donation after circulatory death: European practices and recommendations for the development and optimization of an effective programme. Transpl Int 2016;29:842-59.
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18. Egan TM, 3rd Requard JJ. Uncontrolled donation after circulatory determination of death donors (uDCDDs) as a source of lungs for transplant. Am J Transplant 2015;15:2031-6. 19. Egan T, Blackwell J, Birchard K, et al. Assessment of lungs for transplant recovered from uncontrolled donation after circulatory determination of death donors. Ann Am Thorac Soc 2017;14(Suppl 3):S251. 20. Valdivia D, Gomez de Antonio D, Hoyos L, Campo-Ca~naveral de la Cruz JL, Romero A, Varela de Ugarte A. Expanding the horizons: uncontrolled donors after circulatory death for lung transplantation-First comparison with brain death donors. Clin Transpl 2019;33:e13561. 21. Suberviola B, Mons R, Ballesteros MA, et al. Excellent long-term outcome with lungs obtained from uncontrolled donation after circulatory death. Am J Transplant 2019;19:1195-201. 22. Valenza F, Citerio G, Palleschi A, et al. Successful transplantation of lungs from an uncontrolled donor after circulatory death preserved in situ by alveolar recruitment maneuvers and assessed by ex vivo lung perfusion. Am J Transplant 2016;16:1312-8. 23. Suzuki Y, Tiwari JL, Lee J, et al. Should we reconsider lung transplantation through uncontrolled donation after circulatory death? Am J Transplant 2014;14:966-71. 24. Levvey B, Keshavjee S, Cypel M, et al. Influence of lung donor agonal and warm ischemic times on early mortality: analyses from the ISHLT DCD lung transplant registry. J Heart Lung Transplant 2019;38:26-34. 25. Tsui SSL, Oniscu GC. Extending normothermic regional perfusion to the thorax in donors after circulatory death. Curr Opin Organ Transplant 2017;22:245-50. 26. Moradiellos FJ, Naranjo JM, Cordoba M, et al. Clinical lung transplantation after ex vivo evaluation of uncontrolled non heart-beating donors lungs: initial experience. J Heart Lung Transplant 2011;30:S38. 27. Machuca TN, Mercier O, Collaud S, et al. Lung transplantation with donation after circulatory determination of death donors and the impact of ex vivo lung perfusion. Am J Transplant 2015;15:993-1002. 28. Bozso S, Vasanthan V, Luc JG, Kinaschuk K, Freed D, Nagendran J. Lung transplantation from donors after circulatory death using portable ex vivo lung perfusion. Can Respir J 2015;22:47-51. 29. Chambers DC, Yusen RD, Cherikh WS, et al. The Registry of the International Society for Heart and Lung Transplantation. The Registry of the International Society for Heart and Lung Transplantation: thirty-fourth Adult Lung and Heart-Lung Transplantation Report-2017; Focus Theme: allograft ischemic time. J Heart Lung Transplant 2017;36:1047-59.
ISHLT REGISTRY ANALYSIS
Donation after circulatory death in lung transplantation—five-year follow-up from ISHLT Registry Dirk Van Raemdonck, MD, PhD,a Shaf Keshavjee, MD, MSc,b Bronwyn Levvey, RN,c Wida S. Cherikh, RN,d Greg Snell, MD,c Michiel Erasmus, MD,e Andre Simon, MD,f Allan R. Glanville, MD,g Stephen Clark, MD,h Frank D’Ovidio, MD,i Pedro Catarino, MD,j Kenneth McCurry, MD,k Marshall I. Hertz, MD,l Rajamiyer Venkateswaran, MD,m Peter Hopkins, MD,n Ilhan Inci, MD,o Rajat Walia, MD,p Daniel Kreisel, MD, PhD,q Jorge Mascaro, MD,r Daniel F. Dilling, MD,s Philip Camp, MD,t David Mason, MD,u Michael Musk, MD,v Michael Burch, MD,w Andrew Fisher, MD,h Roger D. Yusen, MD,q Josef Stehlik, MD,x and Marcelo Cypel, MDb, for the International Society for Heart and Lung Transplantation From the aUniversity Hospitals Leuven, Leuven, Belgium; bUniversity of Toronto, Toronto, Ontario, Canada; cAlfred Hospital, Melbourne, Victoria, Australia; dUnited Network for Organ Sharing, Richmond, Virginia; eUniversity Medical Center Groningen, Groningen, The Netherlands; fHarefield Hospital, London, United Kingdom; gSt Vincent’s Hospital, Sydney, New South Wales, Australia; hFreeman Hospital, Newcastle upon Tyne, United Kingdom; iColumbia University Presbyterian Hospital, New York, New York; jRoyal Papworth Hospital, Cambridge, United Kingdom; kCleveland Clinic, Cleveland, Ohio; lUniversity of Minnesota, Minneapolis, Minnesota; mWythenshawe Hospital, Manchester, United Kingdom; nThe Prince Charles Hospital, Brisbane, Australia; oUniversity Hospital Zurich, Zurich, Switzerland; pSt. Joseph’s Hospital & Medical Center, Phoenix, Arizona; qWashington University, St Louis, Missouri; rUniversity Hospitals Birmingham, Birmingham, United Kingdom; sLoyola University Medical Center, Chicago, Illinois; tBrigham and Womens Hospital, Boston, Massachusetts; uBaylor University Medical Center, Dallas, Texas; vFiona Stanley Hospital, Perth, Australia; w Great Ormond Street for Children, London, United Kingdom; and the xUniversity of Utah, Salt Lake City, Utah.
KEYWORDS: lung transplantation; donors after circulatory death; donor lung allograft; survival; mortality risk factors
BACKGROUND: This study aimed to examine intermediate-term outcomes of lung transplantation (LTx) recipients from donors after circulatory death (DCD). METHODS: We examined the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Transplant Registry data for patients transplanted between January 2003 and June 2017 at 22 centers in North America, Europe, and Australia participating in the DCD Registry. The distribution of continuous variables was summarized as median and interquartile range (IQR) values. Wilcoxon rank sum test was used to compare distribution of continuous variables and chi-square or Fisher’s exact test for categorical variables. Kaplan-Meier survival rates after LTx from January 2003 to June 2016 were compared between DCD-III (Maastricht category III withdrawal of life-sustaining therapy [WLST])
Reprint requests: Dirk Van Raemdonck, MD, PhD, Department of Thoracic Surgery, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium. Telephone: +32 16-346823. Fax: +32 16-346824. E-mail address: [email protected] 1053-2498/$ - see front matter Ó 2019 International Society for Heart and Lung Transplantation. All rights reserved. https://doi.org/10.1016/j.healun.2019.09.007
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The Journal of Heart and Lung Transplantation, Vol 38, No 12, December 2019 only and donors after brain death (DBD) using the log-rank test. Risk factors for 5-year mortality were investigated using Cox multivariate proportional-hazards model. RESULTS: The study cohort included 11,516 lung transplants, of which 1,090 (9.5%) were DCD lung transplants with complete data. DCD-III comprised 94.1% of the DCD cohort. Among the participating centers, the proportion of DCD-LTx performed each year increased from 0.6% in 2003 to 13.5% in 2016. DCD donor management included extubation in 91%, intravenous heparin in 53% and pre-transplant normothermic ex vivo donor lung perfusion in 15%. The median time interval from WLST to cardiac arrest was 15 minutes (IQR: 11-22 minutes) and to cold flush 32 minutes (IQR: 26-41minutes). Compared with DBD, donor age was higher in DCD-III donors (46 years [IQR: 34-55] vs 40 years [IQR: 24-52]), bilateral LTx was performed more often (88.3% vs 76.6%), and more recipients had chronic obstructive pulmonary disease and emphysema as their transplant indication. Five-year survival rates were comparable (63% vs 61%, p = 0.72). In multivariable analysis, recipient and donor ages, indication diagnosis, procedure type (single vs bilateral and double LTx), and transplant era (2003-2009 vs 2010-2016) were independently associated with survival (p < 0.001), but donor type was not (DCD-III vs DBD; hazard ratio, 1.04 [0.90-1.19], p = 0.61). CONCLUSION: This ISHLT DCD Registry report with 5-year follow-up demonstrated similar favorable long-term survival in DCD-III and DBD lung donor recipients at 22 experienced centers globally. These data indicate that more extensive use of DCD-LTx would increase donor organ availability and may reduce waiting list mortality. J Heart Lung Transplant 2019;38:1235−1245 Ó 2019 International Society for Heart and Lung Transplantation. All rights reserved.
The first successful use of donors after circulatory death (DCD) for lung transplantation (LTx) was reported in 1995 by Love et al1 from University of Wisconsin. It was another decade before the practice became more widespread in other LTx programs around the world. Several series from individual institutions and national organizations have reported comparable early- and medium-term recipient outcomes after LTx from controlled DCDs vs standard donors after brain death (DBD).2 Only a few reports have demonstrated worse outcomes for primary graft dysfunction (PGD)3 and bronchiolitis obliterans syndrome.4 A systematic review and recent meta-analysis of 11 observational cohort studies could not demonstrate any difference in 1year mortality, PGD, and acute rejection after LTx from DCD vs DBD.5 In 2011, a working group within the International Society for Heart and Lung Transplantation (ISHLT) initiated a DCD Registry with the help of the United Network for Organ Sharing. Programs contributing to the ISHLT Thoracic Transplant Registry with documented DCD LTx cases were invited to enroll and contribute data on preset DCD variables to the ISHLT database. A first DCD Registry report was published by Cypel et al6 in 2015 comparing early outcomes in 306 DCD vs 3,992 DBD transplants performed at 10 centers in North America, Europe, and Australia between January 2003 and June 2013. One-year survival after LTx did not differ between groups (89% vs 88%, respectively). Despite a significant growth in DCD multiorgan donation in many countries and the promising results previously reported, the percentage of LTx using DCDs remains substantially low in many centers with many donor lungs not being used.7 Concerns about the warm ischemic injury, lack of established protocols, uncertainty regarding the potential and actual donor conversion rate, and public scrutiny may be some factors involved.8
Following the decision in 2017 by the ISHLT Board Of Directors to incorporate relevant DCD variables into the main ISHLT Thoracic Transplant Registry for future transplants, data collection into the stand-alone ISHLT DCD Registry was concluded with transplants performed through June 30, 2017. This study aimed to provide a final report of the DCD Registry, examine the DCD transplant process, the donor and recipient characteristics, and to compare 5-year survival in LTx recipients from DCDs to those with DBDs.
Methods Study design This study was a retrospective DCD Registry cohort of all lung transplants performed between January 2003 and June 2017 by 22 participating institutions from North America including US (8) and Canada (1), Europe (9), and Australia. (4) The analysis included DCD data reported to the ISHLT DCD Registry through August 30, 2018. The control group was identified within the main ISHLT Transplant Registry as a cohort of lung recipients transplanted using DBDs during the same study period within the centers described above. Patients bridged to transplant with extracorporeal life support therapy and retransplantations were excluded.
Definitions DCD donors were classified into 5 categories. DCD-I to IV were defined according to the Maastricht classification reported by Kootstra et al in 1995.9 DCD-V was defined as donors after euthanasia as practiced in countries with existing legislation.10 Important time points of the DCD process and time intervals were captured as defined in the previous report.6 Three-time intervals (T1: from the withdrawal of life-sustaining therapy (WLST) till hypotension with systolic blood pressure <50 mm Hg; T2:
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from WLST till cessation of cardiac output; T3: from WLST till start of pulmonary flush) were then calculated and survival stratification was performed based on the length of these intervals.
Variables Several categorical variables were collected in order to establish current DCD practices. Donor characteristics included age, gender, mechanism of brain injury, and Maastricht category; use of heparin; use of steroids; use of fibrinolytics; extubation during WLST; use of nasogastric tube; use of bronchoscopy; and ex vivo lung perfusion (EVLP) for assessment. Recipient characteristics included age, medical diagnosis, and procedure type (single vs. bilateral and double). The primary endpoint was 5-year survival after lung transplantation.
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Compared with the first half, donors in the second half of the study period were older (47 years [IQR 35-56] vs 42 years [IQR 27-51] for DCD, p < 0.0001; and 42 years [IQR 26-53] vs 38 years [IQR 22-50] for DBD, p < 0.001; Supplementary Table S1 available online at www.jhltonline.org). The cause of fatal brain injury leading to DCD was anoxia (29%), cerebrovascular and stroke (42%), and head trauma (17%). Compared with the first half, donors of DBD recipients in the second half of the study period suffered less head trauma as cause of donor brain injury (16.5% vs 24.5% for DCD; not significant [NS] and 24.2% vs 27.5% for DBD, p < 0.001; Supplementary Table S1, available online).
Transplant process characteristics Statistical Analysis Distribution of continuous variables was summarized as median (interquartile range [IQR] values) by donor type (DCD vs DBD) and study period (first half: 2003-2009 vs. second half: 2010-June 2016). Wilcoxon rank sum test was used to compare distribution of continuous variables and chi-square or Fisher exact test for categorical variables presented as percentages. For survival analysis, DCDIII only and DBD transplants between January 2003 and June 2016 were included. Kaplan-Meier survival rates were compared between DCD-III and DBD transplants using the log-rank test. A multivariable Cox regression analysis was performed to identify risk factors associated with patient mortality within 5 years of DBD and Maastricht category III DCD transplants between January 2003 and June 2016. Categorical risk factors included recipient gender and diagnosis; donor type, gender, and mechanism of death; procedure type; and transplant era. Continuous risk factors included recipient age, donor age, and lung allograft ischemic time.
Results Donor characteristics During the study period, 11,516 LTx were performed by 22 institutions, including 1,167 (10.1%) from DCDs and the remaining from DBDs. A total of 1,090 DCD donor records (9.5%) were submitted in the DCD Registry indicating a submission rate of 93.4%. The total number of lung transplants by the individual participating centers are listed in Table 1. The proportion of DCD to total lung transplants in the 22 institutions gradually increased during the study period from 0.6% (3 of 530) in 2003 to 13.5% (146 of 1,081) in 2016 (Figure 1). Among the DCD transplants, 94.1% were from Maastricht category III, 3.9% category IV, and 1.3% category V controlled donors and 0.6% category II and 0.1% category I uncontrolled donors (Table 2). Practices related to DCD process before WLST were use of heparin (53%), corticosteroids (58%), and fibrinolytics (0.2%); and extubation (91%), presence of nasogastric tube (62%), and use of EVLP (15%) after graft retrieval. The use of EVLP for DCD-LTx has nearly doubled between 2009 and 2017 (Table 3). dPM Tage edian donor age among DCD-III transplants was 46 years (IQR: 34-55) compared with 40 (IQR: 24-52) in DBD (p < 0.0001). DCD-III male gender percentage was 57%.
The distribution of the pre-defined time intervals in the DCD process is shown in Figure 2. Among DCD-III transplants performed between 2003 and June 2016, no significant differences were noticed in survival within 12 months for different lengths (<10minutes vs. 10-20minutes vs > 20minutes) for interval 1 (p = 0.14) and interval 2 (p = 0.51). Similarly, no differences in survival were observed for total duration (<30minutes vs 30-45minutes vs > 45minutes) of interval 3 (p = 0.30). More bilateral and double lung transplants were performed in DCD-III compared with DBD (88.3% vs 76.6%, respectively, p < 0.0001; Table 4). Compared with the first half, DBD recipients in the second half of the study period had more double lung transplants (88.7% vs 83.6% for DCD; NS and 78.9% vs 73.0% for DBD, p < 0.001; Supplementary Table S1, available online). On average, ischemic times for DCD lung transplants were longer than DBD (6.0 hours (IQR: 5.0-7.4) vs 5.1 hours (IQR: 4.1-6.2 hours), p < 0.0001). Compared with the first half, DBD recipients in the second half of the study period had longer ischemic times (6.0 hours (IQR: 5.0-7.6) vs 6.0 hours (IQR: 4.6-7.4) for DCD; NS and 5.2 hours (IQR 4.2-6.4) vs 5.0 hours (IQR 4.1-6.0) for DBD, p < 0.001; Supplementary Table S1, available online).
Recipient characteristics The distribution of recipient age and transplant indication in the DCD and DBD groups are demonstrated in Figure 3. There was no significant difference in the age distribution (Figure 3a). Compared with the first half, recipients in the second half of the study period were older (55 years [IQR: 41-61] vs 53 years [IQR: 37-59] for DCD, p < 0.05; and 57 years [IQR: 46-63] vs 54 years [IQR: 39-60] for DBD, p < 0.001; Supplementary Table S1, available online). Diagnosis distribution was different between both study groups, with more emphysema and more cystic fibrosis recipients and fewer pulmonary fibrosis recipients in the DCD group (Figure 3b). Compared with the first half, recipients in the second half of the study period had more often pulmonary fibrosis as transplant diagnosis (19.1% vs 14.2% for DCD, p = 0.05; and 30.0% vs 21.4% for DBD, p < 0.001; Supplementary Table S1, available online).
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Table 1 Lung Transplant Centers Participating in the ISHLT DCD Registry with Transplants Performed between January 1, 2003 and June 30, 2017
Country
Transplant center
Australia
St Vincent’s Hospital The Prince Charles Hospital The Alfred Hospital Fiona Stanley Hospital University Hospital Gasthuisberg Leuven The Toronto General Hospital Universitair Medisch Centrum Groningen University Hospital Zurich St Joseph’s Hosp & Medical Center Loyola University Medical Center and Hines VA Hospital Brigham and Women’s Hospital University of Minnesota Medical Center, Fairview Barnes-Jewish Hospital/ Washington University The Presbyterian Hospital in New York City/Columbia Presbyterian Medical Center The Cleveland Clinic Foundation Baylor University Medical Center Great Ormond Street Hospital for Children The Freeman Hospital Harefield Hosp Wythenshawe Hospital Queen Elizabeth Hospital Papworth Hospital
Belgium Canada Netherlands Switzerland USA
United Kingdom
All
DCD transplants performed
Number of transplants with DCD donor data submitted
Percent of transplants with DCD donor data submitted
79 33
79 26
100.0 78.8
148 13 116
148 7 116
100.0 53.8 100.0
160
160
100.0
111
111
100.0
21 18
21 17
100.0 94.4
10
10
100.0
11
10
90.9
30
30
100.0
15
15
100.0
56
53
94.6
88
39
44.3
12
10
83.3
5
5
100.0
71 88 28 14 40 1,167
67 86 27 13 40 1,090
94.4 97.7 96.4 92.9 100.0 93.4
Abbreviations: DCD, donation after circulatory death; ISHLT, International Society for Heart and Lung Transplantation; VA, Veterans Affairs.
Post-transplant outcomes Thirty-day survival was 96% in the DCD group and 97% in the DBD group (p = 0.30), while 1- year survival was 89% in the DCD group and 88% in the DBD group (p = 0.44; Figure 4a). Five-year survival was 63% in the DCD-III group and 61% in the DBD group (p = 0.72; Figure 4b). In the DCD group, donor age did not influence recipient post-transplant survival within 1 year (p = 0.93; Figure 5a). The mechanism of brain injury within the DCD group also did not influence survival rates through 1 year (p = 0.82; Figure 5b). Bilateral and double lung transplantation, compared with single lung transplantation, resulted in significantly higher
5-year survival after DBD (p < 0.001; Figure 6a). In DCD, the survival of the bilateral and double lung transplantation at 5 years was numerically higher than single lung transplantation, but this difference did not reach statistical significance (p = 0.13; Figure 6b).
Risk factors for 5-year mortality The results of Cox multivariable model of 5-year posttransplant mortality with corresponding hazard ratios (HR) are shown in Figure 7 and Supplementary Table S2 (available online). On multivariable analysis, transplant diagnosis (bronchiectasis versus pulmonary fibrosis; HR: 1.48
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Figure 1 Annual number of DBD and DCD lung transplants at participating hospitals between January 1, 2003 and June 30, 2016. DBD, donors after brain death; DCD, donation after circulatory.
[1.21,1.80]; and other indications vs pulmonary fibrosis: HR 1.22 [1.09,1.37]), procedure type ([single lung versus bilateral and double lung]: HR 1.21 [1.11,1.32]), and transplant era (2003-2009 vs. 2010-June 2016: HR 1.18 [1.10,1.27]) were all independently associated with survival (p < 0.001). More importantly, donor type (DCD-III vs DBD) was not (HR 1.04 [0.90,1.19]; p = 0.61). Continuous risk factors for patient mortality within 5 years were recipient age (p < 0.001) and donor age (p < 0.001), but not allograft ischemic time (p = 0.236).
Discussion This report of the ISHLT DCD Registry presents intermediate-term results of DCD LTx. The total number of DCD cases reported to the Registry have more than tripled since its first publication in 2015.6 Six active lung transplant centers in the United Kingdom joined the Registry in 2018 transferring all their data on DCD lung transplants with the help of the United Kingdom National Health Service Blood and Transplant organization. The present multicenter, international study, thereby, is the largest report to date evaluating the survival of recipients receiving LTx from (controlled) DCD donors. Excellent post-transplant recipient outcome was demonstrated with this type of donor in 22 experienced and high-volume centers across North America, Europe, and Australia with 30-day, 1-year, and 5-year survival rates similar to those seen in DBD lung recipients. These data should reassure other centers to initiate DCD LTx as a safe donor source to expand their donor lung pool. DCD practice is still largely underutilized, even in some developed countries.7,11-14 Moreover, the conversion rate from potential to actual DCD donors varies widely between countries and may well be related to donor management and comfort therapy given at the time of WLST to limit the agonal phase.15 There is wide variability in practice, even between countries with high DCD rates.16
Maastricht category III comprised 94.1% of the DCD cohort in the ISHLT Registry. Very few LTx were reported from uncontrolled (Maastricht category I and II) DCDs. Despite the enthusiasm that uncontrolled donors are a potential valuable organ source,17,18 the conversion rate for LTx is reported to be frustratingly low.19 Current DCD-I and II practice remains anecdotal with only small series,20,21 and a few successful cases22,23 reported to date. After all, the lung allograft is exposed to a longer no-flow, warm ischemia phase and is, therefore, more at risk to develop PGD after LTx.20 In a more in-depth analysis of ISHLT DCD Registry data, Levvey et al24 studied the different time points and intervals during the DCD process that the investigators at the inception of data collection hypothesized may influence organ quality and thus recipient outcomes.24 Out of 465 cases, 84.5% of the DCD donors after WLST reached asystole in ≤30 minutes, 96.5% in ≤60 minutes with only 3.5% taking >60 minutes to reach asystole. Out of 301 cases with documented data to calculate the warm ischemic time
Table 2 Number of DCD Lung Transplants at Participating Hospitals by Category between January 1, 2003 and June 30, 2017 Maastricht category (I) Dead on arrival (uncontrolled) (II) Unsuccessful resuscitation (uncontrolled) (III) Awaiting cardiac arrest (controlled) (IV) Cardiac arrest in a brain dead donor (controlled) (V) Euthanasia (controlled) All
N
% 1 6
0.1 0.6
1,026 43
94.1 3.9
14 1,090
1.3 100.0
Abbreviations: DCD, donation after circulatory death Adapted from Kootstra et al9 and Detry et al.10
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The Journal of Heart and Lung Transplantation, Vol 38, No 12, December 2019 EVLP Use Reported by Transplant Year in DCD Lung Transplants at Participating Hospitals, January 1, 2003 and June 30, 2017 EVLP No
Transplant year 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 All
Yes
All
N
%
N
%
N
%
1 5 8 25 40 53 47 74 66 73 76 97 103 42 710
100.00 100.00 100.00 100.00 97.56 88.33 88.68 90.24 92.96 87.95 82.61 71.32 83.06 80.77 85.23
0 0 0 0 1 7 6 8 5 10 16 39 21 10 123
0 0 0 0 2.44 11.67 11.32 9.76 7.04 12.05 17.39 28.68 16.94 19.23 14.77
1 5 8 25 41 60 53 82 71 83 92 136 124 52 833
100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00
Abbreviations: DCD, donation after circulatory death; EVLP, ex vivo lung perfusion.
(WIT) interval, 90% of the DCD lungs suffered a WIT ≤30 minutes and 99% ≤75 minutes from WLST to cold pulmonary flush. No negative influence on 30-day and 1-year survival could be demonstrated when length of donor agonal and warm ischemic times were analyzed by 30-minute intervals and tertiles.24 In a multivariable model, donor agonal time and WIT were not associated with 1-year recipient mortality. Also in the present report with more significant numbers, we did not observe a difference in recipient survival with these pre-defined time intervals during the DCD process, confirming that even longer intervals (>30-60 minutes) from WLST to cold pulmonary flush can result in
favorable post-transplant outcomes. If adopted widely, this may further expand the current DCD donor pool. Additional findings of interest were observed in this study. First, we report that the majority of donors (91%) were extubated before WLST. Secondly, only half of the donors were pre-treated with heparin following countryspecific legislation. Thus, absence of anticoagulation does not seem to impact outcomes adversely. Thirdly, only 15% of DCD allografts underwent pre-transplant assessment by normothermic EVLP; the majority of such cases were done at one institution. This low percentage likely reflects the perception of each participating center of the real need or
Figure 2 The distribution of time intervals in the DCD process among DCD lung transplants between January 1, 2003 and June 30, 2017. Interval 1 = time from WLST to start of agonal phase (determined by systolic blood pressure < 50 mm Hg). Interval 2 = time from WLST to the cessation of cardiac output and asystole. Interval 3 = time from WLST to start cold flush perfusion. Horizontal line = median; vertical bars = 5th to 95th percentile. DBD, donors after brain death; DCD, donation after circulatory; WLST, withdrawal of life-sustaining therapy.
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Table 4 Distribution of Procedure Type for DBD and Maastricht category III DCD Lung Transplants Performed at Participating Hospitals between January 1, 2003 and June 30, 2017 Donor type DBD
Procedure type Bilateral or double lung Single lung All
DCD (category III)
Total
N
%
N
%
N
%
7,979 2,435 10,414
76.62 23.38 100.00
905 120 1,025
88.29 11.71 100.00
8,884 2,555 11,439
77.66 22.34 100.00
Abbreviations: DBD, donors after brain death; DCD, donation after circulatory.
benefit of EVLP in assessing lungs from DCD-III. The data provided here demonstrates the safety of standard-criteria controlled DCD LTx without EVLP. The exact role of EVLP for controlled DCD LTx could not be analyzed from this study and therefore remains unclear. Nevertheless, a form of in situ evaluation with normothermic regional perfusion25 or ex-situ assessment with machine perfusion before acceptance provides better safety margin when using donor lungs from uncontrolled DCDs26 and extended-criteria DCD-III lungs27,28 including the ones with long time from WLST to arrest, although successful
transplants have been reported without post-mortem EVLP evaluation.21 Survival analyses in DCD-III lung transplants showed some interesting findings. Firstly, no difference in 1- year survival was observed when stratified by donor age. Also, the mechanism of brain injury in the potential DCD-III, in contrast to the initial findings in the first report,6 no longer influenced recipient outcomes. Not surprisingly and following previous ISHLT annual reports,29 5-year survival in DBD recipients was significantly better after bilateral and double compared with single LTx. For DCD-III recipients,
Figure 3 Distribution of recipient age (a) and diagnosis (b) for DBD and Maastricht category III DCD lung transplants performed at participating hospitals between January 1, 2003 and June 30, 2017. CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; DBD, donors after brain death; DCD, donation after circulatory; PAH, pulmonary arterial hypertension.
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Figure 4 (a) One-year and (b) 5-year post-transplant survival in the DCD vs DBD groups. Transplants performed between January 2003 and June 2016 are used for survival calculations, and only Maastricht category III was included in the DCD group. DBD, donors after brain death; DCD, donation after circulatory.
this difference in 5-year survival did not reach statistical significance presumably as a result of lower number of cases in this group. In a multivariable model, transplant indication, procedure type, and transplant era were significant risk factors for mortality within 5 years for DBD and DCD-III lung recipients. In addition, recipient age, donor age, but not total lung allograft ischemic time were continuous risk factors for mortality within 5 years. These findings are also consistent with previously published ISHLT annual reports.29 Despite increased risk factors (older donor and recipient ages, more pulmonary
fibrosis, longer ischemic times) in the second half of the study period, the risk for 5-year mortality was lower (Figure 7), which may have been influenced by the higher number of double lung transplants in the second half of the study. Variables in the DCD process such as EVLP use were not included in the model, so no conclusions on the possible value of pretransplant EVLP can be drawn from this study. In addition, the impact of possible differences in DCD practice between continents was not analyzed. Although this cohort is the largest to date, our study has limitations. First, the centers reporting data to the ISHLT
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Figure 5 One-year survival for DCD transplants by (a) donor age and (b) mechanism of donor brain injury. Transplants performed between January 1, 2003 and June 30, 2016 are used for survival calculations, and only Maastricht category III was included in the DCD group. DBD, donors after brain death; DCD, donation after circulatory.
Figure 6 Survival within 5 years for (a) DBD and (b) DCD transplants by procedure type. Transplants performed between January 1, 2003 and June 30, 2016 are used for survival calculations, and only Maastricht category III was included in the DCD group. DBD, donors after brain death; DCD, donation after circulatory.
DCD Registry are highly committed to DCD LTx and have well-established DCD protocols, trained personnel, and overall outstanding outcomes. Thus, these excellent results may not be immediately generalizable if DCD LTx was expanded to less experienced centers. Secondly, some critical data that could reflect donor lung quality and be related to recipient outcomes may not be captured in the DCD Registry. For example, data on PGD in the first 72 hours after transplantation, length of mechanical ventilation, and chronic lung allograft dysfunction rates were not available for all participating institutions in the current registry. Thirdly, we acknowledge the limitation of not having sufficient data from DCD-I and DCD-II donors. As such, our DCD analyses were limited to the most widely used DCD-III donors. Finally, significant differences in donor and recipient characteristics may have played a role in the findings. DCD donors were older, and DCD lung recipients had more bilateral and double LTx and more often had a diagnosis of chronic obstructive pulmonary disease and emphysema. We had no control over the selection process of individual patients for DCD lung transplantation in the 22
participating institutions as this was a retrospective observational study. Some differences in acceptance of DCD vs DBD lungs as it relates to the recipient selection may therefore exist. The outcome may well have been influenced by a selection bias with less sick recipients receiving DCD lungs. However, participating centers in individual countries had to follow the allocation rules that are mostly patient-oriented. The fact that there has been a marked increase in DCD use over the study period examined (Figure 1) would suggest that the centers included in this cohort are getting increasingly comfortable with the use of DCD lungs and using them according to the allocation algorithm in recipients with a wide range of clinical characteristics. The multivariable analysis we present intended to correct for these baseline differences. Moreover, DCD lung selection criteria and the yield of capable DCD lung donors at each center were not collected and remain unknown. In summary, LTx using controlled DCD donation yielded excellent short and intermediate-term outcomes in 22 experienced centers with survival comparable to results achieved using DBD donors. The ISHLT Registry is the
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Figure 7 Risk factors for patient mortality within 5 years of transplant for DBD and Maastricht category III DCD lung transplants performed at participating hospitals between January 1, 2003 and June 30, 2016.Hazard ratios for continuous risk factors (recipient age, donor age, and ischemic time) are shown for third quartile compared with first quartile. The reference groups for categorical variables are listed after the colon (i.e., male recipient, pulmonary fibrosis diagnosis, DBD donor type, male donor, CVA and stroke mechanism of donor injury, double lung transplant, and 2010-June 2016 transplant era). COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular accident; DBD, donors after brain death; DCD, donation after circulatory death; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension;Tx, transplantation.
most extensive report on DCD LTx with an extended follow-up. We believe this report supports measures to implement and increase DCD lung donation and will promote wider use of DCD LTx, increase donor organ availability and potentially contribute to reduced waiting list mortality.
The DCD Registry has been funded by the International Society for Heart and Lung Transplantation, Dallas, TX. Paper was presented at the 2019 Annual Meeting and Scientific Sessions of the International Society for Heart and Lung Transplantation, Orlando, FL, April 3-6, 2019.
Disclosure statement
Supplementary data
S.K. and M.C. are founders and shareholders of XOR Labs Toronto and Perfusix Canada and are consultants for Lung Bioengineering, Inc, Silverspring, MD. D.V.R and M.I.H. are members of the OCS Lung advisory board of Transmedics, Andover, MA. D.F.D received clinical trial research support from Lung Bioengineering, Inc, Silverspring, MD. D.K. has a pending patent entitled “Compositions and methods for detecting CCR2 receptors.” None of the other authors have conflicts of interest to disclose. The authors would like to thank Aparna Sadavarte, MS from the United Network for Organ Sharing in Richmond, VA for preparing the analysis datasets for this manuscript. The authors acknowledge the contribution of all data coordinators at the 22 participating institutions. The authors are grateful to Sally Rushton for her tremendous help in transferring data from the National Health Service Blood and Transplant in the United Kingdom into the United Network for Organ Sharing database.
Supplementary data associated with this article can be found in the online version at www.jhltonline.org/.
Supplementary materials Supplementary material associated with this article can be found in the online version at https://doi.org/10.1016/j.hea lun.2019.09.007.
References 1. Love RB, Stringham JC, Chomiak PN, et al. Successful lung transplantation using a non-heart-beating donor. J Heart Lung Transplant 1995;14:S88. 2. Ceulemans LJ, Inci I, Van Raemdonck D. Lung donation after circulatory death. Curr Opin Organ Transplant 2019;24:288-96. 3. Puri V, Scavuzzo M, Guthrie T, et al. Lung transplantation and donation after cardiac death: a single center experience. Ann Thorac Surg 2009;88:1609-14; discussion 14-5.
Van Raemdonck et al.
ISHLT DCD Lung Transplant Registry Final Report
4. Sabashnikov A, Patil NP, Popov AF, et al. Long-term results after lung transplantation using organs from circulatory death donors: a propensity score-matched analysisy. Eur J Cardiothorac Surg 2016;49:46-53. 5. Krutsinger D, Reed RM, Blevins A, et al. Lung transplantation from donation after cardiocirculatory death: a systematic review and metaanalysis. J Heart Lung Transplant 2015;34:675-84. 6. Cypel M, Levvey B, Van Raemdonck D, et al. International Society for Heart and Lung Transplantation donation after circulatory death registry report. J Heart Lung Transplant 2015;34:1278-82. 7. Villavicencio MA, Axtell AL, Spencer PJ, et al. Lung transplantation from donation after circulatory death: United States and single-center experience. Ann Thorac Surg 2018;106:1619-27. 8. Cypel M, Levvey B, Van Raemdonck D, et al. Lung transplantation using controlled donation after circulatory death donors: trials and tribulations. J Heart Lung Transplant 2016;35:146-7. 9. Kootstra G, Daemen JH, Oomen AP. Categories of non-heart-beating donors. Transplant Proc 1995;27:2893-4. 10. Detry O, Le Dinh H, Noterdaeme T, et al. Categories of donation after cardiocirculatory death. Transplant Proc 2012;44:1189-95. 11. Morrissey PE, Monaco AP. Donation after circulatory death: current practices, ongoing challenges, and potential improvements. Transplantation 2014;97:258-64. 12. Domınguez-Gil B, Haase-Kromwijk B, Van Leiden H, et al. Current situation of donation after circulatory death in European countries. Transpl Int 2011;24:676-86. 13. Mooney JJ, Hedlin H, Mohabir PK, et al. Lung quality and utilization in controlled donation after circulatory determination of death within the United States. Am J Transplant 2016;16:1207-15. 14. Rakhra SS, Opdam HI, Gladkis L, et al. Untapped potential in Australian hospitals for organ donation after circulatory death. Med J Aust 2017;207:294-301. 15. Snell GI, Levvey BJ, Levin K, Paraskeva M, Westall G. Donation after Brain Death versus Donation after Circulatory Death: lung Donor Management Issues. Semin Respir Crit Care Med 2018;39:138-47. 16. Gardiner D, Wind T, Cole B, et al. European vignettes in donation after circulatory death. Prog Transplant 2017;27:286-90. 17. Domınguez-Gil B, Duranteau J, Mateos A, et al. Uncontrolled donation after circulatory death: European practices and recommendations for the development and optimization of an effective programme. Transpl Int 2016;29:842-59.
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18. Egan TM, 3rd Requard JJ. Uncontrolled donation after circulatory determination of death donors (uDCDDs) as a source of lungs for transplant. Am J Transplant 2015;15:2031-6. 19. Egan T, Blackwell J, Birchard K, et al. Assessment of lungs for transplant recovered from uncontrolled donation after circulatory determination of death donors. Ann Am Thorac Soc 2017;14(Suppl 3):S251. 20. Valdivia D, Gomez de Antonio D, Hoyos L, Campo-Ca~naveral de la Cruz JL, Romero A, Varela de Ugarte A. Expanding the horizons: uncontrolled donors after circulatory death for lung transplantation-First comparison with brain death donors. Clin Transpl 2019;33:e13561. 21. Suberviola B, Mons R, Ballesteros MA, et al. Excellent long-term outcome with lungs obtained from uncontrolled donation after circulatory death. Am J Transplant 2019;19:1195-201. 22. Valenza F, Citerio G, Palleschi A, et al. Successful transplantation of lungs from an uncontrolled donor after circulatory death preserved in situ by alveolar recruitment maneuvers and assessed by ex vivo lung perfusion. Am J Transplant 2016;16:1312-8. 23. Suzuki Y, Tiwari JL, Lee J, et al. Should we reconsider lung transplantation through uncontrolled donation after circulatory death? Am J Transplant 2014;14:966-71. 24. Levvey B, Keshavjee S, Cypel M, et al. Influence of lung donor agonal and warm ischemic times on early mortality: analyses from the ISHLT DCD lung transplant registry. J Heart Lung Transplant 2019;38:26-34. 25. Tsui SSL, Oniscu GC. Extending normothermic regional perfusion to the thorax in donors after circulatory death. Curr Opin Organ Transplant 2017;22:245-50. 26. Moradiellos FJ, Naranjo JM, Cordoba M, et al. Clinical lung transplantation after ex vivo evaluation of uncontrolled non heart-beating donors lungs: initial experience. J Heart Lung Transplant 2011;30:S38. 27. Machuca TN, Mercier O, Collaud S, et al. Lung transplantation with donation after circulatory determination of death donors and the impact of ex vivo lung perfusion. Am J Transplant 2015;15:993-1002. 28. Bozso S, Vasanthan V, Luc JG, Kinaschuk K, Freed D, Nagendran J. Lung transplantation from donors after circulatory death using portable ex vivo lung perfusion. Can Respir J 2015;22:47-51. 29. Chambers DC, Yusen RD, Cherikh WS, et al. The Registry of the International Society for Heart and Lung Transplantation. The Registry of the International Society for Heart and Lung Transplantation: thirty-fourth Adult Lung and Heart-Lung Transplantation Report-2017; Focus Theme: allograft ischemic time. J Heart Lung Transplant 2017;36:1047-59.