Ex Vivo Lung Perfusion Assessment Research Articles

The combination of postmortem sevoflurane ventilation and in situ topical cooling provides improved 6 hours lung preservation in an uncontrolled DCD porcine model

BackgroundRecent clinical series on donation after uncontrolled cardiovascular death (uDCD) reported successful transplantation of lungs preserved by pulmonary inflation up to 3h post-mortem. This study aims to investigate the additive effects of in situ lowering of intrathoracic temperature and sevoflurane preconditioning on lung grafts in a porcine uDCD model. MethodsAfter uDCD induction, donor pigs were allocated to one of the following groups: Control – static lung inflation only (SLI); TC – SLI + continuous intrapleural topical cooling (TC); or TC+Sevo – SLI + TC + sevoflurane. Lungs were retrieved 6h post-asystole and evaluated via ex vivo lung perfusion (EVLP) for 6h. A left single lung transplant was performed using lungs from the best performing group, followed by 4h of graft evaluation. ResultsAnimals that received topical cooling achieved intrathoracic temperature < 15°C within 1 hour after chest filling of coolant. Only lungs from donors that received TC and TC+Sevo completed the planned post-preservation 6h EVLP assessment. Despite similar early performance of the two groups on EVLP, the TC+Sevo group was superior - associated with overall lower airway pressures, higher pulmonary compliances, less edema development, and less release of inflammatory cytokines. Transplantation was performed using lungs from the TC+Sevo group, and excellent graft function was observed post-reperfusion. ConclusionPreservation of uDCD lungs with a combination of static lung inflation, topical cooling and sevoflurane treatment maintains good pulmonary function up to 6h post-mortem with excellent early post-lung transplant function. These interventions may significantly expand the clinical utilization of uDCD donor lungs.

Lung Transplantation From Controlled and Uncontrolled Donation After Circulatory Death (DCD) Donors With Long Ischemic Times Managed by Simple Normothermic Ventilation and Ex-Vivo Lung Perfusion Assessment.

Donation after cardiac death (DCD) donors are still subject of studies. In this prospective cohort trial, we compared outcomes after lung transplantation (LT) of subjects receiving lungs from DCD donors with those of subjects receiving lungs from donation after brain death (DBD) donors (ClinicalTrial.gov: NCT02061462). Lungs from DCD donors were preserved in-vivo through normothermic ventilation, as per our protocol. We enrolled candidates for bilateral LT ≥14years. Candidates for multi-organ or re-LT, donors aged ≥65years, DCD category I or IV donors were excluded. We recorded clinical data on donors and recipients. Primary endpoint was 30-day mortality. Secondary endpoints were: duration of mechanical ventilation (MV), intensive care unit (ICU) length of stay, severe primary graft dysfunction (PGD3) and chronic lung allograft dysfunction (CLAD). 121 patients (110 DBD Group, 11 DCD Group) were enrolled. 30-day mortality and CLAD prevalence were nil in the DCD Group. DCD Group patients required longer MV (DCD Group: 2days, DBD Group: 1 day, p = 0.011). ICU length of stay and PGD3 rate were higher in DCD Group but did not significantly differ. LT with DCD grafts procured with our protocols appears safe, despite prolonged ischemia times.

Outcomes After Transplantation of Lungs Subjected to Prolonged Cold Ischaemic Time Following Ex-Vivo Lung Perfusion

<h3>Purpose</h3> Ex vivo lung perfusion (EVLP) rewarms donor lungs to normothermia following a period of cold static preservation (CIT1) and returns the lungs to a state of cold static preservation following EVLP (CIT2). We hypothesize that EVLP interrupts cold ischemic injury and allows for safe additional cold ischemic time after EVLP. <h3>Methods</h3> We performed a retrospective review of data from the Toronto Lung Transplant Program Database. Adult patients who underwent bilateral lung transplant following EVLP assessment between January 2008 and December 2020 were included. CIT1, EVLP, and CIT2 times were collected and outcomes including PGD grade 3 at 72 hours and 30-day and 12-month mortality were assessed. <h3>Results</h3> A total of 1186 bilateral lung transplants were performed over the study period of which 315 were performed following EVLP assessment. Mean[SD] CIT1 of the lungs was 4.7h[1.6]. Mean[SD] EVLP time was 4.5h[1.5]. The first lung had a mean[SD] CIT2 of 3.8h[2.1] and the second had a mean[SD] CIT2 of 6.0h[2.2]. Survival was similar when comparing CIT2<6 hours versus CIT2>6 hours of the second lung (p=0.53) (Figure). PGD3 rate was also similar between those groups (18.1% vs 17.2%, p=1). <h3>Conclusion</h3> Prolonged (>6h) ischemic time following EVLP assessment (CIT2) did not affect short- and long-term mortality in our patients. Therefore we feel that using a period of CIT after EVLP assessment is acceptable, and it provides us flexibility in terms of logistics, widening geographical reach of our program, and allows us to make lung transplantation a semi-elective procedure.

Predicting donor lung acceptance for transplant during ex vivo lung perfusion: The EX vivo lung PerfusIon pREdiction (EXPIRE)

Ex vivo lung perfusion (EVLP) has being increasingly used for the pretransplant assessment of extended-criteria donor lungs. Mathematical models to predict lung acceptance during EVLP have not been reported so far. Thus, we hypothesized that predictors of lung acceptance could be identified and used to develop a mathematical model describing the clinical decision-making process used in our institution. Donor lungs characteristics and EVLP physiologic parameters included in our EVLP registry were examined (derivation cohort). Multivariable logistic regression analysis was performed to identify predictors independently associated with lung acceptance. A mathematical model (EX vivo lung PerfusIon pREdiction [EXPIRE] model) for each hour of EVLP was developed and validated using a new cohort (validation cohort). Two hundred eighty donor lungs were assessed with EVLP. Of these, 186 (66%) were accepted for transplantation. ΔPO2 and static compliance/total lung capacity were identified as independent predictors of lung acceptance and their respective cut-off values were determined. The EXPIRE model showed a low discriminative power at the first hour of EVLP assessment (AUC: 0.69 [95% CI: 0.62-0.77]), which progressively improved up to the fourth hour (AUC: 0.87 [95% CI: 0.83-0.92]). In a validation cohort, the EXPIRE model demonstrated good discriminative power, peaking at the fourth hour (AUC: 0.85 [95% CI: 0.76-0.94]). The EXPIRE model may help to standardize lung assessment in centers using the Toronto EVLP technique and improve overall transplant rates.

Assessment of Lobar Oxygenation during Ex-Vivo Lung Perfusion May Predict Postoperative Outcomes

<h3>Purpose</h3> Assessment of marginal donor lungs during asanguineous ex vivo lung perfusion (EVLP) can be challenging due to limited objective parameters. We hypothesized that determination of PaO2/FiO2 (P/F) ratio from each lobar vein can provide valuable information regarding lobar function. The aim of this study is to determine lobar vein P/F ratio during EVLP and correlate with standard EVLP assessment parameters as well as post-transplant outcomes. <h3>Methods</h3> Data from 139 lungs from 75 donors assessed in asanguineous EVLP from Feb 2016 to April 2020 were analyzed for this study. Transplant suitability of lungs was determined based on standard EVLP parameters. pO2 was assessed from each pulmonary vein at the time of standard evaluation. In transplanted EVLP lungs, primary graft dysfunction (PGD) was assessed at 72 hours. <h3>Results</h3> In the favorable group (defined as PGD grade 0-1), both P/F ratio at left atrium (P/F LA) and P/F ratio at lower lobe pulmonary vein (P/F LPV) were significantly higher than that of the unfavorable group (non-suitable or PGD grade 2-3) (LA, 496±77 vs. 444±74 mmHg, P < 0.001; LPV, 888±82 vs. 307±101 mmHg, p < 0.001). In receiver operating characteristic curve analysis for unfavorable, P/F ratio LPV showed the highest AUC with threshold of 342, sensitivity 0.60 and specificity 0.74 than that of other standard parameters (Table 1). Regarding PGD at 72 hours in transplanted lungs, P/F LA on EVLP assessment was not different between PGD≥2 and PGD≤1 groups (483± 67 vs. 495± 77 mmHg, p = 0.564, Figure], while P/F LPV in PGD≥2 was significantly lower than that in PGD≤1 (332± 88 vs. 388±82 mmHg, p = 0.015]. <h3>Conclusion</h3> These results suggest that determination of lobar P/F ratio during EVLP can provide additional, valuable information for lung assessment. Deterioration of lobar function might be masked assessment of only LA P/F ratio and potentially lead to a greater incidence of high-grade PGD after lung transplantation.

Lipopolysaccharide Levels in Ex Vivo Lung Perfusion are Associated with Lung Function and Suitability for Transplantation

Purpose Ex vivo lung perfusion (EVLP) has emerged as an important platform to assess marginal donor lungs prior to transplantation. Derived from the outer membrane of gram-negative bacteria, lipopolysaccharide (LPS) can stimulate strong immune responses. Studies have shown that donor lungs infected with bacteria may have worse outcomes, suggesting bacteria-induced donor lung injury. However, no large-scale studies have looked at the relationship between LPS levels and donor lung performance on EVLP. Methods LPS levels were measured after one and four hours of perfusion in n=100 clinical EVLP cases. To assess the effects of LPS on lung inflammation, IL-6, 8, 10, and 1β, sTNF-R1, sTREM-1 and ET-1 levels were measured with an ELISA-based platform. Biochemical and physiological assessments were compared to LPS levels. Finally, LPS levels and recipient intensive care unit length of stay after transplantation were investigated. Results There was a significant increase from 0.14 [0.09-0.21] to 0.23 [0.13-0.38] EU/mL (p Conclusion This study demonstrates the trends and importance of circulating LPS levels during EVLP assessment of human donor lung injury. We show that high LPS levels and increasing levels over time were associated with poor donor lung performance in EVLP. These results support the need for therapeutic strategies to target LPS during EVLP, which may improve lung function and rescue more donor lungs for transplantation.

Prediction of donor related lung injury in clinical lung transplantation using a validated ex vivo lung perfusion inflammation score

Ex vivo lung perfusion (EVLP) is an isolated organ assessment technique that has revolutionized the field of lung transplantation and enabled a safe increase in the number of organs transplanted. The objective of this study was to develop a protein-based assay that would provide a precision medicine approach to lung injury assessment during EVLP. Perfusate samples collected from clinical EVLP cases performed from 2009 to 2019 were separated into development (n = 281) and validation (n = 57) sets to derive and validate an inflammation score based on IL-6 and IL-8 protein levels in perfusate. The ability of an inflammation score to predict lungs suitable for transplantation and likely to produce excellent recipient outcomes (time on ventilator ≤ 3 days) was assessed. Inflammation scores were compared to conventional clinical EVLP assessment parameters and associated with outcomes, including primary graft dysfunction and patient care in the ICU. An inflammation score accurately predicted the decision to transplant (AUROC 68% [95% CI 62-74]) at the end of EVLP and those transplants associated with short ventilator times (AUROC 73% [95% CI 66-80]). The score identified lungs more likely to develop primary graft dysfunction at 72-hours post-transplant (OR 4.0, p = 0.03). A model comprised of the inflammation score and ∆PO2 was able to determine EVLP transplants that were likely to have excellent recipient outcomes, with an accuracy of 87% [95% CI 83-92]. The adoption of an inflammation score will improve accuracy of EVLP decision-making and increase confidence of surgical teams to determine lungs that are suitable for transplantation, thereby improving organ utilization rates and patient outcomes.

An extracellular oxygen carrier during prolonged pulmonary preservation improves post-transplant lung function

The use of a novel extracellular oxygen carrier (EOC) preservation additive known as HEMO2Life has recently been shown to lead to a superior preservation of different types of solid organs. Our study aimed to investigate the effect of this EOC on extending lung preservation time and its mechanism of action. Donor pigs were randomly allocated to either of the following 2 groups (n = 6 per group): (1) 36 hours cold preservation or (2) 36 hours cold preservation with 1 g/liter of EOC. The lungs were evaluated through 12 hours of normothermic ex vivo lung perfusion (EVLP) followed by a left-single lung transplant into a recipient pig. Grafts were reperfused for 4 hours, followed by right pulmonary artery clamping to assess graft oxygenation function. During EVLP assessment, EOC-treated lungs showed improvements in physiologic parameters, whereas the control lungs deteriorated. After a total of 48 hours of preservation (36 hours cold + 12 hours normothermic EVLP), transplanted grafts in the treatment group displayed significantly better oxygenation than in the controls (PaO2/FiO2: 437 ± 36 mmHg vs 343 ± 27 mmHg, p = 0.041). In addition, the use of EOC led to significantly less edema formation (wet-to-dry ratio: 4.95 ± 0.29 vs 6.05 ± 0.33, p = 0.026), less apoptotic cell death (p = 0.041), improved tight junction preservation (p = 0.002), and lower levels of circulating IL-6 within recipient plasma (p = 0.004) compared with non-use of EOC in the control group after transplantation. The use of an EOC during an extended pulmonary preservation period led to significantly superior early post-transplant lung function.

Validation of a Rapid Molecular Assessment Platform and Cytokine Score for Integration with Ex Vivo Lung Perfusion (EVLP) Assessment

EVLP has been adopted as a method to evaluate donor lungs prior to transplantation. The inclusion of an objective, protein-based assessment of lung quality during EVLP has remained elusive due to current slow time-to-answer technology. Our team has recently reported a cytokine-based score that can more accurately reflect donor lung injury. In this study, we evaluated the ability of a novel diagnostic platform to provide a timely multiplexed cytokine score that reflects lung quality during EVLP. To compare the accuracy of our testing methods, cytokine levels of interleukin-6 (IL-6), IL-8, IL-10, and IL-1β were simultaneously measured in perfusate samples prospectively collected every 15 minutes from five clinical EVLP cases on a standard ELISA and a custom rapid (<45min) platform (n=79). For cytokine assay validation, perfusate samples collected at 4 hours of EVLP from 2018-19 were retrospectively tested on the rapid platform (n=62). Diagnostic performance was then compared between the new cohort on the rapid platform and our previously reported inflammation score performance (n=346). In our prospective cohort, the rapid cytokine assessment platform provided equivalent performance to standard ELISA (R2=0.97 (IL-6); R2=0.96 (IL-8); R2=0.95 (IL-10); R2=0.95 (IL-1β)). Using the rapid platform, the classification of lungs declined for transplant using our cytokine-based score of lung injury was the same in our retrospective cohort compared to our previously reported scores (lung score=45 vs. 40, p=0.50; AUROC=69% vs. 68%, p=0.87). Also consistent with our prior results, donor organs with the best cytokine scores (Category 1: Top 25th percentile) had the shortest ICU length of stay (3 days [95%CI: 2-6]). We have performed a retrospective validation and initial prospective test of a rapid perfusate diagnostic platform that measures lung injury biomarkers in less than 45 minutes-well within the typical 4-6 hour EVLP assessment and decision-making time frame. Data from our EVLP cytokine score performance on the rapid diagnostic platform will serve as a foundation for future integration into the clinical EVLP operating room. By enabling molecular testing during EVLP, these results represent another step towards better-assisting clinicians to more precisely select suitable lungs for transplantation.

Perfusate Metabolite Profiles in Ex Vivo Lung Perfusion Predict Graft Quality of Lungs Donated after Circulatory Death

The use of donation after circulatory death (DCD) lungs may expand the donor pool for lung transplantation. However, due to the variable quality of DCD lungs, many undergo ex vivo lung perfusion (EVLP) for evaluation. DCD lung assessment is challenging but can be greatly aided by biomarker readouts that predict transplant outcome. In this study, we performed a metabolomics analysis of human DCD lungs to identify predictive metabolites that may be clinically useful during EVLP assessment. EVLP perfusate was collected from 20 DCD lungs and evaluated on EVLP. Lungs were divided into 2 groups: 1) Good outcome (n = 11), with no primary graft dysfunction grade 3 (PGD3); 2) Poor outcome (n = 9), including PGD3 (n = 5) and declined lungs due to poor performance on EVLP (n = 4). Metabolomics profiling of perfusate samples taken at 1 h and 4 h of EVLP were processed by liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry. Bioinformatics and pathway analysis were performed with MetaboAnalyst webserver. In total, 275 metabolites were detected. Five metabolites at 1 h and 16 metabolites at 4 h of EVLP were significantly different between good and poor outcome groups (FDR < 0.05, fold change (FC) ≥1.5). Multiple amino acid levels were significantly higher and lipid levels were significantly lower in poor outcome lungs at 1 h and 4 h of EVLP. Metabolomic pathway analysis revealed that aminoacyl-tRNA biosynthesis, and glycine, serine and threonine pathways were affected. While several metabolites achieved statistical significance, it was notable that lysine and ornithine levels separated good vs. bad outcome groups at 1 h and 4 h with minimal overlap (Fig 1). We identified significantly altered metabolites in DCD lungs that distinguish between good and poor recipient outcomes. Future biomarker validation via a larger sample size is necessary prior to their use to optimally select post-EVLP DCD donor lungs for transplantation.

Assessment of Donor Lung Aspiration on the Ex Vivo Lung Perfusion (EVLP) Platform

Donor aspiration of gastric contents represents a significant risk for lung injury and severe primary graft dysfunction after lung transplantation. Concern about possible aspiration is a common reason for clinicians to decline donor lungs for transplantation. The presence of bile acid in donor bronchial wash (BW) or bronchoalveolar lavage (BAL) fluid may indicate that a donor has aspirated. Previous reports have also shown that aspiration of bile acids cause increased inflammation in the lung. Ex vivo lung perfusion (EVLP) has become an important platform to assess questionable or "marginal" donors. In this study, we examined the relationship between possible donor aspiration and physiologic and biologic assessment of inflammation on EVLP. Large airway BW samples were collected from 270 donors (n=111 non-EVLP, n=159 EVLP) prior to transplantation. Bile acid levels were measured in BW samples using a commercially available colorimetric assay and clinically approved platform. Protein and biochemical measurements were made in perfusate samples collected hourly after the start of EVLP. The majority of donor lungs with clinically suspected aspiration were successfully transplanted after EVLP assessment (58% [23/40]). Donor bile acid levels were significantly higher in donor lungs that were ultimately declined for transplantation at the end of EVLP (0.28 vs. 0.12 μM, p<0.05, n=143). During EVLP there was a positive correlation between bile acid in the donor BW and inflammation (IL-8 levels (r=0.19, p<0.05, n=159)). Similarly, there was an increase in biochemical markers of cell death ([Ca2+]) in the EVLP perfusate of donors with high bile acid levels in BW (r=0.27, p<0.001, n=142). Following EVLP and transplantation, we observed no significant effects of donor bile acid levels on recipient ICU length-of-stay (r=0.09, p=0.35, n=117). Suspected donor aspiration can be assessed using the EVLP platform. Bile acid levels measured in the donor lung are associated with increased inflammation and lung injury observed during EVLP, but not recipient outcomes post-EVLP. Therefore, EVLP may be an ideal platform to identify marginal donor lungs suspected of aspiration but are ultimately suitable for clinical transplantation.

Commonly Used Criteria to Initiate Ex-Vivo Lung Perfusion Have No Significant Impact on Early Post Lung-Transplant Outcomes

Ex-vivo lung perfusion (EVLP) is a complex, expensive assessment tool suggested to predict successful early graft function and therefore which 'extended' lungs should be used. Theoretic 'graft at-risk' criteria for EVLP initiation used in EVLP trials include: donor age >55yrs, PaO2/FIO2 (PF) <300, abnormal chest X ray, aspiration, >10 unit transfusion, DCD, expected graft ischemia time (GIT) >6hrs. Our centre routinely uses extended donor lungs without EVLP. DonateLife records and clinical databases were combined, with univariate and multivariate analyses undertaken to clarify the relation between EVLP initiation criteria and lung-transplant (LTx) outcomes. 304 LTx were performed 2014 to 2018 from 704 donor referrals (=42% conversion rate, =11.3 LTx per million population, cf US = 7.0 LTx PMP). 69% of LTx performed had >1 criteria for EVLP assessment (25% = 2, 5.2% = >3 criteria). Table 1 outlines the incidence and effect of these criteria. A PF <300 and GIT >6hrs had small effects on outcomes <90dys. Multivariate analyses noted no donor criteria association with PGD3. Mechanical ventilation hours are associated with type of LTx and recipient's diagnosis (Table 2). At least 1 recommended criteria for EVLP initiation was present in the majority of our LTx. These did not predict early outcomes- with very acceptable results seen in all subgroups. However, the relevance of combination or extreme criteria in lungs not used is unknown. Based on this study, the true utility of EVLP to enhance LTx acceptability and success rates, beyond good clinical management alone, requires an RCT.

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

The mortality rate for individuals on the wait list for lung transplant is 15% to 25%, and still only 20% of lungs from multiorgan donors are used for lung transplant. The lung donor pool may be increased by assessing and reconditioning high-risk extended criteria donor lungs with ex vivo lung perfusion (EVLP), with similar short-term outcomes. To assess the long-term outcomes of transplant recipients of donor lungs treated with EVLP. This retrospective cohort single-center study was conducted from August 1, 2008, to February 28, 2017, among 706 recipients of donor lungs not undergoing EVLP and 230 recipients of donor lungs undergoing EVLP. Donor lungs undergoing EVLP. The incidence of chronic lung allograft dysfunction and allograft survival during the 10-year EVLP era were the primary outcome measures. Secondary outcomes included donor characteristics, maximum predicted percentage of forced expiratory volume in 1 second, acute cellular rejection, and de novo donor-specific antibody development. This study included 706 patients (311 women and 395 men; median age, 50 years [interquartile range, 34-61 years]) in the non-EVLP group and 230 patients (85 women and 145 men; median age, 46 years [interquartile range, 32-55 years]) in the EVLP group. The EVLP group donors had a significantly lower mean (SD) Pao2:fraction of inspired oxygen ratio than the non-EVLP group donors (348 [108] vs 422 [88] mm Hg; P < .001), higher prevalence of abnormal chest radiography results (135 of 230 [58.7%] vs 349 of 706 [49.4%]; P = .02), and higher proportion of smoking history (125 of 204 [61.3%] vs 322 of 650 [49.5%]; P = .007). More recipients in the EVLP group received single-lung transplants (62 of 230 [27.0%] vs 100 of 706 [14.2%]; P < .001). There was no significant difference in time to chronic lung allograft dysfunction between the EVLP and non-EVLP group (70% vs 72% at 3 years; 56% vs 56% at 5 years; and 53% vs 36% at 9 years; log-rank P = .68) or allograft survival between the EVLP and non-EVLP groups (73% vs 72% at 3 years; 62% vs 58% at 5 years; and 50% vs 44% at 9 years; log-rank P = .97) between the 2 groups. All secondary outcomes were similar between the 2 groups. Since 2008, 230 of 936 lung transplants (24.6%) in the Toronto Lung Transplant Program were performed after EVLP assessment and treatment. Use of EVLP-treated lungs led to an increase in the number of patients undergoing transplantation, with comparable long-term outcomes.

Validation of an EVLP Perfusate Diagnostic Test for the Prediction of Lung Transplant Outcomes

Purpose Ex vivo lung perfusion (EVLP) has become an invaluable tool in clinical lung transplantation (LTx). EVLP has enabled the assessment and rescue of donor organs that would have otherwise been discarded for LTx; however, determining which marginal organs are suitable for transplant remains challenging and relies largely on clinical assessment expertise. To this end, we describe our efforts to develop and validate a perfusate-based diagnostic test that will assist transplant teams in the EVLP decision-making process. Methods From 2008 to 2017, approximately 300 clinical EVLP cases were performed. A retrospective study was conducted using biobanked perfusate samples to develop and validate a set of biological mediators that predict: (i) whether a lung would be acceptable for transplant following EVLP; and (ii) the contribution of that donor lung to a favorable recipient outcome. A prospective study of an additional 50 EVLP cases is currently underway to further validate the EVLP predictive test. Results Using simple regression, a model that included donor characteristics and perfusate-derived mediators of inflammation (e.g., interleukin 6 and 8, and others) predicted whether or not a lung would be deemed acceptable for transplant with an overall accuracy of 70% [95% CI: 64-76%] (n=259). When the transplanted cases were further sub-stratified for recipient outcomes (e.g., ICU length of stay), our score's predictive performance improved to 83% [95% CI: 76-90%] (n=139). Next, a visual representation of the model was created and used in real-time alongside our clinical EVLP cases. In the ongoing test set of approximately 25 EVLP cases, the model accuracy is maintained at 71%. Conclusion We have developed and validated an EVLP test in the largest known cohort of EVLP cases to date. This score is able to predict whether a marginal donor lung will be acceptable for transplant following EVLP assessment. Furthermore, we can determine thresholds, independent of any recipient factors, that are associated with excellent transplant outcomes. This test represents a major step forward in the utilization of EVLP in lung transplantation by providing a useful metric that will better assist transplant teams to select lungs for successful outcomes on EVLP and subsequent transplantation.

A porcine ex vivo lung perfusion model with maximal argon exposure to attenuate ischemia-reperfusion injury.

Argon (Ar) is a noble gas with known organoprotective effects in rodents and in vitro models. In a previous study we failed to find a postconditioning effect of Ar during ex vivo lung perfusion (EVLP) on warm-ischemic injury in a porcine model. In this study, we further investigated a prolonged exposure to Ar to decrease cold ischemia-reperfusion injury after lung transplantation in a porcine model with EVLP assessment. Domestic pigs (n = 6/group) were pre-conditioned for 6 hours with 21% O2 and 79% N2 (CONTR) or 79% Ar (ARG). Subsequently, lungs were cold flushed and stored inflated on ice for 18 hours inflated with the same gas mixtures. Next, lungs were perfused for 4 hours on EVLP (acellular) while ventilated with 12% O2 and 88% N2 (CONTR group) or 88% Ar (ARG group). The perfusate was saturated with the same gas mixture but with the addition of CO2 to an end-tidal CO2 of 35-45 mmHg. The saturated perfusate was drained and lungs were perfused with whole blood for an additional 2 hours on EVLP. Evaluation at the end of EVLP did not show significant effects on physiologic parameters by prolonged exposure to Ar. Also wet-to-dry weight ratio did not improve in the ARG group. Although in other organ systems protective effects of Ar have been shown, we did not detect beneficial effects of a high concentration of Ar on cold pulmonary ischemia-reperfusion injury in a porcine lung model after prolonged exposure to Ar in this porcine model with EVLP assessment.

An observational study of Donor Ex Vivo Lung Perfusion in UK lung transplantation: DEVELOP-UK.

Many patients awaiting lung transplantation die before a donor organ becomes available. Ex vivo lung perfusion (EVLP) allows initially unusable donor lungs to be assessed and reconditioned for clinical use. The objective of the Donor Ex Vivo Lung Perfusion in UK lung transplantation study was to evaluate the clinical effectiveness and cost-effectiveness of EVLP in increasing UK lung transplant activity. A multicentre, unblinded, non-randomised, non-inferiority observational study to compare transplant outcomes between EVLP-assessed and standard donor lungs. Multicentre study involving all five UK officially designated NHS adult lung transplant centres. Patients aged ≥ 18 years with advanced lung disease accepted onto the lung transplant waiting list. The study intervention was EVLP assessment of donor lungs before determining suitability for transplantation. The primary outcome measure was survival during the first 12 months following lung transplantation. Secondary outcome measures were patient-centred outcomes that are influenced by the effectiveness of lung transplantation and that contribute to the health-care costs. Lungs from 53 donors unsuitable for standard transplant were assessed with EVLP, of which 18 (34%) were subsequently transplanted. A total of 184 participants received standard donor lungs. Owing to the early closure of the study, a non-inferiority analysis was not conducted. The Kaplan-Meier estimate of survival at 12 months was 0.67 [95% confidence interval (CI) 0.40 to 0.83] for the EVLP arm and 0.80 (95% CI 0.74 to 0.85) for the standard arm. The hazard ratio for overall 12-month survival in the EVLP arm relative to the standard arm was 1.96 (95% CI 0.83 to 4.67). Patients in the EVLP arm required ventilation for a longer period and stayed longer in an intensive therapy unit (ITU) than patients in the standard arm, but duration of overall hospital stay was similar in both groups. There was a higher rate of very early grade 3 primary graft dysfunction (PGD) in the EVLP arm, but rates of PGD did not differ between groups after 72 hours. The requirement for extracorporeal membrane oxygenation (ECMO) support was higher in the EVLP arm (7/18, 38.8%) than in the standard arm (6/184, 3.2%). There were no major differences in rates of chest radiograph abnormalities, infection, lung function or rejection by 12 months. The cost of EVLP transplants is approximately £35,000 higher than the cost of standard transplants, as a result of the cost of the EVLP procedure, and the increased ECMO use and ITU stay. Predictors of cost were quality of life on joining the waiting list, type of transplant and number of lungs transplanted. An exploratory model comparing a NHS lung transplant service that includes EVLP and standard lung transplants with one including only standard lung transplants resulted in an incremental cost-effectiveness ratio of £73,000. Interviews showed that patients had a good understanding of the need for, and the processes of, EVLP. If EVLP can increase the number of usable donor lungs and reduce waiting, it is likely to be acceptable to those waiting for lung transplantation. Study limitations include small numbers in the EVLP arm, limiting analysis to descriptive statistics and the EVLP protocol change during the study. Overall, one-third of donor lungs subjected to EVLP were deemed suitable for transplant. Estimated survival over 12 months was lower than in the standard group, but the data were also consistent with no difference in survival between groups. Patients receiving these additional transplants experience a higher rate of early graft injury and need for unplanned ECMO support, at increased cost. The small number of participants in the EVLP arm because of early study termination limits the robustness of these conclusions. The reason for the increased PGD rates, high ECMO requirement and possible differences in lung injury between EVLP protocols needs evaluation. Current Controlled Trials ISRCTN44922411. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 85. See the NIHR Journals Library website for further project information.