key: cord-0973278-f71igyzd
authors: Hirdman, Gabriel; Niroomand, Anna; Olm, Franziska; Lindstedt, Sandra
title: Taking a Deep Breath: an Examination of Current Controversies in Surgical Procedures in Lung Transplantation
date: 2022-05-16
journal: Curr Transplant Rep
DOI: 10.1007/s40472-022-00367-0
sha: 55a6742a134f1295536762dc34d32599a61db2fa
doc_id: 973278
cord_uid: f71igyzd

PURPOSE OF REVIEW: This article reviews controversial questions within the field of lung transplantation, with a focus on data generated within the last 3 years. We aim to summarize differing opinions on a selection of topics, including bridge-to-transplantation, intraoperative machine circulatory support, bronchial anastomosis, size mismatch, delayed chest closure, and ex vivo lung perfusion. RECENT FINDINGS: With the growing rate of lung transplantations worldwide and increasing numbers of patients placed on waiting lists, the importance of determining best practices has only increased in recent years. Factors which promote successful outcomes have been identified across all the topics, with certain approaches promoted, such as ambulation in bridge-to-transplant and widespread intraoperative ECMO as machine support. SUMMARY: While great strides have been made in the operative procedures involved in lung transplantation, there are still key questions to be answered. The consensus which can be reached will be instrumental in further improving outcomes in recipients.

The surgical approach to lung transplantation has benefited from numerous advances since the first successful procedure in 1963 [1] . As the field and perspectives have evolved, practices now reflect an increased understanding of the pathological processes involved and have improved graft longevity.

Questions of what constitutes best practices have yet to be answered, resulting in a continued debate on pre-, peri-, and post-operative concerns. Here, we present a brief discussion of topics critical to lung transplantation today, reviewing the literature released in the past 3 years.

Due to the differences between the number of organs available and the demand for them, patients may wait on the transplant list for variable durations of time, with 54% of listed adults in 2019 having spent between 3 months and 2 years waiting for a transplant [2] . Patients may deteriorate while waiting for a lung transplant, and technical life support may be necessary until a suitable organ is available. This has led to the concept of "bridging to transplantation," where critically ill patients are placed on extracorporeal membrane oxygenation (ECMO) prior to receiving a donor lung (Table 1) . When considering the experiences centers have had with the implementation of bridging to transplantation, two central themes arise: the importance of high center volume, ECMO experience, and the role of ambulation for transplantation success. There has been a noted association between a lung transplant center's volume and its mortality rates [12] . This correlation also appears to hold true when considering patients who are bridged to transplant, leading to the conclusion that with time and experience, the outcomes observed in bridged patients improve. In a 2018 study at a high-volume center in Vienna, across 71 adults with the intention to bridge, successful short-term and long-term outcomes concluded that a bridge to transplantation was appropriate in carefully selected patient populations [7•] . The group reported an intention-to-treat 1-year survival of 70% and a 5-year survival rate of 51%. At another high-volume center, Kukreja et al. reported a 68% successful transplant rate in 76 patients placed on ECMO with the intention to bridge to transplant and showed a 97% 1-year survival conditional upon discharge [8] . These outcomes demonstrate the feasibility of bridging-to-transplant and the potential successes that could be attained in centers with high volumes.

For these high-volume centers, it may even be the case that the program can place riskier patients on ECMO while still preserving outcomes. In a study by Tipograf et al., though there were differences between the lung allocation scores in patients bridged to transplant on ECMO compared to those who were not, those bridged patients were found to have no significant differences in survival [3•] . This outcome is attributed to stringent protocols and patient selection. Bridge to transplant appears to still be a viable option within smaller centers, but the results are subject to more variability. In one smaller study of the thirteen patients who received preparatory ECMO, seven were successfully bridged to transplant, but only four survived past 1 year [9] .

Several studies have highlighted the advantage high-volume centers appear to have relative to lower volume ones [3, 9, 10] . Hayes et al. specifically analyzed for this very effect, finding a discrepancy in outcomes when examining the volume of a center [10] . It was determined there was a post-transplant hazard associated with low volume centers, in contrast with the finding of no adverse influence of ECMO in high volume ones. In another analysis of center volume, Halpern et al. examined center-stratified outcomes to observe again that high volume centers with bridge-totransplant had similar survival rates to non-bridged patients [6] . This is an effect of not just case volume, but also time. At a single high-volume center, when bridge-to-transplant patients were allocated to distinct eras, Benazzo [13] [14] [15] . While results over time may have improved when considering bridge to a first transplant, a firm conclusion has not been reached on placing patients for bridging to retransplant. In the Vienna study, in the 16% of patients who were bridged to retransplantation out of the entire bridging group, there was a decrease in survival compared to the first time transplants group, leading to a call for caution by the authors [7 •]. When Hayanga et al. examined 99 patients who were bridged, there was a greater incidence of prolonged ventilation and reduced 1-year survival in those bridged to retransplantation compared to first transplant (67% vs. 83%) [16••] . Other schools of thought have suggested that ECMO could even be a contraindication to retransplantation, with the caveat that survival rates have improved with time [17] . Within this discussion lies a debate on ethics. As eloquently explained by Hayanga, re-operative lung transplantation raises a moral quandary of how one can justify the distribution of a precious resource repeatedly to one patient and not another as both waits on the same list [16••] . This argument might not, however, hold as well for younger patients.

Moral dilemmas, such as whether to place patients on ECMO in the first place, become less relevant as we gain more information on practices which contribute to success. One factor rising in prominence in recent years has been the role of ambulatory bridging. According to Hoetzenecker et al., the use of ECMO enabling the patient to participate in physical therapy pre-transplantation may prevent deconditioning of the patient [7•]. The loss of strength that occurs in a patient spending time in the intensive care unit correlates with increased morbidity and mortality [18] . While most agree that ambulation can contribute to post-operative success, Kukreja et al. note that half of the successfully bridged patients in their cohort were non-ambulatory [8] . However, when examining factors that lead to a successful bridgeto-transplant, several studies highlighted ambulation as an independent predictor for survival [3, 4] .

All the possibilities and potential impact of ECMO bridge to transplant raises the question: where should the field bridge to next? An unresolved question is which patient population we should select. How conservative should patient selection be when bridging? Tipograf et al. showed good outcomes as they stringently delisted patients who failed to perform but had a lower percentage of patients reach transplantation (56%) [3•] . Is a more conservative approach to patient selection justified when considering the use of marginal donor organs in bridge-to-transplant recipients?

Extracorporeal life support (ECLS) should be considered in more than just the lead-up to transplantion. Discussion within the field revolves around the type and superiority of machine support (MSC) -if any at all -that should be used intraoperatively ( Table 2 ). Patients may be placed either on cardiopulmonary bypass (CPB) or ECMO or alternatively be off-pump with one-lung ventilation (OLV) conducted sequentially. These three options come with their own advantages and disadvantages. The tradeoff for hemodynamic stability in mechanical circulatory support (MCS) is the risk of cannulation, heparinization, and the known effects of non-physiological shear stress and artificial surfaces [25, 26] . While sequential OLV avoids these pitfalls, hemodynamic instability may ensue, or there may be severe hypotension following pressure on the heart [25] . Other points of concern include the high FiO2 needed in reperfusion which has been shown to be a risk factor for PGD development [27] . The use of CPB in a study by Diamond et al. was identified as an independent risk factor for severe PGD [27] . Opinions are divided, with some who report that there can be similar post-operative outcomes between offpump cases which required emergency conversion to CPB and elective "on-pump" [22] . Despite this, in Mohite et al.'s study of 302 transplants, patients who were off-pump were found to have better PaO2/FiO2 ratios and shorter time on ventilation, in the ICU, and hospital stay.

When considering the application of ECMO, some advocate its use in all patients regardless of indication. Under a guideline of routine application of intraoperative ECMO to all patients within the Vienna center, remarkably low percentages of PGD were reported, with only a 10% incidence of any grade of PGD 1-3 [20 ••]. Two-year survival was reported at 86%, and the authors attributed the success to ECMO's ability to control flow to reperfuse the graft gradually. Of note, there are potential limitations to such widespread application. The risk of bleeding, especially in heparinized patients, is a non-negligible threat, with 6 of the 13 patients who additionally received post-operative ECMO requiring reoperation for bleeding. Nevertheless, the takeaway from the prospective trial from the Vienna group is that ECMO prolongation should be implemented to avoid severe PGD. This follows an earlier publication by the same group, which retrospectively examined the discrepancies between ECMO use and no intraoperative mechanical support at all [24] . Thromboembolic events occurred in 9 patients who received peripheral ECMO. There were cerebral ischemic events in two patients on prolonged ECMO post-operatively. Nevertheless, the authors concluded that over their 15-year experience using ECMO as their standard MCS device, their widespread and preemptive use of ECMO had resulted in lower rates of PGD and better survival.

Considering those patients already on ECMO as a bridge to transplantation, there should be further studies on how to manage these patients intraoperatively. Hashimoto et al. found no comparable differences between venoarterial (VA) and venovenous (VV) ECMO following bridging with VV-ECMO [23] . The only apparent yet statistically insignificant difference was an increased need for transfusion following a switch to VA. The requirement of arterial cannulation with increased use of heparin in VA-ECMO carries its own set of risks, and the transfusions these patients may require are linked to a higher risk of primary graft dysfunction with increased mortality [27, 28] Other benefits outlined in Hashimoto et al.'s work are theoretical and would require greater investigation, yet the main conclusion of considering a low threshold to conversion between ECMO types is reached by finding comparable results between the two.

The superiority of ECMO is not a universally held opinion. A retrospective review of intraoperative CPB by Taka et al. reported that CPB in patients receiving lungs from extended criteria donors could exhibit favorable outcomes at 87% survival 1-year post-transplant and 81% at 5-years [29] . The ability of this group to remain comparable to transplants from standard criteria donors was attributed to protective allograft reperfusion. A strategy of elective CPB was pursued in this study to avoid the increased pulmonary artery pressure (PAP) that can occur in an implanted lung when offpump. High PAP can lead to acute right-sided heart failure and hemodynamic collapse. Elective CPB also avoids the potential damage from high FiO2 needed during reperfusion. The authors emphasize the importance of simultaneous reperfusion of the lungs, which they believe outweighs the cost of prolonged ischemic time for the first implanted lung. Arguments against ECMO included the influence a variable patient circulatory volume can have on ECMO flow and an inability to perform open pulmonary artery surgery if needed.

In a meta-analysis of over seven studies encompassing 785 patients, there were no significant differences between CPB and ECMO groups, with the caveat that there was a non-statistically significant trend of increasing mortality in those with CPB [30] . There was an increase in PGD rates among the CPB group, as well as increased bleeding. Furthermore, ECMO patients had fewer renal and pulmonary complications. However, based on ICU and hospital lengthsof-stay, the authors of the meta-analysis still came to a recommendation favoring ECMO use.

An important comparison is how MCS performs relative to off-pump transplantation. In Ius et al.'s study comparing 311 patients with ECMO to the 826 without, there were no significant differences in 5-year survival or chronic lung allograft dysfunction between the groups [21] . This excluded CPB use and corrected for patients surviving to discharge, as the authors described that ECMO patients had higher pre-transplant surgical risk profiles. Placing the patients offpump reduces the exposure to risks that come with ECMO use, such as the risk of hypotension and desaturation due to a lack of venous reservoir and the potential for stopped flow following obstruction of the cannula. Further downsides of ECMO include the need for cell saver to retransfuse lost blood, increased IV fluid administration, and poor surgical visibility [25, 29] . Considerations might need to be made with the underlying diagnosis of the patient in mind, as studies have shown that the use of CPB in cystic fibrosis patients led to increased transfusion [31] . In another study of pediatric and adult cystic fibrosis transplants, the use of CPB was an independent predictor of mortality [31, 32] . Recently, a retro-and prospective, multicenter trial by Loor et al. from eight high-volume centers compared PGD3 rates at 48 or 72 h with CPB, ECMO, and off-pump. The early results of the trial, encompassing 852 transplants, indicate an odds ratio for developing PGD3 of 1.89 when comparing CPB vs. ECMO and as high as 4.21 when comparing CPB vs. off-pump [19] .

Innovations to machine circulatory support may decrease the incidence of post-surgical complications, such as PGD.

In studying a new dual-lumen single cannula in VV-ECMO, Budd et al. report on a case of pulmonary hypertension in which they hypothesize this cannula could lead to less complicated placement, decannulation, and decreased risk of infection [33] . Hybrid devices may prove to be an innovative new angle to pursue, with novel circuits being reported on in smaller studies [34, 35] .

In 2018, an ISHLT working group published a consensus statement on airway complications after lung transplantation [36] . The working group summarized known risk factors for airway complications (ACs) such as right-sided anastomoses, organ preservation techniques, and microbiologic contamination. Subsequently, a new grading system for airway complications was proposed which involved categorizing the complications based on pathophysiology. Types were divided between ischemia and necrosis, dehiscence, stenosis, and malacia and then further graded based on location and extent. One of the first large-scale studies published to use the new grading system was Schweiger et al. in 2020 [37] . Their retrospective study examined 1555 patients whom all underwent the single running technique rather than the more commonly used approach of single running on the membranous portion and single stitches on the cartilaginous portion [38] . In total, 45 patients suffered airway complications (or about 2% per anastomosis), and 82% of these could be classified according to the new ISHLT criteria, with the most common being stenosis. Although no instances were reported in their rather large cohort, the authors acknowledge the risk of purse stringing. The Vienna group concluded that a single-running technique was both time-efficient and associated with an extremely low incidence of anastomotic complications and could be used as a standard technique. However, this interpretation was challenged by Chang et al. who argued that the data were derived from a highly experienced group using the same technique for over two decades and that ultimately the choice of anastomosis should remain dependent on the surgeon's judgment [39] . In order to minimize the portion of the airway solely supplied by the bronchopulmonary collaterals, surgeons have shortened the donor bronchus to about one or two rings above the lobar carina [40] . Recently, some authors have argued that an even shorter donor bronchus at the level of the bronchial carina could be beneficial. However, one must consider the risks of a shorter bronchus and the limited salvage options available if airway complications develop, the worst-case scenario being the need for a retransplantation [41] .

The large disparities reported across the literature in rates of ACs continue to be a concern. A retrospective study by Patoir et al. in 2020 identified an AC prevalence of 23% in their 6-year cohort composed of 121 lung transplants [42] . Patoir et al. identified that their high rates of AC might be explained by their use of the organ preservation solution Celsior (IGL Group, Lyon, France) instead of Perfadex (XVIVO Perfusion AB, Göteborg, Sweden). They hypothesize that Celsior could potentially lead to less severe yet more frequent rates as none of those complications mandated surgical intervention. Another study by Chamogeorgakis et al. found an incidence rate of 5% of ACs among 460 bronchial anastomoses using a more traditional running-single suture technique [43] . Four patients could be managed conservatively, eight endoscopically with stents, and four surgically. Two patients had to be retransplanted due to severe distal airway stenosis.

For the surgeon, a crucial detail to consider is whether the size of the donated graft matches the capacity of the recipient to hold it. Misalignment of the recipient and donor lung characteristics can lead to "size mismatch," which is important given the consequences this may have on patient outcomes. There are reports that an oversized lung may lead to ventilatory dysfunction as well as atelectasis and hemodynamic instability [44] . Others have remarked that an oversized graft comes with a decreased risk for PGD grade 3 [45] . The first obstacle in evaluating a size mismatch is determining the methodology for measurement. Commonly, the ratio between the donor and recipient predicted total lung capacity (pTLC) has been utilized [44, 46] . While larger donor lungs may reduce the risk of PGD, the disease etiology must be considered. In chronic obstructive pulmonary disease (COPD) patients, the actual TLC (aTLC) is increased compared to the pTLC, which could hinder the universality of using the pTLC ratio [47] . This would suggest that the aTLC should be used whenever possible, particularly for recipients for whom the information is likely available.

To consider another form of size and potential mismatch measurement, Li et al. suggest a chest x-ray to determine patient aTLC. They observed a relationship between the ratio of the donor to recipient x-rays and PGD incidence rates [47] . The authors referred to x-ray lung height and noted that when considering lung height ratios greater than 1, there was a significantly higher percentage of those who had PGD grade 3 (24%) relative to ratios less than 1 (11%). The benefits of this metric would be its simplicity: off a set of x-rays, lung dimensions could be easily measured and could represent an accurate method for determining relative graft size. Other alternatives to the pTLC ratio have also been suggested, including calculating lung volume using CT images [48] . This approach benefits from the availability of donor CT scans and may facilitate the ease of calculating a mismatch. Jung et al. have compared the volumes derived from CT images and referenced them to values obtained through plethysmography and pulmonary function testing, finding that CT volumes either had a similar or better correlation to the total lung capacity than pTLC [48] .

Surgeons who find that the donor's lung is inappropriately oversized must then consider the outcomes following a resection. Wedge and lobar reductions could increase the pool of available donor organs, which would reduce the wait times of listed potential recipients and reduce wait-list mortality. While the graft might not be the ideal for the recipient, it would likely be preferable to no transplant at all. In a study of volume-reduction surgery, Montoya et al. analyzed downsizing larger lungs achieved by anatomic lobectomies and wedge resections [49 ••] . They report that 38% of their reduction patient cohort had a TLC ratio greater than 1.25 before the transplant and that this patient group faced greater need of post-transplantation ECMO and increased mechanical ventilation and hospital lengths of stay. Survival decreased at the 1-, 3-, and 5-year marks for the resected group. One case study explored the possibility of dividing one donor into two lobar transplants for two small recipients with both surviving at the 3-year follow up [50] . Lobar transplants were also studied by Campo-Canaveral De La Cruz et al., with 75 patients showing no overall survival difference at 1-3-, and 5-years compared to standard transplants [51] .

More work needs to be done to clarify how to proceed in situations in which the graft is mismatched with the recipient. From the ISHLTs 2019 report on the focus theme of size match, there is a remark on the scarcity of literature on this topic despite the importance of size-match when a donor offer is considered for acceptance [52] . Past studies report that either oversized allografts fare better or equivalently in both the short-and long-term [46, 53, 54] . When the ISHLT examined differences in weight, they found that 1-year and 5-year survival in recipients of undersized donors were lower. They also found that undersizing by height was correlated to a lower 1-year survival for recipients who had COPD, alpha-1 antitrypsin deficiency, and cystic fibrosis. This was also true for 5-year survival in the same patient groups but not those recipients with interstitial lung disease (ILD). The report thus concludes that undersizing both height and weight leads to poorer outcomes in all diagnostic groups except for recipients with ILD [52] .

Despite the investigative efforts outlined here and the seminal papers that have helped establish the theory behind size mismatch, as lung transplantation is a rapidly evolving field, studies using the latest data centers can provide are needed. Measuring lung volumes based on CT scans has the promise to positively impact the field and could shed greater light on the topic of size mismatch.

However, with grafts that are overly large for the recipient chest, there may be a need to delay chest closure. Delayed chest closure can also be necessary in transplantations with severe bleeding or pulmonary edema [55] . The rate of this is reported to be as high as 29% in some cases but can vary and the question of outcomes is still unclear [56•]. In a retrospective review of 47 propensity matched recipients, there were no differences in pneumonia, deep found infections, or 6-month composite infections between those with delayed chest closure and those without [56•]. There were, however, more transfusions, intubations, and more severe primary graft dysfunction. These patients also remained in the hospital for longer and had worse pulmonary function tests 6 years out, but there were no effects on survival at 6 months, 1 year, and 5 years.

The findings of more severe PGD were supported by a retrospective review by Shigemura et al., who also found higher post-operative bleeding and mortality was associated with the use of delayed chest closure with open skin and retracted ribs [57] . The center had employed three techniques for delayed chest closure with variations on how the ribs and superficial structures were or were not closed. Across the groups, when compared to primary chest closure, there were higher rates of re-exploration and severe PGD. For those who had their skin re-approximated, however, there were fewer incidences of severe PGD requiring post-operative ECMO, decreased mortality, and a shorter ICU stay compared to primary chest closure. In an older study of 28 patients undergoing bilateral transplantation, seven patients with delayed closure were compared to 21 with primary closure with the result of no wound infections in any of these patients [55] . The delayed closure patients were again found to have higher rates of blood transfusion, higher systolic pulmonary artery pressure, higher rate and duration of CPB, and longer lung ischemic time. This compares favorably to the more recent findings by Yeginsu et al. who report that in 16 patients with delayed chest closure, there was a greater time to extubation and a longer ICU stay [58] . Rates of post-operative wound infection were higher but ultimately there was no difference in survival between the two groups.

Similarly, Mohite et al. focused on the technique associated with delayed chest closure and explored approximation of the skin without closure of the sternum and intercostal spaces [59] . This method may avoid the use of ECMO and could be cost-effective. All the aforementioned studies emphasize the role that technique during delayed chest closure may likely play in influencing the outcomes associated with such procedures.

Given the severe shortage of donor organs, the application of ex vivo lung perfusion (EVLP) presents as a method for evaluating marginal lungs [60••] . Its development may increase the transplanted donor pool and it holds potential as a timepoint at which therapeutic approaches could be applied to recover an injured lung [61] . The method was originally designed to re-evaluate DCD lungs ex vivo in an extracorporeal membrane oxygenation circuit to allow for the ventilation, oxygenation, and perfusion of an explanted lung [62] . Today, EVLP is used in lung transplant centers worldwide [63] [64] [65] [66] [67] .

Currently, three major protocols for EVLP are used: the original Lund protocol, the Toronto protocol, and the Organ Care System. Stig Steen and colleagues in the Lund group pioneered the first ex vivo normothermic perfusion system for lungs in the early 2000s [62, 68] . The Lund protocol uses the novel STEEN solution (XVIVO Perfusion AB, Göteborg, Sweden), a buffered extracellular solution with an optimal colloid osmotic pressure for the prevention of pulmonary edema together with erythrocytes. The target flow rate is 100% of cardiac output (CO) in a continuous flow with an open left atrium (LA) [68] . The Toronto group later modified the original protocol, instead opting for an acellular STEEN perfusate and a lower CO against a closed LA. For ventilation, both respiratory rate and FiO2 were reduced to 7/min and 0.21 respectively (compared to 20/ min and 0.5). The group have reported using this modified protocol to extend EVLP and preservation time, publishing on normothermic perfusion of up to 12 h [69, 70] . The third protocol, the Organ Care System Lung (OCS) developed by Transmedics (Andover, MA, USA) uses their own OCS Lung Solution together with RBCs and a pulsatile flow with an open LA. Other notable differences include a standardized flow of 2-2.5 l/min and an FiO2 of 0.12 [71] .

One of the key differences between the three protocols is the use of cellular vs. acellular perfusate. Several studies have directly compared lung function and performance following the use of either. In a porcine model of extended normothermic EVLP in the organ care system (OCS) which compared acellular to cellular using RBCs and whole blood (WB) protocols, Loor et al. found that only the cellular approaches resulted in clinical standards for transplantation being met at 8 h [72] . After 6 h in acellular perfusion, the lungs showed higher vascular resistance, edema, and worsening compliance. Adding autologous WB to the perfusate showed superior lung preservation compared to the RBCs perfused lungs up to 24 h. In a direct comparison of cellular perfusate and open left atrium to an acellular perfusate and a closed left atrium in swine lungs, Nilsson et al. report lung edema and decreasing compliance after 4 h in EVLP, which were more pronounced in the acellular group [73] . These results point to using cellular perfusates to maximize lung functionality. Despite these preclinical findings, larger human studies have focused on the use of acellular perfusates and have still found favorable outcomes, with Divithotawela et al. reporting no significant difference in time to CLAD between EVLP and non-EVLP recipients [74••] .

There have been a few multi-center studies over the years investigating the safety and outcomes of EVLP for standard criteria (SCD) and extended criteria donor lungs (ECD). The NOVEL trial was the first prospective, multi-center, controlled trial and was initially published in 2014 [75] and later updated to include 110 ECD lungs treated with EVLP [76] . The study reported no significant difference in PGD3 rates at 72 h, ICU stay, or 1-year survival compared to standard LTx. In 2018, the INSPIRE trial investigated the use of OCS's portable EVLP system on SCD lungs and found a decrease in PGD3 rates within the first 72 h as well as no difference in survival at 24 months [77] . This was subsequently followed by the EXPAND trial, utilizing the same protocol on ECD lungs, and similarly found no difference in survival at 24 months post-transplant, however, higher than expected rates of PGD3 were reported [78] . Similarly, the DEVELOP-UK trial, with a modified Lund protocol on ECD lungs, was terminated early due to initial high PGD3 rates and need for ECMO in the EVLP arm within the first 72 h post-transplant [79] . In parallel to the EXPAND trial, PGD3 rates were the highest during the first hours posttransplant but normalized at 72 h and had no detrimental effect on survival, perhaps suggesting a different phenotype of PGD. Other multi-center trials corroborate this, Nilsson et al. reporting on ECD-EVLP cases at two Scandinavian centers using the Lund protocol. No differences were found in long term survival, but PaO2/FiO2 ratios were initially lower and ICU stay was longer in the EVLP cases [66] . In two separate 10-year follow-ups on patients who underwent transplantation with or without EVLP, no significant differences were found between groups in mortality and the incidence of chronic lung allograft dysfunction [74, 80] . Trials investigating the use of initially rejected donor lungs on EVLP report conversation rates as high, or even above 80% [66, 78] . An increase in transplantation volume following the introduction of EVLP has been reported to be 18% in Germany and up to 70% in highly experienced centers such as Toronto, with other centers reporting a significant drop in waitlist times [64, 67, 81] .

EVLP has additionally been proposed as a timepoint for therapeutical intervention, and multiple studies have been published on different interventional approaches. Recently, the Toronto group demonstrated a method to convert A antigen donor lungs into universal donor lungs, further increasing the chance of matching a compatible donor and recipient [82] . Mesenchymal stromal (stem) cells and their extracellular vesicles have also been proposed as a therapeutic for reconditioning ECD lungs and ameliorating ischemiareperfusion injury [83, 84] . Furthermore, novel approaches to improve EVLP are actively being investigated, such as negative pressure ventilation (NPV) and sub-normothermic temperatures to overcome some of the ventilator and metabolic injuries sustained during EVLP [85, 86] .

The brief overview provided here of several prominent topics -bridge to transplant, machine circulatory support, bronchia anastomoses, size mismatch, delayed chest closure, and EVLP -underlines the efforts being made in the field today to further improve upon the results already achieved. While it may appear that there is yet much ground to gain, the substantial strides taken since the dawn of lung transplantation in the early 1960's prove that such goals are attainable.

Author Contribution GH, AN, FO, and SL: Conceptualization, writing, figures, and table design and manuscript editing. All authors have read and agreed to the published version of the manuscript.

Funding Open access funding provided by Lund University. The authors gratefully acknowledge funding received from the Wallenberg Molecular Medicine Foundation.

The authors declare no competing interests.

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Chest X-ray sizing for lung transplants reflects pulmonary diagnosis and body composition and is associated with primary graft dysfunction risk

The feasibility of CT lung volume as a surrogate marker of donor-recipient size matching in lung transplantation. Medicine (Baltimore)

Graft reduction surgery is associated with poorer outcome after lung transplantation: a single-centre propensity scorematched analysis

Bilateral lobar transplants using one donor for two small-sized recipients

Deceased-donor lobar lung transplant: a successful strategy for small-sized recipients

The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: thirty-sixth adult lung and heart-lung transplantation Report-2019; focus theme: donor and recipient size match

Relationship between donor/ recipient lung size mismatch and functional outcome in single lung transplantation for COPD

Donor-recipient size matching and survival after lung transplantation. A cohort study

Outcomes of delayed chest closure after bilateral lung transplantation

Delayed chest closure after lung transplantation: techniques, outcomes, and strategies

Delayed chest closure for oversized lung allograft in lung transplantation: a retrospective analysis from Turkey. Braz

Delayed chest closure with skin approximation after lung transplant in oversized graft

Clinical transplantation of initially rejected donor lungs after reconditioning ex vivo

Current status and future perspectives on machine perfusion: a treatment platform to restore and regenerate injured lungs using cell and cytokine adsorption therapy

Transplantation of lungs from a non-heart-beating donor

Successful lung transplant cases with ex vivo lung perfusion assessment of extended criteria donor lungs

Lung transplantation from initially rejected donors after ex vivo lung reconditioning: the French experience

First experience with ex vivo lung perfusion for initially discarded donor lungs in the Netherlands: a single-centre study

Lung transplantation after ex vivo lung perfusion in two Scandinavian centres

Normothermic ex vivo lung perfusion: does the indication impact organ utilization and patient outcomes after transplantation?

Transplantation of lungs from non-heart-beating donors after functional assessment ex vivo

Technique for prolonged normothermic ex vivo lung perfusion

Normothermic ex vivo lung perfusion in clinical lung transplantation

Normothermic perfusion of donor lungs for preservation and assessment with the Organ Care System Lung before bilateral transplantation: a pilot study of 12 patients

Prolonged EVLP using OCS lung: cellular and acellular perfusates

Comparison of two strategies for ex vivo lung perfusion. J Heart Lung Transplant

Long-term outcomes of lung transplant with ex vivo lung perfusion

This study demonstrates positive long-term outcomes in a large cohort after use of EVLP

The NOVEL lung trial one-year outcomes

The NOVEL study. A multi-center clinical trial studying the safety of ex vivo lung perfusion

Normothermic ex-vivo preservation with the portable Organ Care System Lung device for bilateral lung transplantation (INSPIRE): a randomised, openlabel, non-inferiority, phase 3 study

Portable normothermic ex-vivo lung perfusion, ventilation, and functional assessment with the Organ Care System on donor lung use for transplantation from extendedcriteria donors (EXPAND): a single-arm, pivotal trial

An observational study of donor ex vivo lung perfusion in UK lung transplantation: DEVELOP-UK. Health Technol Assess

Impact of allograft ischemic time on long-term survival in lung transplantation: a Swedish monocentric study

One-year experience with ex vivo lung perfusion: preliminary results from a single center

Ex vivo enzymatic treatment converts blood type A donor lungs into universal blood type lungs

Mesenchymal stromal cell therapy during ex vivo lung perfusion ameliorates ischemia-reperfusion injury in lung transplantation

Engineered mesenchymal stromal cell therapy during human lung ex vivo lung perfusion is compromised by acidic lung microenvironment

Clinical transplantation using negative pressure ventilation ex situ lung perfusion with extended criteria donor lungs

Subnormothermic ex vivo lung perfusion temperature improves graft preservation in lung transplantation