Ex Vivo Lung Perfusion Research Articles

Lung transplantation from donation after circulatory death, evolution, and current status in the United States.

The number of lung transplants from donors after circulatory death has increased over the last decade. This study aimed to describe the evolution and outcomes following lung transplantation donation after circulatory death (DCD) and report the practices and outcomes of ex vivo lung perfusion (EVLP) in this donor population. This was a retrospective study using a prospectively collected national registry. The United Network for Organ Sharing (UNOS) database was queried to identify adult patients who underwent lung transplantation between May 1, 2005, and December 31, 2021. Kaplan-Meier analysis and Weibull regression were used to compare survival in four cohorts (donation after brain death [DBD] with or without EVLP, and DCD with or without EVLP). The primary outcome of interest was patient survival. Of the 21356 recipients who underwent lung transplantation, 20380 (95.4%) were from brain death donors and 976 (4.6%) from donors after circulatory death. Kaplan-Meier analysis showed no difference in the survival time between the two groups. In a multivariable analysis that controlled for baseline differences in donor and recipient characteristics, recipients who received lungs from cardiac death donors after EVLP had 28% shorter survival time relative to donor lungs after brain death without EVLP (hazard ratio [HR] 1.53, 95% confidence interval [CI] 1.10-2.15, p=.01). The early survival differences observed after lung transplants from donors after circulatory death in lungs evaluated with EVLP deserves further investigation.

Is logistically motivated ex vivo lung perfusion a good idea?

Ex vivo lung perfusion (EVLP) is a technique for reconditioning and evaluating lungs. However, the use of EVLP for logistical reasons is still under discussion. In this retrospective study, all EVLPs performed between July 2012 and October 2019 were analyzed for ventilation and perfusion data. After transplantation, primary graft dysfunction (PGD), lung function, chronic lung allograft dysfunction (CLAD)-free survival, and overall survival were analyzed. Fifty EVLPs were performed: seventeen logistic EVLPs led to 15 lung transplantations (LT) and two rejections (LR), and 33 medical EVLPs resulted in 26 lung transplantations (MT) and seven rejections (MR). Pre-EVLP PaO2 was lower for MT than LT (p < 0.05). Dynamic lung compliance remained stable in MT and LT but decreased in MR and LR. Plateau airway pressure started at a higher level in MR (p < 0.05 MT vs. MR at T60) and increased further in LR. After transplantation, there were no differences between MT and LT in PGD, lung function, CLAD-free survival, and overall survival. In addition, the LT group was compared with a cohort group receiving standard donor lungs without EVLP (LTx). There were no significant differences between LT and LTx for PGD, CLAD-free survival, and overall survival. FVC was significantly lower in LT than in LTx after 1 year (p = 0.005). We found that LT lungs appear to perform better than MT lungs on EVLP. In turn, the outcome in the LT group was comparable with the LTx group. Overall, lung transplantation after EVLP for logistic reasons is safe and makes transplantation timing controllable.

A Randomized, Multicenter, Blinded Pilot Study Assessing the Effects of Gaseous Nitric Oxide in an Ex Vivo System of Human Lungs.

Normothermic ex vivo lung perfusion (EVLP) is used to evaluate and condition donor lungs for transplantation. The objective of this study was to determine whether administration of exogenous nitric oxide during EVLP contributes to improvement of lung health. A multicenter, blinded, two-arm, randomized pilot study evaluated the effect of gaseous nitric oxide (gNO) administered during EVLP on donor lungs rejected for transplantation. gNO introduced into the perfusate at 80 parts per million (ppm) was compared with perfusate alone (P). An open-label substudy assessed inhaled nitric oxide gas (iNO) delivered into the lungs at 20ppm via a ventilator. Primary endpoints were an aggregate score of lung physiology indicators and total duration of stable EVLP time. Secondary endpoints included assessments of lung weight and left atrium partial pressure of oxygen (LAPO2). Twenty bilateral donor lungs (blinded study, n = 16; open-label substudy, n = 4) from three centers were enrolled. Median (min, max) total EVLP times for the gNO, P, and iNO groups were 12.4 (8.6, 12.6), 10.6 (6.0, 12.4), and 12.4 (8.7, 13.0) hours, respectively. In the blinded study, median aggregate scores were higher in the gNO group compared to the P group at most time points, suggesting better lung health with gNO (median score range [min, max], 0-3.5 [0, 7]) vs. P (0-2.0 [0, 5] at end of study). In the substudy, median aggregate scores did not improve for lungs in the iNO group. However, both the gNO and iNO groups showed improvements in lung weight and LAPO2 compared to the P group. The data suggest that inclusion of gNO during EVLP may potentially prolong duration of organ stability and improve donor lung health, which warrants further investigation.

Glucagon-like peptide-1 stimulates acute secretion of pro-atrial natriuretic peptide from the isolated, perfused pig lung exposed to warm ischemia.

Glucagon-like peptide-1 (GLP-1) has proven to be protective in animal models of lung disease but the underlying mechanisms are unclear. Atrial natriuretic peptide (ANP) is mainly produced in the heart. As ANP possesses potent vaso- and bronchodilatory effects in pulmonary disease, we hypothesised that the protective functions of GLP-1 could involve potentiation of local ANP secretion from the lung. We examined whether the GLP-1 receptor agonist liraglutide was able to improve oxygenation in lungs exposed to 2 h of warm ischemia and if liraglutide stimulated ANP secretion from the lungs in the porcine ex vivo lung perfusion (EVLP) model. Pigs were given a bolus of 40 µg/kg liraglutide or saline 1 h prior to sacrifice. The lungs were then left in vivo for 2 h, removed en bloc and placed in the EVLP machinery. Lungs from the liraglutide treated group were further exposed to liraglutide in the perfusion buffer (1.125 mg). Main endpoints were oxygenation capacity, and plasma and perfusate concentrations of proANP and inflammatory markers. Lung oxygenation capacity, plasma concentrations of proANP or concentrations of inflammatory markers were not different between groups. ProANP secretion from the isolated perfused lungs were markedly higher in the liraglutide treated group (area under curve for the first 30 min in the liraglutide group: 635 ± 237 vs. 38 ± 38 pmol/L x min in the saline group) (p < 0.05). From these results, we concluded that liraglutide potentiated local ANP secretion from the lungs.

Remote ex vivo lung perfusion at a centralized evaluation facility.

In the US, only 23% of lungs offered for transplantation are transplanted. Ex vivo lung perfusion (EVLP) allows for evaluation of additional donor lungs; its adoption has been limited by resources and expertise. Dedicated facilities with a centralized lung evaluation system (CLES) could expand access to EVLP. In this unblinded, nonrandomized, traditional feasibility study, 7 US transplant centers referred lungs declined for standard transplantation to a dedicated EVLP facility, which utilized a CLES. EVLP was remotely monitored by the transplant teams. CLES lungs were matched with contemporaneous conventional static cold-preserved controls at each center. A total of 115 recipients were enrolled, and 66 received allografts from 63 donors after EVLP at the dedicated CLES facility. Forty-nine contemporaneous patients served as controls. Primary graft dysfunction grade 3 at 72 hours (PGD3-72 hours) was higher in the CLES group with 16 (24%) vs 2 (4%) in the control (common RD 95% CI, 0.07-0.32; p=0.0009). All recipients survived to 30 days and 1-year survival was similar for both groups (92% controls vs 89% CLES; common RD 95% CI, -0.14-0.08; p=0.58). Total preservation time, hospital and ICU lengths of stay, and time to first extubation were longer in the CLES group. Remote ex vivo perfusion of lung allografts declined for conventional transplantation at a dedicated CLES facility is feasible and resulted in additional transplants. Recipients of allografts assessed with a CLES had a higher rate of PGD3-72 hours, but similar 30-day and 1-year outcomes compared to conventional lung recipients. (NCT02234128).

Lung donation after circulatory death: A single-centre experience with uncontrolled donors with some considerations

IntroductionOrgan shortage represents one of the main issues associated with lung transplantation (LTx). Over the years, in an attempt to increase the donor pool, the use of donors after cardiac death (DCDs) has gradually increased, with good results that bode well for their wider use in the future. MethodsIn this work, our experience with DCDs is presented. In addition, a brief literature review on controlled (c) and uncontrolled (u) DCDs was performed on the studies published in the last four years. ResultsFrom 2018 to 2022 our center performed three LTx with DCDs. All the donors were uDCDs (Maastricht class II). The median warm ischemic time of the graft was 160 min. In all the three LTx, lungs were reconditioned using portable Ex-Vivo-Lung-Perfusion (EVLP) system (Organ Care System, OCS, TransMedics) for a median time of 535 min. All the three LTx were performed with an intraoperative veno-arterial extra-corporeal membrane oxygenation (V-A ECMO), which was prolonged postoperatively in one patient.Grade 3 primary graft disfunction (PGD) at 72 h was observed in one patient. No signs of acute rejection were observed in any patient at the surveillance transbronchial biopsies. One patient died 317 after LTx for consequences of a lung adenocarcinoma diagnosed in the native lung, while the other two are still alive with a preserved graft function. SummaryThe most recent studies confirm similar results between DCDs and DBDs in terms of survival and graft function. Good results can also be achieved in uDCDs if standardized protocols are followed and graft function is monitored by EVLP.Hence, the use of DCDs represents a valid solution to expand the donor pool.

Liquid Ventilation Reconditions Isolated Rat Lungs Following Ischemia-Reperfusion Injury.

Lung transplantation remains the only curative treatment for end-stage pulmonary disease. Lung ischemia-reperfusion injury (IRI) is a major contributor to primary allograft dysfunction and donor organ nonutilization. The alveolar macrophage is a key inflammatory mediator in IRI. Ex vivo lung perfusion (EVLP) has been investigated to rehabilitate lungs before transplant but has failed to provide significant improvements after IRI. We hypothesized that liquid ventilation (LV) could be utilized for ex vivo lung reconditioning in a rat IRI model. We compared EVLP with LV in an isolated ex vivo rat lung with an aqueous ventilant using quantitative physiological and immunological parameters. We observed improved physiological parameters and mechanical clearance of alveolar macrophages and cytokines halting the propagation of the inflammatory response in IRI. While the wide applicability to large animal or human transplantation have yet to be explored, these findings represent a method for lung reconditioning in the setting of significant IRI that could widen the lung organ donation pool and limit morbidity and mortality associated with ischemia-induced primary graft dysfunction.

THE PRESENT AND FUTURE OF EX-VIVO LUNG PERFUSION

A current limiting factor within the field of lung transplantation is the availability of viable donor lungs to meet the increasing recipient demand. Exvivo lung perfusion (EVLP) is a novel technology which involves the active ventilation of lungs in a physiologic-like environment outside of the body. During EVLP, high risk donor lungs can be assessed, treated and repaired prior to transplantation. Indeed, many transplant centers have now reported comparable outcomes of using these extended criteria lungs to conventional donors through the use of EVLP. Pre-clinical studies and case reports have demonstrated EVLP as an ideal intervention for targeted therapeutics to address donor-related complications such as infection, pulmonary emboli, and aspiration-injury. In addition, increasing evidence has been put forth demonstrating that EVLP usage can extend the total length of pulmonary preservation, which may serve a variety of clinical purposes.

Lung transplantation following donation after circulatory death

• Lung transplantation, a potentially life-saving therapy, remains significantly limited due to donor organ availability. • Donation after Circulatory Death (DCD) is a promising clinical endeavor that may increase the donor pool for viable organs with successful post-transplant outcomes. • The clinical setting and circumstances surrounding DCD are important in successful recovery. • Controlled DCD lung transplantation has success rates similar to lung transplantation following Donation after Brain Death (DBD). • The evolving application of extracorporeal circulation technology, both the ex vivo lung perfusion (EVLP) modality as well as the more recent thoracoabdominal normothermic regional perfusion (TA-NRP), could have a leading role in the optimization of DCD transplants soon.

Low levels of nitric oxide promotes heme maturation into several hemeproteins and is also therapeutic

Nitric oxide (NO) is a signal molecule and plays a critical role in the regulation of vascular tone, displays anti-platelet and anti-inflammatory properties. While our earlier and current studies found that low NO doses trigger a rapid heme insertion into immature heme-free soluble guanylyl cyclase β subunit (apo-sGCβ), resulting in a mature sGC-αβ heterodimer, more recent evidence suggests that low NO doses can also trigger heme-maturation of hemoglobin and myoglobin. This low NO phenomena was not only limited to sGC and the globins, but was also found to occur in all three nitric oxide synthases (iNOS, nNOS and eNOS) and Myeloperoxidase (MPO). Interestingly high NO doses were inhibitory to heme-insertion for these hemeproteins, suggesting that NO has a dose-dependent dual effect as it can act both ways to induce or inhibit heme-maturation of key hemeproteins. While low NO stimulated heme-insertion of globins required the presence of the NO-sGC-cGMP signal pathway, iNOS heme-maturation also required the presence of an active sGC. These effects of low NO were significantly diminished in the tissues of double (n/eNOS−/−) and triple (n/i/eNOS−/−) NOS knock out mice where lung sGC was found be heme-free and the myoglobin or hemoglobin from the heart/lungs were found be low in heme, suggesting that loss of endogenous NO globally impacts the whole animal and that this impact of low NO is both essential and physiologically relevant for hemeprotein maturation. Effects of low NO were also found to be protective against ischemia reperfusion injury on an ex vivo lung perfusion (EVLP) system prior to lung transplant, which further suggests that low NO levels are also therapeutic.

217.7: Neutrophil Extracellular Traps Removal Using Ex Vivo Lung Perfusion Restored Lung Function in Gastric Aspiration Damaged Porcine Lungs

Background: Lung transplantation (LTx) is an established therapeutic option for end-stage pulmonary disease. However, it remains hampered by donor lung scarcity. Treatments which could regenerate lungs rejected for transplant should be explored in order to combat waiting list mortality. Aspiration induced acute lung injury (ALI) is one of the contributes to the low utilization of donor lungs. Neutrophil extracellular traps (NETs) are implicated in the inflammation profile of ALI. Reduction of NETs could be used as a therapeutic option with the arrival of devices specific to their removal. NucleoCapture device selectively removes NETs from the blood by utilizing human histone H1.3 protein conjugated to polymer beads. This study investigated the impact of the NETs capture device during ex vivo lung perfusion (EVLP) on ALI damaged lungs. Methods: Healthy pigs (n=12) were stratified into two groups, treated (n=6) and not treated (n=6). All animals received 4ml/kg body weight gastric content distributed equally between the different lung segments using a bronchoscopy to induce acute lung injury. Mild to moderate ARDS was developed over 6 hours and confirmed via blood gas values, chest x-ray imaging and histological examination. Lungs were subsequently explanted en bloc and placed on EVLP for 4 hours. Treated lungs were placed in line with a NucleoCapture device connected to the EVLP circuit and the non-treated group underwent the same EVLP protocol without the device. Results: Aspiration induced ALI was induced in all subjects as confirmed by infiltration on chest x-ray, histopathological examination and by PaO2/FiO2 ratio. Following treatment with the NucleoCapture device during 4 hours of EVLP, the PaO2/FiO2 ratio was significantly increased compared to non-treated lungs and was found to surpass the threshold values suitable for transplantation. Furthermore, macroscopic evaluation of the treated lungs demonstrated improvement relative to both the initial injury as well as comparison with the non-treated cohort. Conclusions: Removal of NETs using the NucleoCapture device did restored lung function in aspiration damaged lungs. The amelioration of lung function by removing NETs shows potential clinical use of the device to increase the donor lung pool for lung transplantation.

315.5: Mesenchymal Stromal Cell Therapy as Promising Option To Increase Organ Availability and Reduce Graft Failure

Introduction: Lung transplantation (LTx) is an established therapeutic option for end-stage pulmonary disease. However, waiting lists are long and the treatments remains hampered by donor lung scarcity accompanied with high early and late mortality rates. Novel treatment options to regenerate marginal donor lungs turned down for transplant are needed to combat both waiting list mortality and post-operative complications such as primary graft dysfunction (PGD). Although donor numbers increase, donor organ utility is low due to acute lung injury (ALI) which can be induced by gastric aspiration. Mesenchymal stromal cells (MSCs) have caught attention for organ regeneration as they display an array of potentially beneficial effects: they are known to be immunomodulatory, antifibrotic and microbiocidal. MSCs have demonstrated tissue regenerative capacities as documented in preclinical studies, e.g., improved function of diseased lungs. Aim: The aim of the current study is to evaluate the effect of MSCs administered to aspiration damaged lungs during ex vivo lung perfusion (EVLP) and to recipients post transplantation with a focus on their capacity to improve damaged lungs and to decrease the incidence of PGD at 72h post transplantation. Materials and Methods: Lung injury was induced in 12 donor pigs using gastric content with a pH of 2. The donor-recipient pairs were randomized to receive MSCs or placebo treatment during the beginning of EVLP and post LTx. Lungs were treated with EVLP for 4 hours followed by a left lung transplantation. The recipient was kept under anesthesia and closely monitored for three days post LTx. In the final phase of the experimental setup an isolated assessment of the transplanted lung was achieved following a right pneumonectomy. Treatment effects were assessed by clinically relevant parameters, including PaO2/FiO2 ratio, pulmonary vascular resistance (PVR), and lactate, further by histopathological changes, immune cell counts in peripheral blood and cytokine and chemokine levels in plasma and bronchoalveolar lavage fluid during the course of the experiment. Results: The lung functionality as evaluated by the PaO2/FiO2 ratios showed significantly increased lung function in treated recipients compared to both the non-treated recipients and to all lungs at the time of confirmed ALI. A tendency of higher PVR was seen among the non-treated recipients however, not significantly. Lactate was unchanged in both groups. Lung injury scores were also reduced in the treated group as compared to the non-treated group and to the lungs after lung injury was induced. On the third day of follow-up of the recipients, all recipients in the treatment group had PGD grade 0, while the non-treated group consisted of one recipient with grade 0, three with grade 2 and two with grade 3. Conclusion: MSC treatment emerges as a promising therapeutic option for restoring injured donor lungs for reacceptance into the donor pool and decreasing the incidence of PGD.

Successful 3-day lung preservation using a cyclic normothermic ex vivo lung perfusion strategy.

SummaryBackgroundCold static preservation (CSP) at higher temperatures (10°C) has been recently shown as an optimal strategy up to 24-36h of preservation. Here, we hypothesized that alternating 10°C static storage with cycles of normothermic ex vivo lung perfusion (EVLP) would provide conditions for cellular “recharge”, allowing for multi-day lung preservation.MethodsDonor lungs from male Yorkshire pigs were preserved using 10°C CSP with two cycles of 4h EVLP. After a total of 3 days of preservation, a left lung transplant was performed followed by 4h of graft evaluation. As controls, 2 lungs were preserved solely with continuous 10°C preservation for 3 days and transplanted.FindingsFor animals receiving lungs preserved using a cyclic EVLP protocol, lung function and histological structures were stable and the recipient systemic partial pressure of oxygen/fraction of inspired oxygen (P/F Ratio) after excluding the contralateral lung was 422 ± 61 mmHg. In contrast, lungs preserved solely in continuous cold static storage at 10°C for 72h developed massive lung failure, resulting in recipient death. Metabolomic analysis revealed that EVLP plays a critical role in the re-vitalization of key central carbon energy metabolites (Glucose, Succinate, N-Acetyl Aspartate) and reducing the expression of the inflammasome activation marker CASP1.InterpretationIn conclusion, we demonstrate for the first time the feasibility of 3-day lung preservation leading to excellent early post-transplant outcomes. The thoughtful combination of cold storage (10°C) and intermittent EVLP can open new opportunities in organ transplantation.FundingThis work was supported by the UHN Foundation (Grant#1013612).

Ex Vivo Lung Perfusion in Lung Transplantation.

Ex vivo lung perfusion (EVLP) is a technique that enables active metabolism of the lung by creating an environment similar to that inside the body, even though the explanted lungs are outside the body. The EVLP system enables the use of lung grafts that do not satisfy the acceptance criteria for lung transplantation (LTx) by making it possible to evaluate the function of the lung grafts and repair lungs in poor condition, thereby reducing the waiting time of patients requiring LTx and consequently mortality.

Determining the role of von Willebrand factor in thrombotic post transplantation complications using ex vivo lung perfusion system

Background and Aims : A major complication of lung transplantation is thrombosis, which may lead to allograft failure. Increased production of procoagulant molecules, such as von Willebrand factor (VWF), is a significant risk factor for thrombus formation. VWF is a pro-coagulant glycoprotein expressed only in endothelial cells and megakaryocytes, which mediates adhesion of platelets to the endothelium/sub-endothelium. External stimuli, including hypoxia can upregulate VWF. Since during organ-transplantation donor organs are under hypoxic conditions, we explored whether this may lead to alterations in VWF expression, and whether ex vivo lung perfusion (EVLP) as an innovative method for organ preservation prior transplantation can moderate the effect of VWF upregulation and its thrombogenic consequences.

Reduction of primary graft dysfunction using cytokine adsorption during organ preservation and after lung transplantation

Despite improvements, lung transplantation remains hampered by both a scarcity of donor organs and by mortality following primary graft dysfunction (PGD). Since acute respiratory distress syndrome (ARDS) limits donor lungs utilization, we investigated cytokine adsorption as a means of treating ARDS donor lungs. We induced mild to moderate ARDS using lipopolysaccharide in 16 donor pigs. Lungs were then treated with or without cytokine adsorption during ex vivo lung perfusion (EVLP) and/or post-transplantation using extracorporeal hemoperfusion. The treatment significantly decreased cytokine levels during EVLP and decreased levels of immune cells post-transplantation. Histology demonstrated fewer signs of lung injury across both treatment periods and the incidence of PGD was significantly reduced among treated animals. Overall, cytokine adsorption was able to restore lung function and reduce PGD in lung transplantation. We suggest this treatment will increase the availability of donor lungs and increase the tolerability of donor lungs in the recipient.

Establishing an economical and widely accessible donation after circulatory death animal abattoir model for lung research using ex vivo lung perfusion.

Ex vivo lung perfusion (EVLP), is a platform that allows simultaneous testing and treatment of the lungs. However, use of EVLP is costly and requires access to lab animals and accompanying facilities. To increase the use of EVLP for research, we developed a method to perform EVLP using abattoir procured lungs. Furthermore, we were also able to significantly decrease costs. Six pair of lungs were procured from abattoir sheep. The lungs were then flushed and stored in ice for 3h. A low-flow (20% of cardiac output) approach, a tidal volume of 6ml/kg bodyweight and total perfusion time of 3 h were chosen. Perfusion fluids and circuits were self-made. Lung biopsies, perfusate collection, respiratory values, circulatory pressures were recorded and hourly blood gas analyses were performed. Mean pO2 remained stable from 60min (49.3 ± 7.1kPa) to 180min (51.5kPa ± 8.0), p=0.66. Pulmonary artery pressure remained ≤15 mm Hg and the left atrial pressure remained between 3 and 5 mm Hg and peak respiratory pressures ≤20 cmH2 O. Lactate dehydrogenase increased from start (96.3 ± 56.4 U/L) to the end of perfusion (315.8 ± 85.0 U/L), p < 0.05. No difference was observed in ATP between procurement and post-EVLP, 129.7 ± 37.4μmol/g protein to 132.0 ± 23.4μmol/g, p=0.92. Sheep lungs, acquired from an abattoir, can be ex vivo perfused under similar conditions as lab animal lungs with similar results regarding e.g., oxygenation and ATP restoration. Furthermore, costs can be significantly reduced by making use of this abattoir model. By increasing accessibility and lowering costs for experiments using lung perfusion, more results may be achieved in the field of lung diseases.

Limitations of arterial partial pressure of oxygen to fraction of inspired oxygen ratio for the evaluation of donor lung function.

Evaluation of donor lung function relies on the arterial oxygen partial pressure to inspired oxygen fraction ratio (PaO2 /FiO2 ) measurement. Hemodynamic, metabolic derangements, and therapeutic intervention occurring during brain dead observation may influence the evaluation of gas exchange. We performed a mathematical analysis to explore the influence of the extrapulmonary determinants on the interpretation of PaO2 /FiO2 in the brain-dead donor and during Ex-Vivo Lung Perfusion (EVLP). High FiO2 and increased mixed venous oxygen saturation, caused by increased delivery and reduced consumption of oxygen, raise the PaO2 /FiO2 despite substantial intrapulmonary shunt. Anemia does not modify the PaO2 /FiO2 -intrapulmonary shunt relationship. During EVLP, the reduced artero-venous difference in oxygen content increases the PaO2 /FiO2 without this corresponding to an optimal graft function, while the reduced perfusate oxygen-carrying capacity linearizes the PaO2 /FiO2 -intrapulmonary shunt relationship. Adopting PaO2 /FiO2 to evaluate graft suitability for transplantation should account for extrapulmonary factors affecting its interpretation.

Is there life on the airway tree? A pilot study of bronchial cell vitality and tissue morphology in the ex vivo lung perfusion (EVLP) era of lung transplantation.

Ex vivo lung perfusion (EVLP) is a relevant procedure to increase the lung donor pool but could potentially increase the airway tree ischemic injury risk. This study aimed to evaluate the direct effect of EVLP on the airway tree by evaluating bronchial cell vitality and tissue signs of injury on a series of 117 bronchial rings collected from 40 conventional and 19 EVLP-treated lung grafts. Bronchial rings and related scraped bronchial epithelial cells were collected before the EVLP procedure and surgical anastomosis. The preimplantation interval was significantly increased in the EVLP graft group (p < 0.01). Conventional grafts presented cell viability percentages of 47.07 ± 23.41 and 49.65 ± 21.25 in the first and second grafts which did not differ significantly from the EVLP group (first graft 50.54 ± 25.83 and second graft 50.22 ± 20.90 cell viability percentage). No significant differences in terms of histopathological features (edema, inflammatory infiltrate, and mucosa ulceration) were observed comparing conventional and EVLP samples. A comparison of bronchial cell viability and histopathology of EVLP samples retrieved at different time intervals revealed no significant differences. Accordingly, major bronchial complications after lung transplant were not observed in both groups. Based on these data, we observed that EVLP did not significantly impact bronchial cell vitality and airway tissue preservation nor interfere with bronchial anastomosis healing, further supporting it as a safe and useful procedure.

Prone ex vivo lung perfusion protects human lungs from reperfusion injury

We previously reported beneficial effects of prone positioning during ex vivo lung perfusion (EVLP) using porcine lungs. In this study, we sought to determine if prone positioning during EVLP was beneficial in human donor lungs rejected for clinical use. Human double lung blocs were randomized to prone EVLP (n=5) or supine EVLP (n=5). Following 16 h of cold storage at 4°C and 2h of cellular EVLP in either the prone or supine position. Lung function, compliance, and weight were evaluated and transplant suitability determined after 2h of EVLP. Human lungs treated with prone EVLP had significantly higher partial pressure of oxygen/fraction of inspired oxygen (P/F) ratio [348 (291-402) vs. 199 (191-257) mm Hg, p=0.022] and significantly lower lung weight [926(864-1078) vs. 1277(1029-1483) g, p=0.037] after EVLP. 3/5 cases in the prone group were judged suitable for transplant after EVLP, while 0/5 cases in the supine group were suitable. When function of upper vs. lower lobes was evaluated, prone EVLP lungs showed similar P/F ratios and inflammatory cytokine levels in lower vs. upper lobes. In contrast, supine EVLP lungs showed significantly lower P/F ratios [68(59-150) vs. 467(407-515) mm Hg, p=0.012] and higher tissue tumor necrosis factor alpha levels [100.5 (46.9-108.3) vs. 39.9 (17.0-61.0) ng/ml, p=0.036] in lower vs. upper lobes. Prone lung positioning during EVLP may optimize the outcome of EVLP in human donor lungs, possibly by improving lower lobe function.