Normothermic ex vivo lung perfusion: Does the indication impact organ utilization and patient outcomes after transplantation?

Normothermic ex vivo lung perfusion: Does the indication impact organ utilization and patient outcomes after transplantation?

Cypel et al Transplantation Normothermic ex vivo lung perfusion: Does the indication impact organ utilization and patient outcomes after transplanta...

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Cypel et al

Transplantation

Normothermic ex vivo lung perfusion: Does the indication impact organ utilization and patient outcomes after transplantation? Marcelo Cypel, MD, MSc, Jonathan C. Yeung, MD, PhD, Laura Donahoe, MD, Manyin Chen, MD, Ricardo Zamel, PhD, Konrad Hoetzenecker, MD, PhD, Kazuhiro Yasufuku, MD, PhD, Marc de Perrot, MD, MSc, Andrew F. Pierre, MD, MSc, PhD, Thomas K. Waddell, MD, MSc, PhD, and Shaf Keshavjee, MD, MSc ABSTRACT

100

Results: During the study period, a total of 1106 lung transplants were performed in our institution. In this period, 372 EVLPs were performed, 255 (69%) of which were accepted for transplantation, resulting in 262 transplants. Utilization rates were 70% (140 of 198) for group 1, 82% (40 of 49) for group 2, 63% (69 of 109) for group 3, and 81% (13 of 16) for group 4 (P ¼ .42, Fisher’s exact test). Recipient age (P ¼ .27) and medical diagnosis (P ¼ .31) were not different across the 4 groups. Kaplan–Meier survival by EVLP indication group demonstrated no differences. Thirty-day mortality was 2.1% in group 1, 5% in group 2, 2.9% in group 3, and 0% in group 4 (P ¼ .87, Fisher’s exact test). The median days of mechanical ventilation, intensive care unit stay, and hospital stay were 2, 4, and 21 in group 1; 2, 3, and 21 in group 2; 3, 5, and 28 in group 3; and 2, 4, and 17 in group 4 (P ¼ .29, .17, and .09, respectively, Kruskal–Wallis rank-sum test). Conclusions: Clinical implementation of EVLP has allowed our program to expand the annual lung transplantation activity by 70% in this time period. It has improved confidence in the utilization of DCD lungs and BDD lungs, with an average 70% utilization of post-EVLP treated donor lungs with excellent outcomes, while addressing significant challenges in donor lung assessment and the logistics of ‘‘real-life’’ clinical lung transplantation. (J Thorac Cardiovasc Surg 2019;-:1-9)

From the Lung Transplant Program, University Health Network and Division of Thoracic Surgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada. This paper was reviewed under the direction of Dr Thomas A. D’Amico. Read at the 98th Annual Meeting of The American Association for Thoracic Surgery, San Diego, California, April 28-May 1, 2018. Received for publication June 5, 2018; revisions received June 10, 2019; accepted for publication June 16, 2019.

Percentage alive

50

25

0

P = .83 0

1

2

3 4 5 6 Time from transplant (Years)

7

8

9

375

296

212

133

81

45

10

90

58

36

25

13

8

4

7

8

9

Number at risk No

706

573

463

Yes

231

191

135

0

1

2

3 4 5 6 Time from transplant (Years) EVLP Received

No

Yes

Survival of EVLP and non-EVLP transplants. Central Message Lung transplantation using ex vivo lung perfusion (EVLP) provided excellent outcomes for recipients. The type of indication for EVLP did not affect utilization rates or outcomes after transplantation.

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Methods: All EVLP procedures performed at our institution between October 2008 and December 2017 were examined. The EVLPs were divided into 4 groups based on the indication for the procedure: group 1, high-risk brain death donors (HR-BDD); group 2, standard-risk donation after cardiac death (S-DCD); group 3, high-risk donation after cardiac death (HR-DCD); and group 4, logistics (LOGISTICS, the need for prolongation of preservation time or organ retrieval by a different transplantation team).

75

EVLP Received

Background: Ex vivo lung perfusion (EVLP) is being increasingly applied as a method to evaluate and treat donor lungs for transplantation. However, with the previous limited worldwide experience, no studies have been able to evaluate the impact of indication for EVLP on organ utilization rates and recipient outcomes after lung transplantation (LTx). We examined these outcomes in a large-cohort, single-center series of clinical EVLP cases.

Perspective In this large single-center series of clinical ex vivo lung perfusion (EVLP), we demonstrate the wide range of benefits from using this technology to safely increase lung transplantation activities. We also for the first time describe the use of EVLP to address not only high-risk donors, but also transplantation logistics, ultimately allowing transplantations that were not possible previously.

See Commentary on page XXX.

Address for reprints: Marcelo Cypel, MD, MSc, Division of Thoracic Surgery, Department of Surgery, University of Toronto, Toronto General Hospital, 200 Elizabeth St, 9N969, Toronto, ON M5G 2C4, Canada (E-mail: marcelo. [email protected]). 0022-5223/$36.00 Copyright Ó 2019 by The American Association for Thoracic Surgery https://doi.org/10.1016/j.jtcvs.2019.06.123

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Abbreviations and Acronyms BDD ¼ donor after brain death DCD ¼ donor after cardiocirculatory death EVLP ¼ ex vivo lung perfusion ECMO ¼ extracorporeal membrane oxygenation FiO2 ¼ fraction of inspired oxygen ICU ¼ intensive care unit LTx ¼ lung transplantation PGD ¼ primary graft dysfunction PaO2 ¼ partial pressure of oxygen

Scanning this QR code will take you to the article title page to access supplementary information. To view the AATS Annual Meeting Webcast, see the URL next to the webcast thumbnail.

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Lung transplantation (LTx) is lifesaving therapy for patients with end-stage lung diseases; however, the number of patients waiting for LTx still greatly exceeds the number of donors available. On average, only approximately 20% of lungs from multiorgan brain-dead donors (BDD) and <5% of donors after cardiocirculatory death (DCD) are used for transplantation.1,2 Given the large number of lungs currently declined for transplantation, increased utilization of currently available lungs is the most promising means of increasing LTx activity. Normothermic ex vivo lung perfusion (EVLP) is an innovative method for donor organ management that has significant potential to increase donor lung utilization by several means: (1) improving lung assessment and testing of organ quality; (2) facilitating organ self-repair mechanisms; (3) providing a stable platform for active drug or molecular treatments; and (4) safely prolonging the preservation period to assist with transplantation logistics.3-9 Results of EVLP transplantation for extended criteria BDD or DCD donors have only been reported in small series of cases, with good outcomes.5,8,10,11 However, given the previous limited experience, no studies have been able to evaluate the impact of indication for EVLP on organ utilization rates and recipient outcomes after LTx. Thus, the objective of the present study was to examine these outcomes in a large-cohort, single-center experience of clinical EVLP cases. METHODS Study Design This was a single-institution, retrospective study using prospectively collected data. All EVLP procedures performed at our institution between

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October 2008 and December 2017 were examined. Outcomes of consecutive recipients undergoing transplantation after normothermic EVLP divided into groups for indication were evaluated. This study was approved by our institutional Research Ethics Board.

Donor Procedures Donor lungs were retrieved in a standard fashion, transported from the donor hospital to our center under standard conditions of cold storage in a low-potassium dextran solution (Perfadex; XVIVO Perfusion, Gothenburg, Sweden), and placed in the Toronto EVLP system.5 The organs were then perfused for 4 to 6 hours with hourly functional assessments. Generally, lungs with a partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) (P/F ratio) of 400 mm Hg and stable or improving pulmonary artery pressure, airway pressures, or dynamic compliance were considered transplantable. Lungs were generally excluded for transplantation if the P/F ratio was <400 mm Hg or they demonstrated >15% deterioration in the other functional parameters noted above, reflecting progression of significant pulmonary deterioration during the procedure.

EVLP Groups The EVLPs were divided into 4 groups based on indication for the procedure:  Group 1, high-risk brain death donors (HR-BDD): donors with any of the following: low PaO2 (<300 mm Hg) or declining donor P/F ratio, bronchoscopic findings concerning for aspiration or pneumonia, pulmonary edema, significant infiltrates on donor chest X-ray, massive pulmonary embolism, high-risk donor history  Group 2, standard-risk donation after cardiac death (SR-DCD): DCD donors meeting standard International Society for Heart and Lung Transplantation donor criteria12 and with an interval between withdrawal of life-sustaining treatment and cardiac arrest <60 minutes  Group 3, high-risk DCD (HR-DCD): donors with the same risk factors as described for group 1, along with an interval between withdrawal of lifesustaining treatment and cardiac arrest >60 minutes and uncontrolled DCD  Group 4, standard-risk BDD (LOGISTICS): donors not meeting group 1 criteria but requiring prolonged preservation owing to resource availability or organ retrieval by a different transplantation team.

Recipients Selection of recipients was done according to our usual practice, based on blood type, size of the organ (ie, total lung capacity), and wait list status. There were no exclusion criteria for recipients to receive EVLP lungs, with the exception of our first 20 cases, in which retransplantations and ECMO bridge-to-transplant recipients were excluded.5 Care after LTx, including fluid management, antibiotic prophylaxis, immunosuppression, and surveillance bronchoscopy, was provided for all groups according to our standard practice.

EVLP Procedure The Toronto EVLP technique has been described in detail elsewhere.3,5 In brief, we use an acellular perfusate solution (Steen solution; XVIVO Perfusion). The lungs are placed in the EVLP dome and perfused with a centrifugal pump at 40% of the calculated donor cardiac output at 37 C. Left atrial pressure is kept at 4 to 6 mm Hg, and pulmonary artery pressure is normally <13 mm Hg. We perform protective ventilation with an FiO2 of 40%, a tidal volume of 7 mL/kg, and a positive end-expiratory pressure of 5 cmH2O. At the end of EVLP, the lung block is cooled down in the circuit to 10 C over a 10-minute period. Thereafter, perfusion and ventilation are stopped (FiO2 was increased to 50% for lung storage), and the trachea is clamped to maintain the lungs

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180

150

Number of Cases

Lung transplants 120

90 EVLPs 60

30

17 20

16 20

15 20

20

20

14

13

12 20

11 20

10 20

09 20

20

08

0

Group 1 (high-risk BDD)

Group 2 (standard DCD)

20 0 20 8 0 20 9 1 20 0 1 20 1 12 20 1 20 3 14 20 1 20 5 1 20 6 17

20 0 20 8 0 20 9 1 20 0 1 20 1 12 20 1 20 3 14 20 1 20 5 1 20 6 17

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Year

Group 3 (high-risk DCD)

Group 4 (logistics)

Number of EVLPs Performed

40

30

20

10

20 0 20 8 09 20 1 20 0 1 20 1 1 20 2 1 20 3 1 20 4 15 20 1 20 6 17

20 0 20 8 0 20 9 1 20 0 1 20 1 12 20 1 20 3 14 20 1 20 5 1 20 6 17

0

Year Transplanted

No

Yes

FIGURE 1. Number of transplantations and ex vivo lung perfusion (EVLP) procedures performed during the study period (upper) and EVLP procedures performed in each EVLP category (lower). Shaded areas reflect the total number of EVLP procedures. Red represents lungs transplanted after EVLP; blue, lungs declined after EVLP. BDD, Brain death donor; DCD, donor after cardiocirculatory death.

in an inflated state. A back table terminal flush with cold Perfadex is then performed, and the lungs are statically preserved at 4 C in Perfadex until transplantation.

Study Endpoints The primary endpoint was survival comparison of recipients receiving EVLP lungs stratified by EVLP indication group. Secondary endpoints

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TABLE 1. Overall donor lung utilization (donor offers/transplants) rates, 2008-2017 Parameter Donors, n

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

246

287

265

282

324

287

336

369

459

456

Transplants, n

86

102

84

102

104

133

115

128

145

170

Utilization, %

34

35

31

36

32

46

34

34

31

37

included utilization rates after EVLP by group, International Society for Heart and Lung Transplantation primary graft dysfunction (PGD) grade 3 (P/F<200 mm Hg) at 72 hours post-LTx, time on mechanical ventilation, intensive care unit (ICU) and hospital lengths of stay, and 30-day mortality.

RESULTS Donor Lungs Between October 2008 and December 2017, 1106 lung transplants were performed in our institution. In this same period, 372 EVLPs were performed, of which 255 were accepted for transplantation (overall utilization rate of 69%; 95% confidence interval [CI], 64%-73%), resulting in 262 transplants. The volume of EVLP procedures increased yearly at our hospital. The volume of EVLPs per indication over time is shown in Figure 1. The overall

Statistical Methods All statistics were calculated with GraphPad Prism 7 (GraphPad Software, La Jolla, Calif). Results are given as median and range. The Kruskal–Wallis test was performed to compare numeric data among the 4 groups, and Fisher’s exact test was used for categorical data. Kaplan– Meier curves were used for survival plots, and the log-rank test was used to compare proportional hazards of survival.

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Percentage alive

75

50

25

0

P = .83

EVLP Received

0

1

2

3 4 5 6 Time from transplant (Years)

7

8

9

Number at risk No

706

573

463

375

296

212

133

81

45

10

Yes

231

191

135

90

58

36

25

13

8

4

0

1

2

7

8

9

3 4 5 6 Time from transplant (Years) EVLP Received

No

Yes

FIGURE 2. Survival of ex vivo lung perfusion EVLP (n ¼ 262) and non-EVLP (n ¼ 844) transplants. Shaded areas represent confidence limits.

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Transplantation

TABLE 2. Donor baseline characteristics Group 1 (N ¼ 140)

Group 2 (N ¼ 40)

Group 3 (N ¼ 69)

Group 4 (N ¼ 13)

P value

Age, y, median (IQR)

39 (25-54)

49 (40-60)

48 (39-54)

49 (43-63)

.002

Abnormal chest X-ray, n (%)

94 (68)

16 (40)

48 (69)

3 (23)

.0007

P/F ratio at retrieval, mean  SD

320  106

352  111

408  90

.001 .439

Characteristic

415  73

Positive bronchoalveolar lavage fluid culture, n (%)

86 (61)

23 (57)

47 (68)

8 (61)

Smoking history, n (%)

85 (60)

26 (65)

40 (58)

8 (61)

Total preservation time, min, median (IQR)

855 (743-952)

764 (652-881)

865 (770-965)

.81

892 (797-997)

.008

organ utilization (donor offers/transplants) is shown in Table 1. Survival Outcomes for EVLP Versus Non-EVLP Transplantations Short- and long-term survival from recipients receiving standard preservation lungs and EVLP lungs were similar, with a hazard ratio of 0.97 (95% CI, 0.75-1.27; P ¼ .83) for EVLP versus standard preservation (Figure 2). Donor Characteristics Baseline characteristics for the 4 EVLP groups are presented in Table 2. Donors in group 1 were younger (P ¼ .002) and had a lower P/F ratio (P ¼ .001) at the time of retrieval than all other groups, and groups 1 and 3 had more chest X-ray abnormalities than the other 2 groups (P ¼ .0007). Donor lungs from group 2 had significantly shorter total preservation times compared with the other groups (P ¼ .008). Utilization Rates by EVLP Group Utilization rates for the 4 EVLP groups were 70% (95% CI, 64%-77%; 140 of 198) for group 1, 82% (95% CI, 69%-90%; 40 of 49) for group 2, 63% (95% CI,

54%-72%; 69 of 109) for group 3, and 81% (95% CI, 57%-93%; 13 of 16) for group 4 (P ¼ .09, Fisher’s exact test). All 3 donor lungs that were not utilized in group 4 were cases for which our team was not able to be present at the donor procedure and the organ retrieval was performed by another transplantation team. The mean dynamic compliance at the end of EVLP was 65  27 mL/cmH2O in the declined lungs and 76  43 mL/cmH2O in the accepted lungs (P ¼ .042). The mean peak airway pressure at the end of EVLP was significantly higher in lungs declined after EVLP (16  5 cmH2O vs 14  3.2 cmH2O; P ¼ .01). No significant differences in pulmonary venous PaO2 were observed between accepted and nonaccepted lungs. Recipient Characteristics Recipient characteristics in the 4 EVLP groups are summarized in Table 3. There were minor differences among the 4 groups in recipient age, medical diagnosis for transplantation, and urgency category for transplantation. Recipients in group 1 were less likely than those in the other 3 groups to receive double lung transplants (64.2% vs 82.5% in group 2, 82.6% in group 3, and 84.6% in group 4; P ¼ .01).

TABLE 3. Recipient baseline characteristics Group 1 (N ¼ 140)

Group 2 (N ¼ 40)

Group 3 (N ¼ 69)

Group 4 (N ¼ 13)

P value

Age, yr, median (IQR)

60 (52-64)

60 (50-66)

56 (40-64)

61 (45-68)

.33

ILD, n (%)

70 (50)

18 (45)

25 (36.2)

9 (69.2)

.09

COPD, n (%)

39 (27.8)

12 (30)

13 (18.8)

2 (15.3)

.28

CF, n (%)

20 (14)

6 (15)

10 (14.5)

2 (15.3)

.99

2 (5)

4 (5.8)

0 (0)

.45

Characteristic

PPH, n (%)

3 (2.1)

Status 3* (high urgency), n (%)

48 (34.2)

15 (37.5)

27 (39.1)

4 (30.7)

.88

Double lung transplant, n (%)

90 (64.2)

33 (82.5)

57 (82.6)

11 (84.6)

.01

IQR, Interquartile range; ILD, interstitial lung disease; COPD, chronic obstructive pulmonary disease; CF, cystic fibrosis; PPH, primary pulmonary hypertension. *Canadian Recipient Status 3: rapidly deteriorating patients admitted to hospital requiring high-flow oxygen, right heart failure or in the intensive care unit on ventilation/ extracorporeal life support.

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IQR, Interquartile range; P/F, partial pressure of oxygen/fraction of inspired oxygen ratio.

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TABLE 4. Recipient Short-Term Outcomes Group 1 (N ¼ 140)

Outcome PGD 2-3 at 72 h, %

Group 2 (N ¼ 40)

18.5

PGD 3 at 72 h, %

6.5

PGD 3 at 24 h, %

11.5

ECMO post-LTx, %

Group 3 (N ¼ 69)

Group 4 (N ¼ 13)

P value

20

17.3

15

12.5

10.1

0

.37

10

15.1

15.4

.88

3.5

5

10

.97

7.6

.28

Ventilation, d, median (IQR)

2 (1.5-5)

2 (1-6)

3 (2-7)

2.5 (1-8)

.29

ICU stay, d, median (IQR)

4 (2-9)

3 (2-12)

5 (3-18)

4 (2-12)

.17

Hospital stay, d, median (IQR)

21 (16-40)

21.5 (17-41)

28 (18-62)

17 (13-31)

.09

2.1

5

2.9

0

.71

30-d mortality, %

PGD, Primary graft dysfunction; ECMO, extracorporeal membrane oxygenation; IQR, interquartile range; ICU, intensive care unit.

Clinical Outcomes of EVLP Recipients by Group There were no important differences in short-term outcomes among the 4 groups (Table 4). The incidence of PGD at 72 hours, time on mechanical ventilation, time in the ICU, and 30-day mortality were similar across the

groups. There was a tendency toward an increased length of hospital stay in group 3 (median, 28 days vs 21, 21, and 17 in groups 1, 2, and 4 respectively; P ¼ .09). Patient survival and chronic lung allograft disease-free survival were similar among the 4 groups (Figure 3, A and B).

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CLAD

Survival 100

Percentage free of CLAD

100

Percentage alive

75

50

25

2 3 4 5 6 7 8 Time from transplant (Years) Number at risk Donor category

0

A

1

HR BDD 126 108 72

25

56

36

21

13

7

4

9

3

S DCD

34

29

22

15

10

8

7

4

3

1

HR DCD

52

41

32

13

11

6

4

2

1

0

Logistics

16

11

7

5

0

0

0

0

0

0

0

1

2 3 4 5 6 7 8 Time from transplant (Years)

9

Donor category HR BDD

50

0

P = .97

S DCD

HR DCD

Logistics

P = .88 0

2 3 4 5 6 7 8 Time from transplant (Years) Number at risk Donor category

0

75

B

1

HR BDD 126 84

9

55

35

21

11

6

4

3

0

S DCD

35

25

17

10

6

6

3

1

0

0

HR DCD

52

32

13

10

6

4

2

2

0

0

Logistics

14

7

3

3

0

0

0

0

0

0

0

1

2 3 4 5 6 7 8 Time from transplant (Years)

9

Donor category HR BDD

S DCD

HR DCD

Logistics

FIGURE 3. Overall patient survival (A) and chronic lung allograft dysfunction–free survival (B) among the 4 ex vivo lung perfusion (EVLP) groups. Confidence limits are reported in Table E1. BDD, Brain death donor; DCD, donor after cardiocirculatory death.

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DISCUSSION In this study, we reviewed our experience with normothermic EVLP as a means to reevaluate the function and improve the quality of injured donor lungs. A total of 272 EVLP transplants were evaluated, making this the largest experience with clinical EVLP reported to date. Concordant with our earlier publications, outcomes of recipients receiving these lungs have similar outcomes as conventional transplantation.5,10 The main goal of the study was to analyze whether the specific indication for EVLP has an effect on organ utilization and patient outcomes. In our program, EVLP has been used mainly for 2 indications: high-risk BDD donors and DCD. Although the use of EVLP for high-risk BDD has been well established, the need for routine use of EVLP in SR-DCDs has been controversial.13 Even in our own center, the use of EVLP in DCD lungs that otherwise have no obvious concerns at the time of organ assessment has not been routine and remains at the surgeon’s discretion.14 In contrast, extended-criteria DCD, including donors that do not arrest within 1 hour after withdrawal of life support treatment, and uncontrolled DCDs, EVLP appears to be a critical requirement. Although utilization rates of these lungs are lower compared with other EVLP indications, a substantial number of patients could undergo safe transplantation using this strategy, with equivalent outcomes as seen in the other groups. Interestingly, we noted a larger proportion of single lung transplantation in the high-risk BDD group compared with the other groups. We believe that this is due to the fact that these donors can often have more substantial injury in one lung, which becomes even more evident during EVLP assessment, but that the functional, bronchoscopic, and radiographic stability of the contralateral lung during perfusion reassures the team of the safety of proceeding with single lung transplantation. We have salvaged considerably more single lungs for successful transplantation in our program in this way. This report also introduces for the first time the use of EVLP to address logistical challenges of lung transplantation. Sixteen EVLP procedures in these series were performed for logistical reasons, mostly to allow for a delay in transplantation initiation. However, 3 lungs in this category ended up not meeting EVLP criteria for transplantation, which we felt was related to poor organ retrieval and preservation technique performed by a retrieval team unknown to our center, although we cannot rule out the possible presence of other subclinical injuries. These lungs were included in the logistic category, because our accepting surgeon would have transplanted them directly without EVLP if our own team had performed the organ retrieval. Importantly, the remaining 13 patients in this category had excellent transplantation

outcomes despite a median preservation time of approximately 15 hours, by using a combination of EVLP and cold static preservation. As we continue to extend this concept and confirm these results in subsequent studies, LTx could conceivably be transformed into a more elective procedure.9,15 This could have a major impact on current transplantation practice. For example, LTx could be delayed to the daytime, with obvious advantages for surgical, anesthesia, and operating room staff performance under optimal conditions. In addition, an elective delay of LTx could be used to address donor- or recipient-related logistical challenges. Indeed, although obtaining precise data is difficult, logistical challenges likely play major roles in declining organs for transplantation. Additional advantages of safe prolongation of donor lung preservation could include opportunities for expanding the geographical reach for donors, improving donor–recipient immunologic matching, avoiding the need to rush during difficult lung explants, and allowing patients to live several hours away from the transplantation center so as to avoid the adverse financial and social consequences of relocation. Our conversion rate (ie, use of lungs after EVLP) has been higher (70%) than the those reported by other centers. Unlike other programs, our group started clinical EVLP after a very solid and extensive experience with preclinical EVLP. Furthermore, specialists in EVLP methodology perform the procedures at our institution and follow very strict standard operating procedures. The variation in utilization rate is also directly related to the degree of injury of the donor organs. As our experience grew, we pushed the limits to organs that we did not consider in the beginning, for example, donors with confirmed aspiration of gastric contents or DCDs taking longer than 2 hours to arrest. As expected, the utilization rate decreased when we started including such donors. However, the overall gain to transplantation activity was greater as we began rescuing organs that we would never use before. This is reflected by a 100% increase in lung transplantation activity in this past year compared with 2008. The limitations of the present study are inherent to its retrospective design and potential for bias. In addition, although a prospectively collected database was used, details of donor lung assessment can be subjective, and thus categorization of lungs within the 4 defined groups might not be perfectly accurate. To that end, clinical judgment as an aspect of EVLP indications can also be a subject of criticism. In summary, in our large EVLP series, the indication for EVLP was not significantly associated with short- and longterm recipient outcomes. Clinical implementation of EVLP was temporally associated with a significant expansion of lung transplantation activity. It has enhanced the confident

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utilization of DCD lungs and BDD lungs, with an average 70% utilization of post-EVLP treated donor lungs with excellent outcomes, while addressing significant challenges in donor lung assessment and logistics of real-life clinical lung transplantation. Webcast You can watch a Webcast of this AATS meeting presentation by going to: https://aats.blob.core.windows.net/ media/18Apr30/20ABC%201.Plenary%20Sessions/S57% 20-%20Part%201/S57_2.mp4.

Cypel et al

12.

13.

14.

15.

sion: a prospective randomized clinical trial. J Heart Lung Transplant. 2017; 36:744-53. de Perrot M, Bonser RS, Dark J, Kelly RF, McGiffin D, Menza R, et al. Report of the ISHLT working group on primary lung graft dysfunction, part III: donor-related risk factors and markers. J Heart Lung Transplant. 2005;24:1460-7. Cypel M, Levvey B, Van Raemdonck D, Erasmus M, Dark J, Love R, et al. International Society for Heart and lung Transplantation Donation After Circulatory Death Registry report. J Heart Lung Transplant. 2015; 34:1278-82. Machuca TN, Mercier O, Collaud S, Tikkanen J, Krueger T, Yeung JC, 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. Hsin MK, Iskender I, Nakajima D, Chen M, Kim H, dos Santos PR, et al. Extension of donor lung preservation with hypothermic storage after normothermic ex vivo lung perfusion. J Heart Lung Transplant. 2016;35: 130-6.

Key Words: lung transplantation, ex vivo lung perfusion, donor utilization

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Conflict of Interest Statement Drs Cypel, Waddell, and Keshavjee serves as consultants for Lung Bioengineering/United Therapeutics, are founders of Perfusix Canada and of XOR Labs Toronto, and received research support from XVIVO Perfusion. Drs Waddell, Keshavjee, and Cypel hold Patent #US20170036006A1 (published 2017-02-09), and application status is pending. All other authors have nothing to disclose with regard to commercial support. References 1. Wigfield C. Donation after cardiac death for lung transplantation: a review of current clinical practice. Curr Opin Organ Transplant. 2014;19:455-9. 2. Valapour M, Lehr CJ, Skeans MA, Smith JM, Carrico R, Uccellini K, et al. OPTN/SRTR 2016 annual data report: lung. Am J Transplant. 2018;18(Suppl 1):363-433. 3. Cypel M, Yeung JC, Hirayama S, Rubacha M, Fischer S, Anraku M, et al. Technique for prolonged normothermic ex vivo lung perfusion. J Heart Lung Transplant. 2008;27:1319-25. 4. Cypel M, Liu M, Rubacha M, Yeung JC, Hirayama S, Anraku M, et al. Functional repair of human donor lungs by IL-10 gene therapy. Sci Transl Med. 2009;1:4ra9. 5. Cypel M, Yeung JC, Liu M, Anraku M, Chen F, Karolak W, et al. Normothermic ex vivo lung perfusion in clinical lung transplantation. N Engl J Med. 2011;364: 1431-40. 6. Aigner C, Slama A, H€ otzenecker K, Scheed A, Urbanek B, Schmid W, et al. Clinical ex vivo lung perfusion–pushing the limits. Am J Transplant. 2012;12: 1839-47. 7. Sage E, Mussot S, Trebbia G, Puyo P, Stern M, Dartevelle P, et al. Lung transplantation from initially rejected donors after ex vivo lung reconditioning: the French experience. Eur J Cardiothorac Surg. 2014;46:794-9. 8. Warnecke G, Moradiellos J, Tudorache I, K€uhn C, Avsar M, Wiegmann B, et al. Normothermic perfusion of donor lungs for preservation and assessment with the Organ Care System Lung before bilateral transplantation: a pilot study of 12 patients. Lancet. 2012;380:1851-8. 9. Yeung JC, Krueger T, Yasufuku K, de Perrot M, Pierre AF, Waddell TK, et al. Outcomes after transplantation of lungs preserved for more than 12 h: a retrospective study. Lancet Respir Med. 2017;5:119-24. 10. Cypel M, Yeung JC, Machuca T, Chen M, Singer LG, Yasufuku K, et al. Experience with the first 50 ex vivo lung perfusions in clinical transplantation. J Thorac Cardiovasc Surg. 2012;144:1200-6. 11. Slama A, Schillab L, Barta M, Benedek A, Mitterbauer A, Hoetzenecker K, et al. Standard donor lung procurement with normothermic ex vivo lung perfu-

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Discussion Dr G. Alexander Patterson (St Louis, Mo). Thank you, Mr Chairman and Dr Moon. It is a terrific honor for me to be able to discuss this paper. I have to say that I think the program committee has a serious ethical lapse in judgment, in that I used to run this program for a few years many years ago. Dr Marc R. Moon (St Louis, Mo). And they were able to scrape by and keep it going when you left? Dr Patterson. Yes, or resuscitate it, that’s right [Laughter]. It is a great honor. I also want to point out that we had a terrific reception at the AATS Foundation reception last night, and Marcelo, many of you don’t know, is a former AATS Scholar, and that’s got to be one of the best investments that the AATS makes in those scholarships, supporting the careers of talented young people like Marcelo. So, I urge you to go to the Foundation desk and make a donation. Marcelo is also a Canada Research Chair in transplantation. That is a phenomenal honor and is a testament to his outstanding scholarship. So, this is a landmark contribution and the work has the potential to really move the needle on lung transplantation, but I do have a couple of questions for Marcelo. Number one, if this is such a terrific technology, why is it that its application has not been more widely accepted? Is it a matter of cost or is it a matter of manpower? In our own program we have a donor retrieval center that maybe is like Rich Battafarano a few minutes ago said that’s like in vivo lung perfusion, if you like. So, Marcelo, what are your thoughts on that?

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Dr Marcelo Cypel (Toronto, Ontario, Canada). Well, thank you very much, Dr Patterson. That’s a very good question. I think as with much of innovative technology, it can take some time for full adoption. I would argue that over the last few years, the number of lungs undergoing this procedure has increased overall worldwide and even in the US. As an example, just over the last 12 months, over 60 EVLP procedures were done at one facility in LB in Maryland, which is a centralized center. But other centers committed to perfusion research, such as Cleveland, Pittsburgh, and Duke, have also increased their activities in their own centers. They also have increased their activities in their own centers. So, I think we are seeing an increase in the slope. Now in terms of logistics and manpower, I think that’s a very important aspect of that. Some high-volume centers will be able to create capability in their own institutions, but for the average size centers they may benefit from these more centralized services where they just send the lung and don’t need to create their own structure there. Dr Patterson. Can I ask, Marcelo, how has this technology, your use of EVLP, evolved over time? Dr Cypel. Again, I think that is very important. In the beginning of our experience around 2008 when we moved this procedure from the lab to the clinical, basically myself and Dr Keshavjee were doing the first 10 to 20 procedures, and then clearly that became obvious that was not feasible in the long run, and so we transitioned that to research fellows that were doing EVLP procedures in the lab. And even then, after the volume increased, we didn’t think that it became sustainable, and so we created this new category of professionals called organ perfusion specialists, and basically what they do is perfusion of lungs. Now they are starting to do livers and kidneys as well. So, we have 3 of those professionals at our institution who do 1 call in 3. But of course, we also pair them with research fellows who are interested in that, and the perfusion department also provides support. So, it became a lot more automatic now for the clinical team not having to have hands-on participation in the procedure. Dr Patterson. And can I ask one more question? I noticed on your slide, the EVLP donors in group 1 were

more likely to be utilized as single-lung grafts than double. Why is that? Dr Cypel. That’s I think a very interesting finding. If you think about many of these donors, they do have concerns at the donor time or the donor retrieval that previously we wouldn’t necessarily even take those organs for transplantation. And so, we put those lungs in the circuit and we find out that there is a left lower lobe consolidation or a position of pulmonary edema and we end up saving the other lung for transplantation. So, I think it’s more due to unilateral injury that in the past we would not necessarily even use the other lung. Dr Moon. I hate to be capitalistic about this, but what happens if you have a set of lungs, you bring them here, you are paying your surgeon to take care of these lungs, and then you decide they are no good. Who pays for all that? Is that billed to a patient somehow? Dr Cypel. I think the financial model would be different between different health systems. So just as an example, in Canada this is funded by the Ministry of Health, and we built in the model that about 40% of the lungs would be discarded after EVLP, and so that’s accepted. I think in the US, maybe some of the surgeons practicing in the US may help with that answer, but I think the costs may have to be transferred or shared with OPOs, hospitals, or patients. Dr Moon. And is there a large capital expense to initiate the program or is this an expense per patient, or do you have to buy a whole bunch of equipment and then decide maybe I don’t want to do that so often? Dr Cypel. There is an initial capital cost. The commercially available platforms cost, if I am right, about $300,000, the hardware, and then for each procedure they cost between $40,000 and $50,000 of disposables. And, of course, it’s not only buying the equipment. You have to create a team that knows how to use it. It’s very clear to us that any deviation from the SOPs of the procedure can make a big impact in the ultimate ability to transplant the organ. So I do feel there is an initial higher cost. And that’s, again, when each center may decide whether to create that capability or whether to use the commercially available services. Dr Moon. Maybe I should ask Dr Keshavjee this, but does your center serve as an example center where we can go to and learn how to do this procedure? Dr Cypel. Yes, we are always open, and we do receive a lot of visitors from other institutions.

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TABLE E1. Confidence limits (CLs) for Figure 3 Donor group Figure 3, A 1

2

3

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Figure 3, B 1

2

3

4

9.e1

Years

Number at risk

Percentage alive

Lower 95% CL

Upper 95% CL

1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3

108 72 56 36 21 13 7 29 22 15 10 8 7 4 41 32 13 11 6 4 2 11 7 5

85.7 74.5 72.3 65.8 63.2 52.8 52.8 85.3 76.1 71.3 65.9 58.5 58.5 48.8 86.5 82.3 71.7 65.7 59.2 59.2 59.2 86.7 86.7 86.7

79.8 67.1 64.7 56.9 53.5 40.6 40.6 74.2 62.9 56.8 49.9 40.8 40.8 29.3 77.7 72.4 58.4 50.4 42.2 42.2 42.2 71.1 71.1 71.1

92.0 82.7 81.0 76.2 74.6 68.7 68.7 98.1 92.1 89.7 86.9 84.0 84.0 81.1 96.3 93.5 88.0 85.8 82.9 82.9 82.9 100.0 100.0 100.0

1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3 4 5 6 7 1 2 3

84 55 35 21 11 6 4 25 17 10 6 6 3 1 32 13 10 6 4 2 2 7 3 3

92.3 82.3 73.5 70.6 56.4 50.7 50.7 90.8 81.9 59.3 51.9 51.9 51.9 51.9 89.5 71.0 71.0 63.9 53.3 53.3 53.3 100.0 66.7 66.7

87.4 74.7 63.9 60.2 41.6 35.2 35.2 81.4 68.3 41.0 33.0 33.0 33.0 33.0 80.2 56.0 56.0 46.7 33.1 33.1 33.1 100.0 37.9 37.9

97.6 90.7 84.5 82.9 76.3 73.2 73.2 100.0 98.1 85.7 81.5 81.5 81.5 81.5 99.8 90.1 90.1 87.6 85.8 85.8 85.8 100.0 100.0 100.0

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Normothermic ex vivo lung perfusion: Does the indication impact organ utilization and patient outcomes after transplantation? Marcelo Cypel, MD, MSc, Jonathan C. Yeung, MD, PhD, Laura Donahoe, MD, Manyin Chen, MD, Ricardo Zamel, PhD, Konrad Hoetzenecker, MD, PhD, Kazuhiro Yasufuku, MD, PhD, Marc de Perrot, MD, MSc, Andrew F. Pierre, MD, MSc, PhD, Thomas K. Waddell, MD, MSc, PhD, and Shaf Keshavjee, MD, MSc, Toronto, Ontario, Canada Lung transplantation using ex vivo lung perfusion (EVLP) provided excellent outcomes for recipients. The type of indication for EVLP did not affect utilization rates or outcomes after transplantation.

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