INTRODUCTION — Donor lung preservation refers to the process of maintaining and protecting a donor lung from the time of lung procurement up until implantation in the recipient. Many factors such as temperature, perfusion volume and pressure, oxygenation, and degree of inflation may impact the likelihood of lung injury during storage or at the time of reperfusion, and also the function of the lung after transplantation.
Much of the experimental work in lung transplantation over the past decade has focused on optimizing methods of lung preservation to reduce the impact of ischemia-reperfusion injury on post-transplant lung function.
The preservation of donor lungs for lung transplantation will be reviewed here. An overview of lung transplantation and discussions of donor evaluation and management, the lung transplantation procedure, early postoperative care, and primary graft dysfunction are provided separately. (See "Lung transplantation: An overview" and "Lung transplantation: Deceased donor evaluation" and "Lung transplantation: Procedure and postoperative management" and "Primary lung graft dysfunction".)
DONOR LUNG PROCUREMENT — The donor lung procurement operation is coordinated with several teams in the multi-organ donor, especially the cardiac personnel. The procurement is performed such that the lungs and the heart may routinely be used for separate recipients (table 1) [1]. Key goals include preventing in situ thrombosis and vasospasm and stabilizing the lung for static cold storage. Other issues related to lung donation after brain death or cardiac death are discussed separately. (See "Lung transplantation: Deceased donor evaluation", section on 'Donation after brain death' and "Lung transplantation: Deceased donor evaluation", section on 'Donation after circulatory death'.)
Donation after brain death — The lung procurement operation is usually performed through a median sternotomy [1,2]. In sequence, the pulmonary arteries are dissected free from the ascending aorta and the superior vena cava is dissected free up to the innominate bifurcation. After the heart and lungs are exposed, the donor is anticoagulated with intravenous heparin (300 units per kg). A perfusion cannula is placed in the pulmonary artery at least 1.5 cm distal to the pulmonary valve. A cardioplegia catheter is placed in the ascending aorta if the heart is being procured. (See "Diagnosis of brain death".)
When all teams are ready, we routinely administer a bolus of prostaglandin E1 (PGE1, alprostadil) 500 mcg into the main pulmonary artery. The PGE1 can also be mixed with the preservation solution for treatment during pulmonary allograft flushing in-situ. Once the blood pressure starts to decrease, the inferior vena cava is transected; the left atrial appendage or the interatrial groove is vented; and the aorta is cross-clamped [1,2]. The heart is perfused with cardioplegia solution and vented through the left atrium. The cold pulmonary flush for the lungs, which is preferably a low-potassium dextran (eg, Perfadex), is given antegrade in the amount of 60 mL/kg, or about 4 L total at 4°C while ventilation is continued. It is important to make sure the pulmonary flush solution is infused under gravity drainage no higher than 30 cm above the donor to avoid high pressure injury to the pulmonary vasculature (see 'Steps to optimize lung preservation' below). The cold flush solution is allowed to flow into both pleural cavities to provide the necessary topical cooling of the lungs.
The superior vena cava and azygos vein are transected. The main pulmonary artery is transected at its midpoint, usually at the cannulation site. The aorta is transected. The heart is then attached only by the pulmonary veins. Starting at the right inferior pulmonary vein, an incision is made halfway between the coronary sinus and the right inferior pulmonary vein. Then, under direct visualization from inside the atrium, an atrial cuff encompassing all four pulmonary veins is cut to preserve adequate sewing cuffs for the heart and both lungs. The heart is removed.
A retrograde flush with 1 L of cold low-potassium dextran is then performed by instilling 250 mL into each pulmonary vein while ventilation is still continued. Again, this should be done by gravity drainage only, without the use of pressure bags. The proximal trachea just below the larynx is mobilized. The lungs are inflated to a peak pressure of 20 cm H2O with an FIO2 of 50 percent, the trachea is stapled at its proximal end with the lungs partially inflated with two firings of a TA-30 blue stapler and cut in between, to prevent any airway contamination of the surgical field. Note: A longer length of trachea is obtained to facilitate intubation for ex-vivo lung perfusion (EVLP) if desired.
The lungs are placed in triple sterile bags with 2 L of cold Perfadex inside and then placed on ice in a cooler for transport. Note that ice is not to be placed in direct contact with the organ.
Donation after cardiac death — A slightly different initial sequence is used for donation after cardiac death (DCD, also known as non-heart-beating donation or donation after circulatory determination of death) [3-5]. The first step is systemic heparinization, which is usually given prior to withdrawal of life sustaining therapies, although some hospitals will not allow the use of any heparin prior to declaration of death [6]. After reintubation of the donor, a median sternotomy is rapidly performed; the pericardium is opened and the pulmonary artery cannulated (left atrial appendage is transected) and flushed and the lungs topically cooled with ice slurry, before any other dissection is performed. After flushing, the procedure follows that for donation after brain death, as described above. (See "Management of the deceased organ donor", section on 'Donation after circulatory determination of death'.)
Of note, the use of DCD hearts has been introduced, which may alter the lung preservation procedure slightly. Methods for combined heart and lung procurement from DCD donors include mechanical circulation reinstituted using modified extracorporeal membrane oxygenation (ECMO) or DCD procurement followed by ex-vivo machine perfusion for the heart. The former strategy is becoming increasingly popular and is known in the literature as normothermic regional perfusion (NRP). The incorporation of this step generally involves accessing the femoral vessels prior to withdrawal of life support or central venous cannulation after death is declared. Once death has been declared, the previously placed catheters are exchanged for cannulas and regional perfusion is initiated after the cerebral arterial supply has been ligated. The impetus for this step comes largely from the abdominal and cardiac transplant worlds but given the simultaneous nature of procurement it is germane to lung procurement [7,8]. It remains to be seen whether these techniques of procurement for DCD hearts and abdominal organs will impact the quality of lung procurement and preservation.
One large single-center observational study evaluated lung transplant outcomes after rapid-recovery of lungs combined with abdominal NRP from 60 donations after cardiac death compared with 209 donations after brain death (DBD) [9]. The study found similar overall survival (98 versus 94 percent at one year, 68.7 versus 69 percent at five years) with a modest increase in grade 3 primary graft dysfunction with NRP (10 versus 3.4 percent at 72 hours post-transplant).
While preliminary evidence suggests that the lungs are not adversely affected by NRP, there is growing concern amongst some centers this may not be the case, especially with cardiac NRP. Research efforts are underway to clarify this question. NRP also raises several ethical concerns, leading to changes in guideline recommendations for DCD protocols [10]. (See "Lung transplantation: Deceased donor evaluation", section on 'Donation after circulatory death'.)
STEPS TO OPTIMIZE LUNG PRESERVATION — The optimal lung preservation solution, storage temperature, inflation volume, oxygen concentration, and pharmacologic additives needed to enhance lung graft success continue to be investigated. However, several lung preservation techniques have been developed to protect the procured donor lungs from the major insults (eg, brain death, ischemia, anoxia, extended storage, and reperfusion) that may contribute to primary graft dysfunction and long-term mortality [11,12]. (See "Primary lung graft dysfunction".)
Generally, preservation of the procured lungs is initiated with a hypothermic pulmonary artery flush of 50 to 60 mL/kg with a preservative solution, coupled with the topical administration of a cold solution [13,14]. Flushing uniformly cools the lung tissue and removes blood from the pulmonary vascular bed, thereby preventing thrombosis and endothelial injury from retained neutrophils [15]. Thereafter, the lungs are transported at 4 to 8°C in a partially inflated state. Specifics of this process are discussed below and are listed in the table (table 2).
Preservation solution — Experimental work and clinical reports have favored the use of extracellular solutions over intracellular (high potassium, low sodium crystalloid) type preservation solutions [16-24]. Examples of extracellular solutions include low-potassium dextran (LPD)-glucose solution (eg, Perfadex), developed specifically for lung preservation, and Cambridge solution, Celsior, and Papworth, which are other solutions that are used less commonly. Papworth contains Ringer's lactate, mannitol, albumin, and donor blood. Euro-Collins and University of Wisconsin are intracellular solutions that were used historically, with unsuitably high potassium concentrations for the lung. Currently, Perfadex is the preservation solution used in the vast majority of lung transplant programs worldwide.
The key components of LPD solutions are the dextran and low-potassium concentration. Dextran-40 in the LPD solution functions as an oncotic agent, tending to keep water in the intravascular compartment, and thereby decreasing interstitial edema formation. Dextran-40 also has rheologic properties that reduce the aggregation of erythrocytes and circulating thrombocytes, which may improve the microcirculation and reduce cellular activation [25]. The low-potassium concentration maintains normal pulmonary artery pressures during infusion. A further development is the dextran-glucose-based extracellular solution. The addition of glucose is designed to support aerobic metabolism and maintain cell integrity during prolonged ischemia. Perfadex is an LPD-glucose solution that is now available worldwide and is used by most lung transplant centers. The addition of glucose to a lung preservation solution takes advantage of the unique aspect of lung physiology in transplantation. The inflated lung has the ability to supply oxygen directly to its parenchyma; thus, even during storage, low level aerobic metabolism is supported.
Several studies have found better post-transplant outcomes (eg, frequency of primary graft dysfunction, duration of ventilator dependence, and 30-day mortality) with individual extracellular solutions [18,19,21-23,26]. As an example, a retrospective study examined outcomes among 310 consecutive lung transplant recipients whose donor lungs were preserved with Euro-Collins, Papworth, or Perfadex solution [27]. Lung preservation with Papworth solution was associated with increased mortality compared with the other solutions; preservation with Perfadex was associated with a decreased incidence of primary lung graft dysfunction at 48 hours. Another study retrospectively examined the likelihood of primary lung graft dysfunction among 157 consecutive patients whose donor lungs were preserved with one of three lung preservation solutions (Perfadex, Euro-Collins, and Papworth) [26]. Perfadex was superior in preventing moderate to severe grades of primary graft dysfunction, and a trend towards superiority in other early post-transplant outcomes was also noted [28-30]. In a separate retrospective study, LPD (4161 recipients) was compared with University of Wisconsin solution (294 recipients) [24]. LPD was associated with a lower mortality at one year among high risk recipients, but no overall mortality difference was noted between the groups. The use of LPD-glucose preservation solutions has likely contributed to the ability to extend cold ischemic times well beyond the traditional teaching of four to six hours.
Pharmacologic additives — Two pharmacologic agents, prostaglandins and glucocorticoids, have been broadly used for lung preservation. These drugs have been given as pretreatment of the donor before flushing, as part of the flush perfusate itself, and as a treatment for the recipient during and after reperfusion. Other aspects of management of potential lung transplant donors are discussed in detail separately. (See "Lung transplantation: Deceased donor evaluation".)
Prostaglandins — Prostaglandin E1 (PGE1, alprostadil) and I2 (PGI2, prostacyclin, iloprost [a PGI2 analog]) were originally chosen for lung preservation because their vasodilator activity offset the cold or potassium-induced vasoconstriction of the preservation solution and allowed a more even distribution of perfusion [31]. Subsequent study has found that prostaglandins have additional properties, particularly down regulation of proinflammatory cytokine expression that are probably more important in ameliorating ischemia-reperfusion injury [32-35]. Many centers routinely inject PGE1 into the pulmonary artery just before flushing and also add PGE1 into the preservation solution based on the experimental evidence, although clinical trial data in humans are lacking.
Methylprednisolone — High-dose methylprednisolone has become an empirical standard therapy to most clinical protocols because of its broad anti-inflammatory actions [36-38]. Methylprednisolone, 15 mg/kg, is typically administered intravenously to the donor before procurement and to the recipient immediately before reperfusion. The use of hormonal therapy in deceased donors is discussed in more detail separately. (See "Management of the deceased organ donor", section on 'Hormonal therapy'.)
Temperature of preservation solution — While the optimal temperature has been debated, most centers use a practical and easily achievable flush temperature of preservation solution that has been kept on ice. Traditionally, this has been considered to be 4 to 8°C [12], although unpublished data have shown ice storage temperatures closer to 0°C. Hypothermia reduces metabolic activity such that cell viability can be preserved in the face of ischemia (5 percent of the metabolic rate at 37°C). Cold temperature preservation thus continues to be an important component of lung preservation [39,40].
However, the conventional practice of storage on ice has been called into question by a proof of concept study that showed good pulmonary mechanics and no increase in duration of mechanical ventilation after a combination of ice storage, followed by prolonged graft storage at 10°C [41]. These observations suggest that this approach deserves further study.
Anterograde and retrograde flush — Anterograde flush refers to the administration of flush solution through the pulmonary artery with drainage from the pulmonary veins. The usual volume is 50 to 60 mL/kg, or 4 L. Retrograde flush refers to the administration of the flush solution to each pulmonary vein, usually 250 mL to each vein, with drainage through the pulmonary artery. The combination of both procedures appears to achieve better lung function and most transplant centers combine an anterograde flush followed by a retrograde flush [42].
In an experimental model, a retrograde flush improved lung preservation, compared with anterograde flush alone [43]. This effect was attributed to a more effective clearance of red cells within the capillaries and better distribution of the flush solution. It also provides the added advantage of removing any clot or emboli in the pulmonary arteries.
Volume of preservation solution — Although scientific data are limited regarding the ideal volume of preservation solution, typically 4 L or about 60 mL/kg of perfusate is infused after lung extraction, as this effectively clears the lungs of blood cells and uniformly cools the lungs [12]. Usually this takes 10 to 15 minutes to complete [14].
Pressure of preservation solution infusion — Data are limited regarding the optimal pulmonary artery pressure for infusion of the preservation solution. The need for complete clearance of the vascular bed has to be balanced against the risk of injury to the low-pressure pulmonary vasculature [12]. We typically use a perfusion pressure in the lower range (10 to 15 mmHg) and avoid exceeding a maximum perfusion pressure of 22 mmHg (30 cm H2O) [44,45]. This is easy to achieve by hanging the flush solution bags at no more than 30 cm above the donor and flushing with gravity perfusion pressure while always avoiding pressure bags or squeezing the preservation bags.
Lung inflation — Inflation of the lungs with an oxygen mixture during the ischemic period appears to protect the lung; however, scientific information regarding ideal oxygen concentration and inflation pressure is limited [46,47]. Based on studies in animal models, three primary mechanisms are thought to contribute to the protective effect of inflation with oxygenated air:
●Efficient aerobic metabolism is maintained
●Integrity of pulmonary surfactant is preserved
●Epithelial fluid transport is improved
Lung inflation is generally limited to 50 to 75 percent of the total lung capacity (based on visual assessment) or to an airway pressure of 20 cm H2O to avoid over distension during the pressure fluctuations of air transport [47,48]. Usually, an inspired oxygen tension (FiO2) ranging from 30 to 50 percent is used. Once the lungs have been inflated, the trachea is clamped for storage.
Storage temperature — The ideal temperature for donor lung storage remains unclear. Static hypothermic preservation decreases cellular metabolic activity and preserves the cellular function, however cold storage may compound some aspects of ischemia-reperfusion injury [11]. Specifically in the lung, hypothermia may result in increased extravascular fluid and pulmonary vasoconstriction, contributing to diminished oxygen exchange and increased vascular resistance after reperfusion. Some experimental work has suggested that lungs preserved for an extended time at 10°C instead of on ice only had superior lung function after transplantation [41]. However, the most common temperature for lung storage continues to be whatever the organ remains at in a cooler while on iced saline, which is thought to be 0°C or lower, as the logistics of transportation may prolong storage time and necessitate the margin of safety provided by the lower temperature. Commercially available advanced static hypothermic storage devices have become an alternative method to ensure more stable temperature for the organ through a system that keeps the lung consistently between 4 and 8˚C [49].
Ischemic time — The acceptable limits of ischemic time are not known, although based on animal experiments, the longer the ischemic time, the greater the risk of reperfusion injury. Clinically, the underlying state (eg, injury, age) of the donor lung will define what duration of ischemia will be tolerated by that lung. Ischemic times up to eight hours are generally considered acceptable, although we frequently utilize lungs with 8 to 12 hours of cold ischemia times with good outcomes [50].
The risks of primary graft dysfunction and 30-day mortality may increase with more than eight hours of ischemia; however, ischemic times of up to 12 hours have been successfully reported [11,51-53]. Therefore, the decision to accept lungs with longer ischemic times is made with the consideration of the constellation of other predictive risk factors in the lung donor (eg, age, clinical variables, smoking history) and also consideration of the status or condition of the recipient. Early registry data suggested that donor age >55 years and longer ischemic times were associated with worse outcomes [54]. However, subsequent data in an era of modern preservation techniques did not identify donor age as a risk factor when combined with extended ischemic times, although donor age >50 is independently associated with incremental decreased survival [55].
An International Society for Heart and Lung Transplantation (ISHLT) registry analysis noted that lung allograft ischemic times increased between the years 2009 to 2015 [56]. While 30-day survival was significantly lower in recipients of organs with ischemic times of greater than six hours compared with ischemic times of four to six hours, overall survival at five and six years and freedom from bronchiolitis obliterans syndrome (BOS) were actually improved in the organs with longer ischemic times [56]. This was recently confirmed in an updated registry analysis [57].
DONOR AND RECIPIENT SIZE MATCHING — It is important to estimate the size of the donor lung required for the particular recipient [58]. An oversized lung may lead to space compatibility issues and an undersized lung may lead to a more severe reperfusion injury syndrome.
Chest radiograph measurements of the recipient and donor are typically used to help estimate size matching. In general, differences between recipient and donor vertical chest dimensions are more forgiving than horizontal size differences in chest cavities. Other methods for comparing lung capacity between recipient and donor have also been employed. Typically, the total lung capacity (TLC), both actual (measured) and predicted (calculated using standard equations based on height and sex), of the recipient patient are known. The predicted TLC of the donor lung can be calculated based on the standard (GLI) [59]or simplified [60,61]prediction formulas based on age, height, and sex. Thus, the recipient and donor are matched based on the calculated donor TLC that will fit into the chest (donor TLC falls between the actual and predicted recipient TLC volumes).
Computed tomography (CT) may also serve as a useful adjunct for real-time matching of donor and recipient based on CT lung volume measurements [62]. Increasingly, the United Network for Organ Sharing (UNOS) embeds the donor’s CT scan within the website, which will likely facilitate more real-time assessments of size.
If a significant size mismatch is identified, a planned non-anatomic lung volume reduction or lobar lung transplants can be appropriately anticipated and planned for if needed. Our standard pneumoreduction technique involves anatomic right middle lobe and lingular resections for right and left lungs, respectively. While these standard reduction techniques are helpful in the short-term for chest closure, they are associated with lower pulmonary function and poorer overall survival [63].
Data from registries and long-term follow-up suggest that size mismatches are associated with poorer short- and long-term outcomes. One group assessed lung transplant outcomes based on size matching in 550 patients transplanted between 1983 and 2020 [58]. Grade 3 primary graft dysfunction was lower and overall survival and chronic lung allograft dysfunction (CLAD)-free survival were higher when the ratio of donor to recipient predicted TLC was between 0.8 and 1.2.
Patients with restrictive disease receiving a single lung transplant (SLT) may be at particularly high risk of suffering from undersized allografts. In one registry series of lung transplant recipients with restrictive lung disease, 9 percent of 3500 single-lung allografts and 13 percent of 3100 double-lung allografts were undersized (predicted TLC ratio <0.8) [64]. However, SLT recipients of undersized allografts experienced increased mortality (HR 1.711; 95% CI 1.146-2.557), while those receiving bilateral transplant with undersized grafts did not (HR 1.199; 95% CI 0.737-1.952).
LOCAL VERSUS DISTANT LUNG PROCUREMENT — Traditionally, transplant programs have employed their own procurement surgeons and/or residents and fellows to procure organs at distant locations, believing that these individuals share a similar approach to organ assessment. In 2017, the Organ Procurement and transplantation Network (OPTN) increased the distance across which organs could be allocated. The result of this action has been predictably that transplant teams are traveling farther to donor hospitals and subsequent graft ischemic times are longer [65]. During the COVID-19 pandemic, outside surgical teams were discouraged from traveling to donor hospitals. As a result, there has been an increased reliance on local surgeons at the donor hospital.
Whether these new arrangements have a net positive effect or are cause for concern was addressed in a study that analyzed results of transplantation of lungs from local and distant donors [66]. Locally procured lungs were associated with shorter ischemic times, lower cost, and a greater likelihood of daytime surgery.
A recent development in procurement has been the formation of private procurement agencies. There are currently at least four such groups operating around the country, contracting with local surgeons, and providing logistical support in addition to surgeon access. Further data are needed in order to assess the utility and quality of the pretransplantation support provided by these agencies.
NEW APPROACHES TO ORGAN PRESERVATION — Maintaining organ viability during preservation is an important prerequisite for successful outcome after transplantation. A variety of approaches to reducing lung injury during storage are under investigation. Some examples are as follows.
Experimental pharmacologic agents — Several pharmacologic and biologic agents have shown some benefit in experimental models of lung transplantation, but have not been validated in human studies [32,33,36,37,67-74], including:
●Prostaglandin E2 (PGE2)
●Inhaled carbon monoxide
●Oxygen free radical scavengers, such as superoxide dismutase, catalase
●Glutathione, allopurinol, dimethylthiourea, and deferoxamine
●Platelet-activating factor antagonists
●Complement inhibitors (sCR-1)
●Inhaled nitric oxide, nitroglycerin, and nitroprusside
●Phosphodiesterase-5 inhibitors (eg, sildenafil)
●Exogenous surfactant
●Endothelin-1 (ET-1) receptor antagonists
Other interventions currently in various phases of investigation include [72,75-77]:
●Adenosine A2a receptor agonists
●Alpha-1 antitrypsin [75]
●IL-10 gene therapy [76,77]
The use of these agents to prevent or treat primary graft dysfunction is discussed separately. (See "Primary lung graft dysfunction".)
Normothermic ex-vivo perfusion (after cold static preservation) — As the number of patients awaiting a lung transplant and the number of deaths on the transplant waiting list have increased, the community has sought to increase donor lung availability. Unfortunately, the utilization rate of multiorgan donors for lung transplant remains low, at less than 30 percent. Acceptable, but less-than-ideal, donor lungs can make up for part of this shortfall if they can be preserved for a longer period after procurement to facilitate a more thorough quality evaluation. As a result, alternative preservation techniques have been developed [78], including ex-vivo lung perfusion (EVLP; also known as ex-vivo reconditioning or ex-situ lung perfusion) [79-84].
Normothermic EVLP is being increasingly investigated and applied clinically. EVLP is an important assessment and treatment platform to manage donor lungs and is generally used with a period of protective cold static preservation before and after normothermic EVLP. There is mounting evidence that normothermic ex-vivo perfusion and ventilation of lungs is an effective method for assessing organs outside of the context of a multiorgan donor. That said, this method of organ preservation and assessment has not been shown to be safer or superior to cold static preservation for standard criteria donor organs and its ability to truly and reliably rehabilitate, as opposed to just reassess organs, remains to be determined. (See 'Steps to optimize lung preservation' above.)
An acellular EVLP technique has been developed that can maintain donor lungs for up to 12 hours at body temperature with minimal on-going injury [79,83,85,86]. EVLP also allows evaluation of lung function after procurement ex-situ [86]. In one method of normothermic EVLP (the Toronto EVLP system), the lungs are flushed with cold Perfadex solution for transportation and after arrival at the transplant center or lung rehabilitation facility placed in an EVLP chamber. Following cannulation of the pulmonary artery and left atrium, anterograde flow is initiated with room temperature perfusate, and the temperature is gradually increased to 37°C. When 32°C is reached, ventilation is begun using a tidal volume of 7 mL/kg (ideal donor body weight) at seven breaths/minute.
Seven United States transplant centers coordinated a centralized reperfusion site for EVLP of declined donor lungs utilizing the Toronto EVLP System, leading to 66 transplanted allografts from 105 donors over four years [87]. Although the rate of primary graft dysfunction was significantly increased compared with a contemporaneous non-EVLP cohort (24 versus 4 percent), lung function (FEV1), bronchiolitis obliterans syndrome grade, and survival were similar at one year, suggesting feasibility of this approach.
In studies using The US Food and Drug Administration- (FDA)-approved commercial device compatible with this technique (the XVIVO Perfusion System [XPS]), the outcomes of EVLP-treated otherwise unacceptable lungs appear similar to conventional donor lungs. In an observational cohort study, 63 recipients of EVLP-treated allografts were compared with 340 recipients of conventionally managed donor allografts [88,89]. Allograft survival for EVLP and conventional donor lung recipients was 79 versus 85 percent at one year, 71 versus 73 percent at three years, and 58 versus 57 percent at five years. Freedom from chronic lung allograft dysfunction, lung function test parameters, and acute rejection episodes were similar between the groups.
Preliminary data suggest that prompt implantation of lungs after removal from the XPS device may improve outcomes, although this remains controversial. In a retrospective analysis of 110 recipients of lungs that had undergone EVLP on the XPS device, post-EVLP cold ischemic times of greater than 287 minutes were associated with significantly increased rates of high-grade PGD at 72 hours and decreased survival [90]. A limitation of this study is that the causes of longer post EVLP cold ischemic time are not known and may have contributed to the poorer outcomes. Further study of this observation is needed.
Another question is whether EVLP might improve (or worsen) the function of lung allografts that are considered as standard criteria donors. In a randomized, single-center trial, 80 recipient-donor pairs that met standard acceptability criteria were assigned to EVLP or standard management [91]. The incidence of primary graft dysfunction (PGD) >1 was slightly lower in the EVLP group at all time points although the difference did not reach significance (5.7 percent versus 19.5 percent at 24 hours, p = 0.10). The durations of intubation and hospital stay were comparable between the groups, as was the 30-day survival.
A preliminary study demonstrated that a combination of cold static preservation and normothermic EVLP could substantially increase safe preservation time of donor lungs. Patients receiving lungs with more than 12 hours of preservation time (97 patients) had similar outcomes compared with patients receiving lungs with a shorter preservation period (809 patients) [92].
In one preclinical study using a well-established porcine model, lung preservation time could be extended up to three days by alternating four-to-six hour periods of EVLP with cold storage [93]. Pigs that were transplanted using this "cyclic EVLP" approach did uniformly well, indicating the future therapeutic potential of this combination cold storage and EVLP technique.
Normothermic ex-vivo perfusion (no cold static preservation) — As an alternative approach to normothermic ex-vivo perfusion, technologies that remove the necessity for extended cold static storage altogether are being investigated. The Organ Care System (OCS) lung device is a portable normothermic ex-vivo preservation unit that serves the dual purpose of lung perfusion and ventilation. It has been approved by the FDA for use in standard and extended criteria donor lungs, as an alternative to static cold storage, based on the studies described below [94-96].
Using the OCS device requires transport of the machine with the procurement team to the donor hospital. Procurement of the lungs proceeds in the standard fashion, but, as opposed to being placed in cold storage, the lungs are immediately placed on the OCS device where they are perfused with a mixture of blood and preservation solution, rather than the acellular perfusate utilized with the XPS device (see 'Normothermic ex-vivo perfusion (after cold static preservation)' above). Following successful initiation, the lungs are ventilated and perfused continuously in the OCS unit and transported back to the recipient hospital. En route, the graft is continuously monitored with real-time measurements of temperature, hematocrit, arterial oxygenation (SaO2), pulmonary artery pressure, and tidal volume (amongst others). Supplementation of the blood perfusate with glucose and bicarbonate help maintain homeostasis.
Following published evidence from small pilot studies, the OCS lung device was more formally evaluated in the multi-center phase 3 randomized INSPIRE trial [95]. Standard criteria donors (age <65, partial pressure of oxygen/fraction of inspired oxygen [PaO2/FiO2] >300 mmHg) were randomly assigned to conventional cold static storage versus utilization of the OCS lung device. The OCS lung device yielded overall less PGD grade 3 during the first 72 hours and similar 30-day survival compared with cold static storage. In addition, there was no significant difference in safety with the OCS lung device versus standard cold storage.
Following the publication of the INSPIRE trial [95] and FDA approval for OCS device use in standard criteria donors, interest turned to the potential for use in extended criteria donors (ie, age >55, PaO2/FiO2 <300 mmHg, donation after cardiac death [DCD] donors, ischemic time >6 hours). Ninety-one eligible donors were enrolled in the EXPAND single-arm study, and the utilization rate was 87 percent [96]. The rate of PGD grade 3 was 6.4 percent at 72 hours. Thirty-day, 60-day, and one-year survival were all greater than 90 percent. Based on these results, the FDA approved the OCS lung device for extended criteria donors.
As with the XPS system described above (see 'Normothermic ex-vivo perfusion (after cold static preservation)' above), it remains to be determined, in the long term, what role the OCS lung device will play in routine lung procurement. Certainly, the logistics of its use are more complicated and resource intensive, but as many have demonstrated, it has the potential to greatly expand a center’s geographic reach [97] and to increase the time available for the critical assessment of the "marginal" organ.
EX-VIVO PERFUSION: FUTURE DIRECTIONS — The available evidence suggests that lungs procured and then maintained in an ex-vivo system can be safely transplanted with acceptable outcomes. The primary well-demonstrated benefit of ex-vivo perfusion is in extending the time for assessment of marginal donors, particularly in cases of donation after cardiac death. It is premature to claim that ex-vivo perfusion can rehabilitate these less-than-ideal organs, but methods for administering agents that can achieve this ultimate goal are under investigation.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lung transplantation".)
SUMMARY AND RECOMMENDATIONS
●Definitions – Donor lung procurement refers to the process of separating the lungs from the donor and stabilizing them for cold static storage. Donor lung preservation refers to the process of maintaining a donor lung from the time of procurement until reperfusion in a way that will optimize post-transplantation function. (See 'Introduction' above.)
●Procurement procedure
•Just prior to procurement, the donor is anticoagulated with heparin and a bolus of prostaglandin E1 (PGE1, alprostadil) is administered into the pulmonary artery. (See 'Donor lung procurement' above.)
•During procurement, lungs are flushed with a low-potassium dextran (LPD)-glucose preservation solution antegrade and retrograde at a temperature of 4 to 8°C and stored at 4 to 8°C to reduce metabolic activity. An infusion of 60 mL/kg (about 4L) of perfusate solution at a pressure not higher than 30 cm H2O is sufficient to clear the lungs of blood cells and cool the lungs uniformly. (See 'Steps to optimize lung preservation' above.)
•PGE1 is added to the flush solution to reduce the production of inflammatory cytokines and offset cold-induced pulmonary vasoconstriction. (See 'Prostaglandins' above.)
•To avoid overdistension, lung inflation is generally limited to 50 to 75 percent (visually) of the total lung capacity or to an airway pressure of 20 cm H2O. A fraction of inspired oxygen (FiO2) between 30 and 50 percent is used. (See 'Lung inflation' above.)
●Storage temperature – Preservation at 4 to 8°C decreases cellular metabolic activity and preserves the cellular function, however, cold storage may compound some aspects of ischemia-reperfusion injury. (See 'Storage temperature' above.)
●Ischemic time – In general, the longer the ischemic time between procurement and reimplantation, the greater the risk of reperfusion injury. Ischemic times of up to eight hours are generally considered acceptable, although we frequently utilize lungs that are otherwise acceptable after 8 to 12 hours of cold ischemia time with good outcomes. (See 'Ischemic time' above.)
●Ex vivo lung perfusion (EVLP) – EVLP is an emergent and promising technique to increase the number and quality of available allografts. Two systems have been approved by the US Food and Drug Administration (FDA): (1) XVIVO Perfusion System (XPS) for otherwise unacceptable lungs and (2) Organ Care System (OCS) for standard organ preservation as well as extended criteria organs. (See 'Normothermic ex-vivo perfusion (after cold static preservation)' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Marcelo Cypel, MD, MSc, FRCSC, Tom Waddell, MD, MSc, PhD, FRCS, FACS, and Shaf Keshavjee, MD, MSc, FRCSC, FACS, who contributed to earlier versions of this topic review.
