Long-term Outcomes of Lung Transplant With Ex Vivo Lung Perfusion | Cardiothoracic Surgery | JAMA Surgery | JAMA Network
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Figure 1.  Patients Included in the Study
Patients Included in the Study

BDD indicates brain death donor; DCD, donation after cardiac death; and EVLP, ex vivo lung perfusion.

Figure 2.  Freedom From Death or Retransplant
Freedom From Death or Retransplant

BDD indicates brain death donor; DCD, donation after cardiac death; and EVLP, ex vivo lung perfusion.

Figure 3.  Freedom From Chronic Lung Allograft Dysfunction
Freedom From Chronic Lung Allograft Dysfunction

BDD indicates brain death donor; DCD, donation after cardiac death; and EVLP, ex vivo lung perfusion.

Table 1.  Donor Characteristics
Donor Characteristics
Table 2.  Recipient Characteristics
Recipient Characteristics
1.
Chambers  DC, Yusen  RD, Cherikh  WS,  et al; 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(10):1047-1059. doi:10.1016/j.healun.2017.07.016PubMedGoogle ScholarCrossref
2.
Sage  E, Mussot  S, Trebbia  G,  et al; Foch Lung Transplant Group.  Lung transplantation from initially rejected donors after ex vivo lung reconditioning: the French experience.  Eur J Cardiothorac Surg. 2014;46(5):794-799. doi:10.1093/ejcts/ezu245PubMedGoogle ScholarCrossref
3.
Valapour  M, Paulson  K, Smith  JM,  et al.  OPTN/SRTR 2011 annual data report: lung.  Am J Transplant. 2013;13(suppl 1):149-177. doi:10.1111/ajt.12024PubMedGoogle ScholarCrossref
4.
Snell  GI, Griffiths  A, Levvey  BJ, Oto  T.  Availability of lungs for transplantation: exploring the real potential of the donor pool.  J Heart Lung Transplant. 2008;27(6):662-667. doi:10.1016/j.healun.2008.03.009PubMedGoogle ScholarCrossref
5.
Yeung  JC, Krueger  T, Yasufuku  K,  et al.  Outcomes after transplantation of lungs preserved for more than 12 h: a retrospective study.  Lancet Respir Med. 2017;5(2):119-124. doi:10.1016/S2213-2600(16)30323-XPubMedGoogle ScholarCrossref
6.
Tikkanen  JM, Cypel  M, Machuca  TN,  et al.  Functional outcomes and quality of life after normothermic ex vivo lung perfusion lung transplantation.  J Heart Lung Transplant. 2015;34(4):547-556. doi:10.1016/j.healun.2014.09.044PubMedGoogle ScholarCrossref
7.
Cypel  M, Yeung  JC, Liu  M,  et al.  Normothermic ex vivo lung perfusion in clinical lung transplantation.  N Engl J Med. 2011;364(15):1431-1440. doi:10.1056/NEJMoa1014597PubMedGoogle ScholarCrossref
8.
Cypel  M, Yeung  JC, Machuca  T,  et al.  Experience with the first 50 ex vivo lung perfusions in clinical transplantation.  J Thorac Cardiovasc Surg. 2012;144(5):1200-1206. doi:10.1016/j.jtcvs.2012.08.009PubMedGoogle ScholarCrossref
9.
Boffini  M, Ricci  D, Bonato  R,  et al.  Incidence and severity of primary graft dysfunction after lung transplantation using rejected grafts reconditioned with ex vivo lung perfusion.  Eur J Cardiothorac Surg. 2014;46(5):789-793. doi:10.1093/ejcts/ezu239PubMedGoogle ScholarCrossref
10.
Fildes  JE, Archer  LD, Blaikley  J,  et al.  Clinical outcome of patients transplanted with marginal donor lungs via ex vivo lung perfusion compared to standard lung transplantation.  Transplantation. 2015;99(5):1078-1083. doi:10.1097/TP.0000000000000462PubMedGoogle ScholarCrossref
11.
Wallinder  A, Riise  GC, Ricksten  SE, Silverborn  M, Dellgren  G.  Transplantation after ex vivo lung perfusion: A midterm follow-up.  J Heart Lung Transplant. 2016;35(11):1303-1310. doi:10.1016/j.healun.2016.05.021PubMedGoogle ScholarCrossref
12.
Cypel  M, Yeung  JC, Hirayama  S,  et al.  Technique for prolonged normothermic ex vivo lung perfusion.  J Heart Lung Transplant. 2008;27(12):1319-1325. doi:10.1016/j.healun.2008.09.003PubMedGoogle ScholarCrossref
13.
Kootstra  G, Daemen  JHOA, Oomen  AP.  Categories of non–heart-beating donors.  Transplant Proc. 1995;27(5):2893-2894.PubMedGoogle Scholar
14.
Meyer  KC, Raghu  G, Verleden  GM,  et al; ISHLT/ATS/ERS BOS Task Force Committee; ISHLT/ATS/ERS BOS Task Force Committee.  An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome.  Eur Respir J. 2014;44(6):1479-1503. doi:10.1183/09031936.00107514PubMedGoogle ScholarCrossref
15.
Gutierrez  C, Ghezzo  RH, Abboud  RT,  et al.  Reference values of pulmonary function tests for Canadian Caucasians.  Can Respir J. 2004;11(6):414-424. doi:10.1155/2004/857476PubMedGoogle ScholarCrossref
16.
Christie  JD, Carby  M, Bag  R, Corris  P, Hertz  M, Weill  D; ISHLT Working Group on Primary Lung Graft Dysfunction.  Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part II, definition: a consensus statement of the International Society for Heart and Lung Transplantation.  J Heart Lung Transplant. 2005;24(10):1454-1459. doi:10.1016/j.healun.2004.11.049PubMedGoogle ScholarCrossref
17.
Oto  T, Levvey  BJ, Whitford  H,  et al.  Feasibility and utility of a lung donor score: correlation with early post-transplant outcomes.  Ann Thorac Surg. 2007;83(1):257-263. doi:10.1016/j.athoracsur.2006.07.040PubMedGoogle ScholarCrossref
18.
Saxena  P, Zimmet  AD, Snell  G, Levvey  B, Marasco  SF, McGiffin  DC.  Procurement of lungs for transplantation following donation after circulatory death: the Alfred technique.  J Surg Res. 2014;192(2):642-646. doi:10.1016/j.jss.2014.07.063PubMedGoogle ScholarCrossref
19.
Whitson  BA, Prekker  ME, Herrington  CS,  et al.  Primary graft dysfunction and long-term pulmonary function after lung transplantation.  J Heart Lung Transplant. 2007;26(10):1004-1011. doi:10.1016/j.healun.2007.07.018PubMedGoogle ScholarCrossref
20.
Tikkanen  JM, Singer  LG, Kim  SJ,  et al.  De novo DQ donor-specific antibodies are associated with chronic lung allograft dysfunction after lung transplantation.  Am J Respir Crit Care Med. 2016;194(5):596-606. doi:10.1164/rccm.201509-1857OCPubMedGoogle ScholarCrossref
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    Original Investigation
    October 9, 2019

    Long-term Outcomes of Lung Transplant With Ex Vivo Lung Perfusion

    Author Affiliations
    • 1Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada
    JAMA Surg. 2019;154(12):1143-1150. doi:10.1001/jamasurg.2019.4079
    Key Points

    Question  What are the long-term outcomes of transplant recipients of donor lungs treated with ex vivo lung perfusion?

    Findings  In this cohort study, donor lungs treated with ex vivo lung perfusion were more injured than conventional donor lungs, but there was no difference in survival or chronic lung allograft dysfunction between recipients of conventional donor lungs and donor lungs treated with ex vivo lung perfusion.

    Meaning  During the era of ex vivo lung perfusion, transplant activity has increased without compromising outcomes in lung transplant recipients.

    Abstract

    Importance  The mortality rate for individuals on the wait list for lung transplant is 15% to 25%, and still only 20% of lungs from multiorgan donors are used for lung transplant. The lung donor pool may be increased by assessing and reconditioning high-risk extended criteria donor lungs with ex vivo lung perfusion (EVLP), with similar short-term outcomes.

    Objective  To assess the long-term outcomes of transplant recipients of donor lungs treated with EVLP.

    Design, Setting, and Participants  This retrospective cohort single-center study was conducted from August 1, 2008, to February 28, 2017, among 706 recipients of donor lungs not undergoing EVLP and 230 recipients of donor lungs undergoing EVLP.

    Exposure  Donor lungs undergoing EVLP.

    Main Outcomes and Measures  The incidence of chronic lung allograft dysfunction and allograft survival during the 10-year EVLP era were the primary outcome measures. Secondary outcomes included donor characteristics, maximum predicted percentage of forced expiratory volume in 1 second, acute cellular rejection, and de novo donor-specific antibody development.

    Results  This study included 706 patients (311 women and 395 men; median age, 50 years [interquartile range, 34-61 years]) in the non-EVLP group and 230 patients (85 women and 145 men; median age, 46 years [interquartile range, 32-55 years]) in the EVLP group. The EVLP group donors had a significantly lower mean (SD) Pao2:fraction of inspired oxygen ratio than the non-EVLP group donors (348 [108] vs 422 [88] mm Hg; P < .001), higher prevalence of abnormal chest radiography results (135 of 230 [58.7%] vs 349 of 706 [49.4%]; P = .02), and higher proportion of smoking history (125 of 204 [61.3%] vs 322 of 650 [49.5%]; P = .007). More recipients in the EVLP group received single-lung transplants (62 of 230 [27.0%] vs 100 of 706 [14.2%]; P < .001). There was no significant difference in time to chronic lung allograft dysfunction between the EVLP and non-EVLP group (70% vs 72% at 3 years; 56% vs 56% at 5 years; and 53% vs 36% at 9 years; log-rank P = .68) or allograft survival between the EVLP and non-EVLP groups (73% vs 72% at 3 years; 62% vs 58% at 5 years; and 50% vs 44% at 9 years; log-rank P = .97) between the 2 groups. All secondary outcomes were similar between the 2 groups.

    Conclusions and Relevance  Since 2008, 230 of 936 lung transplants (24.6%) in the Toronto Lung Transplant Program were performed after EVLP assessment and treatment. Use of EVLP-treated lungs led to an increase in the number of patients undergoing transplantation, with comparable long-term outcomes.

    Introduction

    The early outcomes of lung transplant have improved significantly, leading to a steady increase in the number of lung transplants performed worldwide.1 This increased demand has resulted in a persistent shortage of donor lungs, which in turn has resulted in a 15% to 20% mortality rate among individuals on the wait list.2,3 To meet the demand, the lung transplant community has adopted the use of extended criteria for donors, but despite loosening donor selection criteria, only 20% of lungs from multiorgan donors are ultimately transplanted.3,4 This low rate of transplantation is primarily owing to uncertainty regarding donor lung function in marginal donors and the fear of severe primary graft dysfunction (PGD) with its associated morbidity and mortality.

    Ex vivo lung perfusion (EVLP) has been developed as a technique to allow assessment and treatment of high-risk donor lungs. Using this technique, lungs are perfused and ventilated ex vivo at body temperature in lung-protective physiologic conditions. This technique allows assessment to be performed, which may include additional testing of the organ before transplant, and the possibility of repair during the organ preservation period. Furthermore, EVLP has allowed lung preservation times to go beyond 12 hours safely, leading to benefits around transplant logistics.5

    Several studies have shown similar short-term and medium-term outcomes for recipients receiving high-risk donor lungs treated with EVLP compared with recipients of standard-risk donor lungs.2,6-11 Here, we present the long-term results of recipients of lungs treated with EVLP in our program. To our knowledge, this is the largest cohort of recipients of EVLP-treated donor lungs with the longest follow-up reported so far.

    Methods
    Study Design

    This was a single-center cohort study of prospectively collected data. All adult recipients who underwent single-lung or bilateral-lung transplant between August 1, 2008, and February 28, 2017, were included. We included retransplant recipients and patients bridged to transplant with invasive mechanical ventilation or extracorporeal life support. The University Health Network Research Ethics Board approved this study and, because approval was applied for retrospectively, waived the requirement for informed consent (REB 17-5826). Our program collects the data used in the study prospectively into our research database. However, when we publish data, we still require study-specific research ethics board approval, and this was applied for retrospectively. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. Our program collects the data used in the study prospectively into our research database. However, when we publish data, we still require study specific research ethics board approval, and this was applied for retrospectively.

    Selection of recipients for transplant and posttransplant care was in keeping with our usual practice and was the same in both groups. Donor lungs were allocated to recipients on the basis of blood group, total lung capacity, and wait-list status (urgency).

    Previous publications have outlined our donor selection and EVLP selection criteria.7,8,12 In brief, high-risk donor lungs were defined as those that had the best Pao2:fraction of inspired oxygen (FiO2) ratio less than 300 mm Hg, pulmonary edema, poor lung compliance, donation after cardiac death (Maastricht categories III and IV13), and high-risk history, such as questionable history of aspiration. Donor lungs with established pneumonia, severe mechanical lung injury, and evidence of aspiration of gastric contents are generally excluded. From September 1, 2008, to January 31, 2010, all lungs donated after cardiac death (DCD lungs) were subjected to EVLP before lung transplant as part of the human ex vivo perfusion trial.7 Since then, DCD lungs are subjected to EVLP at the discretion of the operating surgeon on call. In general, if DCD lungs meet standard criteria for transplantation and time from withdrawal of life support therapy to cardiac arrest is less than 60 minutes, direct transplant is considered.

    EVLP Protocol

    We used the previously published normothermic EVLP protocol.7,12 Lung function evaluation was carried out after 5 minutes of ventilation on 100% FiO2, 10 mL/kg tidal volume, and 10 breaths per minute respiratory rate. Hourly lung evaluation was performed measuring the Pao2:FiO2 ratio in pulmonary vein effluent (in units of millimeters of mercury), pulmonary artery pressure (in units of millimeters of mercury), dynamic compliance (in units of milliliter per centimeters of water), and peak airway pressures (in units of centimeters of water). Ex vivo lung radiography and flexible bronchoscopy were routinely performed at 1 hour and 3 hours of EVLP, and additionally as needed. The decision to accept EVLP-evaluated lungs was made only after at least 3 hours of EVLP evaluation. Acceptance criteria were a Pao2:FiO2 ratio greater than 400 mm Hg, stable or improved peak airway pressure, pulmonary vascular resistance, compliance, and improved radiograph findings.

    Quiz Ref IDFor EVLP, the cold ischemia time was divided into 2 parts. Cold ischemia time 1 refers to the time between lung procurement and initiation of EVLP. Cold ischemia time 2 refers to the time between the end of EVLP to beginning of the implantation surgery. The warm ischemia time is the time from the start of the lung implantation to the release of the pulmonary artery clamp. Total preservation time includes cold ischemia time 1 + EVLP time + cold ischemia time 2 + warm ischemia time.

    Recipient Follow-up

    After discharge, routine clinic follow-up occurred weekly during the first 3 months after transplant, then every 3 months for the first year, every 6 months for the second year, and then annually. Routine clinical assessments included pulmonary function tests, chest radiograph, and blood testing. Transplant bronchoscopies and anti–HLA antigen antibody testing were performed routinely at 2 weeks, 6 weeks, and 3, 6, 9, 12, 18, and 24 months and when clinically indicated.

    Our protocols for recipient treatment did not change significantly during the study period. Our program accepts HLA antigen–sensitized recipients and if there is a positive virtual crossmatch at the time of transplantation, the patients will undergo plasmapheresis and receive IgG and 3 to 5 mg/kg of antithymocyte globulin perioperatively. All patients received triple-drug immunosuppression with a calcineurin inhibitor (cyclosporine or tacrolimus), cell-cycle inhibitor (azathioprine or mycophenolate mofetil or mycophenolic acid), and prednisone. There has been no change in the frequency of use of these drugs during the study period.

    Study End Points

    Quiz Ref IDPrimary end points were allograft survival (freedom from retransplantation and death from all causes) and freedom from chronic lung allograft dysfunction (CLAD). Chronic lung allograft dysfunction was defined according to the International Society of Heart and Lung Transplantation criteria for the diagnosis of bronchiolitis obliterans syndrome on the basis of a 20% or more decrease in forced expiratory volume in 1 second from the posttransplant baseline.14 Each patient who met CLAD criteria was screened by 2 independent authors (T.M. and J.M.T.) to exclude alternate causes and validate the diagnosis.

    Secondary end points assessed included the highest percentage of predicted forced expiratory volume in 1 second,15 the occurrence of biopsy-proven acute rejection episodes, and the development of de novo donor-specific antibodies (DSAs). In addition, early outcomes included the duration of intensive care unit stay, hospital stay, and PGD grade at 72 hours according to International Society of Heart and Lung Transplantation criteria.16

    The data were obtained mainly from the Toronto Lung Transplant Program database where CLAD, survival, duration of stay, acute rejection, pulmonary function test result, and other data are housed. For HLA antigen antibody data, separate review of medical records was performed. The reviewers were not specifically blinded for any clinical data when assessing CLAD or the other outcomes, but the review was performed for the database separately from this study.

    Statistical Analysis

    Statistical analysis was performed with SPSS software, version 24 (IBM Corp), with results for continuous data expressed as medians with interquartile range (IQR). Numeric data were compared with a t test and categorical data were compared with a Fisher exact test. Analyses of survival and freedom from CLAD were performed using the log-rank test. All P values were from 2-sided tests and results were deemed statistically significant at P < .05.

    Results
    Association of EVLP With Lung Transplant Activity

    Quiz Ref IDThe increased use of extended criteria donor lungs starting in 2000 allowed our program to increase the number of lung transplants from approximately 50 per year to approximately 100 per year in 2010 despite a relatively stable number of multiorgan donors. The program activity then plateaued at about 100 lung transplants per year. However, since the initiation of our EVLP program in 2008, the number of lung transplants has steadily increased, to an annual record level of 170 lung transplants in 2017 (eFigure 1 in the Supplement).

    Our EVLP activity and conversion rate (percentage of EVLP treatments leading to transplants) are shown in eFigure 2A and eFigure 2B in the Supplement. The number and conversion rate of EVLP-treated donor lungs is a mean of 69.0% (343 of 497) in our overall experience. This rate changes over time as we continue to introduce additional EVLP therapeutic interventions.

    Demographics

    A total of 936 lung transplant recipients met the inclusion criteria during the study period, of which 230 were recipients of EVLP-treated donor lungs (Figure 1). The median follow-up time was 898 days (range, 1-3364 days) in the EVLP group and 1182 days (range, 1-3411 days) in the non-EVLP group.

    Donor Characteristics

    Donor characteristics are presented in Table 1.17 The EVLP group had a higher percentage of DCD donors (95 [41.3%]) compared with the non-EVLP group (46 of 706 [6.5%]). The EVLP group donors had a significantly lower mean (SD) Pao2:FiO2 ratio than the non-EVLP group donors (348 [108] vs 422 [88] mm Hg; P < .001), higher prevalence of abnormal chest radiography results (135 of 230 [58.7%] vs 349 of 706 [49.4%]; P = .02), and higher proportion of donors with a smoking history (125 of 204 [61.3%] vs 322 of 650 [49.5%]; P = .007). Total median preservation time was prolonged in the EVLP group (914 minutes [IQR, 808-999.5 minutes] vs 481 minutes [IQR, 407-579.5 minutes]; P < .001). The median Oto donor score (range, 0-18; based on age, status with respect to a history of smoking, Pao2:FiO2 ratio, chest radiographs, and bronchoscopic findings; higher scores indicate the presence of more risk factors) was higher in the EVLP group (5.53 [IQR, 3-8] vs 4.09 [IQR, 2-6]; P < .001). The highest Oto donor score category is defined by a score of more than 7. The EVLP group had a significantly higher percentage of donors in this category compared with non-EVLP group (63 of 204 [30.9%] vs 85 of 650 [13.1%]; P < .001). Very few donor lungs did not meet 1 or more extended criteria (>55 years of age, Pao2:FiO2 ratio <300 mm Hg, abnormal chest radiograph results, ischemic time >6 hours, smoking history >20 pack-years, chest trauma, abnormal bronchoscopic findings, or positive microbiology test results). Only 15 of 937 donors (1.6%) of donors met all the criteria for standard donation and none of these donor lungs underwent EVLP.

    Recipient Characteristics

    Recipient characteristics are shown in Table 2. Baseline demographic characteristics were similar among the groups, with the exception that more recipients in the EVLP group received single-lung transplants (62 of 230 [27.0%] vs 100 of 706 [14.2%]; P < .001).

    The most common indication for lung transplant was interstitial lung disease (EVLP group, 111 of 230 [48.3%]; and non-EVLP group, 327 of 706 [46.3%]), followed by chronic obstructive pulmonary disease (EVLP group, 60 of 230 [26.1%]; and non-EVLP group, 161 of 706 [22.8%]). The percentage of patients bridged to lung transplant in the EVLP group was 6.5% (15 of 230) and in the non-EVLP group was 5.9% (42 of 706). Approximately one-fifth of the recipients in both groups had a positive donor-specific virtual crossmatch (EVLP group, 52 of 230 [22.6%]; and non-EVLP group, 151 of 706 [21.4%]).

    Primary Outcomes

    Quiz Ref IDOverall graft survival was similar among the groups (Figure 2A). Estimated allograft survival between the EVLP and non-EVLP groups was 73% vs 72% at 3 years, 62% vs 58% at 5 years, and 50% vs 44% at 9 years after transplant (log-rank P = .97). Comparable survival rates were found in single-lung transplants in both groups, as shown in Figure 2B. The survival outcomes for DCD and brain death donor lung recipients were not different (Figure 2C and D).

    Chronic lung allograft dysfunction–free survival is shown in Figure 3A. Quiz Ref IDThere were no significant differences between the groups. Estimated long-term CLAD-free survival for the EVLP and non-EVLP groups were 70% vs 72% at 3 years, 56% vs 56% at 5 years, and 53% vs 36% at 9 years (log-rank P = .68). A subanalysis of single-lung transplant recipients (Figure 3B), DCD lung transplant recipients (Figure 3C). and brain death donor lung transplant recipients (Figure 3D) did not show any differences in CLAD-free survival. There was no difference in CLAD or survival rates in bilateral-lung transplant recipients between the EVLP and non-EVLP groups. We also analyzed whether the transplant surgeon had any bearing on the outcomes, but there were no differences between groups in overall freedom from death or freedom from CLAD in our cohort.

    Secondary Outcomes

    eTable 1 in the Supplement shows the maximum posttransplant predicted percentage of forced expiratory volume in 1 second values and mean time to achieve this value in the 2 groups. There was no significant difference between the EVLP group and non-EVLP group. De novo DSAs occurred in both groups in similar proportions, and there was no difference between the groups according to their virtual cross match status (eTable 1 in the Supplement).

    Most patients developed their first acute cellular rejection and de novo DSAs within the first 6 months. eFigures 3 and 4 in the Supplement show acute cellular rejection-free survival and de novo DSA-free survival. There were no differences between the groups.

    As we have accrued more patients, we have updated and validated our prior findings regarding early posttransplant outcomes (eTable 2 in the Supplement). In the EVLP group, fewer patients had PGD grades 2 and 3 at 72 hours compared with the non-EVLP group. They also stayed in the hospital fewer days compared with the non-EVLP group, although there was no difference in intensive care unit stay. The shorter length of hospital stay was seen specifically in bilateral-lung transplant recipients and was not driven by the higher proportion of single-lung transplant recipients in the EVLP group.

    Discussion

    In this study, we show that recipients who received high-risk donor lungs that were evaluated and treated with EVLP had similar overall and CLAD-free survival compared with conventional donor lung recipients. With an increasing demand for donor organs and a scarcity of suitable organs, EVLP has enabled us to significantly increase our lung transplant activity during the last 10 years. Ex vivo lung perfusion treatment accounts for nearly one-fourth of our lung transplant activity in the past decade. In the pre-EVLP era, most EVLP-eligible donor lungs would have been discarded. In our experience, the availability of EVLP also increases the number of conventional lung transplants. Knowing that we can use EVLP, we have been confident in sending our retrieval team to evaluate donor lungs that were seemingly very high risk. In some instances, some of these donor lungs met the criteria for conventional donations after our on-site assessment while others were accepted for EVLP followed by transplantation.

    More single-lung transplants were performed in the EVLP group. This finding highlights the unique ability of EVLP to evaluate donor lungs in a more detailed and controlled manner to salvage one lung rather than discarding both lungs from seemingly unacceptable high-risk donors. Ex vivo lung perfusion enables us to assess physiological parameters to the lung lobar levels. We can also perfuse a single lung if necessary. As the overall length of stay in hospital was reduced in the EVLP group, we specifically examined if shortened length of stay was owing to more single-lung transplants occurring in this group. However, the overall length of stay was similar in patients receiving a single-lung transplant but shorter in recipients of a bilateral-lung transplant treated with EVLP (eTable 2 in the Supplement).

    The EVLP group also had significantly more DCD lung donors than did the conventional donor group. This finding reflects in part our program’s approach to DCD lung donors, as we consider them to be higher risk than brain death donors. With increasing evidence showing that DCD lung donation in selected donors is safe and feasible without EVLP, our program has started to transplant DCD donor lungs without EVLP according to surgeon comfort level.18 However, EVLP has allowed us to increase the time from withdrawal of life support to cardiac arrest to up to 3 hours and still use the donor lungs if they function adequately with EVLP.

    Although EVLP donor lungs had significantly lower Pao2 at the time of assessment and multiple other risk factors, careful assessment and reconditioning of these lungs with EVLP translated to similar short-term and long-term posttransplant outcomes. High-risk donors are often rejected owing to fear of early graft failure and development of PGD. Previous studies have shown that PGD can lead to poor long-term survival and CLAD development.19 In our study, even though the EVLP group had more high-risk donors compared with the non-EVLP group, the EVLP group had fewer patients with PGD grade 2 and 3 at 72 hours, as well as reduced duration of hospital stay. This finding further confirms previous study results.6-8

    There was no difference in the time to the first acute cellular rejection between the 2 groups. In an earlier study, EVLP treatment was associated with de novo DSA development,20 but in this larger study with longer follow-up, there was no difference in DSA development between the EVLP and non-EVLP groups. Therefore, although EVLP reconditioning involves an additional machine perfusion stage, this does not appear to affect the rate of de novo DSA development in EVLP-perfused donor lungs.

    Limitations and Strengths

    There are several limitations to our study. First, this is a retrospective single-center study and our findings may not be directly applicable to other centers. Second, the Toronto Lung Transplant Program EVLP protocol differs from that of other lung perfusion systems in several ways and there have been no comparative studies between different EVLP systems, to our knowledge. Also, we do not have data on the specific donor management of individual lungs and there may have been heterogeneity in donor lung management given the very large catchment area including both Canada and United States. We did not perform propensity score–adjusted analyses and there may be a possibility of confounding by indication. We also lack long-term data on quality of life of our patients, although in a previous study,6 there were no differences in quality of life in up to 5 years of follow-up. Furthermore, we did not perform a priori power calculations as our patient sample was limited to the transplants we have performed.

    We also did not perform cost analyses in this study. The upfront costs of EVLP are certainly higher than standard cold static preservation. For example, EVLP costs in Canada are about $15 000 in the United States (Can$19 938.75), while in the United States, costs are approximately $45 000 D (Can$59 816.25). However, one needs to have a more holistic view of overall costs of lung transplant, including organ acquisitions fee and the costs of keeping a patient on the wait list using significant medical resources and not contributing to society.

    However, despite the limitations, this study is the largest study of EVLP, to our knowledge, and all patients received standardized care, allowing for reliable comparison of recipients receiving EVLP-treated or non EVLP donor lungs.

    Conclusions

    Ex vivo lung perfusion allows for improved assessment of donor lungs that otherwise would have been rejected for transplantation owing to concerns about lung quality. Ex vivo lung perfusion has enabled our program to significantly and safely increase our lung transplant activity to offer lung transplantation to more individuals in need of this life-saving therapy. This study confirms the similar long-term outcomes of EVLP-treated high-risk extended criteria donor lungs compared with conventional donor lungs. We will continue to use this platform to develop more advanced and personalized treatment strategies to treat and repair donor lungs to further improve recipient outcomes while increasing lung transplant availability.

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    Article Information

    Accepted for Publication: July 7, 2019.

    Corresponding Author: Jussi M. Tikkanen, MD, Toronto General Hospital, 200 Elizabeth St, Toronto, ON M5G 2C4, Canada (jussi.tikkanen@uhn.ca).

    Published Online: October 9, 2019. doi:10.1001/jamasurg.2019.4079

    Author Contributions: Drs Divithotawela and Tikkanen had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Divithotawela, Cypel, Martinu, Chow, de Perrot, Yeung, Keshavjee, Tikkanen.

    Acquisition, analysis, or interpretation of data: Divithotawela, Cypel, Martinu, Singer, Binnie, Chow, Chaparro, Waddell, Pierre, Yasufuku, Donahoe, Keshavjee, Tikkanen.

    Drafting of the manuscript: Divithotawela, Chow, Tikkanen.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Divithotawela, Cypel, Yeung, Tikkanen.

    Obtained funding: Keshavjee.

    Administrative, technical, or material support: Divithotawela, Cypel, Chow, de Perrot, Yasufuku, Keshavjee, Tikkanen.

    Supervision: Divithotawela, Cypel, Martinu, Singer, Chaparro, Pierre, Keshavjee, Tikkanen.

    Conflict of Interest Disclosures: Dr Cypel reported receiving personal fees from Lung Bioengeneering; and receiving funding from XOR Labs Toronto and Perfusix Canada outside the submitted work. Dr Waddell reported receiving grants from Canadian Institutes of Health Research and nonfinancial support from Xenios/Fresenius during the conduct of the study; and having a patent to US8247175132B2 issued, a patent to US9944950B2 issued, a patent to CA2944922A1 pending and licensed, a patent to CA2966282A1 issued, a patent to US10091986B2 issued and licensed, and a patent to WO201818100A1 issued. Dr de Perrot reported receiving personal fees from Bayer outside the submitted work. Dr Keshavjee reported receiving research funding from Perfusix Canada and XOR Labs Toronto; receiving grants from United Therapeutics outside the submitted work; and having a patent to XOR Lung Perfusion pending. Dr Tikkanen reported receiving nonfinancial support from Perfusix Canada during the conduct of the study; and personal fees from CSL Behring and Boehringer-Ingelheim outside the submitted work. Drs Cypel, Waddell, and Keshavjee are founders of Perfusix Canada. This company provides ex vivo lung perfusion (EVLP) services to University Health Network. Owing to conflict of interest relative to EVLP activities as lung transplant surgeons in the institution, Drs Cypel, Waddell, and Keshavjee do not receive any payments from Perfusix Canada. Furthermore, with respect to the provision of EVLP services, Perfusix Canada is a nonprofit company that does not generate profit from EVLP activities provided for University Health Network patients. Drs Cypel, Waddell, and Keshavjee are also founders of XOR Labs Toronto, a company dedicated to development of EVLP machines. The XOR Labs Toronto EVLP machine is in development phase and was not used in the performance of this study. Lung Bioengineering acquired Perfusix USA in 2015, a company that was cofounded by Drs Cypel, Waddell, and Keshavjee. Currently, Drs Cypel, Waddell, and Keshavjee are paid consultants for Lung Bioengineering. They give strategic advice to Lung Bioengineering lung perfusion center as members of its Scientific Advisory Board. The data in the current study were collected from consented University Health Network patients in a UHN Research Ethics Board–approved study. No other disclosures were reported.

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