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Annals of Cardiothoracic Surgery logoLink to Annals of Cardiothoracic Surgery
. 2020 Jan;9(1):1–9. doi: 10.21037/acs.2020.01.02

Ex-vivo lung perfusion versus standard protocol lung transplantation—mid-term survival and meta-analysis

Adam Chakos 1,2,, Paule Ferret 1, Benjamin Muston 1, Tristan D Yan 1,2,3, David H Tian 1,4
PMCID: PMC7049550  PMID: 32175234

Abstract

Background

While extended criteria lung donation has helped expand the lung donor pool, utilization of lungs from donors of at least one other solid organ is still limited to around 15–30%. Ex-vivo lung perfusion (EVLP) offers the ability to expand the number of useable lung grafts through assessment and reconditioning of explanted lungs, particularly those not initially meeting criteria for transplantation. This meta-analysis aimed to examine the mid- to long-term survival and other short-term outcomes of patients transplanted with EVLP-treated lungs versus standard/cold-storage protocol lungs.

Methods

Literature search of ten medical databases was conducted for original studies involving “ex-vivo lung perfusion” and “EVLP”. Included articles were assessed by two independent researchers, survival data from Kaplan-Meier curves digitized, and individual patient data imputed to conduct aggregated survival analysis. Meta-analyses of suitably reported outcomes were conducted using a random-effects model.

Results

Thirteen studies met inclusion criteria, with a total of 407 EVLP lung transplants and 1,765 as per standard/cold storage protocol. One study was a randomized controlled trial while the remainder were single-institution cohort series of varying design. The majority of donor lungs were from brain death donors, with EVLP lungs having significantly worse PaO2/FiO2 ratio and significantly greater rate of abnormal chest X-ray. Aggregated survival analysis of all included studies revealed no significant survival difference for EVLP or standard protocol lungs (hazard ratio 1.00; 95% confidence interval: 0.79–1.27, P=0.981). Survival at 12, 24, and 36 months for the EVLP cohort was 84%, 79%, and 74%, respectively. Survival at 12, 24, and 36 months for the standard protocol cohort was 85%, 79%, and 73%, respectively. Meta-analysis did not find a significant difference in risk of 30-day mortality or primary graft dysfunction grade 3 at 72 hours between cohorts.

Conclusions

There was no significant difference in mid- to long-term survival of EVLP lung transplant patients when compared to standard protocol donor lungs. The incidence of 30-day mortality and primary graft dysfunction grade 3 at 72 hours did not differ significantly between groups. EVLP offers the potential to increase lung donor utilization while providing similar short-term outcomes and mid- to long-term survival.

Keywords: Ex-vivo lung perfusion (EVLP), lung transplantation, meta-analysis, survival

Introduction

While lung transplantation (LTx) for patients with end-stage pulmonary disease can be a life-saving measure, the scarcity of suitable donor lungs results in up to 30% of these patients dying while on the waiting list (1,2). Obtaining donor organs for LTx is particularly problematic, with donors of at least one other solid organ only having suitable lungs in 15–30% of cases according to current assessment criteria (3-5). End-of-life care, be it in the intensive care unit or otherwise, often results in damage to potential grafts and even under optimal donor circumstances, brain death still has the deleterious effect of causing neurogenic edema and a cytokine storm-induced inflammatory response (6).

Standard transplant protocols developed and refined since the 1960’s involve infusion of the donor lung with a specially formulated perfusate before inflation of the lung, stapling of the trachea, and cold preservation until transplantation (7). In contrast, ex-vivo lung perfusion (EVLP) involves continuous ventilation and perfusion of donor lungs, offering the potential to both extend the ability to functionally assess grafts, as well as recondition them to a transplant-suitable standard, thereby expanding the available pool of grafts (8). EVLP can be administered via several different established protocols which vary perfusate composition, flow, temperature, pressure, and ventilation, with off-the-shelf EVLP equipment such as the “XVIVO Perfusion System (XPS)”, “Organ Care System (OCS)”, and “Vivoline LS-1” now on the market (1).

While extended-criteria lungs have been shown to have comparable follow-up survival outcomes to standard criteria lungs using standard lung transplant methods, the use of EVLP to further expand the donor pool raises the question of EVLP recipient long-term outcomes (3,8,9). The objective of this meta-analysis was to aggregate mid- to long-term survival data and available post-operative outcomes from studies comparing LTx recipients who received EVLP treated grafts to those receiving standard protocol (cold-preservation) grafts.

Methods

Literature search

Ten medical literature databases were queried from their dates of inception to August 2019. These included Medline, Embase, PubMed, and the Ovid “Evidence-Based Medicine Reviews” collection, which includes the Cochrane databases, as well as national college and government repositories. A broad search strategy was deliberately used, using terms “ex-vivo lung perfusion” (as a whole term and individually) and “EVLP”.

Two independent researchers (P.F. and B.M.) screened reference list results and full texts, with inclusion at each stage determined by consensus with the senior researcher (A.C.). Studies were included if they were comparative studies reporting primary mid- to long-term outcome data for recipients after lung transplant using standard protocol or EVLP. Studies needed to include at least five transplant recipients per arm. Non-comparative studies, animal studies, case reports, conference abstracts, reviews, and editorials were excluded. Where duplicate series exist, the study containing the most complete and up-to-date data was retained. The reference list of all included studies was examined to identify further articles meeting the inclusion criteria.

The primary endpoint was overall Kaplan-Meier survival reported to at least 6-months. Secondary endpoints were determined as those reported in at least half of included studies and included 30-day mortality, post-operative graft dysfunction grade 3 at 72 h, intensive care unit length of stay (LOS), and hospital LOS.

Quality analysis

A 19-point metric adopted from the Canadian Institute of Health Economics was used to assess included studies’ quality. This tool was designed with a Delphi methodology of health research stakeholders to evaluate the quality of case series, with examined domains including the number of centers data was collected from, study design, completeness of recipient and donor baseline data reporting, completeness of intraoperative and post-operative outcome reporting, and potential indicators of bias or conflict (Table S1). Total scores for each study were tallied to determine quality strata, with studies scoring below 12 deemed standard quality, 12 to 14 moderate quality, and 14 to 19 high quality.

Table S1. Canadian Institute of Health Economics quality appraisal checklist (modified).

Domain Description
1 Was the hypothesis/aim/objective of the study clearly stated (e.g., PICO)?
2 Was the study conducted prospectively (stated as such)?
3 Were the cases collected in more than one centre?
4 Were patients recruited consecutively?
5 Were the characteristics of the patients included in the study described?
6 Were the eligibility criteria (i.e., inclusion and exclusion criteria) for entry into the study clearly stated?
7 Did patients enter the study at a similar point in the disease?
8 Was the intervention of interest clearly described?
9 Were additional interventions (co–interventions) clearly described?
10 Were relevant outcome measures established a priori?
11 Were the relevant outcomes measured using appropriate objective/subjective methods?
12 Were the relevant outcome measures made before and after the intervention?
13 Were the statistical tests used to assess the relevant outcomes appropriate?
14 Was follow–up long enough for important events and outcomes to occur?
15 Were losses to follow–up reported?
16 Did the study provided estimates of random variability in the data analysis of relevant outcomes?
17 Were the adverse events reported?
18 Were the conclusions of the study supported by results?
19 Were conflicts of interest reported?

Statistical analysis

Data extraction was performed by two independent researchers (P.F. and B.M.) with data checking and validation by the senior researcher (A.C.). Where data was expressed as median and range or interquartile range, it was converted to mean and standard deviation using statistical methods to facilitate pooling (10,11). Furthermore, where no standard deviation or range was provided, a sample value was imputed as the mean of other provided values (12,13). Pooling was performed using meta-analysis of proportions or means. Differences in baseline data and outcomes were summarized as relative risk (RR) and mean difference (MD) for proportion and continuous data, respectively, with 95% confidence intervals (95% CI) provided. A random effects model was applied for all analyses to account for between-study variance due to recipient and donor selection, procedural, and care differences not accounted for in institutional series. Studies with zero-event outcomes in both arms were not weighted in meta-analysis.

Survival data was aggregated using the method for secondary survival analysis developed by Guyot and colleagues (14). This approach imputes individual patient time-to-event data, taking digitized Kaplan-Meier survival curves (Engauge Digitizer, Mark Mitchell, GitHub) and patient number-at-risk data as inputs. The imputed individual patient data is then pooled as an overall cohort and aggregated survival curves generated. Hazard ratio (HR) between EVLP and standard treatment protocol is calculated from Kaplan-Meier data using a Cox proportional hazard model (15). Proportionality was tested with a Schoenfeld residual test.

Publication bias was examined with funnel plots and also by Egger’s test for study endpoints. Heterogeneity amongst studies were assessed using the I2 statistic, with consideration of I2 confidence intervals (16). I2 thresholds of 0–49%, 50–74%, and ≥75% were considered as low, moderate, and high heterogeneity, respectively (17). Potential sources of heterogeneity and inconsistency of treatment effect were identified and explored with the aid of leave-one-out sensitivity analyses.

Two-tailed P values less than 0.05 were deemed as significant. All statistics were performed with R (R foundation for statistical computing, Vienna, Austria).

Results

Literature search identified 2,252 references with 174 full-text articles screened for inclusion. Reference list search of initially included articles led to the identification of one additional study. In all, 13 studies were included for analysis (PRISMA diagram provided in Figure S1) (4,5,8,18-27). One randomized controlled trial (RCT) was included (27), while four studies were prospective, non-randomized trials (18,20-22), six were retrospective series (4,5,8,23,25,26), and two were series with their design not fully described (19,24). One study was rated as standard quality, four as moderate quality, and eight as high quality (Table S2). The majority of studies had small EVLP cohorts, with a median cohort size of 14 patients, and the largest EVLP cohort of 151 patients contained in the RCT by Warnecke et al. All but one study were from European centres.

Figure S1.

Figure S1

PRIMSA flow chart detailing the literature search process for EVLP versus standard protocol lung transplantation.

Table S2. Study details.

Author, year Country Recruitment years Study design Quality (NIH) Mean F/U (y) Demographic
Retro-/prospective Single/multi-centre Type Group Patients (n)
Aigner, 2012 Austria 2010–2011 P S Series MQ 0.77 EVLP 9
0.77 Std 119
Fildes, 2015 2014 MC Series SQ EVLP 9
Std 46
Fisher, 2016 England 2012–2014 P MC Series HQ 1 EVLP 18
1 Std 184
Ghaidan, 2019 Sweden 2006–2007 R S Series MQ 10 EVLP 6
10 Std 15
Koch, 2018 Germany 2016–2017 R S Series MQ 1 EVLP 9
1 Std 41
Mussot, 2014 France 2011–2013 P S Series MQ 1 EVLP 31
1 Std 81
Nilsson, 2019 Sweden, Denmark 2011–2015 P MC Series HQ 1 EVLP 54
1 Std 271
Tikkanen, 2015 Canada 2008–2012 R S Series HQ EVLP 63
Std 340
Valenza, 2014 Italy 2011–2013 S Series HQ 0.71 EVLP 7
0.71 Std 28
Wallinder, 2016 Sweden 2011–2015 R S Series HQ 1.63 EVLP 27
1.35 Std 145
Warneke, 2018 Germany 2011–1014 P MC RCT HQ 2 EVLP 151
2 Std 169
Zeriouh, 2016 UK 2007–2014 R Series HQ 0.5±0.5* EVLP 14
2±2.3* Std 308
Zhang, 2019 Netherlands 2012–2016 R S Series HQ 3 EVLP 9
3 Std 18

*, converted from median (interquartile range) or median (range) for pooling. R, retrospective; P, prospective; S, single-centre; MC, multi-centre; SQ, standard quality; MQ, moderate quality; HQ, high quality; EVLP, ex-vivo lung perfusion; Std, standard protocol (cold storage).

The thirteen comparative studies contained in-total 2,172 lung transplant recipients, with 1,765 transplanted using standard/cold storage protocol and 407 transplanted with EVLP lungs. Where reported, the mean follow-up ranged from 0.7–10 years, with a median of 1-year follow-up.

The mean age of EVLP lung transplant recipients was 51.3 years (95% CI: 49.7–52.9; n=385), with 53.3% males (95% CI: 50.0–56.5; n=884/1,640), while standard protocol lung transplant recipients had a mean age of 48.6 years (95% CI: 46.6–50.6, n=1,765), with 54.0% males (95% CI: 50.0–58.0, n=722/1,321). The pooled recipient cohorts differed only in that COPD was more prevalent in the EVLP recipients (40.4% vs. 32.8%, P=0.046). Recipient baseline details and risk are summarized in Table 1 and further detailed in Table S3.

Table 1. Recipient baseline characteristics.

Characteristic EVLP, % (95% CI) n reported Standard, % (95% CI) n reported RR, MD (95% CI) I2 P
Patients 407 1,765
Males 50.6 (45.1–56.2) 162/319 54.0 (50.0–58.0) 722/1,321 0.96 (0.83–1.10) 16 0.541
Age (years) 51.3 (49.7–52.9) 385 48.6 (46.6–50.6) 1,765 0.99 (−0.79–2.78) 17 0.275
IPF/ILD 26.2 (20.2–33.2) 109/407 19.9 (14.4–26.8) 390/1,765 1.03 (0.79–1.35) 23 0.8
COPD* 40.4 (28.4–53.6) 118/400 32.8 (25.4–41.3) 525/1,737 1.23 (1.00–1.50) 35 0.046
Cystic fibrosis 24.6 (19.0–31.1) 94/407 21.8 (15.4–29.9) 388/1,765 1.12 (0.85–1.49) 31 0.411
PA hypertension 6.9 (4.6–10.3) 20/351 4.9 (3.8–6.4) 69/1,478 1.38 (0.76–2.50) 0 0.289
Re-transplant 2.8 (0.8–9.2) 2/99 5.5 (2.8–10.7) 28/526 0.50 (0.14–1.81) 0 0.289

*, COPD patients include those listed as alpha-1 antitrypsin deficient. CI, confidence interval; RR, relative risk; MD, mean difference; EVLP, ex-vivo lung perfusion; IPF/ILD, idiopathic pulmonary fibrosis/interstitial lung disease; COPD, chronic obstructive pulmonary disease; PA, pulmonary artery.

Table S3. Recipient baseline data.

Author, year Group Patients (n) Males (n) Age (years) Indication
IPF/ILD COPD + α1 CF Pulm A HTN Re–xplant Other
Aigner, 2012 EVLP 9 6 50.0±16.1* 4 3 2 1
Std 119 58 42.8±10.4* 0
Fildes, 2015 EVLP 9 5 53±9.4 1 6 1 1
Std 46 22 49±12 3 24 9 3 7
Fisher, 2016 EVLP 18 13 49.0±13.3* 7 5 4 1 0 1
Std 184 106 51.0±3.3* 47 40 47 3 0 47
Ghaidan, 2019 EVLP 6 3 54.1±10.4 1 4 1 0 0
Std 15 6 42.6±14.8 1 5 7 1 0 1
Koch, 2018 EVLP 9 6 55±7 2 8 0 0 0 1
Std 41 24 55±6 10 22 3 0 1 5
Mussot, 2014 EVLP 31 11 40.0±9.8* 3 9 15 4
Std 81 39 41.0±13.9* 12 16 40 13
Nilsson, 2019 EVLP 54 52±12 13 21 11 1 0 8
Std 271 51±13 68 111 33 16 0 43
Tikkanen, 2015 EVLP 63 31 50.3±14.6 22 20 14 3 1 3
Std 340 199 52.3±14.2 121 90 67 14 14 34
Valenza, 2014 EVLP 7 38±15 0 0 4 3
Std 28 49±14 11 0 10 7
Wallinder, 2016 EVLP 27 55±13 6 11 5 1 4
Std 145 52±14 35 54 10 11 13 22
Warnecke, 2018 EVLP 151 77 50.4±13.1 49 46 31 13 12
Std 169 106 50.0±13.6 57 52 40 6 14
Zeriouh, 2016 EVLP 14 6 44.7±23.2* 0 7 4 0 3
Std 308 154 43.7±18.7* 23 127 118 15 25
Zhang, 2019 EVLP 9 4 53±13.3 1 6 2
Std 18 8 50±9.5 2 12 4

*, converted from median (interquartile range) or median (range) for pooling. IPF/ILD, interstitial pulmonary fibrosis/interstitial lung disease; COPD + α1, chronic obstructive pulmonary disease (including alpha-1 antitrypsin deficiency); Pulm A HTN, pulmonary artery hypertension; EVLP, ex-vivo lung perfusion; Std, standard protocol (cold storage).

Despite high heterogeneity for some patient/donor baseline parameters, baseline data sensitivity analysis showed these were often due to factors such as inter-study variation in the number of DCD donors or donor PaO2/FiO2 ratio. Reasons for study exclusion were not identified and sensitivity analysis of study endpoints did not demonstrate individual studies changing overall findings of significance (with the exception of 30-day mortality).

Overall there were 2,178 lung donors, with 413 EVLP and 1,765 standard protocol donors. While not detailed across all studies, the majority of all grafts were from brain-dead donors (DBD, 88.0%; 95% CI: 80.4–93.0%). Mean age of EVLP donors was 47.3 years (95% CI: 44.5–50.1; n=359) and standard donors, 45.6 years (95% CI: 43.4–47.8; n=1,360). As expected with EVLP’s application for graft reconditioning, EVLP donors had significantly greater rates of abnormal chest X-ray [62.0%; (95% CI: 48.2–74.1%), versus 36.6% (95% CI: 25.6–49.2%), P=0.011], and poorer PaO2/FiO2 ratio [287 mmHg (95% CI: 217–358) versus 439 mmHg (95% CI: 427–451), P<0.001]. This difference in PaO2/FiO2 was further accentuated when the pooled PaO2/FiO2 included only studies that provided pre-EVLP values of PaO2/FiO2 (excluding Warnecke et al.): EVLP 272 mmHg (95% CI: 218–326, n=190), versus, standard 440 mmHg (95% CI: 426–454, n=1,126), MD −154 mmHg (95% CI: −214 – −94.3], I2=95%, P<0.001). Pooled donor baseline details are provided in Table 2 and per-study data in Table S4.

Table 2. Pooled donor baseline characteristics.

Characteristic EVLP, % (95% CI) n reported Standard, % (95% CI) n reported RR, MD (95% CI) I2 P
Patients 413 1,765
Males 53.3 (47.4–59.2) 147/275 47.1 (40.7–53.6) 515/1,106 1.16 (0.94–1.43) 48 0.176
Age (years) 47.3 (44.5–50.1) 359 45.6 (43.4–47.8) 1,360 2.08 (−1.35–5.5) 65 0.234
DBD 82.1 (67.0–91.2) 173/213 91.8 (83.4–96.1) 1,154/1,271 0.90 (0.74–1.10) 97 0.303
DCD 20.6 (9.8–38.3) 38/176 9.7 (4.6–19.2) 116/1,190 1.99 (0.61–6.45) 88 0.251
Smoking history 37.1 (23.3–53.5) 96/319 34.2 (24.0–46.1) 384/985 1.17 (0.97–1.40) 0 0.095
Abnormal CXR 62.0 (48.2–74.1) 165/294 36.6 (25.6–49.2) 366/959 1.63 (1.12–2.36) 82 0.011
PaO2/FiO2 (mmHg)* 287 [217–358], n=341 341 439 [427–451] 1,295 −138 (−208–−67.4) 98 <0.001

Number of EVLP donors is greater than number of recipients due to studies where discarded graft characteristics could not be distinguished from retained grafts. *, pooled values for all included studies. Note: pre-EVLP PaO2/FiO2 was provided for all studies except Warnecke et al., which provided post-EVLP values. PaO2/FiO2 excluding Warnecke (i.e., pre-EVLP values only): EVLP 272 mmHg (95% CI: 218; 326, n=190), standard 440 mmHg (95% CI: 426–454; n=1,126), MD −154 mmHg (95% CI: −214 – −94.3, I2=95%; P<0.001). CI, confidence interval; RR, relative risk; MD, mean difference; EVLP, ex-vivo lung perfusion; DBD, donation after brain death; DCD, donation after circulatory death; CXR, chest X-ray; PaO2/FiO2, gradient partial pressure arterial oxygen over fraction of inspired oxygen.

Table S4. Donor baseline data.

Author, year Group n patients Males (n) Age DBD (n) DCD (n) Smoking Hx (n) Abnormal CXR (n) PaO2/FIO2 (mmHg) Ventilator time (days) Cause of death
Intracranial bleed (n) CVA/stroke (n) Cardiac (n) Trauma (n) Suicide (n)
Aigner, 2012 EVLP 13 42.1±12.5* 208.5±40.0* 7.6±4.7* 5 2 6
Std 119 477.0±114.2*
Fildes, 2015 EVLP 9 5 54±10.1 229±73 1.69±0.68
Std 46 16 45±13.1 450±87 2.08±1.73
Fisher, 2016 EVLP 18 10 50.5 13 5 307.0±97.1*
Std 184 86 44 152 31
Ghaidan, 2019 EVLP 6 50.0±7.1* 3 154.2±37.9*
Std 15
Koch, 2018 EVLP 11 8 54±14 11 0 6 10 270±74 4 1 0 2 1
Std 41 21 54±16 41 0 18 18 413±96 19 8 0 9 0
Mussot, 2014 EVLP 31 45.9±13.3* 31 0 9 22 278.6±69.9*
Std 81 46.4±16.4* 81 0 17 16 397.6±105.1*
Nilsson, 2019 EVLP 54 54 0
Std 271 271 0
Tikkanen, 2015 EVLP 63 32 43.1±14.9 36 27 34 39 384±102
Std 340 160 45.8±17.6 322 18 163 170 456±76
Valenza, 2014 EVLP 7 54±9 7 0 4 6 264±78 3.9 6 0
Std 28 40±15 28 0 8 11 453±119 17 9
Wallinder, 2016 EVLP 27 47±18 2 20 218±86 2.3 3
Std 145 50±17 426±82
Warnecke, 2018 EVLP 151 79 42.2±14.4 27 65/141 438.5±80.0^
Std 169 102 40.2±13.7 27 76/161 431.7±73.8^
Zeriouh, 2016 EVLP 14 9 48.7±14.1* 11 3 7 4 428 2.7±0.8* 12 0 5 1
Std 308 121 43.3±13.4 248 60 143 75 435 2.0±1.5* 202 23 69 31
Zhang, 2019 EVLP 9 4 41±12.7 6 3 4 286±100 4.0±0.9* 3 2 1
Std 18 9 52±16.3 11 7 8 452±59 4.3±1.5* 3 6 3

*, converted from median (interquartile range) or median (range) for pooling. ^, final PaO2/FiO2– Warnecke et al. excluded lungs with PaO2/FiO2 <300 mmHg (initial values not provided). DBD, donation after brain death; DCD, donation after circulatory death; Hx, history; CXR, chest X-ray; PaO2/FiO2, arterial partial oxygen pressure to fraction inspired oxygen ratio; CVA, cerebrovascular accident; EVLP, ex-vivo lung perfusion; Std, standard protocol (cold storage).

The mean EVLP time was 234 min (95% CI: 215−253, n=294). EVLP was performed using the proprietary XVIVO system (XVIVO, Denver, CO, USA) in five studies, Vivoline LS-1 (Vivoline Medical AB, Lund, Sweden) in three studies, Organ Care System (OCS-TransMedics Inc., Boston, MA, USA) in two studies, and not-fully described or administered with custom circuits in four studies (Table S5). The majority of patients received double-lung transplants. Intraoperative parameters were similar between EVLP and standard protocol groups (Table 3).

Table S5. Operative data.

Author, year Group Ventilator-bridged (n) ECMO-bridged (n) Single lung (n) Double lung (n) Ischaemic time (min) Ischaemic time second lung (min) EVLP time (min) CPB use (n) Intra-op ECMO(n) EVLP system
Aigner, 2012 EVLP 1 0 9 579.8±55.4* 216.5±35.5* 4 Custom/NS
Std
Fildes, 2015 EVLP 0 9 Custom/NS
Std 0 46
Fisher, 2016 EVLP 2 16 16 7 Vivoline LS–1
Std 24 152 116 6
Ghaidan, 2019 EVLP 0 0 0 6 Custom/NS
Std 1 1 0 15
Koch, 2018 EVLP 0 1 7^ 434±94 506±96 9 XVIVO
Std 0 0 41 291±72 374±84 39
Mussot, 2014 EVLP 0 31 447 447 243 XVIVO
Std 0 81 360 360
Nilsson, 2019 EVLP 5 1 7 47 200±94 29 Vivoline LS–1
Std 12 16 37 234 125
Tikkanen, 2015 EVLP 6 4 15 48 XVIVO
Std 19 13 45 295
Valenza, 2014 EVLP 1 3 1 6 700 268±104 5 Custom/NS
Std 1 5 14 14 446±140 8
Wallinder, 2016 EVLP 1 0 5 22 275.7±142.8* 4 Vivoline LS–1 AND XVIVO
Std 7 10 32 113 36
Wernecke, 2018 EVLP 7 7 0 151 220.8±91.7 OCS
Std 9 9 0 169
Zeriouh, 2016 EVLP 0 14 342±149 2 OCS
Std 0 308 20
Zhang, 2019 EVLP 720±84 231.0±44.6* 3 XVIVO
Std 474±162 6

ECMO, exta-corporeal membrane oxygenation; CPB, cardiopulmonary bypass; Intra-op, intraoperative; EVLP, ex-vivo lung perfusion; Std, standard protocol (cold storage). *, converted from median (interquartile range) or median (range) for pooling. ^, Koch et al. included 1 bilobar transplant in the EVLP group.

Table 3. Pooled intraoperative data.

Characteristic EVLP, % (95% CI) n reported Standard, % (95% CI) n reported RR, MD (95% CI) I2 P
Patients 407 1,765
Ventilator bridged 7.1 (4.7–10.7) 20/308 5.1 (3.9–6.7) 49/968 1.43 (0.86–2.38) 0 0.166
ECMO bridged 7.2 (3.1–15.8) 16/317 6.3 (4.3–9.1) 54/968 1.12 (0.60–2.10) 12 0.718
Single lung transplant 11.0 (6.4–18.2) 31/398 10.1 (5.8–16.9) 152/1,628 1.11 (0.65–1.90) 40 0.708
Double lung transplant 88.3 (80.8–93.1) 366/398 89.2 (82.2–93.7) 1,468/1,628 1.00 (0.95–1.04) 50 0.918
Intraoperative ECMO 40.9 (25.0–59.1) 63/147 28.0 (12.1–52.2) 240/995 1.63 (0.94–2.83) 89 0.080
EVLP time (minutes) 234 (215–253) 292

CI, confidence interval; RR, relative risk; MD, mean difference; EVLP, ex-vivo lung perfusion; ECMO, extra-corporeal membrane oxygenation.

The primary outcome of Kaplan-Meier survival was reported from 12 to 120 months. Survival data in the single RCT was only available for the per-protocol, rather than the intention-to-treat, population, hence, the number at risk is reduced from the total number of patients reported for baseline and intraoperative data (27). Aggregated survival for individual patient data demonstrated almost identical survival profiles for both EVLP and standard/cold storage protocol lung transplant recipients. Survival at 12, 24, and 36 months for the EVLP cohort was 84%, 79%, and 74%, respectively, compared to 85%, 79%, and 73%, for the same time periods in the standard protocol cohort. Cox proportional hazard analysis demonstrated a hazard ratio of 1.00 (95% CI: 0.79–1.27; P=0.981; Figure 1).

Figure 1.

Figure 1

Aggregated survival for all included studies. HR, hazard ratio (Cox proportional model); EVLP, ex-vivo lung perfusion.

Leave-one-out analysis of Kaplan-Meier data was conducted to examine the sensitivity of Kaplan-Meier and hazard ratio results to individual patient data from each study. No single study was found to significantly influence survival outcomes. The aggregated survival curves from the non-randomized studies (and no matching between arm— excluding Warnecke et al.) is provided in Figure S2 (HR 1.16; 95% CI: 0.89–1.51; P=0.276).

Figure S2.

Figure S2

Kaplan-Meier survival post-transplant for all non-randomized series (ie: excluding the RCT by Warnecke et al.). EVLP, ex-vivo lung perfusion; HR, hazard ratio.

Operative outcomes were inconsistently reported across included studies, with only 30-day mortality, primary graft dysfunction grade 3 at 72 h (PGD3), extubation time, ICU LOS, and hospital LOS reported for the majority of studies. The 30-day mortality was similar between EVLP and standard cohorts, RR 2.04 (95% CI: 0.88–4.72, I2=0%, P=0.095), however, this result was obtained after exclusion of one particular study (27), which detailed each early death as non-EVLP related (due to iatrogenic surgical complications, patients’ compliance with medications, and patients’ cardiac risk factors). Including all studies gave a significant 30-day mortality result for EVLP: RR 2.39 (95% CI: 1.07–5.35, I2=0%, P=0.034). Primary graft dysfunction grade 3 at 72 hours did not reach significance (RR 1.15; 95% CI: 0.69–1.89, I2=0%, P=0.592). While continuous outcomes such as extubation time, intensive care unit, and hospital LOS were widely reported, heterogeneity of reporting and non-availability of standard deviation data meant the majority of data required imputation and multiple assumptions to allow pooling, and hence, it was not conducted. Per-study outcome data are detailed in Table S6, and pooled secondary outcomes in Table 4 and Figures 2,3.

Table S6. Recipient outcomes.

Author, year Group Patients (n) In-hospital mortality (n) 30-day mortality (n) Post-op ECMO (n) Extubation time (h) Pneumonia (n) Primary graft dysfunction (n) ICU LOS (d) Hospital LOS (d)
Aigner, 2012 EVLP 9 1 0 1 62.4±45.6 0 5.6±1.6 28.9±16.9
Std 119 5 110.4±196.8 9.7±9.4 27.8±19
Fildes, 2015 EVLP 9 0 0 2 19 54
Std 46 1 1 8 10 39
Fisher, 2016 EVLP 18 1 72 5 14.5 [1.7–98] 28 [16–100]
Std 184 6 38 32 4.3 [0.4–100.6] 28 [2–99]
Ghaidan, 2019 EVLP 6 0 0
Std 15 0 1
Koch, 2018 EVLP 9 1 1 221±307 0 12.5±13.4 26±16
Std 41 0 1 0 124±249 0 18.9±57 26±16
Mussot, 2014 EVLP 31 1 24 [0–43] 3 9 [2–45] 37
Std 81 3 24 [0–34] 7 6 [2–28] 28
Nilsson, 2019 EVLP 54 1 18 [2–912] 4 [2–65] 30
Std 271 4 7 [0–2,280] 3 [1–156] 28
Tikkanen, 2015 EVLP 63
Std 340
Valenza, 2014 EVLP 7 0 0 1 72 2 10 [5–18]
Std 28 0 0 2 36 9 5.5 [4–21.5]
Wallinder, 2016 EVLP 27 1 2 79±44 3 8±9
Std 145 8 6 120±26 17 8±13
Wernecke, 2018 EVLP 141^ 9 6 15 3
Std 165^ 11 0 26 7
Zeriouh, 2016 EVLP 14 2 74 [13–924] 2 5 [3–39] 23 [18–76]
Std 308 12 34 [19–942] 25 6 [3–21] 32 [22–51]
Zhang, 2019 EVLP 9 0 0 0 11 [4–26] 31 [27–46]
Std 18 0 0 2 5.2 [3–13] 42 [25–50]

*, converted from median (interquartile range) or median [range] for pooling. ^, Wernecke et al. reported both intention-to-treat and per-protocol data. Per-protocol data listed. ECMO, extra-corporeal membrane oxygenation; CPB, cardiopulmonary bypass; Intra-op, intraoperative; EVLP, ex-vivo lung perfusion; Std, standard protocol (cold storage).

Table 4. Pooled post-operative outcomes (where reported).

Characteristic EVLP, % (95% CI) n reported Standard, % (95% CI) n reported RR, MD (95% CI) I2 P
Patients* 397 1,761
30-day mortality^ 5.7 (3.4–9.5) 11/253 3.5 (2.5–4.9) 29/1,005 2.04 (0.88–4.72) 0 0.095
PGD grade 3 at 72 h 9.7 (4.5–19.8) 15/247 10.5 (5.9–18.0) 82/829 1.15 (0.69–1.89) 0 0.592

*, total number of patients for reported outcomes reduced since Warnecke et al. only provided Kaplan-Meier follow up for the per-protocol population, not the intention-to-treat population. ^, Warnecke et al. excluded following sensitivity analysis; deaths not directly attributable to EVLP. CI, confidence interval; RR, relative risk; MD, mean difference; EVLP, ex-vivo lung perfusion; PGD, primary graft dysfunction.

Figure 2.

Figure 2

The 30-day mortality post-transplant. EVLP, ex-vivo lung perfusion; RR, relative risk; CI, confidence interval.

Figure 3.

Figure 3

Primary graft dysfunction grade 3 at 72 h post-transplant. EVLP, ex-vivo lung perfusion; PGD, primary graft dysfunction; RR, relative risk; CI, confidence interval.

Publication bias in meta-analysed endpoints was not identified from visual inspection of funnel plots or application of Egger’s test (Figures S3,S4). Point values of heterogeneity for secondary outcomes remained at zero (I2=0%) for the sensitivity analysis of secondary outcomes.

Figure S3.

Figure S3

Funnel plot for secondary outcome: 30–day mortality.

Figure S4.

Figure S4

Funnel plot for secondary outcome: primary graft dysfunction (PGD) at 72 hours post-operatively.

Discussion

This meta-analysis combined results from 13 different studies detailing mid- to long-term survival data to demonstrate that there was no significant survival difference for transplant recipients receiving donor lungs treated with EVLP versus standard/cold storage protocol lungs. Neither 30-day mortality or grade 3 primary graft dysfunction at 72 h post-transplant (PGD3 at 72 h) were found to differ significantly between EVLP and standard cohorts.

The direction of primary and secondary outcomes of this meta-analysis were found to be concordant with all included studies, with the exception of the INSPIRE RCT, which identified a significantly greater 30-day mortality in the EVLP group but also a significant reduction in PGD3 at 72 h for EVLP patients. The authors of that study accounted for the significant 30-day mortality signal as non-EVLP related (due to iatrogenic surgical complications, patients’ compliance with medications, and patients’ cardiac risk factors) and this led to that outcome’s exclusion from this meta-analysis (27).

The PaO2/FiO2 threshold for acceptance of donor grafts varies between centres (22), as well as how this value is measured (for example, variations in time points, positive end expiratory pressure). However, this was not shown to significantly affect overall survival outcomes between EVLP and standard protocol lungs at a meta-analysis level, nor within included studies, which included donor lungs with pre-EVLP pooled mean PaO2/FiO2 value of 272 mmHg [and as low as 150 mmHg (4)]. Collectively, this information could be used to shape EVLP donor acceptance criteria and potentially further increase the number of donor lungs accepted for EVLP, for example from DCD donors, who typically have worse PaO2 values (4,23,25). The divergent but statistically non-significant survival curves evidenced with the removal of the RCT (Figure S2) likely reflect the fact that the INSPIRE RCT made up a large proportion of the pooled EVLP cohort and required both EVLP and standard donor groups to have similarly high PaO2/FiO2 ratios for acceptance. This was in contrast to the other included studies, where EVLP was used for reconditioning grafts with poorer pre-EVLP PaO2/FiO2 ratios.

PGD3 at 72 hours has been found to correlate with increased 30-day, 90-day, and 1-year mortality (26,28), as well as chronic lung allograft dysfunction (27). While the reduction in PGD3 at 72 h was only significant in the INSPIRE RCT, a reduced incidence of PGD3 at 72 h in EVLP transplant recipients was a finding shared by several other included studies (5,18,26). Though these studies’ findings on PGD3 did not reach significance and had smaller cohorts than the RCT, they all noted an absence of PGD3 events in their EVLP recipients, and other non-zero event studies similarly noted non-significant lower incidences. This was the case despite a worse PaO2/FiO2 in the meta-analysis EVLP donor group and in individual studies, where poorer PaO2/FiO2 donor lungs were accepted for EVLP treatment. Unlike other included studies, the INSPIRE RCT was exceptional in its exclusion of donors with PaO2/FiO2 <300 mmHg for both EVLP and standard groups. Although PGD3 was a secondary outcome in this meta-analysis, it’s non-significant difference between EVLP and standard groups in combination with the non-significant survival difference at follow-up is potentially valuable, as it adds weight to the restorative ability of EVLP and its potential for good long-term outcomes.

Other secondary outcomes examined and commented upon in many studies were post-transplant extubation time and ICU length of stay, with concerns that using high-risk lungs for EVLP may lead to an increase in these parameters and their associated risks (8,23). Pooling of these continuous outcomes was precluded by heterogeneity in reporting and a need to impute data for the majority of included studies. While the limitations of vote counting in meta-analysis are acknowledged (29), only one of thirteen included studies found significantly longer extubation times and ICU length of stay for EVLP (22).

While the constituent studies of this meta-analysis applied varying EVLP protocols and methodologies, it is clear that EVLP provides the ability to expand the pool of available donor lungs by reconditioning and reassessing lungs not considered suitable under standard criteria lung transplant. Using marginal lungs under extended-criteria for standard protocol lung transplant has been reported as doubling utilization rates to around 30–40% (30,31). Using EVLP however, studies in the present analysis reported conversion rates from EVLP evaluated lungs to transplant ranging from 34% to 97% (8,20,21,23,24,26). This allowed increased donor utilization, ranging from 33% to 50% (8,22,23). Along with the non-significant differences in outcomes found in this meta-analysis, this demonstrates the real possibility of EVLP to reduce the number of lung transplant wait-list deaths. Additionally, it adds weight to the argument that satisfactory results can be obtained with more than one EVLP protocol (22).

This meta-analysis is potentially limited by it being largely comprised of institutional series, however, RCT in this area are difficult since transplanting initially rejected or marginal (beyond extended criteria) donor lungs as a control arm would be ethically difficult to justify (21). Although statistical heterogeneity was low in meta-analysis endpoints, it remained moderate to high for some baseline and intraoperative characteristics. This heterogeneity is likely due to differences in centers’ donor criteria and operative methods (for example, single versus double lung), and sensitivity analysis did not demonstrate an effect on significance of outcomes. This does not however, mean that all sources of heterogeneity were able to be accounted for and the authors acknowledge that even where I2 point values were low, I2 confidence intervals often still included at least moderate heterogeneity values (16). Additionally, many studies were retrospective and included a range of recruitment years and recruitment period lengths. As EVLP methodology and knowledge (and lung transplant more broadly) is a rapidly-evolving field, this may have introduced some learning-curve type confounding effect (25).

Conclusions

Aggregated patient survival data analysis of EVLP and standard/cold-storage lung transplant recipients demonstrated no significant difference in survival at mid- to long-term follow-up. Meta-analysis demonstrated lungs accepted for EVLP had significantly lower PaO2/FiO2 ratio and a greater incidence of radiographic abnormality, however, this did not translate to a significant difference in overall survival, 30-day mortality, or primary graft dysfunction grade 3 at 72 h between EVLP and standard cohorts. EVLP offers the ability to expand the lung donor pool with acceptable mid- to long-term survival outcomes.

Acknowledgments

None.

Footnotes

Conflicts of Interest: The authors have no conflicts of interest to declare.

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