A narrative review on ex vivo lung perfusion: up-to-date role in lung transplantation

Introduction

Background

Ex vivo lung perfusion (EVLP) was first described by Steen et al. out of Lund, Sweden in 2001 (1). The technique involves perfusing and ventilating the lung once outside the donor and before implantation in the recipient of lung transplantation (LTx). It can be used to further evaluate donor lungs, preserve lung function, and provide therapeutics.

Since its introduction in 2001, EVLP has been adopted by several institutions, with the first standardized procedure developed out of Sweden by Steen’s team. This protocol, termed the “Lund” protocol, continues to be in use. EVLP has shown promising results, with successful clinical trials demonstrating non-different short-term mortality between traditional LTx and EVLP (2), and longer-term studies demonstrating no significant difference in chronic lung allograft dysfunction and allograft survival between LTx after EVLP and non-EVLP LTx (3). Since, there have been two additional protocols developed: the Toronto protocol and the TransMedics Organ Care System (OCS) protocol. The EVLP can be applied at the recipient site, at a third-party location, or through portable EVLP (4).

Rationale and knowledge gap

Whatever protocol and location are used, however, the introduction of EVLP has been critical in the venture to expand the donor pool, with reports that centers that utilize it have greatly increased the size of their transplant program; the Toronto group, for example, has expanded annual transplantation by 70% (5). The expansion of the donor pool through EVLP can be attributed to a number of benefits that EVLP confers. It allows for the assessment and interrogation of previously declined lungs that may end up acceptable (6), increases preservation time and thus distance that donor lungs can travel (6-8), and provides an opportunity for isolated therapeutics to the donor lungs that may qualify previously inappropriate lungs for transplantation (9). However, despite these benefits, not all institutions utilize EVLP, nor do those that utilize it do so in the same manner. Additionally, given the novelty of EVLP across the LTx community, there continues to be a need for a narrative review.

Objective

Herein, we present an overview of the current applications of EVLP in LTx, including utilization at our institution. We aim to answer how EVLP is conducted, when and why centers utilize it, and early outcomes. We also aim to summarize its diagnostic, prognostic, therapeutic, and preservative use. We present this article in accordance with the Narrative Review reporting checklist (available at https://ccts.amegroups.com/article/view/10.21037/ccts-24-34/rc).

Methods

Studies listed on PubMed from March 2000, when EVLP was first described, until July 2024 were screened and considered for inclusion. Search language included: EVLP; ex vivo lung perfusion; ex vivo lung therapeutics; ex vivo lung assessment; ex vivo lung preservation. Publications that pertained to EVLP, reported novel data, or reviewed previously peer-reviewed manuscripts were included. Only articles published in English were included. This is summarized in Table 1.

Discussion

EVLP techniques

Location of EVLP

When conducting EVLP, there are three common methods (4). The first is to directly utilize EVLP, immediately placing the donor lungs in a mobile EVLP system and transporting it to the recipient. This removes cold ischemia time (CIT) altogether. The second possibility is to put the donor lungs on ice, transport them traditionally to the recipient site where an EVLP system is waiting, and utilize EVLP on-site. The last option is to incorporate a third-party center that has stationary EVLP. In this scenario, the lungs are put on ice for transport to the third-party facility, placed on EVLP for evaluation, and then again placed on ice for transport to the recipient site. This results in two runs of CIT. All three strategies are reasonable and come with different pros and cons, such as difficulty in setting up within a system, cost, reproducibility, and ischemic time, and although not the focus of this article, these have been described in depth in previous reviews (4).

Major systems

There are also three major systems currently in use (4,5). The Lund method expands on the original cellular EVLP utilization and is now termed the “Lund Vivoline LS1” system. It incorporates 2 hours of EVLP time, uses a combination of a perfusate termed the STEEN solution and packed red blood cells, and targets a flow of 100% of cardiac output (CO) with an open left atrium. The STEEN solution is a physiological salt solution containing human serum albumin, dextran 40, and electrolytes with physiological colloid-osmotic pressure (10). It ventilates with a ventilator at a respiratory rate (RR) of 10–15 breaths per minute, tidal volume (TV) of 5–7 mL/kg, fraction of inspired oxygen (FiO₂) of 0.50, and a positive end-expiratory pressure (PEEP) of 5 cmH₂O.

The Toronto protocol was built off the Lund method and is the most used protocol today (5). This system incorporates 4–6 hours of EVLP time, uses an acellular STEEN perfusate, and targets flow at 40% CO. It similarly utilizes a ventilator for ventilation, at a RR of 7 breaths per minute, TV of 7 mL/kg, an FiO₂ of 0.21, and a PEEP of 5 cmH₂O. The Toronto protocol differs in that the perfusate is acellular, the perfusion flow is lower, and the left atrial pressure is positive and closed (5). The technique is described in depth in previous reports (10). In summary, an endotracheal tube is inserted into the donor trachea, and cannulas are placed in the pulmonary artery and the left atrial cuff. The circuit is primed with STEEN solution, methylprednisolone, heparin, and imipenem/cilastatin. The lungs are then slowly rewarmed, the flow rate is set, and ventilation begins. Thus, the donor lungs are both ventilated and perfused.

The final system is a mobile form of EVLP, the OCS. The OCS utilizes EVLP for however long the transport time is, and has its own perfusate made of a high-oncotic solution with RBCs targeting a hematocrit of 15–25% (7). It targets a flow of 2–2.5 L/min. Unlike the previous two systems, it ventilates with a Bellows pump, and operates at a RR of 10 breaths per minute, TV of 6, FiO₂ of 0.21, and a PEEP of 5 cmH₂O. Similar to the previous protocols, studies have demonstrated that lung transplants utilizing OCS are non-inferior to standard LTx (6).

EVLP outcomes

As briefly discussed above, outcomes using EVLP have been equivalent to standard LTx (3,6,8,11-13). Additional studies have corroborated this finding. Meta-analysis by Chakos et al. evaluating thirteen papers and 407 EVLP transplants found that there was no significant difference in 30-day mortality or primary graft dysfunction (PGD) grade 3 at 72 hours after transplant between EVLP patients and standard transplantation patients (11). A prospective and randomized clinical trial of 80 recipients found that short-term outcomes, such as intubation time, ICU length of stay, and hospital length of stay were not statistically significantly different between EVLP recipients and standard recipients. In addition, the authors found that, although not reaching significance, the EVLP patients had a lower incidence of graft dysfunction at all time points and lower rates of postoperative prolonged extracorporeal membrane oxygenation (12). Studies have examined OCS in isolation as well. A randomized, open-label, prospective study of 320 patients found that the treatment cohort, receiving OCS, had similar 30-day and 12-month survival, with lower rates of PGD grade 3 (6).

EVLP applications

Prolonging preservation time

Despite the great need for increased availability of lung donors and greater geographical reach, LTx remains largely limited by the ischemic time of the donor lungs. Critically, EVLP can increase the preservation time of donor lungs. The Toronto group compared lung recipients that had a preservation time (ischemic time + time on EVLP, if applicable) of <12 hours to those that had a preservation time >12 hours (14). In the former study, 5% of the <12 hours group were treated with EVLP while 95% of the >12 hours group were. Median length of stay in the ICU and the hospital, PGD at 72 hours, and survival were found to be not significantly different between the two groups, demonstrating the ability of EVLP to expand the barrier for preservation time.

Animal models continue to push the limits of EVLP preservation as well. Ali et al. recently reported on the successful use of cyclic EVLP. They show that utilizing EVLP intermittently in a 3-day preservation protocol can result in excellent post-transplant outcomes (15). Further studies confirm these findings, showing that intermittent EVLP results in better oxygenation, higher adenosine triphosphate, more preserved mitochondria, and less extracellular lung water volume when compared to lungs that did not undergo cyclic EVLP (16).

EVLP may also increase preservation time by potentially reducing the negative impact of extended ischemic time. Mallea and co-authors demonstrate that, in a centralized EVLP facility, EVLP can break up cold ischemic time and thus extend preservation (17). They break up an extended cold ischemic time by allowing a first run, then placing the lungs on EVLP for a period of normothermic perfusion and ventilation, and then allowing a second run. They thus allow for restoration of donor lung O₂ and nutritional reserves and wash away metabolites that may have already formed during the first run of cold ischemic time. The authors demonstrate that extended cold ischemic times in both the first run (>5.68 hours) and the second run (>4.25 hours) of cold ischemia were not associated with increased 1-year mortality (17).

Expanding the donor pool

Additionally, the use of EVLP can provide an increased donor pool by re-evaluating lungs that have been initially declined and safely incorporating them (18). Ghaidan et al. report on 10-year outcomes after utilization of EVLP on previously declined lungs, and demonstrate there is no difference between conventional LTx and EVLP transplantation in forced expiratory volume in 1 second or post-operative survival (18). This has been corroborated in the NOVEL study, a prospective study comparing outcomes between traditional lung transplant patients and those receiving previously declined lungs that were then treated with EVLP (19). The authors demonstrate the early outcomes after LTx and 1-year survival between the two groups were not significantly different. The evaluation of metabolites (20,21), and apoptosis markers (22) have been shown to be reliable clinical indicators of donor lung health while on EVLP, and soluble intercellular adhesion has been shown to have higher association with PGD (23). These measurable data points can help surgeons reliably select previously declined lungs that are likely to be successful if selected as donor lungs.

Additional parameters, such as the evaluation of gas exchange, are possible under EVLP (24). One of these measurements is that of the partial pressure of oxygen (PO₂) (25), and studies have shown that the change of PO₂ under EVLP is a significant predictor of lung acceptance (26). The same study found that total lung capacity, peak inspiratory pressure, and driving pressure similarly predicted lung donor acceptance. In fact, some markers of gas exchange also improve over the span of the use of EVLP, such as PaO₂:FiO₂ (2). Lung compliance under EVLP has similarly been demonstrated to predict early outcomes in LTx (27-29). Swine and human lungs assessed under EVLP show a number of correlations between peak airway pressure, plateau pressure, dynamic compliance, static compliance and PaO₂/FiO₂ ratio, pulmonary vascular resistance, and pulmonary artery pressure (30). These metrics can better allow surgeons to select appropriate lungs for transplantation.

Therapeutics during EVLP

EVLP has been shown, through experimental models, as a potential avenue for therapeutic intervention, including drug, gene, and stem cell therapy (31). One of these possibilities is the attenuation of donor lung inflammation (32). Numerous experimental and animal studies, summarized by Iske et al., demonstrate that the use of EVLP can both reduce release of inflammatory mediators and increase anti-inflammatory processes. This includes a reduction in proinflammatory cytokines and an increase in the expression of interleukin 10 (IL-10). Additionally, administration of adenosine agonists reduces tumor necrosis factor (TNF)-α, and IFN-γ (33).

Additionally, Machuca et al. present a study in which donor lungs with a clot are effectively treated with thrombolysis while on EVLP to resolve the clot without putting the donor in danger of any thrombolytic side effects (34). Others have demonstrated the prevention of viral diseases, such as Hepatitis C, when donor lungs are treated while on EVLP (35). Similarly, the treatment of infected lungs with antibiotics reduced bacterial counts and improved lung function (36,37).

Similar to the administration of adenosine agonists to reduce pro-inflammatory markers, surgeons can administer additional therapeutics while donor lungs are on EVLP, such as thrombolytic plasmin. Providing thrombolytic plasmin has demonstrated a reduction in edema, hemorrhage, and cell apoptosis (38,39). Additional targets have been described in animal models, including methylprednisolone (40), pyrrolidine dithiocarbamate (41), neutrophil elastase inhibitor (42), and stem cells (43,44).

Therapeutic applications continue to expand and now include gene therapy (45). As highlighted in a review paper by Nykänen et al., gene therapy may be able to effectively target ischemia-reperfusion injury, acute lung rejection, chronic lung allograft dysfunction, and more. Importantly, it can do so while the donor lung is isolated from the recipient, thus limiting the impact of the therapy on other organ systems in the recipient (45). Our group has utilized EVLP as a platform to study changes in microRNA expression after cold storage and reperfusion, which can be utilized to develop novel therapeutics that target key inflammatory signaling pathways of lung ischemia-reperfusion injury (46,47).

EVLP at The Cleveland Clinic

EVLP continues to be utilized and expanded upon at The Cleveland Clinic. At our institution, the indications for EVLP are: (I) marginal donor lungs with P/F ratio below 300, suspected edema by imaging or lung weight, or donor OR concerns like abnormal bronchoscopic findings, PE, infarcted areas, consolidation or impaired compliance; (II) standard donor lungs for logistics like COVID testing or change of recipient; and (III) donor after circulatory death (DCD) lungs with agonal time more than 60 minutes. Additionally, there is some variance in the evaluation and use of EVLP in DCD vs. donor after brain death (DBD) lungs. For DBD lungs with P/F ratio <300, lung recruitment is usually tried in the donor OR after opening the chest. Another ABG sample is obtained with the opportunity of using these lungs for straight LTx if P/F ratio improved. However, for DCD lungs, this cannot be done.

New prognostic tools

Cleveland Clinic’s lung transplant program has exceeded 2,400 LTx; a milestone that has been reached by only a handful of centers in the world. Since the establishment of the Cleveland Clinic’s EVLP program, more than 200 cases of EVLP have been performed leading to more than 120 cases of successful LTx. In the last four years, the percentage of LTx through EVLP to the total annual LTx was around 30%. Only 9% of the EVLP LTx recipient had PGD grade 3, and their 1-month and 1-year survival rates were 98% and 93%, respectively. These outcomes are significantly better than the international survival rates for LTx, which are 90% (1-month) and 80% (1-year), and the reported PGD rates by other groups ranging from 17% to 27% (48-50).

Our program has previously reported on our consensus around a number of EVLP subtopics, including assessment, preservation, treatment and more (51). We have developed a novel scoring system to evaluate donor lungs on EVLP including change in extravascular lung water volume (52). The study utilized ultrasound directly on the procured lung while on EVLP in order to assess B-lines and edema and derive a score from the information gathered. Ultrasound images were graded as follows: Grade 0 =0% B-lines, Grade 1 =1–25% B-lines, Grade 2 =26–50%, Grade 3 =51–75%, and Grade 4 =>76% B-lines coverage or white-out. The score, termed direCt Lung Ultrasound Evaluation (CLUE), showed statistically significant correlation with lung weight in both human and porcine models, and PaO₂/FiO₂ ratio in human models, demonstrating a critical opportunity for diagnosis and prognosis of procured lungs while on EVLP. Follow-up studies at our institution of this method have found that diagnostic studies such as CLUE are able to make significantly important distinctions between suitable and non-suitable lungs for transplant under EVLP (53).

Additional studies at our center have further demonstrated the prognostic abilities through EVLP. We have shown that in evaluating previously declined donor lungs, lower lung weight is associated with higher PaO₂/FiO₂ ratios and greater transplant suitability at 2 hours after EVLP treatment. This further allows us to predict which lungs, which would otherwise be declined, might benefit from EVLP and ultimately be deemed suitable for transplant (54). We have also reported that higher lung weights after EVLP are associated with poor outcomes, including lower transplant suitability rate, higher incidence of PGD grade 3, and longer intensive care unit (ICU) stays (55).

Based on the previous studies and coinciding with the growing clinical experience of our EVLP program, we have established a novel scoring system to help surgeons prognosticate the suitability of previously declined donor lungs incorporating multiple lung assessment parameters, termed the comprehensive lung evaluation EVLP score (COMPLETE). The score is measured by assigning a value of 0 to 3, with 3 being the worst, to each of the following parameters: lung weight measurement, ultrasound evaluation, airway pressure, lung compliance, PaO₂/FiO₂ ratio, lactate level, deflation, palpation, bronchoscopy, and X-ray (56). The COMPLETE score has been shown to be significantly higher in non-suitable donor lungs, and is correlated with increased ICU length of stay, greater time to extubation, and incidence of PGD grade 3. We have reported the clinical validation of the COMPLETE score at our institution (57).

Back-table assessment of donor lungs prior to EVLP

Our center has also described the use of pulmonary artery angioscopy to evaluate, and treat, pulmonary emboli in donor lungs under EVLP (Figure 1) (58). Five out of 16 lungs in the study were found to have pulmonary emboli, and 2 of those were ultimately treated with good outcomes including extubation on post-op day 1 and a PGD grade of 1 at 72 hours. In an extension of that study, 52 lungs were evaluated and 15 were ultimately found to have pulmonary emboli, had the emboli removed, and 10 were transplanted. Of the 10 patients, none had a PGD grade of 3 at 72 hours (59). We have also combined multiple prognostic tools to better assess the suitability of donor lungs that might undergo EVLP (60). Lungs were evaluated back-table by CLUE, lung weight, inspection, and palpation in order to identify which would not be recoverable by EVLP, thus reducing resource waste.

Figure 1 EXPLORE on the back-table prior to initiation of EVLP. (A,B) demonstrate our surgeons performing angioscopy, (C,D) are the evacuated clots on the back table, measure (C) and mapped (D). EXPLORE, ex vivo pulmonary artery angioscopy; EVLP, ex vivo lung perfusion.

EVLP cases

We present 3 EVLP cases from our program that demonstrate the clinical application in LTx.

Case 1

A young brain-dead donor (31-year-old) with a high body mass index (BMI =41 kg/m²) and no smoking history. The PaO₂/FiO₂ ratio was 221 at the donor hospital with bogginess in the donor lungs on back-table evaluation. For these reasons, the lungs were placed on EVLP at our center and after 3 hours of evaluation, the CLUE score was 0.7 and the COMPLETE score was 4, which are acceptable criteria for transplant. The lung allograft function after transplant was excellent with PGD grade 1 at 72 hours (Figure 2). This case is an example of donor lungs that would not be transplanted without recruitment and re-evaluation on EVLP.

Figure 2 Case 1 EVLP for low PaO₂/FiO₂ and bogginess of the lung on back-table evaluation after procurement. (A) Chest-X-ray of the donor, (B) donor lung assessment on back-table, (C) recipient chest-X-ray at 72 hours after transplant. EVLP, ex vivo lung perfusion.

Case 2

A 45-year-old brain-dead donor with BMI of 22 and smoking history (cigar 10 years). The PaO₂/FiO₂ ratio was 405 at the donor hospital and the lungs were placed on EVLP for logistic reasons given they were an expedited offer to our program. This allowed time to bring the recipient to our center and run the COVID-19 testing. Prior to EVLP, large clots were removed by angioscopy on the back-table (EXPLORE). After 3 hours of EVLP evaluation, the CLUE score was 0.4 and the COMPLETE score was 3, which are acceptable criteria for transplant. The lung allograft function after the transplant was excellent with PGD grade 0 at 72 hours (Figure 3). This case is an example of extending preservation time for over 11 hours (CIT1: 5 hours & 22 minutes, EVLP: 3 hours, CIT2: 3 hours & 13 minutes). Additionally, utilizing EXPLORE angioscopy, in this case, allowed the removal of pulmonary emboli prior to transplant which could have been easily missed and might have led to an unfavorable post-transplant outcome.

Figure 3 Case 2 EVLP for logistic reasons in an expedited offer. (A) Blood clots were removed by back-table angioscopy (EXPLORE) prior to EVLP, (B) lung allograft after EVLP, (C) recipient chest-X-ray at 72 hours after transplant. EVLP, ex vivo lung perfusion; EXPLORE, ex vivo pulmonary artery angioscopy.

Case 3

A 45-year-old DCD donor with a BMI of 31 and no history of smoking. The PaO₂/FiO₂ ratio was 491 at the donor hospital and agonal time was 16 minutes. Large blood clots were removed from the left pulmonary artery on the back-table and, subsequently, the decision was to place the lungs on EVLP at our center. After 3 hours of EVLP, the CLUE score was 1.13, and the COMPLETE score was 18. Additionally, the peak pressure steadily increased (15 at 1 hour, 19 at 2 hours, and 22 at 3 hours) with massive water secretions on bronchoscopy examination of the airway. Given these findings, the lungs were deemed unsuitable for LTx (Figure 4). In the era before EVLP, the lungs could have been considered for transplant based on donor chest-X-ray and good PaO₂/FiO₂ ratio after removal of the clots in the donor hospital operating room. The pulmonary edema in this case could be secondary to reperfusion injury after removal of the blood clots. This is an example of where EVLP can save the recipient from unexpected deterioration from graft function post-transplant.

Figure 4 Case 3 EVLP for incidental findings of large blood clots in the left pulmonary artery at the donor hospital. (A) Donor chest-X-ray, (B) blood clots removed from the lung on the back-table, (C) bronchoscopy evaluation of airway secretions during EVLP. EVLP, ex vivo lung perfusion.

Limitations

Although this provides a relatively exhaustive review of the current literature on EVLP, this was not a systematic review. Thus, selection bias is an inherent limitation of this review. Additionally, the authors did not include “grey literature” such as theses, non-peer-reviewed abstracts, or opinion pieces. Thus, there may be hypotheses, evidence, or viewpoints on EVLP that are not included. Lastly, the authors utilize EVLP themselves, and thus retain an inherent bias towards the progression of EVLP as a clinical tool. This may bias the manuscript to favorably view EVLP. However, despite these limitations, this review provides the most comprehensive overview of EVLP to date.

Conclusions

EVLP has provided a number of opportunities in the lung transplant field in recent years. It allows for an extended and in-depth analysis of lungs, especially allografts from extended donor criteria, that may have otherwise been declined for transplant. It also expands our donor pool, allowing for prolonged preservation time of donor lungs while also providing a method for more rigorous assessment of previously denied lungs. A number of techniques are described, and each has been compared to traditional LTx and found to have non-inferior outcomes. In addition to the ability to increase the donor field with greater preservation and evaluation of lungs, EVLP has also shown promise in the treatment of donor lungs before implantation, likely improving transplant outcomes. Our institution has had the opportunity to utilize EVLP and grow our diagnostic and prognostic application in LTx with it. We have developed novel assessments approached from our growing experience and continue to pursue ways to expand the utilization of EVLP. There remains room for further development in the field of EVLP, in particular therapeutic applications.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Current Challenges in Thoracic Surgery for the series “Lung Transplantation: New Frontiers”. The article has undergone external peer review.

Peer Review File: Available at https://ccts.amegroups.com/article/view/10.21037/ccts-24-34/prf

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://ccts.amegroups.com/article/view/10.21037/ccts-24-34/rc

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://ccts.amegroups.com/article/view/10.21037/ccts-24-34/coif). The series “Lung Transplantation: New Frontiers” was commissioned by the editorial office without any funding or sponsorship. H.E. served as the unpaid Guest Editor of the series and serves as an unpaid editorial board member of Current Challenges in Thoracic Surgery from September 2024 to August 2026. H.E. also received speaking honorarium with LifeNet Health, Edward’s LifeSciences, and Artivion. K.S.A. has an issued US and WO patent for “Evaluation of lungs via ultrasound” and a pending US, WO, CA, EP, and AU patent for “Evaluation of donor lungs during ex vivo lung perfusion”. He has received honoraria for lectures and training from XVIVO Inc. and for a presentation from Transmedics in the last 36 months. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All clinical procedures described in this study were performed in accordance with the ethical standards of the institutional and/or national research committee(s) (IRB# 18-1545) and with the Helsinki Declaration (as revised in 2013). Written informed consent was not obtained from recipients for ex vivo lung perfusion, as it is an FDA-approved procedure and not required under the IRB approval.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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