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. 2023 Apr 19;278(2):288–296. doi: 10.1097/SLA.0000000000005887

Evaluating the Impact of Ex Vivo Lung Perfusion on Organ Transplantation

A Retrospective Cohort Study

John K Peel *,†,‡, Eleanor M Pullenayegum ‡, David Naimark ‡,§, Meghan Aversa †, Mingyao Liu †,∥,, Lorenzo Del Sorbo †,¶,#, Kali Barrett ‡,#, Beate Sander ‡,¶,**,††, Shaf Keshavjee †,∥,¶,✉
PMCID: PMC10321509  PMID: 37073734

Background:

Ex vivo lung perfusion (EVLP) sustains and allows advanced assessment of potentially useable donor lungs before transplantation, potentially relieving resource constraints.

Objective:

We sought to characterize the effect of EVLP on organ utilization and patient outcomes.

Methods:

We performed a retrospective, before-after cohort study using linked institutional data sources of adults wait-listed for lung transplant and donor organs transplanted in Ontario, Canada between 2005 and 2019. We regressed the annual number of transplants against year, EVLP use, and organ characteristics. Time-to-transplant, waitlist mortality, primary graft dysfunction, tracheostomy insertion, in-hospital mortality, and chronic lung allograft dysfunction were evaluated using propensity score-weighted regression.

Results:

EVLP availability (P=0.01 for interaction) and EVLP use (P<0.001 for interaction) were both associated with steeper increases in transplantation than expected by historical trends. EVLP was associated with more donation after circulatory death and extended-criteria donors transplanted, while the numbers of standard-criteria donors remained relatively stable. Significantly faster time-to-transplant was observed after EVLP was available (hazard ratio=1.64 [1.41–1.92]; P<0.001). Fewer patients died on the waitlist after EVLP was available, but no difference in the hazard of waitlist mortality was observed (HR=1.19 [0.81–1.74]; P=0.176). We observed no difference in the likelihood of chronic lung allograft dysfunction before versus after EVLP was available.

Conclusions:

We observed a significant increase in organ transplantation since EVLP was introduced into practice, predominantly from increased acceptance of donation after circulatory death and extended-criteria lungs. Our findings suggest that EVLP-associated increases in organ availability meaningfully alleviated some barriers to transplant.

Keywords: organ preservation, lung transplantation, health services research, ex-vivo lung perfusion

Lung transplantation is the only definitive treatment for end-stage lung disease refractory to medical therapy; however, there persists critical scarcity of suitable lungs for transplantation: demand for lung transplantation exceeds organ availability.1–3 Mortality rates of 15% to 30% have been reported among those waitlisted for transplant, due in large part to organ scarcity.2–6 This bottleneck around donor lung availability may be attributable to conservative organ selection criteria.7,8 It has been reported that potentially useable lungs are frequently rejected using standard criteria.7 Attempts to expand the donor pool have included optimization of mechanical ventilation for donors, and consideration of donation after circulatory death (DCD) and “extended-criteria” donors.9,10 However, limited evidence and concerns about the risk of graft dysfunction with these “marginal-risk” donors have limited these strategies.10,11 Ex vivo lung perfusion (EVLP) is a promising technology which may increase organ supply by enabling further objective evaluation and rehabilitation of “marginal-risk” or initially rejected donor lungs, outside the body before transplant.10–14

The decision to fund EVLP and integrate it into transplant programs must be supported by evidence that considers the resource allocation implications of the technology. Our group previously evaluated the costs associated with EVLP, but the resource allocation and clinical implications remained unclear.15 Thus, we sought to determine whether EVLP had a meaningful impact on organ transplantation rates. Secondary objectives of this study were to characterize the effect of EVLP availability on donor lung characteristics, and on pretransplant and posttransplant patient outcomes.

METHODS

Study Overview

We performed a retrospective, before-after cohort study of patients waitlisted for first lung transplant in the Toronto Lung Transplant Program at University Health Network (UHN) in Ontario, Canada, between 2005 and 2019, and donor organs transplanted during this period. UHN is the only lung transplant program in Ontario, 1 of 4 in Canada, and is the largest in the world. We received ethics approval (UHN REB #20-5888) and adhered to the STROBE and RECORD guidelines (Supplemental Table S1, Supplemental Digital Content 1, http://links.lww.com/SLA/E581).16,17

Data Sources

Data was derived from the institutional Organ Transplant Tracking Record, Electronic Patient Record, and Toronto Lung Transplant Program databases. Records were linked deterministically according to medical record number and transplant ID.18

Population and Setting

We included donor lungs procured for transplantation in the program during the study period, excluding organs refused at retrieval, accepted solely for research, or sent to another center. We included adults 16 years or older waitlisted for first lung transplant at UHN during the study period. We excluded patients planned for repeat or multiorgan transplantation.

Exposure

We grouped patients according to EVLP availability into 3, a priori defined eras based on referral date (patients) or retrieval date (organs) relative to when EVLP was introduced into practice: pre-EVLP (January 2005–August 2008); early EVLP (August 2008–December 2012); and modern (January 2013–December 2019).15 To minimize misclassification risk, outcomes in the pre-EVLP era were censored at January 1, 2013, and posttransplant observations were limited to 2500 days.

An additional exposure of interest was EVLP use. For these analyses, we compared transplantation of lungs treated with cold-static preservation to those with EVLP. EVLP was performed according to the Toronto protocol.19

Evaluating the Impact of EVLP on Organ Transplantation

To evaluate whether EVLP availability was associated with increased transplantation, we performed an interrupted time-series using segmented regression with 2 breakpoints at the transitions between EVLP eras. This technique reduces the potential for maturation bias by comparing observed trends after an intervention to those expected by preintervention trajectories. To determine whether EVLP use corresponded to increases in the number of lungs transplanted, we regressed the annual number of transplants against year, using a negative binomial model with EVLP use treated as an effect modifier. The negative binomial distribution was selected to model “overdispersed” count data (ie, data with variance greater than the mean).20–22 P values for interaction <0.05 indicate that EVLP significantly impacted organ transplantation rates.

To determine whether EVLP differentially affected transplantation of “low-risk” versus “marginal-risk” organs, we constructed a negative binomial model regressing the annual number of transplants against year, with the following effect modifiers: EVLP use, donor type [DCD vs neurologically defined death (NDD)], and extended versus standard-criteria donor. We considered “low-risk” donors to be standard-criteria, NDD donors. Donors were classified as extended-criteria if they fulfilled at least one of the following criteria: age ≥55; smoking history ≥20 pack years; PaO2:FiO2 ratio <300 mm Hg; donor intubated ≥5 days.23 Nonlinearity was incorporated using restricted cubic splines with three knots. “Marginal-risk” donors included DCD and extended-criteria donors. Model fit was assessed using adjusted R 2.

Evaluating the Impact of EVLP on Patient Outcomes

We compared time-to-transplant, waitlist mortality, in-hospital mortality, tracheostomy insertion, duration of mechanical ventilation, primary graft dysfunction grade 3 or higher at 72 hours (PGD3) and freedom-from-CLAD between EVLP eras. We excluded the early EVLP era from these analyses. UHN introduced clinical funding for EVLP in 2013. The 2008–2013 was expected to reflect the consequences of EVLP’s implementation instead of the technology’s intended use: a priori planned exclusion of the early EVLP era was an attempt to minimize unmeasured confounding related to technology implementation.15

We performed inverse probability of treatment weighted (IPTW) analysis to account for differences across eras unrelated to EVLP availability. We calculated weights using propensity scores estimated by a generalized boosted model accounting for age, sex, ABO blood group, smoking, hypertension, diabetes, estimated glomerular filtration rate,24 transplantation from home versus hospital, and pretransplant life-support (Supplemental Table S2, Supplemental Digital Content 2, http://links.lww.com/SLA/E582).25–32 We did not adjust for donor characteristics because they are along the causal pathway. Balance was assessed using density plots of propensity scores, and plots of the standardized mean difference and Kolmogorov-Smirnov statistics (Supplemental Figs. S1, S2, Supplemental Digital Content 2, http://links.lww.com/SLA/E582).25,33 All weighted analyses were performed using the average treatment effect on the treated estimate and to evaluate the consequence of withholding EVLP in the modern era, thereby accounting for selection-maturation bias.28,30

IPTW-weighted linear, logistic, negative binomial, and cox regressions were used to evaluate continuous, binary, count, and survival-type outcomes, respectively. All regressions accounted for EVLP era, primary diagnosis (Supplemental Table S2, Supplemental Digital Content 2, http://links.lww.com/SLA/E582), single versus bilateral transplant, donor type, extended versus standard-criteria donor, waitlist duration (per-day), and posttransplant mechanical ventilation >72 hours.

Statistical Analysis

Analyses were performed in R (R-project.org, ver. 4.0.1), with a 2-sided level of significance of 0.05 unless otherwise specified.34 Univariable comparisons were performed using analysis of variance for continuous variables and Fisher exact or χ2 tests for categorical variables. One-tailed nonparametric P values for IPTW-weighted regressions were estimated as the probability of sampling bootstrapped coefficients equal to, or more extreme than, the nil-effect value.15 95% CIs were constructed using 1000 bootstrap iterations.30 The proportional hazards assumption was assessed using plots of summed scaled Schoenfeld residuals. We conducted a sensitivity analysis comparing the pre-EVLP era to all patients included after EVLP was available (post-EVLP), including both the early and modern EVLP eras, to assess whether our results would be affected by our exclusion of the early EVLP era (Supplemental Figs. S5, S6, Supplemental Digital Content 3, http://links.lww.com/SLA/E583).

RESULTS

Donor Organ Characteristics

During the study period, 1895 lungs were transplanted: 296 in the pre-EVLP era, 406 in the early era, and 1193 in the modern era (Table 1). In the modern era, 410 organs were managed on EVLP. Compared with the pre-EVLP era, transplanted organs in the modern era were from older donors [47 (±18) vs 42 (±17) years; P<0.001], and a larger proportion were from obese donors [275 (23.1%) vs 36 (12.2%); odds ratio (OR)=2.16 (1.48–3.24); P<0.001] and from donors mechanically ventilated for a longer mean duration [3.15 (±4.13) vs. 1.68 (±2.19) days; P<0.001]. Within the modern era, EVLP-treated donors had a longer duration of mechanical ventilation before procurement than those donors of non-EVLP lungs [4.42 (±5.46) vs 2.48 (±3.0) days; P<0.001]. The proportion of DCD donors was significantly higher in the modern era [292 (25%) vs 6 (2%); OR=15.6 (7.0–43.4); P<0.001]. During the modern era, ~66% of EVLP-treated lungs were transplanted (Supplemental Fig. S3, Supplemental Digital Content 2, http://links.lww.com/SLA/E582).

TABLE 1.

Donor Organ Characteristics

Pre-EVLP Early EVLP Modern EVLP Overall
No EVLP (N=296) EVLP (N=64) No EVLP (N=342) EVLP (N=410) No EVLP (N=783) EVLP (N=474) No EVLP (N=1421)
Age (y) 42.1 (16.9) 43.4 (14.9) 45.1 (18.3) 44.4 (15.9) 47.9 (18.4) 44.2 (15.8) 46.0 (18.2)
Female, n (%) 150 (50.7) 31 (48.4) 180 (52.6) 139 (33.9) 368 (47.0) 170 (35.9) 698 (49.1)
Weight (kg) 72.2 (17.1) 82.0 (22.1) 74.0 (19.0) 82.7 (19.2) 75.7 (20.1) 82.6 (19.6) 74.6 (19.3)
Height (cm) 169 (12.6) 170 (9.77) 169 (13.7) 173 (10.7) 169 (15.2) 172 (10.6) 169 (14.3)
Underweight, n (%) 9 (3.0) 17 (4.2) 10 (2.4) 38 (4.9) 11 (2.3) 63 (4.4)
Healthy BMI, n (%) 151 (51.0) 26 (40.6) 155 (45.3) 137 (33.4) 322 (41.1) 163 (34.4) 628 (44.2)
Overweight, n (%) 96 (32.4) 18 (28.1) 108 (31.6) 149 (36.3) 260 (33.2) 167 (35.2) 464 (32.7)
Obese, n (%) 36 (12.2) 19 (29.7) 62 (18.1) 114 (27.8) 161 (20.6) 133 (28.1) 259 (18.2)
Donation after circulatory death, n (%) 6 (2.0) 26 (40.6) 19 (5.6) 198 (48.3) 94 (12.0) 224 (47.3) 119 (8.4)
Neurologically defined death, n (%) 290 (98.0) 38 (59.4) 322 (94.2) 212 (51.7) 689 (88.0) 250 (52.7) 1301 (91.6)
Extended-criteria donor, n (%) 161 (54.4) 43 (67.2) 187 (54.7) 301 (73.4) 494 (63.1) 344 (72.6) 842 (59.3)
Standard-criteria donor, n (%) 135 (45.6) 21 (32.8) 155 (45.3) 109 (26.6) 289 (36.9) 130 (27.4) 579 (40.7)
Mean total lung capacity (L) (SD) 6.12 (1.40) 6.28 (1.13) 6.18 (1.26) 6.64 (1.16) 6.27 (1.31) 6.59 (1.16) 6.22 (1.32)
Mean PaO2:FiO2 (SD) 420 (125) 361 (104) 441 (89.3) 359 (108) 427 (97.8) 359 (107) 429 (102)
Mean mechanical ventilation duration (d) (SD) 1.68 (2.19) 2.72 (2.41) 1.93 (1.77) 4.42 (5.46) 2.48 (3.00) 4.17 (5.15) 2.20 (2.61)
Diabetes, n (%) 16 (5.4) 32 (7.9) 57 (13.9) 92 (11.7) 61 (12.9) 136 (9.6)
Coronary artery disease, n (%) 11 (3.7) 6 (9.4) 17 (5.0) 28 (6.8) 49 (6.3) 34 (7.2) 77 (5.4)
Infection, n (%) 16 (5.4) 28 (6.9) 26 (6.3) 37 (4.7) 29 (6.1) 78 (5.5)
ABO blood group A, n (%) 119 (40.2) 20 (31.3) 136 (39.8) 161 (39.3) 300 (38.3) 181 (38.2) 555 (39.1)
ABO blood group AB, n (%) 8 (2.7) 10 (2.5) 20 (1.7) 6 (1.3) 32 (2.3)
ABO blood group B, n (%) 28 (9.5) 10 (15.6) 45 (13.2) 37 (9.0) 108 (13.8) 47 (9.9) 181 (12.7)
ABO blood group O, n (%) 139 (47.0) 33 (51.6) 151 (44.2) 207 (50.5) 358 (45.7) 240 (50.6) 648 (45.6)
X-ray at organ retrieval, n (%)
 Normal x-ray 146 (49.3) 23 (35.9) 113 (33.0) 218 (53.2) 471 (60.2) 241 (50.8) 730 (51.4)
 Atelectasis 42 (14.2) 9 (14.1) 91 (26.6) 13 (3.2) 44 (5.6) 22 (4.6) 177 (12.5)
 Diffuse consolidation 6 (2.0) 14 (21.9) 17 (5.0) 16 (3.9) 17 (2.2) 30 (6.3) 40 (2.8)
 Focal consolidation 85 (28.7) 16 (25.0) 98 (28.7) 135 (32.9) 209 (26.7) 151 (31.9) 392 (27.6)
Donor cause of death, n (%)
 Anoxia 23 (7.8) 7 (10.9) 35 (10.2) 89 (21.7) 104 (13.3) 96 (20.3) 162 (11.4)
 Cardiovascular NR 14 (3.4) 70 (17.1) 60 (7.7) 73 (15.4) 76 (5.3)
 Medically-assisted suicide NR NR NR 8 (2.0) 9 (1.1) 8 (1.7) 9 (0.6)
 Other 23 (7.8) 20 (4.9) 25 (6.1) 35 (4.5) 30 (6.3) 73 (5.1)
 Stroke 138 (46.6) 27 (42.2) 203 (59.4) 119 (29.0) 346 (44.2) 146 (30.8) 687 (48.3)
 Trauma 56 (18.9) 11 (17.2) 57 (16.7) 57 (13.9) 152 (19.4) 68 (14.3) 265 (18.6)
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Donor characteristics were stratified by EVLP era and by EVLP use. Continuous variables are presented as mean (SD). Categorical variables are presented as count (%). Table cells representing data from fewer than 6 patients were combined with adjacent cells to minimize the risk of reidentification; where this was not possible, data was not reported (NR).

BMI indicates body mass index; EVLP, ex vivo lung perfusion.

Effect of EVLP on Organ Transplantation

The number of organs transplanted annually increased over the study period (Fig. 1A). Compared with the trend expected from the pre-EVLP era, we observed a significantly steeper increase in organ availability during the modern EVLP era (P=0.0143 for interaction); this increase in annual transplants during the modern era was greater than that expected from historical trends, suggesting that EVLP availability at our center was associated with a significant increase in organ transplantation.

FIGURE 1.

FIGURE 1

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EVLP improves organ availability. (A) The overall number of organs transplanted increased over the study period. We performed an interrupted time-series analysis using segmented regression with 2 break-points (vertical dotted lines at 2008 and 2013). The gray points indicate the annual number of organs for transplant, while each colored line is the linear regression estimate for that EVLP era, with surrounding 95% CI. A significantly steeper increase in organ availability was observed in the modern EVLP era (blue) versus the pre-EVLP era (red) (P=0.0143). (B) EVLP availability was associated with increased availability of donor organs. EVLP was attributable to this increase beyond the expected increase over time. Red circles indicate cold-static preserved organ transplantation, whereas blue triangles represent transplantation with EVLP-treated lungs. Since the magnitude of the increase (the steepness of the line) for EVLP is greater than that for non-EVLP, we may further interpret that this increase in organ availability is associated with EVLP and not simply due to the passage of time. EVLP indicates ex vivo lung perfusion.

We compared the number of annual transplants stratified by EVLP use (Fig. 1B). The majority of increased transplantation was related to utilization of EVLP-treated organs, while the number of non-EVLP transplants increased only slightly over the study period. The P value for interaction (P<0.001) indicated that EVLP use was associated with a statistically significant increase in the rate of transplantation. The slope of the increase for EVLP was significantly steeper than that for non-EVLP transplants in the same year, suggesting that the increase in organ availability was associated with EVLP use, and not simply due to the passage of time.

To examine whether EVLP differentially affected “low-risk” versus “marginal-risk” organs, the number of organs available annually was regressed against year, with interactions for EVLP use, donor type (NDD/DCD), and status as an extended versus standard criteria donor (Fig. 2). Adjusted R 2 of 0.915 indicated excellent model fit. Most transplants were non-EVLP, NDD lungs. EVLP affected the number of organs available for transplant differently among DCD/NDD and extended/standard criteria donors: when stratifying by donor type and extended-criteria donors, EVLP had a significant effect on organ availability (P<0.001 for interaction). Transplantation of extended-criteria donors increased over the study period, while the numbers of standard-criteria lungs remained relatively stable. We observed a statistically significant non-linear relationship between organ utilization and year (P<0.001), with the inflection point visually occurring around the start of the modern EVLP era. The nonlinear increase in extended-criteria + DCD donors treated with EVLP was particularly steep. This finding suggests that the introduction of EVLP may enable transplantation of extended-criteria + DCD lungs previously considered unsuitable. We observed an association between EVLP availability and increased acceptance of extended-criteria lungs for transplant in the modern era even among cold-static (non-EVLP) preserved organs. These results suggest that changes in donor organ management occurring around the time of EVLP implementation resulted in greater willingness to transplant extended-criteria and DCD donors, even when those organs were not ultimately treated with EVLP.

FIGURE 2.

FIGURE 2

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EVLP increases transplantation of extended-criteria and donation after circulatory death donors. EVLP was associated with increases in donor organs by preferentially increasing the number of DCD and extended criteria donor organs. The number of lungs available for transplantation each year was regressed against year using a negative binomial model with restricted cubic splines, and EVLP use, donor type, and status as an extended versus standard criteria donor treated as effect modifiers. The annual number of standard criteria (red) and extended criteria (blue) donors were plotted over time with accompanying trend lines produced by linear regression. The top row of panels depicts neurologically defined donors while the plots on the bottom row depict organs retrieved from donation after circulatory death. The plots on the left depict cold-static preserved organs (circles), while those on the right depict the organs that were treated with EVLP (triangles). The dashed vertical lines in each plot separate the pre-EVLP, early EVLP, and modern EVLP eras. DCD indicates donation after circulatory death; EVLP, ex vivo lung perfusion; NDD, neurologically defined death.

Effect of EVLP Availability on Patient Outcomes

A larger proportion of patients in the modern era underwent transplantation [761/853 (89%)] versus the pre-EVLP era [289/356 (81%)]. Patients in the modern era tended to be older, higher urgency, and with higher frequency of comorbid conditions (Supplemental Table S3, Supplemental Digital Content 2, http://links.lww.com/SLA/E582). A greater proportion of patients in the modern era had restrictive lung disease. In unadjusted analyses, fewer patients in the modern EVLP era required mechanical ventilation >72 hours immediately posttransplant, and fewer patients had tracheostomy insertion or chronic lung allograft dysfunction in the modern EVLP era.

We observed shorter median time-to-transplant in the modern era [66 (55–74) days vs 126 (101–168) days], with significantly higher likelihood of transplantation per day [hazard ratio (HR)=1.64 (1.41–1.92); P<0.001] (Fig. 3A). Compared with obstructive disease, restrictive disease was associated with a lower likelihood of transplantation [HR=0.80 (0.68–0.93); P=0.001] while suppurative disease was associated with a higher likelihood [HR=1.34 (1.09–1.69); P=0.003] (Supplemental Table S4, Supplemental Digital Content 2, http://links.lww.com/SLA/E582). The unadjusted proportion of patients who died on the waitlist was smaller in the modern era [81/853 (9%) vs 62/356 (17%); OR=0.49 (0.34–0.72); P<0.001]. In IPTW-survival analyses, no significant difference was observed in waitlist mortality between eras [HR=1.19 (0.81–1.74); P=0.176]. However, compared with obstructive disease, restrictive [HR=2.58 (1.46–5.10); P<0.001] and pulmonary vascular diseases [HR=3.87 (1.89–8.57); P=0.001] were associated with higher likelihood of waitlist mortality (Supplemental Table S4, Supplemental Digital Content 2, http://links.lww.com/SLA/E582). In sensitivity analysis, we similarly observed significantly shorter time-to-transplant with no significant difference in the likelihood of waitlist mortality (Supplemental Fig. S7 and Supplemental Table S6, Supplemental Digital Content 3, http://links.lww.com/SLA/E583).

FIGURE 3.

FIGURE 3

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Kaplan-Meier analyses of patient outcomes. Inverse probability of treatment (IPTW)-weighted Kaplan-Meier analyses of time to transplant, time to waitlist mortality, and freedom from chronic lung allograft dysfunction (CLAD). Median survival times are shown by the dashed lines. IPTW-weighted cox regression results are presented as hazard ratios (HR) with corresponding 95% CIs and P values for comparisons between eras, with the pre-EVLP era as reference. (A) Cumulative incidence plot of time to transplant. Median time-to-transplant was significantly shorter in the modern EVLP era [66 (55–74) days vs 126 (101–168) days], with a significantly higher likelihood of transplantation per waitlist day [HR=1.64 (1.41–1.92); P<0.001], suggesting that EVLP availability improved access to transplantation during the study period. (B) Kaplan-Meier survival curve of time to waitlist mortality. There was no significant association between EVLP availability and the likelihood of waitlist mortality among waitlisted patients [HR=1.19 (0.81–1.74); P=0.176]. (C) Kaplan-Meier survival estimates of freedom from CLAD. No statistically significant difference was observed in the likelihood of CLAD across era, regardless of whether patients received EVLP-treated [HR=0.95 (0.63–1.43); P=0.417] or non-EVLP lungs [HR=1.31 (0.97–1.87); P=0.043]. Median survival estimates ranged between 1294 (1075–1537) days for the modern era without EVLP to 1678 (1380–2094) days in the pre-EVLP era. CLAD indicates chronic lung allograft dysfunction; EVLP, ex vivo lung perfusion; HR, hazard ratio; IPTW, inverse probability of treatment-weighted.

Patients in the modern era required shorter duration mechanical ventilation [4.3 (1.8–7.0) days; P<0.001 with EVLP; 4.5 (2.3–6.9) days; P<0.001 without EVLP] compared with those in the pre-EVLP era (Supplemental Table S4, Supplemental Digital Content 2, http://links.lww.com/SLA/E582). Relatively, those in the modern era receiving EVLP-treated lungs were ventilated for 0.57 (0.42–0.84) times as long, and modern era recipients of non-EVLP lungs were ventilated for 0.52 (0.41–0.73) times as long (Supplemental Table S4, Supplemental Digital Content 2, http://links.lww.com/SLA/E582). Shorter mechanical ventilation duration in the modern era corresponded to significantly lower likelihood of tracheostomy insertion. Compared with the pre-EVLP era [40/289 (14%)], we did not observe a difference in the likelihood of PGD3 across eras [53/265 (20%); OR=0.82 (0.43–1.71; P=0.301) in the modern era with EVLP, versus 107/496 (22%); 1.16 (0.73–1.87); P=0.253 in the modern era without EVLP]. In-hospital mortality was overall rare, but significantly fewer in-hospital deaths were observed in the modern era with EVLP [10/265 (4%); OR=0.33 (0.12–0.75); P=0.005] and without EVLP [25/496 (5%); OR=0.39 (0.18–0.85); P=0.01] compared with the pre-EVLP era [24/289 (8%)]. We observed largely similar patient outcomes from sensitivity analysis to those from the main analysis (Supplemental Fig. S7, Supplemental Table S6, Supplemental Digital Content 3, http://links.lww.com/SLA/E583).

Smaller proportions of patients experienced CLAD in the modern era [52/263 (20%) with EVLP; 121/492 (25%) without EVLP] versus the pre-EVLP era [137/285 (48%)]. However, we did not observe any significant difference in the hazard of CLAD across eras, regardless of whether patients received EVLP-treated [HR=0.95 (0.63–1.43); P=0.417] or non-EVLP lungs [HR=1.31 (0.97–1.87); P=0.043] (Fig. 3) (Supplemental Table S4, Supplemental Digital Content 2, http://links.lww.com/SLA/E582). Pulmonary vascular disease appeared to have a reduced likelihood of CLAD [HR=0.44 (0.14–0.87); P=0.005] (Supplemental Table S4, Supplemental Digital Content 2, http://links.lww.com/SLA/E582). No significant difference in the likelihood of postdischarge mortality was observed between eras (Supplemental Fig. S4, Supplemental Table S5, Supplemental Digital Content 2, http://links.lww.com/SLA/E582). In sensitivity analysis, we observed significantly lower likelihood of posttransplant mortality in the post-EVLP era for patients who received EVLP-treated lungs as well as for those who received conventionally-preserved lungs (Supplemental Fig. S7, Supplemental Table S6, Supplemental Digital Content 3, http://links.lww.com/SLA/E583). Horizontal trends on the plots of Schoenfeld residuals suggested that there were no major violations of the proportional hazards assumption.

DISCUSSION

Our study has demonstrated significant increases in transplantation coinciding with the implementation of EVLP. Donor characteristics in the modern era tended to reflect more permissive selection. The association between EVLP and increased transplantation was predominantly due to increased acceptance of extended-criteria and extended-criteria + DCD donors. EVLP-associated increases in organ availability coincided with significantly shorter time-to-transplant, shorter postoperative mechanical ventilation, and lower likelihood of tracheostomy insertion or in-hospital mortality, suggesting that these increases in organ availability may be associated with improved access to transplantation and improved patient outcomes.

The evidence is increasingly clear that EVLP has an important role in the evaluation, preservation, and optimization of “marginal-risk” and initially declined donor lungs. Short duration ex vivo evaluation of potential donor lungs was first described in 2006, with the first transplant of EVLP-treated lungs occurring in 2007.35 Since then, EVLP systems have been improved upon to now enable safe transplantation of organs preserved for 12 hours or longer.1,11,36–39 Our finding that EVLP improved organ availability is consistent with the literature that EVLP may expand the donor pool.10,11,14,40,41 Boffini et al10 reported that EVLP increased numbers of organs for transplantation, but this study enrolled only 23 EVLP-treated lungs, with minimal statistical analysis. Similarly, Wallinder et al14 demonstrated that previously-rejected lungs could be safely transplanted after EVLP. The use of EVLP for extended-criteria and extended-criteria + DCD lungs is supported by a large and growing body of evidence, and our study further contributes to this literature.11,40,41 Machuca et al (2015) found shorter hospital length-of-stay following transplantation of DCD lungs treated with EVLP versus without, and Divithotawela and colleagues observed no difference in survival or CLAD between patients receiving EVLP versus cold-static preserved DCD lungs at our center.11,41 In an individual patient data meta-analysis, of 13 studies including 2172 patients (407 EVLP-treated), Chakos et al42 found no significant difference in the likelihood of PGD3, 30-day mortality, or 36-month mortality between patients receiving EVLP-treated versus non-EVLP lungs.

Our observation that likelihood of CLAD and PGD3 were similar across eras, despite increased transplantation of extended-criteria and extended-criteria + DCD lungs in the modern era, is a significant and reassuring finding: although concerns about the risk of graft dysfunction with these “marginal-risk” donors have limited uptake of EVLP, we found no evidence that transplantation with these organs in the modern era was associated with graft dysfunction.10,11 Our observations of shorter duration mechanical ventilation and decreased likelihoods of tracheostomy or in-hospital mortality in the modern era may further encourage the use of EVLP.

Interestingly, we observed increased transplantation of extended-criteria, non-EVLP lungs in the modern era. This finding suggests that having EVLP as an option may modify surgical decision-making, a hypothesis consistent with experiences at other centers: Murala et al43 reported that knowing EVLP is available at their center, in case it is needed, has allowed their team to consider, travel to evaluate, and accept more extended-criteria lungs. In some cases, those additional organs evaluated were deemed suitable for transplantation without EVLP, thereby increasing donor lung availability because of a system-level change produced by having EVLP available.43 This phenomenon of “indirect growth” of the donor pool is anecdotally well acknowledged, and is becoming increasingly well described in the literature.44 Having access to EVLP as a backup for suboptimal quality lungs may alter surgeon willingness to travel to evaluate and accept donor organs; even when EVLP is not used for a case, having it available likely contributes to a behavior change and more aggressive selection.44 Furthermore, given the association between ischemic time and adverse outcome, it has also been suggested that having EVLP available lifts some of the logistic and practical constraints that would otherwise discourage donor lung acceptance. For example, poor weather conditions, potentially protracted travel times, the need for prospective crossmatching, and inadequate operating room availability are all logistic reasons donor lungs might be declined that become less important when EVLP is available.44–47 In some of these instances, EVLP may not be necessary, but without the technology available “just in case,” any of these potential logistics barriers might be reason to decline a donor.

The shorter time-to-transplant in the modern era suggests that EVLP availability may help alleviate the bottleneck around timely transplantation. This finding is consistent with our previous observation that the modern era was associated with lower probability of waitlist occupancy (with consequent higher posttransplant occupancy).15 While the proportion of patients who died on the waitlist was lower in the modern era, we did not observe a difference in the hazard of waitlist mortality between eras using survival analyses. A possible explanation is that EVLP availability does not directly affect the likelihood of waitlist mortality, but EVLP-mediated increases in organ availability and shorter time-to-transplant means there are fewer patients at-risk of waitlist mortality when EVLP is available. Since survival analyses censor patients not at-risk of an outcome, we expect the rate of mortality among waitlisted (at-risk) patients to be similar between eras, which was observed. In addition, the multifactorial etiology of pretransplant deaths may contribute an explanation: restrictive and pulmonary vascular diseases were associated with higher likelihood of waitlist mortality and lower likelihood of receiving an organ. We previously reported a considerably higher incidence of restrictive disease in the modern era: increased enrollment of these higher risk patients reflects a shift in practice that offsets any expected improvement caused by increased organ availability.15 Our observation that the likelihood of PGD3 was not affected by EVLP era may be additionally explained by this phenomenon. Increased transplantation of “higher risk” patients may offset expected reductions in post-transplant graft dysfunction. Nevertheless, our finding that PGD3 likelihood is not higher in the modern era, despite increased transplantation of extended-criteria + DCD lungs, is reassuring.

A limitation is that data linkage across multiple databases was necessary. This exposed our study to the risk of linkage error bias, which we mitigated by analyzing unlinked datasets separately whenever possible. Linkage error may manifest as missing data, misclassification, or erroneous inclusion/exclusion of people from analysis; variable numbers of patients for certain analyses in our study may indicate the presence of linkage error.18 An additional limitation is that donor lungs were grouped according to the date of procurement whereas patients were grouped according to their referral date. As a result, group sizes differ between analyses of donor organs and analyses of transplant patients. For analyses of patient outcomes, we chose to exclude the early era because this era was thought to reflect the transition and consequences of EVLP implementation. However, this may have introduced selection bias and could therefore be considered a limitation. We mitigated this risk by conducting sensitivity analyses inclusive of the early era, which demonstrated similar results except for our observation that post-transplant mortality was significantly less likely in the post-EVLP era. This finding is reassuring, and may encourage the use of EVLP further. It also suggests that our exclusion of the early EVLP era may render our main analysis results more conservative. It is notable that the Toronto Lung Transplant Program at UHN is the largest and most historical lung transplant program in the world. There are few other institutions with similar expertise, resources, or referral volumes. Since it has been previously demonstrated that program volume affects cost-effectiveness, patient outcomes, and overall program efficiency, the external validity of our results may be impacted.48–59 Despite this, our results are proportional to other jurisdictions that similarly reported increases in organ transplantation upon implementation of EVLP to their site.10,11,14,40,41 A limitation in our before-after design is the risk of bias occurring from baseline covariate differences between groups due to the passage of time, which we mitigated statistically by performing interrupted time-series analyses and IPTW. Projections from historical data by interrupted time-series assume linearity; since these relationships may not be linear, this assumption constitutes a limitation. The strengths of IPTW for retrospective observational research outweigh its limitations, but those limitations nevertheless exist and have been previously discussed.15 Notably, we had insufficient surgical variables to evaluate the effect of operative characteristics on our outcomes of interest; one may argue that improvements we observed may be due to differences in surgical technique. While perioperative transfusion, circulatory support, and surgical duration may affect certain outcomes, these variables were not reliably available in the administrative datasets we accessed. We mitigated for this in our analysis of postoperative patient outcomes by stratifying patients in the modern era according to EVLP use, thereby allowing for a more contemporaneous comparison. One might attribute our results to increases in organ donation during the study period. However, the numbers of standard-criteria donors remained relatively stable through the study period, and our time-series analyses suggested that EVLP availability was associated with significant increases in organ availability beyond what would be expected from historical trends (which would account for increases in organ donation). Similarly, one may argue that recent advances in antimicrobial treatment and immunomodulation of donor lungs contribute to the higher rates of transplantation in the modern era. While these are innovative applications of EVLP that may contribute to further increases in donor organ supply in the future, these applications of EVLP were restricted to research purposes at our site during the study period, and only represent a minority of transplants.60–62

Strengths of this study are that we quantified increases in transplantation, distinguished these increases from those expected over time, and characterized how EVLP availability has changed the donor pool. Our study demonstrates that EVLP meaningfully improved access to transplantation by accessing a previously unusable supply of organs.

CONCLUSIONS

This study has demonstrated an association between EVLP and increased organ transplantation. Overall, more permissive organ selection was observed since EVLP’s implementation, with significantly increased acceptance of DCD and extended-criteria lungs for transplantation. EVLP-associated increases in organ availability at our center coincided with significantly shorter time-to-transplant and improved patient outcomes, indicating that EVLP was associated with meaningful improvements in access to lung transplantation.

Supplementary Material

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ACKNOWLEDGMENTS

To the authors thank the late Dr Murray Krahn, Dr. Lianne Singer, the Toronto Lung Transplant Program research team, and the team at the Toronto Health Economics and Technology Assessment (THETA) collaborative for their mentorship and contribution to the study conceptualization.

Footnotes

J.K.P.: This author is the primary author of the work, and this paper represents a component of the author’s PhD dissertation work. This author made substantial contributions to conception and design, acquisition of data, and both analysis and interpretation of data. This author participated in drafting the article and revising it critically. This author gave approval of the version to be published. E.M.P.: This author is a statistical and epidemiology expert. This author sits on the PhD committee for J.K.P. This author made substantial contributions to conception and design, analysis and interpretation of data. This author participated revising the manuscript critically. This author gave approval of the version to be published. D.N.: this author is a statistical and epidemiology expert. This author sits on the PhD committee for J.K.P. This author made substantial contributions to conception and design, analysis and interpretation of data. This author participated revising the manuscript critically. This author gave approval of the version to be published. M.A.: This author is a clinical content-area expert (transplant respirology). This author made substantial contributions to conception and design, and interpretation of data. This author participated revising the manuscript critically. This author gave approval of the version to be published. M.L.: This author is a clinical content-area expert (transplant surgery). This author made substantial contributions to conception and design, and interpretation of data. This author participated revising the manuscript critically. This author gave approval of the version to be published. L.D.S.: This author is a clinical content-area expert (transplant critical care). This author made substantial contributions to conception and design, and interpretation of data. This author participated revising the manuscript critically. This author gave approval of the version to be published. K.B.: This author is a clinical content-area expert (transplant critical care). This author made substantial contributions to conception and design, and interpretation of data. This author participated revising the manuscript critically. This author gave approval of the version to be published. B.S.: This author is a statistical and epidemiology expert. This author is a PhD co-supervisor for J.K.P. This author made substantial contributions to conception and design, acquisition of data, and both analysis and interpretation of data. This author participated in revising the manuscript critically. This author gave approval of the version to be published. S.K.: This author is a clinical content-area expert (transplant surgery and transplant program administration). This author is a PhD co-supervisor for J.K.P. This author made substantial contributions to conception and design, acquisition of data, and both analysis and interpretation of data. This author participated in revising the manuscript critically. This author gave approval of the version to be published.

J.K.P. was involved in study design, data analysis, writing of manuscript, and acquisition of funding. J.K.P. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. E.P. and D.N. were involved in study design, and data analysis. S.K. and B.S. were involved in study design, data analysis, and acquisition of funding. All authors participated in revision of the manuscript and gave approval for publication. All listed authors contributed sufficiently to qualify for authorship.

This research was supported, in part, by a Canada Research Chair in Economics of Infectious Diseases held by Beate Sander (CRC-950-232429). Dr. Keshavjee is Chief Medical Officer of Traferox Technologies and has received consulting fees from Lung Bioengineering, both outside the submitted work.

J.K.P. has been supported by the Canadian Institutes of Health Research (CIHR) CGS-M award, CIHR Fellowship, Ontario Graduate Scholarship, UofT Graduate Fellowship. B.K. scholarship from UHN, and PSI Foundation Resident Research grant. The remaining authors report no conflicts of interest.

Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal's website, www.annalsofsurgery.com.

Contributor Information

John K. Peel, Email: john.peel@mail.utoronto.ca.

Eleanor M. Pullenayegum, Email: eleanor.pullenayegum@sickkids.ca.

David Naimark, Email: David.Naimark@sunnybrook.ca.

Meghan Aversa, Email: meghan.aversa@uhn.ca.

Mingyao Liu, Email: Mingyao.Liu@uhnresearch.ca.

Lorenzo Del Sorbo, Email: Lorenzo.delSorbo@uhn.ca.

Kali Barrett, Email: Kali.Barrett@uhn.ca.

Beate Sander, Email: beate.sander@uhnresearch.ca.

Shaf Keshavjee, Email: shaf.keshavjee@uhn.ca.

REFERENCES

  • 1. Yeung JC, Keshavjee S. Overview of clinical lung transplantation. Cold Spring Harb Perspect Med. 2014;4:a015628–a015628. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. Valapour M, Lehr CJ, Skeans MA, et al. OPTN/SRTR 2016 annual data report: lung. Am J Transplant. 2018;18(suppl 1):363–433. [DOI] [PubMed] [Google Scholar]
  • 3. Canadian Institute for Health Information/Institut canadien d’information sur la santé. Annual Statistics on Organ Replacement in Canada: dialysis, transplantation and donation, 2010 to 2019–6. Ottawa, ON: CIHI; 2020. [Google Scholar]
  • 4. Canadian Institute for Health Information/ Institut canadien d’information sur la santé. Canadian organ replacement register annual report: treatment of end-stage organ failure in Canada, 2004 to 2013. Ottawa, ON: CIHI; 2015. [Google Scholar]
  • 5. Canadian Institute for Health Information (CIHI). Annual statistics on organ replacement in Canada: dialysis, transplantation and donation, 2007 to 2016. CIHI Snapshot. 2017:1–9. doi: 10.1007/s11845-012-0882-x. [DOI]
  • 6. Fisher A, Andreasson A, Chrysos A, et al. An observational study of donor ex vivo lung perfusion in UK lung transplantation: DEVELOP-UK. Health Technol Assess. 2016;20:1–276. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. Fisher AJ. Objective assessment of criteria for selection of donor lungs suitable for transplantation. Thorax. 2004;59:434–437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Chaney J, Suzuki Y, Cantu E, et al. Lung donor selection criteria. J Thorac Dis. 2014;6:1032–1038. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. Mascia L, Pasero D, Slutsky AS, et al. Effect of a lung protective strategy for organ donors on eligibility and availability of lungs for transplantation: a randomized controlled trial. JAMA. 2010;304:2620–2627. [DOI] [PubMed] [Google Scholar]
  • 10. Boffini M, Ricci D, Barbero C, et al. Ex vivo lung perfusion increases the pool of lung grafts: analysis of its potential and real impact on a lung transplant program. Transplant Proc. 2013;45:2624–2626. [DOI] [PubMed] [Google Scholar]
  • 11. Divithotawela C, Cypel M, Martinu T, et al. Long-term outcomes of lung transplant with ex vivo lung perfusion. JAMA Surg. 2019;154:1–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Van Raemdonck D, Neyrinck A, Cypel M, et al. Ex-vivo lung perfusion. Transpl Int. 2014;28:643–656. [DOI] [PubMed] [Google Scholar]
  • 13. Andreasson ASI, Dark JH, Fisher AJ. Ex vivo lung perfusion in clinical lung transplantation—state of the art. Eur J Cardiothorac Surg. 2014;46:779–788. [DOI] [PubMed] [Google Scholar]
  • 14. Wallinder A, Ricksten SE, Silverborn M, et al. Early results in transplantation of initially rejected donor lungs after ex vivo lung perfusion: a case-control study. Eur J Cardiothorac Surg. 2013;45:40–45. [DOI] [PubMed] [Google Scholar]
  • 15. Peel JK, Keshavjee S, Naimark D, et al. Determining the impact of ex-vivo lung perfusion on hospital costs for lung transplantation: a retrospective cohort study. J Heart Lung Transplant. 2022;42:1–50. [DOI] [PubMed] [Google Scholar]
  • 16. Elm von E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370:1453–1457. [DOI] [PubMed] [Google Scholar]
  • 17. Benchimol EI, Smeeth L, Guttmann A, et al. The REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) statement. PLoS Medicine. 2015;12:e1001885. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Doidge JC, Harron KL. Reflections on modern methods: linkage error bias. Int J Epidemiol. 2019;48:2050–2060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Cypel M, Yeung JC, Hirayama S, et al. Technique for prolonged normothermic ex vivo lung perfusion. J Heart Lung Transplant. 2008;27:1319–1325. [DOI] [PubMed] [Google Scholar]
  • 20. Ver Hoef JM, Boveng PL. Quasi-Poisson vs. negative binomial regression: how should we model overdispersed count data? Ecology. 2007;88:2766–2772. [DOI] [PubMed] [Google Scholar]
  • 21. Gardner W, Mulvey EP, Shaw EC. Regression analyses of counts and rates: Poisson, overdispersed Poisson, and negative binomial models. Psychol Bull. 1995;118:392–404. [DOI] [PubMed] [Google Scholar]
  • 22. Peel JK, Trudeau J, Tano R, et al. Determining optimal treatment to correct preoperative anemia and reduce perioperative allogeneic blood transfusions in cardiac surgery: a retrospective cohort study. J Cardiothorac Vasc Anesth. 2021;35:2631–2639. [DOI] [PubMed] [Google Scholar]
  • 23. Aigner C, Winkler G, Jaksch P, et al. Extended donor criteria for lung transplantation—a clinical reality. Eur J Cardiothorac Surg. 2005;27:757–761. [DOI] [PubMed] [Google Scholar]
  • 24. Inker LA, Eneanya ND, Coresh J, et al. New creatinine- and cystatin C-based equations to estimate GFR without race. N Engl J Med. 2021;385:1737–1749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. McCaffrey DF, Griffin BA, Almirall D, et al. A tutorial on propensity score estimation for multiple treatments using generalized boosted models. Stat Med. 2013;32:3388–3414. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. Austin PC, Stuart EA. Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies. Stat Med. 2015;34:3661–3679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27. Austin PC. The use of propensity score methods with survival or time-to-event outcomes: reporting measures of effect similar to those used in randomized experiments. Stat Med. 2014;33:1242–1258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. Schulte PJ, Mascha EJ. Propensity score methods: theory and practice for anesthesia research. Anesth Analg. 2018;127:1074–1084. [DOI] [PubMed] [Google Scholar]
  • 29. Olmos A, Govindasamy P. A practical guide for using propensity score weighting in R. Practical assessment, research, and evaluation. 2015;20:1–8. [Google Scholar]
  • 30. Austin PC. Variance estimation when using inverse probability of treatment weighting (IPTW) with survival analysis. Stat Med. 2016;35:5642–5655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Ali MS, Prieto-Alhambra D, Lopes LC, et al. Propensity score methods in health technology assessment: principles, extended applications, and recent advances. Front Pharmacol. 2019;10:973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. Stuart EA. Matching methods for causal inference: a review and a look forward. Stat Sci. 2010;25:1–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33. Zhou T, Tong G, Li F, et al. PSweight: an R package for propensity score weighting analysis. arXiv. 2021;VV(II):1–35. [Google Scholar]
  • 34. R Core Team. R: A language and environment for statistical computing. 2020.
  • 35. Steen S, Ingemansson R, Eriksson L, et al. First human transplantation of a nonacceptable donor lung after reconditioning ex vivo. Ann Thorac Surg. 2007;83:2191–2194. [DOI] [PubMed] [Google Scholar]
  • 36. 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;5:119–124. [DOI] [PubMed] [Google Scholar]
  • 37. Cypel M, Yeung JC, Liu M, et al. Normothermic ex vivo lung perfusion in clinical lung transplantation. N Engl J Med. 2011;364:1431–1440. [DOI] [PubMed] [Google Scholar]
  • 38. 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;144:1200–1206. [DOI] [PubMed] [Google Scholar]
  • 39. Cypel M, Yeung JC, Keshavjee S. Introducing the concept of semielective lung transplantation through the use of ex vivo lung perfusion. J Thorac Cardiovasc Surg. 2018;156:2350–2352. [DOI] [PubMed] [Google Scholar]
  • 40. Loor G, Warnecke G, Villavicencio MA, et al. Portable normothermic ex-vivo lung perfusion, ventilation, and functional assessment with the Organ Care System on donor lung use for transplantation from extended-criteria donors (EXPAND): a single-arm, pivotal trial. Lancet Respir Med. 2019;7:975–984. [DOI] [PubMed] [Google Scholar]
  • 41. 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. [DOI] [PubMed] [Google Scholar]
  • 42. Chakos A, Ferret P, Muston B, et al. Ex-vivo lung perfusion versus standard protocol lung transplantation-mid-term survival and meta-analysis. Ann Cardiothorac Surg. 2020;9:1–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43. Murala JS, Whited WM, Banga A, et al. Ex vivo lung perfusion: how we do it. Indian J Thorac Cardiovasc Surg. 2021;37:433–444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44. Ahmad K, Pluhacek JL, Brown AW. Ex vivo lung perfusion: a review of current and future application in lung transplantation. Pulm Ther. 2022;8:149–165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45. Fitch ZW, Doberne J, Reynolds JM, et al. Expanding donor availability in lung transplantation: a case report of 5000 miles traveled. Am J Transplant. 2021;21:2269–2272. [DOI] [PubMed] [Google Scholar]
  • 46. Okahara S, Levvey B, McDonald M, et al. A retrospective review of declined lung donors: estimating the potential of ex vivo lung perfusion. Ann Thorac Surg. 2021;112:443–449. [DOI] [PubMed] [Google Scholar]
  • 47. De Wolf J, Puyo P, Bonnette P, et al. Logistic ex vivo lung perfusion for hyperimmunized patients. Ann Thorac Surg. 2016;102:e205–e206. [DOI] [PubMed] [Google Scholar]
  • 48. Vasiliadis H-M, Collet J-P, Penrod JR, et al. A cost-effectiveness and cost-utility study of lung transplantation. JHLT. 2005;24:1275–1283. [DOI] [PubMed] [Google Scholar]
  • 49. Groen H, van der Bij W, Koeter GH, et al. Cost-effectiveness of lung transplantation in relation to type of end-stage pulmonary disease. Am J Transplant. 2004;4:1155–1162. [DOI] [PubMed] [Google Scholar]
  • 50. Charman SC, Sharples LD, McNeil KD, et al. Assessment of survival benefit after lung transplantation by patient diagnosis. J Heart Lung Transplant. 2002;21:226–232. [DOI] [PubMed] [Google Scholar]
  • 51. Hosenpud JD, Bennett LE, Keck BM, et al. Effect of diagnosis on survival benefit of lung transplantation for end-stage lung disease. Lancet. 1998;351:24–27. [DOI] [PubMed] [Google Scholar]
  • 52. Vogl M, Warnecke G, Haverich A, et al. Lung transplantation in the spotlight: reasons for high-cost procedures. JHLT. 2016;35:1227–1236. [DOI] [PubMed] [Google Scholar]
  • 53. George TJ, Beaty CA, Kilic A, et al. Outcomes and temporal trends among high-risk patients after lung transplantation in the United States. JHLT. 2012;31:1182–1191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54. Anyanwu AC, McGuire A, Rogers CA, et al. An economic evaluation of lung transplantation. J Thorac Cardiovasc Surg. 2002;123:411–420. [DOI] [PubMed] [Google Scholar]
  • 55. Ouwens JP, van Enckevort PJ, TenVergert EM, et al. The cost effectiveness of lung transplantation compared with that of heart and liver transplantation in the Netherlands. Transpl Int. 2003;16:123–127. [DOI] [PubMed] [Google Scholar]
  • 56. van den Berg JW, van Enckevort PJ, TenVergert EM, et al. Bronchiolitis obliterans syndrome and additional costs of lung transplantation. Chest. 2000;118:1648–1652. [DOI] [PubMed] [Google Scholar]
  • 57. Mooney JJ, Weill D, Boyd JH, et al. Effect of transplant center volume on cost and readmissions in medicare lung transplant recipients. Annals ATS. 2016;13:1034–1041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58. Hayes D, Tobias JD, Tumin D. Center volume and extracorporeal membrane oxygenation support at lung transplantation in the lung allocation score era. Am J Respir Crit Care Med. 2016;194:317–326. [DOI] [PubMed] [Google Scholar]
  • 59. Hayes D, Hartwig MG, Tobias JD, et al. Lung transplant center volume Ameliorates adverse influence of prolonged ischemic time on mortality. Am J Transplant. 2017;17:218–226. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60. Nakajima D, Cypel M, Bonato R, et al. Ex vivo perfusion treatment of infection in human donor lungs. Am J Transplant. 2016;16:1229–1237. [DOI] [PubMed] [Google Scholar]
  • 61. Michaelsen VS, Ribeiro RVP, Ali A, et al. Safety of continuous 12-hour delivery of antimicrobial doses of inhaled nitric oxide during ex vivo lung perfusion. J Thorac Cardiovasc Surg. 2022;163:841–849.e841. [DOI] [PubMed] [Google Scholar]
  • 62. Cypel M, Feld JJ, Galasso M, et al. Prevention of viral transmission during lung transplantation with hepatitis C-viraemic donors: an open-label, single-centre, pilot trial. Lancet Respir Med. 2020;8:192–201. [DOI] [PubMed] [Google Scholar]

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