Evolving experience with portable ex vivo lung perfusion in lung transplantation: a review

Introduction

Background

For decades the standard for donor lung preservation has been cold storage on ice to reduce metabolic demand and prevent organ deterioration during transport. This strategy has served the lung transplant community well for over 30 years, but cold static preservation at 4 ℃ carries significant limitations which are especially pertinent in the modern era. Total ischemia times are generally limited to 6–8 hours using this method of allograft preservation, which in the current continuous allocation system may set geographic limits for organ procurement and precludes the ability to time-shift transplants to daytime. Additionally, in the case of high-risk donor lungs or marginal function, there is no opportunity to test the lungs and salvage them for transplant. The donor pool is thus limited to standard criteria donor lungs which exacerbates the perennial donor lung shortage. Finally, there remains a high burden of primary graft dysfunction (PGD) in lung transplantation despite decades of progress in donor and recipient management.

Rationale and knowledge gap

Ex vivo lung perfusion (EVLP) technology was initially developed for extended assessment of marginal donor lungs and became an established tool to salvage marginal lungs through the pioneering work of the Toronto group (1,2). This strategy of stationary EVLP for extended assessment of donor lungs has expanded in the last decade and is routinely performed by many transplant centers. Used in this manner, EVLP has increased the use of lungs that otherwise would be discarded, thus effectively expanding the donor lung pool.

In contrast to the stationary EVLP protocols for extended assessment of marginal lungs, portable EVLP represents a fundamental change in donor lung preservation strategy beyond assessment of marginal donor lungs. Conceptually, portable EVLP is a tool that is designed to replace cold static preservation for the entirety of the preservation period regardless of donor criteria. By virtue of placing the lungs on EVLP at the donor site, the 4 ℃ static preservation period during transport between donor site and EVLP center is eliminated. This is more relevant now in the era of centralized EVLP services where a second prolonged period of cold static preservation is required between EVLP center and the recipient transplant center. We are entering an exciting era where transplant centers have many options for donor lung preservation including Paragonix LUNGguard^TM (Waltham, MA, USA), 10 ℃ fridges, and traditional stationary EVLP platforms. It is imperative to place portable EVLP within this dynamic milieu and describe its role in the modern era.

There is a deficit of reports on the use of portable EVLP in the literature. A prior review from Schmack and colleague detailed the results from the early pilot studies on Organ Care System (OCS) Lung demonstrating the feasibility of OCS Lung (3). At the time of this review, the two landmark studies establishing the use of OCS Lung—INSPIRE and EXPAND—were not yet published. Additionally, the clinical applications for OCS Lung at that time were unclear. Another review by our center (Baylor St. Luke's Medical Center) in 2019 followed the publication of the INSPIRE trial and elaborated on the use of OCS Lung in standard criteria donor lungs (4). At that time, the role for OCS Lung in extended criteria donor lungs and for prolonged preservation times were uncertain. Since these two reviews were published, the clinical use of OCS Lung in the modern CAS era of lung allocation has expanded. Additionally, there are multiple donor lung preservation options available to transplant centers, and the current knowledge gap is defining the role of OCS Lung within this milieu.

Objective

In this review, we will highlight the data supporting the use of portable EVLP and clarify its role in the current era of multiple donor lung preservation modalities including stationary EVLP and novel cold static preservation strategies. Furthermore, we will expand on the role of OCS Lung across standard and extended criteria donor lungs and detail its clinical applications in the modern CAS era of lung allocation.

Portable EVLP device—TransMedics OCSTM Lung

The OCS^TM Lung (TransMedics, Andover, MA, USA) is the only device on the market for portable EVLP (Figure 1). It is also the only commercially available EVLP device with FDA approval for use in both standard and extended criteria donor lungs. Standard criteria lungs generally refer to lungs from brain dead donors <55 years of age, partial pressure of oxygen/fraction of inspired oxygen (PaO₂/FiO₂, P/F) ratio >300, clear imaging, and smoking history less than 20 pack years. Extended criteria donor lungs are those that do not meet the criteria above, including donation after circulatory death donors (DCD). The OCS^TM Lung consists of a portable main console which incorporates a pulsatile pump, ventilator, and heating system. The device occupies one seat on the plane or any medical transport vehicle. A disposable module inserts into the main console and includes a sterile chamber for the lung allograft, a gas exchanger membrane, and perfusate reservoir. The device uses a cellular perfusate consisting of OCS^TM solution (proprietary low-potassium dextran solution with glucose) supplemented with 3 units of packed red blood cells. Once the lungs are removed from the donor, they are immediately placed on the OCS^TM Lung device by securing the trachea and the pulmonary artery to the device. There is open drainage of the left atrium into the reservoir. Once the lung allograft is connected, perfusion begins at a low rate (0.5 L/min) which is slowly increased up to the target rate of 1.4–2 L/min while the lungs are gradually warmed. Once the lungs reach the temperature of 34 ℃, ventilation is initiated at a tidal volume of 6 mL/kg donor ideal body weight with positive end expiration pressure (PEEP) of 5 cmH₂O, rate of 12 breaths per minute, and FiO₂ of 12%. When the allograft reaches 37 ℃ a baseline assessment is taken. For the assessment, the pump flow is increased to 2–3 L/min, the gas exchanger deoxygenates the perfusate, and the lungs are ventilated with room air (21% FiO₂). A blood gas is then taken to measure the P/F ratio. Airway pressure, pulmonary artery pressure, pulmonary vascular resistance, temperature, and perfusate oxygen saturation are monitored continuously throughout the preservation period. Once the lungs arrive at the recipient transplant center a final assessment is done which includes a bronchoscopy and manual assessment. The lungs are deemed suitable for transplant if the final assessment P/F ratio is >300 mmHg, physiological parameters are within 10% of baseline, bronchoscopy reveals lack of significant secretions, and manual assessment reveals lack of pulmonary contusions or significant edema. Depending on surgeon preference, in a bilateral sequential lung transplant the first lung can be separated from the device while keeping the second lung perfused until it is ready for implantation. With OCS^TM Lung, perfusion time limits are not set a priori, and perfusion is maintained for the duration of preservation time that is required by each individual case.

Figure 1 TransMedics OCS^TM lung system (A) and schematic of the device components (B). The blood drains from the open left atrium by gravity into the reservoir. The blood then circulates through the pulsatile pump through the gas exchanger and into the pulmonary artery. Copyright permission obtained from TransMedics. OCS, Organ Care System.

OCS^TM Lung compared to stationary EVLP

The only commercially available stationary EVLP device is the XVIVO XPS device (XVIVO, Gotenborg, Sweden) which is the prototypical stationary EVLP platform for extended assessment of lung allografts. This platform uses the Toronto perfusion protocol, which was designed specifically for the application of extended assessment of marginal lungs. There are several major differences in the perfusion protocol compared to OCS^TM Lung. The XPS device uses a centrifugal pump with continuous flow that is set at 40% of calculated donor cardiac output. The perfusate is acellular STEEN Solution^TM (XVIVO). The system also used a closed left atrium strategy. Finally, perfusion times are typically limited to 3–4 hours with an assessment performed every hour. A comparison of OCS Lung and XPS Toronto protocols is detailed in Table 1.

Conceptually, OCS^TM Lung differs from stationary EVLP platforms by supplanting standard cold preservation with normothermic perfusion and ventilation for the entirety of donor lung preservation. Conversely, stationary EVLP platforms require two periods of cold ischemia. The first, termed cold ischemia time 1 (CIT1) is defined as the time between donor aortic cross clamp and the start of EVLP, which includes transport time between the donor site and EVLP facility. The second period, termed cold ischemia time 2 (CIT2) is defined as the period between separation from EVLP and implantation in the recipient, which in the cases of centralized EVLP facilities can be significant. OCS^TM Lung, on the other hand, nearly eliminates cold ischemia time as the lungs are placed on the device immediately after removal from the donor and can remain on the device in the recipient operating room (OR) until ready for implantation. Rather than being primarily a tool for extended assessment of marginal lungs, OCS^TM Lung is designed to nearly eliminate cold ischemia, which may improve lung function and recipient outcomes.

Clinical indications for portable EVLP using OCS^TM Lung

OCS^TM Lung is a versatile tool that may be used for various indications. It may be used similar to the stationary platforms for extended assessment of marginal lungs with the added benefit that the 3–4-hour assessment window can be done during the transport time. A major benefit of OCS^TM Lung is the ability to prolong preservation times safely regardless of donor factors. This practice allows for long distance procurements and time shifting to avoid overnight transplants. At our institution, we use OCS^TM Lung for all the above indications. Overall, we have used OCS^TM Lung in 30–40% of our cases annually with good outcomes.

Standard criteria donor lungs

One major difference in concept between OCS^TM Lung and the stationary EVLP platforms is their application in standard criteria donor lungs. While traditionally most centers do not subject standard lungs to EVLP, the initial randomized trial of OCS^TM Lung was in standard criteria lungs to study the effect of supplanting cold static preservation with normothermic perfusion and ventilation. The INSPIRE trial was a multicenter, international randomized non-inferiority trial comparing preservation using OCS^TM Lung vs. standard cold preservation at 4 ℃ in standard criteria donor lungs. The primary outcome, which was a composite of absence of PGD3 within the first 72 hours after transplant and 30-day survival, was achieved in 79.5% of patients in the OCS^TM Lung group vs. 70.3% in the control group, meeting criteria for non-inferiority. One striking finding of the study was a nearly 50% reduction in PGD3 within 72 hours in the OCS^TM Lung compared to the control group. This was in the face of longer mean total out of body time in the OCS^TM Lung group at 7.9 hours vs. 6.6 hours in the control group (5). We find that perfusion times tend to be longer with OCS^TM Lung compared to the typical 3–4 hours for traditional stationary EVLP assessments, especially if the recipient operation does not commence until after the final assessment after arrival to the recipient center. In our experience, median perfusion times are 7.5 hours. The INSPIRE trial demonstrated the value of OCS^TM Lung to safely extend preservation times in standard criteria lungs while reducing the incidence of high grade PGD.

There is legitimate concern that the application of EVLP on standard criteria lungs may cause them to deteriorate and render them unsuitable for transplant when they otherwise would have been transplanted using standard techniques. The results of the INSPIRE should allay these fears as just one out of 151 cases was not transplanted for a technical problem unrelated to allograft quality. The stationary EVLP platform using the Toronto perfusion protocol has also been studied in standard criteria lungs. The Vienna group randomized 80 standard criteria lungs to a 4-hour EVLP run vs. going straight to transplant as a proof-of-concept study for safety of stationary EVLP in standard donor lungs. Two out of the 39 lungs (5%) in the EVLP group deteriorated during the perfusion time and were not suitable for transplant (6). The authors reasoned that standard lungs that deteriorate on EVLP may have an unrecognized problem that would manifest in the recipient leading to a poor outcome. There may also be differing physiologic effects in standard lungs based on the perfusion protocol used—cellular perfusate with pulsatile flow and open left atrium in OCS^TM Lung vs. acellular perfusate with continuous flow and closed left atrium in the Toronto protocol. Nonetheless, in the standard EVLP cases that were transplanted in the Vienna study, there was no difference in early clinical outcomes compared to the standard group, suggesting it is safe to prolong total preservation time with a 4-hour EVLP run in standard lungs. In our own clinical experience with the OCS^TM Lung in standard criteria donor lungs, we have had only 1 lung deteriorate since we began our EVLP program in 2018. Our overall lung utilization rate using OCS^TM Lung is >95%. This is one of the highest reported utilization rates for EVLP use. Based on the INSPIRE clinical trial and our experience, OCS^TM Lung is a safe way to preserve standard criteria donor lungs, allowing for prolonged preservation times without compromising the utilization rate nor clinical outcomes.

Extended criteria donor lungs

Extended criteria donor lungs or marginal lungs are the bread and butter of stationary EVLP and the Toronto perfusion protocol. Using this protocol, the Toronto group has reported an overall donor lung utilization rate of 69% since the beginning of their EVLP program with similar short and long-term outcomes compared to standard transplants (2,7). These results contrast with the recently reported multicenter study of remote EVLP at a centralized facility. Compared to a contemporary cohort of standard transplants, there was a higher incidence PGD3 at 72 hours in the EVLP group, 24% vs. 4% in the control group, P=0.0009 (8). And the results of the NOVEL trial which is a prospective multicenter clinical trial of 17 transplant centers evaluating the safety of EVLP that started in 2011 has yet to be published.

Given the success of stationary EVLP in salvaging marginal lungs to expand the donor pool, OCS^TM Lung was evaluated in extended criteria donors in the EXPAND trial. This was a multicenter international single-arm trial of OCS^TM Lung for donor lung preservation in extended criteria donor lungs (9). The donor lung utilization rate in the EXPAND trial was 87%, higher than contemporary reports utilizing stationary EVLP, between 60–69% (6,7). Thirty-day survival was excellent at 99%. There was a higher than anticipated incidence of PGD3 within 72 hours at 44%, considering the INSPIRE trial had a 17.7% incidence of PGD3 within 72 hours. However, a more granular analysis of PGD3 in the EXPAND trial revealed that PGD incidence was highest at the 0–24-hour timepoint, and that by 72 hours, which may be a more clinically relevant metric, the incidence of PGD3 was low at 6% (10).

Based on our center’s experience with OCS^TM Lung, the early PGD signal could be related to the use of DCD donors, which may be more susceptible to PGD and comprised a third of cases in the EXPAND trial. Concordant with the EXPAND data, we have found that in cases of early PGD after OCS^TM Lung requiring venovenous extracorporeal membrane oxygenation (VV ECMO), there is quick resolution leading to short postoperative ECMO runs of 1–2 days. While PGD at early timepoints is not benign, there is evidence that PGD grading at later timepoints is a better prediction of mortality (10). In fact, the report on the initial lung bioengineering experience of centralized EVLP demonstrated a similar phenomenon with a high incidence of PGD3 by 72 hours compared to standard transplants but no difference in 1 year survival (8). The phenomenon of early PGD after EVLP without significant long-term morbidity or mortality may represent a unique phenotype of PGD more akin to pulmonary edema. Therefore, while machine perfusion (portable or stationary EVLP) of extended criteria lungs may lead to more pulmonary edema and higher rates of PGD, the lack of long-term sequelae supports its continued use as a valuable tool to expand the donor pool and provide lifesaving transplants to more patients suffering from end stage lung disease.

Safe prolongation of allograft preservation times

The safe prolongation of lung allograft preservation times without compromising clinical outcomes has long been a goal of the lung transplant community. Not only does it enable time shifting to avoid overnight transplants with its myriad benefits, but in the current era of lung allocation according to the composite allocation score (CAS) system, distant lung donor offers may be entertained without time constraint concerns. At our center, in current practice long distance procurements and avoiding overnight transplants are the most common indications for using OCS^TM Lung. We routinely have cases with total preservation times of 14 hours with excellent early graft function. Evaluation of the impact of CAS on lung transplant practices in the US has revealed 80% longer travel distances and longer total ischemia times compared to the previous LAS system (11). In the first 6 months after the implementation of CAS, 54% of the transplants performed at our center came from donors at distant sites with anticipated ischemia time >6 hours, compared to 7% in the six months preceding CAS. Utilizing OCS^TM Lung, we routinely procure lungs from across the continental US, and even Puerto Rico.

With the use of OCS^TM Lung, overnight transplants can be almost entirely avoided. There is clear evidence that nighttime surgery is associated with worse clinical outcomes. Yang and colleagues found that overnight lung transplants were associated with higher postoperative complications and worse 5-year survival (12). Nighttime surgery leads to sleep impairment, reduced team morale and may contribute to burnout (13). For overnight procurements, the lung allograft in the OCS^TM Lung device is taken to the OR where it is managed by a TransMedics clinical specialist until the recipient OR time, which is usually set for first start in the morning. The allograft undergoes a final assessment prior to bringing the recipient to the OR to ensure suitability for transplant. Total preservation times routinely exceed 12 hours using this strategy. Occasionally, the lower lobes may develop edema and atelectasis during prolonged perfusion runs. Recently, we have begun to prone the lungs on the OCS^TM Lung after the final assessment just before the recipient is wheeled into the operative room. This allows for 2−3 hours of prone position prior to separation from EVLP, which we have found significant improvements in lower lobe edema and recruitment.

There are alternative methods for prolonged preservation of lung allografts. The Toronto group evaluated the combination of standard cold preservation on ice and stationary EVLP using the Toronto perfusion protocol as a method for prolonged total preservation. They demonstrated good outcomes with no difference in PGD at 72 hours nor mortality at 1 year compared to standard transplants (14). However, this strategy should be approached with caution. A multicenter retrospective study evaluating the effect of prolonged CIT before and after EVLP found that extending CIT2 to greater than 4.8 hours was associated with an increased risk of high grade PGD and 1-year mortality (15). As such, the role of combining cold static preservation with the standard stationary EVLP for extension of total preservation time remains unknown and deserves further study.

There are now two novel cold static preservation techniques gaining traction in the lung transplant community. The Toronto group pioneered a strategy of static cold preservation at 10 ℃ for prolonged preservation times, and to time shift transplants. They evaluated 70 lungs preserved at 10 ℃ compared to a propensity-matched cohort of 140 transplants that underwent standard preservation. The median preservations times using the 10 ℃ technique were nearly 12.5 hours for the first lung and just over 14 hours for the second lung. The authors found no differences in perioperative complications, PGD, nor 1-year survival in the 10 ℃ group compared to the standard group (16). These data are very promising, and many centers have now begun exploring this technique. However, further work is needed to validate these results.

The other device for cold static preservation on the market is the Paragonix LUNGguard^TM device. It maintains a consistent and controlled preservation environment for the lung allograft with uniform temperature distribution at a range of 4–8 ℃. In a recent study, the LUNGguard^TM device was used to extend preservation time to avoid overnight transplants. Median total ischemia time was 7.8 hours in the time shift group compared to 5.5 hours in the comparison group of non-time shifted cases that also used LUNGguard^TM. There were no cases of PGD in the time shift group and perioperative outcomes were similar compared to the control group (17). The early data suggest that LUNGguard^TM is safe method for donor lung preservation and the national experience with this device is growing rapidly. But again, further work is needed to evaluate short- and long-term outcomes and whether the device is safe for extended preservation times.

A key limitation of the prolonged static preservation techniques is a lack of physiologic monitoring and functional assessment prior to transplantation, especially in allografts that don’t meet standard criteria. As such, prolonged static preservation strategies are potentially limited to a small pool of ideal donor lungs. On the other hand, extending preservation times using OCS^TM Lung can be applied to standard and extended criteria donor lungs with confidence. An added benefit compared to novel cold static preservation devices such as LUNGguard^TM and the 10 ℃ fridge is the ability to continuously monitor the performance of the organ during the entire prolonged preservation period. Additionally, prolonged preservation with normothermic perfusion platforms sets up future opportunities for therapeutic interventions or donor lung modification to enhance graft function. A summary of the clinical applications of OCS Lung and other preservation techniques is detailed in Table 2.

Limitations of OCS Lung

There are certain aspects related to the use of OCS Lung that deserve mention. The only way to use OCS Lung is through TransMedics’ full-service procurement and OCS Lung management service: the National OCS Program (NOP). If the transplant center prefers to use their own procurement surgeons, TransMedics does allow this, however the OCS Lung device must be managed by a TransMedics clinical specialist.

From a clinical perspective, a potential disadvantage of machine perfusion of lung allografts is the development of pulmonary edema during the perfusion period. The pulmonary edema associated with machine perfusion tends to affect lung allografts with extended preservation times and those from DCD donors. The pulmonary edema manifests as a higher incidence of PGD3 at 72 hours. A recent study using the Thoracic Organ Perfusion (TOP) registry, which is a prospective registry of OCS^TM Lung cases, demonstrated a 31.5% incidence of PGD3 in DCD donor lungs managed with OCS. Median cross clamp time was 10 hours (18).

Finally, there is a very limited body of clinical evidence supporting portable EVLP. Further studies from the TOP registry will serve to validate the anecdotal experience and report on the real-world clinical outcomes of the portable EVLP technique. Our review also does not explore in detail the economic effects of using portable EVLP.

Conclusions

The OCS^TM Lung device is the only Food and Drug Administration (FDA) approved device uniquely suited for standard and extended criteria donor lungs capable of safe prolongation of preservation times to enable modern lung transplant practices. It is a versatile one-size-fits all device that can be used to evaluate marginal lungs, enable long distance procurements, and avoid overnight transplants. Its unique advantages over alternate preservation strategies make the OCS^TM Lung an ideal platform for donor lung preservation regardless of donor characteristics and across a range of clinical indications.

Acknowledgments

The authors would like to thank Elizabeth Schwenke for editorial support.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Haytham Elgharably) for the series “Lung Transplantation: New Frontiers” published in Current Challenges in Thoracic Surgery. The article has undergone external peer review.

Peer Review File: Available at https://ccts.amegroups.com/article/view/10.21037/ccts-24-45/prf

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-24-45/coif). The series “Lung Transplantation: New Frontiers” was commissioned by the editorial office without any funding or sponsorship. G.L. reports the following disclosures: consultant, scientific board adviser, and research grant from TransMedics; former consultant (2020), scientific board advisor, research grant from Abiomed Breethe; consultant for Maquet, research grant from Atricure; research grant from JLH Foundation, cofounder and CMO for Organvive. R.F. is supported by an AATS Foundation Grant. TransMedics provides research support to Baylor College of Medicine. 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.

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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