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تعداد آیتم قابل مشاهده باقیمانده : -10 مورد

Primary lung graft dysfunction

Primary lung graft dysfunction
Author:
Vivek N Ahya, MD
Section Editor:
Ramsey R Hachem, MD
Deputy Editor:
Paul Dieffenbach, MD
Literature review current through: Apr 2025. | This topic last updated: Nov 20, 2024.

INTRODUCTION — 

Primary graft dysfunction (PGD) is a type of severe lung injury that occurs within the first 72 hours of lung transplantation and is the most common cause of early mortality. The pathophysiology, risk factors, diagnosis, grading, and strategies to prevent and treat PGD are reviewed here. Other lung transplant-specific complications and management considerations are reviewed separately. (See "Lung transplantation: Procedure and postoperative management" and "Physiologic changes following lung transplantation" and "Noninfectious complications following lung transplantation" and "Airway complications after lung transplantation" and "Bacterial infections following lung transplantation" and "Fungal infections following lung transplantation" and "Viral infections following lung transplantation" and "Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients" and "Evaluation and treatment of acute cellular lung transplant rejection" and "Evaluation and treatment of antibody-mediated lung transplant rejection" and "Induction immunosuppression following lung transplantation" and "Maintenance immunosuppression following lung transplantation" and "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome" and "Pleural complications in lung transplantation".)

DEFINITION AND GRADING — 

PGD is defined by the presence of diffuse pulmonary opacities on thoracic imaging and hypoxemia without other identifiable cause, developing in the first 72 hours after lung allograft implantation [1]. The typical histopathologic pattern of PGD is diffuse alveolar damage.

The definition of PGD was updated in the 2016 consensus report of the International Society of Heart and Lung Transplantation (ISHLT)'s working group on PGD. Key features of the definition include the following (table 1) [1]:

●The presence of PGD requires radiographic findings consistent with pulmonary edema, and its severity is modeled in part on the definition of the acute respiratory distress syndrome (ARDS) [2] (see "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults"). PGD grades are determined by the ratio of the partial pressure of arterial oxygen (PaO2)/fraction of inspired oxygen (FiO2), also called the P/F ratio. If the PaO2 is unavailable, the oxygen saturation (SpO2)/FiO2 or S/F ratio may be utilized instead [1,3].

•PGD grade 0 (no PGD): no opacities on chest radiograph

•PGD grade 1:P/F ratio >300 or S/F ratio >315

•PGD grade 2:P/F ratio = 200 to 300 or S/F ratio = 235 to 315

•PGD grade 3: P/F ratio <200 or S/F ratio <235

●PGD is assessed at four time points, starting at the time of reperfusion of the second lung (T0), and then at 24, 48, and 72 hours (T24, T48, T72).

●The PaO2/FiO2 is ideally measured on a positive end-expiratory pressure (PEEP) of 5 cm H2O at FiO2 1.0; correction may be needed for high altitude.

●Use of extracorporeal lung support (ECLS) with bilateral pulmonary edema on chest radiograph should be graded as grade 3, and ECLS use should be documented. The use of ECLS for nonhypoxic indications without pulmonary edema on chest radiograph should be considered ungradable.

EPIDEMIOLOGY — 

The incidence of PGD is reported to be in the range of 40 percent overall and 25 to 30 percent for PGD grade 3 at 48 and 72 hours [4,5]; it remains the leading cause of early mortality after lung transplantation [6-8].

PATHOPHYSIOLOGY — 

The pathophysiology of PGD is incompletely understood but is thought to be the end result of multiple different types of injuries to the allograft that begin prior to harvesting of the donor lung. Brain death results in hemodynamic instability, inflammation, hypercoagulability, and hormonal deficits that may cause end-organ damage. Additionally, aspiration, pulmonary embolism, fat emboli, traumatic injury, and cardiac dysfunction can contribute to organ dysfunction prior to harvesting. The organ retrieval process may directly cause lung injury due to the deleterious effects of cold ischemia (during transport) and subsequent inflammation triggered by graft rewarming, implantation, and reperfusion. Transfusion of blood products and mechanical ventilation have also been associated with the development of PGD (figure 1) [9-15]. A few of these issues are reviewed in more detail below:

●Donor brain death – Brain death triggers pathophysiologic derangements that lead to hemodynamic instability, hormonal changes, systemic inflammation, and hypercoagulability, increasing the risk of developing organ damage [11,16-19]. For example, proinflammatory cytokine interleukin (IL)-8 levels increase significantly after brain death [19]. Analysis of bronchoalveolar lavage (BAL) fluid or tissue biopsy samples from lung transplant recipients of organs from brain-dead donors has also shown increased levels of IL-8 in patients who develop PGD, with higher levels associated with more severe PGD grades and increased mortality [20]. Despite optimal donor management and donor lung assessment, lung injury may not be recognized before transplantation and manifest post-transplantation as PGD [21]. (See "Lung transplantation: Deceased donor evaluation" and "Management of the deceased organ donor".)

●Lung retrieval/cold storage – To mitigate the deleterious effects of ischemia (due to absence of blood flow) during organ transport, the donor lung is flushed with hypothermic preservation fluid during organ retrieval. While cold storage helps preserve lung allograft integrity, several injurious events may occur during this phase, especially if the duration is prolonged [22]. While the acceptable limits of ischemic time are not certain, most transplant centers try to limit cold ischemic times to less than eight hours [9]. The process of lung retrieval is unique in that the lung is partially inflated with a fraction of inspired oxygen (FiO2) of 0.3 to 0.5 during storage [9]. This permits oxygen consumption and maintenance of aerobic metabolism during the ischemic period. While this may be beneficial to cellular function, studies have also reported increased production of reactive oxygen species (ROS), which may increase lung injury [15]. Additional information on lung retrieval techniques, as well as types and composition of preservation solutions, is available elsewhere. (See "Lung transplantation: Donor lung procurement and preservation".)

●Lung implantation and reperfusion – Ischemia-reperfusion injury after graft implantation and reperfusion is thought to have a central role in the development of PGD [23]. During the ischemic period, pulmonary endothelial cells generate ROS and nitrogen species that contribute to oxidative injury. With reperfusion, numerous cellular mechanisms are triggered or amplified, activating the innate immune system and triggering the release of inflammatory cytokines and other mediators. This process ultimately increases endothelial cell permeability, damages alveolar epithelial cells, increases pulmonary vascular resistance, and reduces surfactant production, leading to the accumulation of edema fluid, decreased lung compliance, and impaired gas exchange [23-26].

RISK FACTORS — 

Over the last decade, multiple studies have identified risk factors for PGD. Donor-, recipient-, and transplant procedure-related variables have been implicated [7].

Donor-specific risk factors

●Donor smoking history – Donor history of cigarette smoking has been reported to be an important risk factor for PGD [6,7,27,28]. For example, any donor smoking history was found to be independently associated with PGD in a large multicenter United States-based prospective cohort study [6]. In a study of 1295 lung transplants performed in the UK, donor smoking history was likewise an independent risk factor for poorer three-year survival [29]; however, this effect on mortality was not seen in a separate cohort from the United States in which smoking history was more precisely defined by including measurement of urinary concentrations of nicotine metabolites [28].

While donor cigarette smoking may be a modifiable risk factor (ie, not using these donors for lung transplantation), widespread avoidance of these donors could result in greater harm, as almost 40 percent of lung donors in both the United States and UK studies had a smoking history or urinary markers of nicotine exposure [28,29]. While avoiding the use of donors who smoke may be beneficial to a specific recipient's risk of PGD, the net impact of excluding these donors would significantly diminish the number of donor lungs available for transplantation and increase waitlist mortality. Furthermore, when comparing survival from the time of placement on the transplant list, the survival probability after receiving an allograft from a donor with a smoking history is greater than remaining on the waitlist and waiting for a nonsmoking donor [29].

Further studies are needed to better understand why smoking is detrimental to early graft function, whether there is a dose effect, and if there are certain recipients who would be at prohibitively high risk for developing PGD or poor outcomes from the use of these donors. In a study of 298 donor lungs deemed unsuitable for use in transplantation, lungs from current smokers had increased pulmonary edema, reduced alveolar fluid clearance rates, and higher levels of interleukin (IL)-8 in bronchoalveolar lavage (BAL) fluid when compared with nonsmokers [30]. Notably, there appeared to also be a dose-dependent effect, with lungs from donors with a less than 20-pack-year history demonstrating better alveolar fluid clearance rates than lungs from donors with a greater smoking history [30].

The role of other inhaled particulates is also uncertain. Long-term exposure to other ambient air pollutants was also not identified as a risk factor for PGD in a cohort of more than 1400 transplant recipients from the United States [31]. The impact of marijuana smoking as an independent risk factor for PGD is uncertain as there is a significant overlap with tobacco exposure [32].

●Donor alcohol use – High alcohol consumption increases the risk for acute respiratory distress syndrome (ARDS) [33,34]. Thus, it's not surprising that a donor history of heavy alcohol use has been associated with PGD grade 3 [35]. In one study, this risk was almost ninefold higher compared with donors without alcohol use [36].

●Donor age – While earlier studies reported donor age to be an important risk factor for PGD, subsequent studies suggest that the impact of donor age may not be as great as initially reported. In an analysis of data from the multicenter Lung Transplant Outcomes Group (LTOG), donor age between 18 and 64 was not significantly associated with PGD risk [37]. The risk of using donors at the extremes of age is uncertain and may confer greater risk [7,38]. Notably, a study of 241 recipients transplanted with lungs from carefully selected donors who were greater than 65 years of age showed comparable rates of PGD and one-year survival to patients who had received transplants from younger donors [39]. In contrast, a retrospective analysis of patients transplanted in France and the UK showed that transplanting older donors (age >60 years) into younger recipients was associated with increased risk of severe PGD, but no differences in one- or five-year post-transplant survival were observed [38].

●Donor race, sex, and lung size – Analyses of the United Network of Organ Sharing (UNOS) registry and the LTOG database have not shown an association between donor race and PGD risk [6,40]. The impact of donor sex or donor–recipient sex mismatch is uncertain, with published reports yielding conflicting results [7,41]. In the previously referenced multicenter study of the LTOG registry, neither sex nor race were identified as independent risk factors for PGD [6]. The increased risk previously attributed to the female sex of donors is more likely related to smaller donor organ size than to donor sex [7].

The thoracic organs from men are generally (approximately 20 percent) larger than lungs from women [42]. Implantation of oversized allografts has been associated with decreased risk of grade 3 PGD and improved survival among bilateral lung transplant recipients. More specifically, a predicted total lung capacity (pTLC) ratio (donor pTLC: recipient pTLC) greater than 1 was associated with significantly lower rates of grade 3 PGD in LTOG registry subjects [43].

●Other probable donor risk factors – Risk factors that are considered probable include aspiration and chest trauma/lung contusion [7]. Indirect evidence comes from one cohort study of 507 transplanted patients, in which those receiving donor lungs with high levels of total bile acids in large airway bronchial washings (a marker of aspiration, n = 49) had increased risk of primary graft dysfunction (HR 2.4, 95% CI 1.3-4.5) compared with the rest of the cohort [44].

Both aspiration and trauma may contribute to extravascular lung water accumulation and increase donor lung weight [45,46]. In a retrospective cohort study of 313 lung transplants, greater lung weight (normalized to height) was associated with more frequent PGD grade 3 (28 versus 7.4 percent for lungs in the highest versus lowest two quartiles, respectively, at 24 hours) [46]. Among the 51 lungs transplanted after undergoing ex vivo lung perfusion, 4 experienced PGD grade 3, all of which were in the highest quartile of lung weight postperfusion.

●Possible donor-related risk factors – Certain donor characteristics are considered possible contributors to PGD. These include traumatic brain injury, shorter time from brain death to cold preservation, and prolonged mechanical ventilation [7]. Additionally, donor fat embolism and thromboembolism may be risk factors for PGD [47]. In one study of 135 recipients, there was a 21- and 5-fold increased risk of developing severe PGD among those who received lungs with fat emboli or thromboemboli, respectively, compared with patients who obtained lungs without these abnormalities [48]. Patients transplanted with lungs from donors after circulatory determination of death (DCD) have been reported to have higher rates of PGD 3 but comparable survival to patients who received organs from donation after brain determination of death [49]. The impact of ex vivo lung perfusion and normothermic regional perfusion technologies PGD rates from DCD organs requires further investigation [49-51]. (See "Lung transplantation: Donor lung procurement and preservation", section on 'New approaches to organ preservation'.)

Recipient-specific risk factors

●Recipient diagnoses – Transplantation for idiopathic pulmonary arterial hypertension, diseases complicated by secondary pulmonary hypertension, idiopathic pulmonary fibrosis (IPF), and sarcoidosis have been associated with increased PGD risk [6,7,25,52-54]. Notably, in the multicenter cohort study from the LTOG database, for every increase in mean pulmonary arterial pressure of 10 mmHg, the risk of PGD increased by 30 percent [6].

●Obesity – A large cohort study and systematic review, among other studies, have identified elevated recipient body mass index (BMI; ≥25 kg/m2) as a risk factor for PGD [6,7,52,55,56]. In the multicenter LTOG study, obesity was associated with a greater than twofold increase in PGD [6]. In addition to weight, higher plasma levels of leptin, a hormone released by adipose tissue with inflammatory properties, have been associated with PGD risk [57]. Distribution of adiposity may also be associated with increased risk. In a study measuring body composition with chest and abdominal CT scans, the volume of subcutaneous but not visceral adipose tissue was associated with PGD risk [58].

●Sex, race, and age – While data are conflicting, it is unlikely that recipient sex, race, or age are important risk factors for PGD. In a pooled, unadjusted, meta-analysis of 13 studies published from 1970 to 2013 involving more than 10,000 patients, both female sex and self-reported Black race were associated with higher rates of PGD [52]. This study, however, had important methodological flaws. There was significant heterogeneity in patient populations, era of transplantation, and PGD definition. In contrast, the multicenter LTOG study of 1255 lung transplant recipients did not identify recipient sex, race, or age as independent risk factors for PGD [6]. Recipient-specific risk factors for patients <18 or >65 years of age have not been clearly identified because data are limited [7].

●Genetics – Polymorphisms in several genes have been associated with PGD risk. These include polymorphisms in long pentraxin-3 (PTX3), IL-17, prostaglandin E2 (PGE2) synthase gene and genetic variations in the Toll interacting protein (TOLLIP) [59-61].

●Left ventricular diastolic dysfunction – Echocardiographic parameters of left ventricular diastolic dysfunction have been associated with increased risk of PGD after adjustment for recipient age, BMI, mean pulmonary artery pressure, and pretransplant diagnosis [62,63]. Elevated left-ventricular end-diastolic pressure (LVEDP >15 mmHg) on pretransplant cardiac catheterization was also associated with PGD grade 3 [64,65].

●Preformed autoantibodies – The presence of preformed antibodies to lung-restricted self-antigens (k-alpha-1 tubulin and collagen type V) has been identified as a risk factor for PGD [66-68].

Perioperative risk factors

●Cardiopulmonary bypass – The use of cardiopulmonary bypass (CPB) is considered an independent risk factor for PGD (odds ratio [OR] 3.4, 95% CI 2.2-5.3) [6,7,52]. The need for CPB is also a marker for greater severity of illness in the recipient; thus, its association with PGD may be confounded by indication. Venoarterial extracorporeal membrane oxygenation (V-A ECMO) is increasingly used as an alternative to CPB for intraoperative cardiopulmonary support [69-71]. A meta-analysis of seven observational studies comparing the two support modalities suggested that rates of PGD as well as other early complications (eg, bleeding, kidney failure) were increased in patients receiving CPB when compared with those who had received V-A ECMO intraoperatively [72]. The underlying mechanism of the increased risk of PGD associated with CPB has not been fully elucidated, but it may be related to elevations in proinflammatory signaling. For example, one report demonstrated higher plasma levels of syndecan-1, a biomarker of endothelial injury, in patients supported with CPB compared with V-A ECMO [73].

●Transfusion – Large-volume intraoperative blood product transfusion is an independent risk factor for PGD [7,74-76]. Transfusion-related acute lung injury (TRALI), mediated by transfused human leukocyte antigen (HLA)-antibodies or antigranulocyte antibodies in the inflamed allograft, has been reported in the setting of PGD [14]. (See "Transfusion-related acute lung injury (TRALI)".)

●Ischemic time – Prolonged ischemic time is known to be a potential risk factor for PGD in adult recipients. However, multicenter observational studies since 2000 have not found an association between ischemic time and the incidence of PGD grade 3 at 48 and 72 hours [6,7]. While the upper limit of safe ischemic times is unknown, standard practice has been to limit cold ischemic times to <8 hours. Safe extension of cold storage time may be possible under controlled conditions and using modern retrieval practices. [77,78] The continued development of ex vivo lung perfusion (EVLP) technologies may also further expand the duration of safe ischemic times. (See "Lung transplantation: Donor lung procurement and preservation", section on 'Ischemic time' and "Lung transplantation: Donor lung procurement and preservation", section on 'Storage temperature' and "Lung transplantation: Donor lung procurement and preservation", section on 'New approaches to organ preservation'.)

●Anastomosis time – A single-center retrospective study reported that a longer time to perform the graft anastomoses and the associated longer warm ischemic time were independent risk factors for developing PGD [79].

●FiO2 during reperfusion – The fraction of inspired oxygen (FiO2) ≥0.4 during reperfusion is associated with an increased risk of PGD at 48 or 72 hours, compared with an FiO2 <0.4 (OR 1.1 per 10 percent increase in FiO2, 95% CI 1.0-1.2) [6].

●Mechanical ventilation – Lung protective ventilation utilizing tidal volumes of 6 to 8 mL/kg calculated utilizing donor rather than recipient ideal body weight has been associated with reduced risk of developing PGD grade 3 and improved one-year survival [80].

●Delayed chest closure — It is unclear whether delayed chest closure is a risk factor for PGD, a marker for PGD development, or reflects other intraoperative challenges. Delayed chest closure is associated with the use of CPB, high transfusion requirements, increased oxygen requirements, and elevated pulmonary artery pressures [81,82].

●Type of transplant procedure – In some studies, single lung transplantation is associated with a greater risk of PGD (OR 2, 95% CI 1.2-3.3) [6], but other studies have not confirmed this association [52].

Post-transplant factors — Several early post-transplant complications/factors may contribute to the development of PGD or complicate diagnostic assessment. These include aspiration, fluid overload, arterial and venous anastomotic complications, hypotension, mechanical ventilation (particularly the use of high tidal volumes), and pneumonia [1].

CLINICAL MANIFESTATIONS — 

The cardinal clinical manifestations of PGD grade 3 are declining oxygenation and diffuse radiographic opacities in the transplanted lung(s) that develop in the first 72 hours following transplant [1]. Other clinical findings typically include decreased pulmonary compliance, increased pulmonary vascular resistance, and intrapulmonary shunting [1].

The severity of PGD is categorized based on the presence or absence of diffuse opacities on chest radiograph and the ratio of arterial oxygen pressure to inspired oxygen concentration (PaO2/FiO2 [P/F ratio]). This is described in greater detail above (table 1). (See 'Definition and grading' above.)

DIAGNOSTIC EVALUATION

Approach — PGD is a diagnosis of exclusion. The diagnostic evaluation of suspected PGD should rule out other conditions with similar clinical and radiographic presentations. These conditions include pulmonary edema secondary to volume overload, left ventricular dysfunction, or pulmonary venous outflow obstruction secondary to left atrial thrombus or mechanical blockage. Bilateral pneumonia (eg, aspiration), transfusion-related acute lung injury (TRALI), and hyperacute or early antibody-mediated rejection can also present with similar radiographic features.

The clinician should also consider that more than one condition may be present, as early complications have overlapping clinical and imaging features [12,83] (see "Noninfectious complications following lung transplantation" and "Bacterial infections following lung transplantation"):

Retrospective crossmatch and HLA antibody testing — Laboratory assessment to evaluate the possibility of hyperacute rejection includes reviewing the transplant recipient’s immunologic tests for pre-existing HLA antibodies and donor human leukocyte antigen (HLA)-typing. In addition to this "virtual crossmatch," a direct crossmatch is performed at the time of transplant. (See "Evaluation and treatment of antibody-mediated lung transplant rejection", section on 'Laboratory'.)

Assess volume status — Review extent of fluid and blood product resuscitation, total fluid intake and output, urine output, kidney function, lactic acidosis, and hemodynamic status. Generally, a conservative fluid management strategy that maintains adequate urine output, oxygen delivery, and systemic blood pressure is recommended [84].

Transthoracic echocardiogram — An echocardiogram can evaluate left ventricular function and rule out significant pericardial effusion.

Transesophageal echocardiogram — In patients with severe PGD, consider transesophageal echocardiogram to assess pulmonary venous outflow; thrombus formation at pulmonary venous/left atrial anastomotic site or vascular complications may rarely cause severe pulmonary edema [85-87]. (See "Noninfectious complications following lung transplantation", section on 'Anastomotic complications'.)

Radiographic imaging — Review of a conventional chest radiograph can identify new opacities in the lung allograft(s), pleural effusions, hemothorax, and pneumothorax [53]. The most frequent manifestation of PGD is bibasilar ground glass or consolidative opacities that may progress to total lung opacification. Focal opacities may suggest lung infection or atelectasis.

Chest computed tomography (CT) is frequently obtained to characterize the pattern of parenchymal opacities. CT or ultrasound modalities may be used to differentiate parenchymal opacities from pleural collections [88].

Bronchoscopy — Bronchoscopy is advised to evaluate for airway obstruction related to mucus or blood clots or bronchial anastomotic abnormalities and to obtain samples of bronchoalveolar lavage (BAL) fluid for microbiologic studies in patients with PGD. Infections that most commonly cause graft failure in the first few days after transplantation are usually bacterial and can originate from the donor or lung recipient, and they may be community-acquired or nosocomial infections. (See "Bacterial infections following lung transplantation".)

Infection with community-acquired respiratory viruses (CARVs), may occur at any time. If present in the donor or recipient prior to transplant, CARVs may cause early lung allograft dysfunction [89]. (See "Viral infections following lung transplantation".)

Bronchoscopy is also helpful in identifying rare early complications of surgery, such as bronchial anastomotic stricture or dehiscence and whole lung torsion with rotation of the lung around its bronchovascular pedicle [90]. (See "Airway complications after lung transplantation".)

DIAGNOSIS — 

The diagnosis of PGD is made in a patient with diffuse pulmonary opacities on thoracic imaging and hypoxemia, developing in the first 72 hours after lung allograft implantation, after exclusion of other identifiable causes. (See 'Diagnostic evaluation' above.)

DIFFERENTIAL DIAGNOSIS — 

The differential diagnosis of PGD includes processes that can cause diffuse pulmonary opacities and hypoxemia in the first 72 hours after lung transplantation. One or more of the following processes may coexist with PGD in a given patient.

●Hyperacute rejection – Hyperacute rejection occurs in the immediate post-transplant period and is mediated by the binding of preformed antibodies to graft antigens (eg, human leukocyte antigen [HLA] or ABO isoagglutinins). Antibodies directed against self-antigens (eg, Collagen V or K-alpha1 tubulin) [91] may also increase PGD risk. Initial evaluation includes review of pretransplant testing for the presence of donor-specific antibodies (DSA) and results of the direct crossmatch. (See 'Retrospective crossmatch and HLA antibody testing' above and "Evaluation and treatment of antibody-mediated lung transplant rejection".)

●Pulmonary edema – Hydrostatic pulmonary edema can be caused by left ventricular dysfunction or volume overload. The steps in the evaluation include assessment of left ventricular function by echocardiography and optimization of volume status, as described above. Perioperative myocardial injury should be evaluated by laboratory testing. (See 'Assess volume status' above and "Perioperative myocardial infarction or injury after noncardiac surgery".)

●Pneumonia – Despite liberal use of prophylactic antibiotics, bacteria are the most common infectious agents in the immediate post-transplant period. The steps to identify infecting organisms are described above and separately. The empiric antimicrobial regimen is adjusted as needed based on test results. (See 'Bronchoscopy' above and "Bacterial infections following lung transplantation".)

●Occlusion of the venous anastomosis – Thrombosis of the venous anastomosis should be suspected if one of the transplanted lungs appears opaque on plain chest radiograph. The most helpful test to evaluate this possibility is a transesophageal echocardiogram. (See "Noninfectious complications following lung transplantation", section on 'Vascular anastomotic complications'.)

●Pleural fluid or hemothorax – Postoperative pleural fluid and hemothorax can cause diffuse opacity on a supine chest radiograph, although the opacity is usually more uniform than pulmonary parenchymal disease. Differentiation may require bedside ultrasound or computed tomography. (See "Pleural complications in lung transplantation".)

●Transfusion-related acute lung injury (TRALI) – (See "Transfusion-related acute lung injury (TRALI)".)

●Aspiration – Aspiration is an uncommon cause of acute respiratory failure in the immediate postoperative period after lung transplantation.

TREATMENT — 

Most patients with PGD that is less than grade 3 severity improve with conventional supportive treatment. Patients with severe PGD may benefit from more intensive supportive measures.

Initial supportive care — The primary treatment strategy for PGD is supportive care, as there is currently no intervention that specifically treats or prevents this complication. As PGD likely represents a form of acute respiratory distress syndrome (ARDS) and has many similar clinical, physiologic, radiographic, and pathologic manifestations, supportive care strategies model those utilized for ARDS treatment [9,15,92]. The general management of ARDS is discussed separately. (See "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults" and "Acute respiratory distress syndrome: Ventilator management strategies for adults".)

PGD treatment typically involves the following:

●Restrictive fluid management strategy – A restrictive fluid management strategy is often recommended but should ensure adequate end-organ perfusion, oxygen delivery, and hemodynamic stability [9,84].

●Lung protection ventilation – Lung protective ventilation, also known as low tidal volume ventilation, is described separately (table 2). Of note, goal tidal volumes should be based on donor rather than recipient ideal body weight [80]. (See "Acute respiratory distress syndrome: Ventilator management strategies for adults", section on 'Invasive mechanical ventilation: Low tidal volume ventilation initial settings'.)

●Empiric antibiotics – As pneumonia is in the differential diagnosis, empiric broad spectrum antibiotics are routinely administered while awaiting microbiologic and histopathologic data. The selection of antimicrobial agents is discussed separately. (See "Bacterial infections following lung transplantation", section on 'Treatment'.)

●Immunosuppression – Post-transplant immunosuppression protocols are typically not modified for PGD unless the recipient is deemed to have superimposed infection, acute cellular or antibody-mediated rejection, kidney failure, encephalopathy, or other complications that require consideration of alternative immunosuppressive agents or dose adjustment. (See "Maintenance immunosuppression following lung transplantation".)

Refractory hypoxemia — Many centers routinely use pulmonary vasodilators such as inhaled nitric oxide (iNO) or inhaled epoprostenol (iEPO) in the immediate postoperative period. Treatment with these agents is typically continued for patients who develop PGD. In those who are not treated empirically, we suggest adding pulmonary vasodilators for those with more severe PGD grade 3 or elevated pulmonary arterial pressures despite supportive care.

We suggest extracorporeal membrane oxygenation (ECMO) support for patients who have severe refractory hypoxemia despite supportive care and pulmonary vasodilator therapy [5]. Retransplantation is generally avoided due to poor outcomes.

●Pulmonary vasodilators – iNO or iEPO reduce pulmonary vasoconstriction/pulmonary artery pressure and improve ventilation-perfusion matching, thereby improving oxygenation [9,93], although evidence demonstrating sustained clinical benefit is limited [9,94,95]. A range of dosing concentrations of iNO has been reported for use in PGD, but 10 to 20 parts per million (ppm) is most commonly utilized [96]. Of note, methemoglobinemia, a side effect of iNO, may occur rarely when used within acceptable dosing guidelines (5 to 80 ppm) (see "Methemoglobinemia").

●Extracorporeal life support (ECLS)/extracorporeal membrane oxygenation (ECMO) – For patients with PGD grade 3 who have refractory hypoxemia (eg, partial pressure of arterial oxygen [PaO2]/fraction of inspired oxygen [FiO2; P/F ratio] <100 mmHg) despite optimal medical treatment and ventilator settings, we initiate ECMO to support oxygenation and reduce lung allograft injury [9]. Outcomes are generally better if ECMO is initiated early, preferably within 24 to 48 hours of transplantation [9,97,98].

Venovenous (V-V) ECMO is used to support oxygenation and reduce lung injury; veno-arterial (V-A) ECMO is only required for those who also need hemodynamic support. Most patients will stabilize on V-V ECMO, and venous cannulation is associated with fewer complications than arterial cannulation [9].

Outcomes for patients receiving ECMO support for PGD, particularly for those only needing V-V ECMO, appear to be improving over time [99-102]. While early mortality is increased among patients who require ECMO support for PGD, compared with those who do not, other reports suggest that long-term survival is comparable [103,104].

A general discussion of outcomes and complications among patients with acute respiratory failure managed at an ECMO center is provided separately. (See "Extracorporeal life support in adults in the intensive care unit: Overview".)

●Retransplantation – Retransplantation has been performed in cases of severe PGD. However, outcomes have generally been poor, and the literature does not support retransplantation for PGD [105]. An analysis of data from the Organ Procurement and Transplantation Network (OPTN) of patients who had undergone retransplantation from January 2001 to May 2006 showed that early retransplantation (within 30 days of initial transplant) had an extremely poor survival, with a one-year survival of only 31 percent [106]. While overall survival following retransplantation has improved [107-110], outcomes after retransplantation for indications other than chronic lung allograft dysfunction (CLAD) remain poor.

PREVENTION — 

As with treatment, no specific intervention or targeted therapy has been shown to prevent PGD. Potential strategies to prevent PGD include appropriate donor lung selection and optimal preservation, storage, intraoperative management, and reperfusion techniques. (See "Lung transplantation: Deceased donor evaluation" and "Lung transplantation: Donor lung procurement and preservation".)

Approaches to reducing risk of PGD may include the following, although supportive data are limited:

●Limiting cold ischemia time – The acceptable limits of cold (4 to 8ºC) ischemic temperatures and times are not known [9]. Ischemic times of up to eight hours are usually considered acceptable. However, with contemporary organ donor management and retrieval processes, longer ischemic times may not increase PGD risk. (See 'Risk factors' above and "Lung transplantation: Donor lung procurement and preservation", section on 'Ischemic time'.)

●Ex vivo lung perfusion (EVLP) – EVLP techniques to evaluate and potentially improve donor lung function may reduce the risk of PGD. However, the data from observational studies are conflicting [111-116]. In a multivariable logistic regression analysis of more than 10,000 patients transplanted between 2015 to 2023 (from the United Network of Organ Sharing database), EVLP was associated with a decreased risk of PGD [117]. Of note, however, EVLP may be associated with an increased risk of PGD in patients transplanted with donation after circulatory death (DCD) organs [118]. (See "Lung transplantation: Donor lung procurement and preservation", section on 'Normothermic ex-vivo perfusion (after cold static preservation)'.)

A portable EVLP system that allows donor lungs to be immediately supported without need for hypothermic conditions during transport may reduce PGD risks and allow for retrieval of organs across greater geographic distances and travel times. To date, however, there have not been studies comparing rates of PGD stage 3 with static to portable EVLP platforms [119]. (See "Lung transplantation: Donor lung procurement and preservation", section on 'New approaches to organ preservation'.)

●Graft reperfusion rate and pressure – Controlled perfusion after allograft implantation has been associated with reduced lung injury and PGD risk. Animal studies have shown that lung preservation and storage under hypothermic and hypoxic conditions can cause structural alterations and damage to type I epithelial alveolar cells and pulmonary endothelial cells [120-122]. Rapid reperfusion of the allograft may increase shear stress and augment injury to the vulnerable alveolar-capillary barrier, resulting in severe pulmonary edema [120]. The severity of lung injury may be mitigated with gradual reperfusion over a 10-minute period by slowly releasing the pulmonary artery clamp [123]. This approach has been adopted into clinical practice at many centers [9].

●Reperfusion FiO2 – A high fraction of inspired oxygen (FiO2; >0.40) has been reported to increase risk for PGD, perhaps by mediating hyperoxia-induced oxidative lung injury [6]. This is a potentially modifiable risk factor. Many transplant programs have adopted the practice of graft reperfusion with lower FiO2 (0.21 to 0.50) [9].

●Prostaglandins – In animal models of lung transplantation, early graft function has been reported to be better when prostaglandin E1 (PGE1, alprostadil) is added to preservation solutions [124,125]. This observation has led many clinical centers to use PGE1 as an additive to lung preservation solutions, although human trials to assess clinical benefit have not been performed. (See "Lung transplantation: Donor lung procurement and preservation".)

EXPERIMENTAL STRATEGIES — 

Significant progress has been made in understanding donor and recipient clinical risk factors and the complex immunologic/inflammatory pathways involved in mediating PGD. Investigation into the impact of genetic variations on cellular and molecular pathways will hopefully lead to trials of more targeted interventions for specific patient populations [25]. The emergence of ex vivo lung perfusion (EVLP) technologies as a potential platform to study novel approaches offers the promise of accelerated development and evaluation of potential therapeutic interventions [126-129].

Below, a few experimental approaches are briefly highlighted:

●Inhaled vasodilators (for prevention)

•Nitric oxide (iNO) – While preclinical studies have shown that organ preservation and graft reperfusion reduce the levels of intrinsic nitric oxide, available evidence from three small, randomized studies did not show benefit in preventing PGD when administered at the time of graft reperfusion or shortly afterward [130-132]. It is not known whether administration of iNO at earlier time points would be beneficial [133].

•Iloprost (ILO) – The role of the pulmonary vasodilator iloprost (ILO), a synthetic analog of prostacyclin PGI2, was evaluated in 84 consecutive patients who were transplanted with intraoperative ECMO support. Inhaled ILO was administered at the time of lung reperfusion. Thirty-two patients received ILO while 52 did not. The investigators utilized propensity score matching and identified two comparable groups of 30 patients and found significantly lower rates of PGD grade 3 on postoperative days 2 and 3 in the ILO-treated group. Additionally, the ILO-treatment group required less mechanical ventilation and had lower lengths of stay in the intensive care unit. Larger randomized studies are needed to confirm this benefit [134].

•Epoprostenol – Administration of inhaled epoprostenol was compared with iNO administration prior to reperfusion of the first transplanted lung in a randomized trial. Rates of PGD stage 3 development were similar in each treatment arm [135].

●Cytokine adsorption – Neutrophils have been implicated in the development of acute lung injury, including primary graft dysfunction after lung transplantation. Neutrophil extracellular traps (NETs) released by neutrophils in response to ischemia-reperfusion injury may further exacerbate lung inflammation. A recent small case series explored the role of cytokine adsorption in line with the intraoperative ECMO circuit to reduce NETs and systemic inflammation after promising findings in a porcine model of lung transplantation [136,137].

●Adenosine 2A receptor agonists – Preclinical studies have shown that adenosine 2A receptor (A2AR) agonists have anti-inflammatory properties that may attenuate ischemia-reperfusion injury. These effects include reduced activation of invariant natural killer T cells, blunting of the neutrophilic oxidative stress response, and limitation of release of pro-inflammatory cytokines. In a phase 1 trial, the A2AR agonist, regadenoson, was administered to 14 lung transplant recipients as a 12-hour continuous infusion starting at the time of skin incision [138]. No dose-limiting toxicities were noted. Although this small study was not powered to detect a difference in PGD rates, PGD grade 3 developed in one patient (7 percent), compared with 25 percent of nonstudy patients who were transplanted during the same time period. Further investigation is required to define the therapeutic potential and safety of this agent.

●Surfactant therapy – Surfactant dysfunction has been shown to occur after ischemia-reperfusion injury [139]. Experimental studies in pigs have found that exogenous surfactant therapy improves pulmonary compliance and alveolar-arterial oxygen gradient after lung transplantation [140,141]. Clinical case reports and an open-label trial have also shown promising results using surfactant in patients with PGD [142,143]. A small, randomized trial of 29 lung transplant recipients suggested benefit for the study patients treated with exogenous surfactant instilled into donor lungs before retrieval compared with usual care; post-transplant surfactant function and early forced expiratory volume in one second (FEV1) were both improved [144]. A meta-analysis of preclinical and clinical studies suggested that exogenous surfactant therapy during lung transplantation improved oxygenation; however, clinical benefit was not established [145]. Questions remain regarding efficacy and optimal timing and dosing of therapy [9].

●Complement inhibition – Complement activation is thought to have a significant role in ischemia-reperfusion injury [146]. Interventions to inhibit complement have been studied. In a randomized, double-blind, multicenter, placebo-controlled trial of 59 patients, treatment with the soluble complement receptor-1 inhibitor TP-10 showed trends towards reduced time on the ventilator and in the intensive care unit, but these findings were not statistically significant. The beneficial effects seemed to be greater in patients who received intraoperative cardiopulmonary bypass support [147]. In another study, nonrandomized lung recipients who developed very severe PGD grade 3 shortly after transplantation were treated with a C1-esterase-inhibitor (C1-INH), which was associated with better outcomes compared with patients with severe PGD who did not receive the study drug [148]. Randomized trials are needed to determine benefit of complement inhibition for PGD prevention or treatment.

●Enhanced alveolar fluid clearance – Impaired alveolar fluid clearance is the hallmark of severe acute respiratory distress syndrome (ARDS) and PGD. Alveolar fluid clearance relies upon the function of amiloride-sensitive epithelial sodium channels (ENaCs) on the apical surface and Na+/K+-ATPase on the basolateral surface of alveolar epithelial cells. AP301 is a synthetic peptide that promotes sodium transport by ENaCs. In a proof-of-concept pilot study, 20 lung transplant recipients with PGD grade >1 received inhaled AP301 or placebo twice daily for seven days or until extubation. Inhalation of AP301 improved gas exchange and led to a shorter duration of mechanical ventilation [149]. Other studies in lung transplantation have not been reported.

●Gene therapy – Gene-based therapy offers the potential to genetically modify organs to repair injured lungs and withstand stressors that contribute to PGD risk. For example, investigators at the University of Toronto utilized gene-therapy approaches to upregulate production of the anti-inflammatory cytokine IL-10 in damaged human lungs maintained on EVLP. Treatment was delivered by intra-airway administration of an adenoviral vector encoding human IL-10. The investigators demonstrated improved oxygenation and a decrease in lung tissue concentration of pro-inflammatory cytokines [150]. Optimization of gene-delivery systems and diminished inflammatory response to the vectors are still important requirements to move this strategy to the clinical lung transplantation setting [151,152].

●Stem cell therapy – In animal models, mesenchymal stromal stem cells (MSC) have been reported to attenuate inflammation and reduce lung injury after various insults. In a report of injured pig lungs supported by EVLP, intravascular administration of MSCs increased parenchymal concentrations of vascular endothelial growth factor (VEGF) and significantly decreased levels of the pro-inflammatory cytokine IL-8 [153]. Additional studies are underway exploring the role of MSCs, including use of genetically modified MSCs in reducing lung injury [154,155].

●Pirfenidone – Pirfenidone is a drug with anti-inflammatory, antifibrotic, and antioxidant properties. It has been approved for the treatment of idiopathic pulmonary fibrosis (IPF) [156]. In a rat model of warm ischemia-reperfusion injury, pirfenidone administered before ischemia attenuated lung injury [157]. In a retrospective analysis, patients transplanted for IPF who were treated with pirfenidone (n = 17) pre-transplant were compared with a control group of patients with IPF not treated with pirfenidone (n = 26). Use of pirfenidone was independently associated with less severe PGD, shorter duration of mechanical ventilation, and shorter length of stay in the intensive care unit. Additional studies are needed to further evaluate the potential protective role of pirfenidone [158,159].

PROGNOSIS

Survival — Early outcomes after lung transplantation have improved, despite an increase in the incidence of PGD [4-6], highlighting the positive impact of contemporary critical care management on supporting patients with this complication. Nevertheless, PGD remains an important cause of early post-transplant morbidity and mortality. In particular, PGD severity at 48 to 72 hours after transplantation correlates with short- and long-term outcomes [160]. In the multicenter Lung Transplant Outcomes Group (LTOG) cohort study, which enrolled 1528 patients between 2011 and 2018, the 26 percent of patients with PGD grade 3 at 48 or 72 hours after transplant had prolonged postoperative mechanical ventilation (nine versus three days) and hospital length of stay (23 versus 18 days) compared with the remainder of the cohort [5]. These patients were also at a 9.8 percent higher absolute risk for death one year after transplant (adjusted odds ratio 1.7, 95% CI 1.2-2.3).

Patients with severe PGD who require ECMO support generally have poorer outcomes compared with lung transplant recipients who did not require ECMO [101-104,161]. If ECMO is needed, earlier initiation in the post-transplant period has been associated with better survival [96]. Early ECMO support may also facilitate the implementation of lung-protective ventilatory strategies. (See 'Refractory hypoxemia' above and "Extracorporeal life support in adults in the intensive care unit: Overview".)

Chronic lung allograft dysfunction — Several, but not all, published reports have found that patients who survive PGD are at increased risk for subsequent development of chronic lung allograft dysfunction (CLAD) [4,25,162-165]. For example, in a retrospective cohort study of 334 lung transplant recipients, the severity of initial PGD correlated with the risk of bronchiolitis obliterans syndrome [162]. (See "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome".)

The etiologic link between PGD and CLAD is not well understood. Plasma donor-derived cell-free DNA, a biomarker for severity of lung injury, has been shown to be associated with subsequent development of CLAD [166]. Severe lung inflammation releases allo- and lung-restricted antigens (eg, collagen type V and k-alpha1 tubulin) that have been implicated in the development of alloimmune and autoimmune responses, which may also increase risk of CLAD [68,167,168].

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

●Definition and grading – Primary graft dysfunction (PGD) after lung transplantation represents a multifactorial injury to the transplanted lung(s) that develops in the first 72 hours after lung transplantation.

The International Society of Heart Lung Transplantation (ISHLT) has proposed a grading system for the classification of PGD based on the ratio of arterial oxygen pressure to inspired oxygen concentration (PaO2/FiO2) ratio (table 1). PGD is graded at four time points, every 24 hours for the first 72 hours after transplantation (T0, T24, T48, and T72 hours). (See 'Definition and grading' above.).

●Clinical manifestations – The cardinal clinical manifestations of PGD are declining oxygenation and diffuse radiographic opacities; additional clinical findings may include decreased pulmonary compliance, increased pulmonary vascular resistance, and intrapulmonary shunting. (See 'Clinical manifestations' above.)

●Diagnostic evaluation – PGD is a diagnosis of exclusion to be made after assessment of volume status, ventilator settings, chest radiograph, echocardiogram, donor-recipient cross-match and screen for donor specific antibodies, bronchoscopy with an airway survey and bronchoalveolar lavage (BAL), and exclusion of infection. (See 'Diagnostic evaluation' above.)

●Treatment

•Initial supportive care – Most patients with PGD that is less than grade 3 severity improve with conventional supportive treatment, including lung protective ventilation and optimal fluid management. Empiric broad spectrum antibiotics are routinely administered while awaiting microbiologic and histopathologic data. (See 'Treatment' above and 'Initial supportive care' above.)

•Severe PGD – For patients with more severe PGD grade 3 (ie, persistent difficulty with oxygenation and/or elevated pulmonary artery pressures), we suggest adding an inhaled pulmonary vasodilator such as nitric oxide (iNO) or epoprostenol (Grade 2C). Based on clinical experience, these agents reduce pulmonary artery pressures and improve oxygenation, although outcomes data are limited. (See 'Refractory hypoxemia' above.)

•Refractory hypoxemia – For patients with severe PGD grade 3 and an inadequate response to optimal ventilator and fluid management and iNO/epoprostenol, we suggest initiating extracorporeal membrane oxygenation (ECMO) (Grade 2C). Most patients will stabilize with venovenous (V-V) ECMO, although some patients may require veno-arterial (V-A) ECMO for hemodynamic support. Early initiation of ECMO support (within 24 hours) has a greater likelihood of success. (See 'Refractory hypoxemia' above.)

•Avoidance of retransplantation – Retransplantation for PGD is generally associated with a poor outcome and is avoided by most transplant centers. (See 'Refractory hypoxemia' above.)

●Prevention – Strategies to prevent PGD include use of adequate donor lung management and selection and optimization of lung preservation, storage, intraoperative management, and reperfusion techniques. (See 'Prevention' above and "Lung transplantation: Donor lung procurement and preservation".)

●Prognosis – PGD severity at 48 to 72 hours after transplantation correlates with short- and long-term outcomes. PGD appears to be a risk factor for subsequent development of chronic lung allograft dysfunction. (See 'Chronic lung allograft dysfunction' above.)

ACKNOWLEDGMENTS — 

The UpToDate editorial staff acknowledges Elbert Trulock, MD, 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.

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  95. Khan TA, Schnickel G, Ross D, et al. A prospective, randomized, crossover pilot study of inhaled nitric oxide versus inhaled prostacyclin in heart transplant and lung transplant recipients. J Thorac Cardiovasc Surg 2009; 138:1417.
  96. Shargall Y, Guenther G, Ahya VN, et al. Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part VI: treatment. J Heart Lung Transplant 2005; 24:1489.
  97. Wigfield CH, Lindsey JD, Steffens TG, et al. Early institution of extracorporeal membrane oxygenation for primary graft dysfunction after lung transplantation improves outcome. J Heart Lung Transplant 2007; 26:331.
  98. Meyers BF, Sundt TM 3rd, Henry S, et al. Selective use of extracorporeal membrane oxygenation is warranted after lung transplantation. J Thorac Cardiovasc Surg 2000; 120:20.
  99. Takahashi T, Terada Y, Pasque MK, et al. Outcomes of Extracorporeal Membrane Oxygenation for Primary Graft Dysfunction After Lung Transplantation. Ann Thorac Surg 2023; 115:1273.
  100. Harano T, Ryan JP, Morrell MR, et al. Extracorporeal Membrane Oxygenation for Primary Graft Dysfunction After Lung Transplantation. ASAIO J 2021; 67:1071.
  101. Hartwig MG, Walczak R, Lin SS, Davis RD. Improved survival but marginal allograft function in patients treated with extracorporeal membrane oxygenation after lung transplantation. Ann Thorac Surg 2012; 93:366.
  102. Bermudez CA, Adusumilli PS, McCurry KR, et al. Extracorporeal membrane oxygenation for primary graft dysfunction after lung transplantation: long-term survival. Ann Thorac Surg 2009; 87:854.
  103. Boffini M, Simonato E, Ricci D, et al. Extracorporeal membrane oxygenation after lung transplantation: risk factors and outcomes analysis. Ann Cardiothorac Surg 2019; 8:54.
  104. Bellier J, Lhommet P, Bonnette P, et al. Extracorporeal membrane oxygenation for grade 3 primary graft dysfunction after lung transplantation: Long-term outcomes. Clin Transplant 2019; 33:e13480.
  105. Aigner C, Jaksch P, Taghavi S, et al. Pulmonary retransplantation: is it worth the effort? A long-term analysis of 46 cases. J Heart Lung Transplant 2008; 27:60.
  106. Kawut SM, Lederer DJ, Keshavjee S, et al. Outcomes after lung retransplantation in the modern era. Am J Respir Crit Care Med 2008; 177:114.
  107. Sommer W, Ius F, Kühn C, et al. Technique and Outcomes of Less Invasive Lung Retransplantation. Transplantation 2018; 102:530.
  108. Collaud S, Benden C, Ganter C, et al. Extracorporeal Life Support as Bridge to Lung Retransplantation: A Multicenter Pooled Data Analysis. Ann Thorac Surg 2016; 102:1680.
  109. Halloran K, Aversa M, Tinckam K, et al. Comprehensive outcomes after lung retransplantation: A single-center review. Clin Transplant 2018; 32:e13281.
  110. Dawodu G, Gulati S, Bugacov H, et al. Worth a Double Take? An In-Depth Review of Lung Retransplantation. J Clin Med 2023; 12.
  111. Yeung JC, Krueger T, Yasufuku K, et al. Outcomes after transplantation of lungs preserved for more than 12 h: a retrospective study. Lancet Respir Med 2017; 5:119.
  112. Cypel M, Yeung JC, Liu M, et al. Normothermic ex vivo lung perfusion in clinical lung transplantation. N Engl J Med 2011; 364:1431.
  113. Divithotawela C, Cypel M, Martinu T, et al. Long-term Outcomes of Lung Transplant With Ex Vivo Lung Perfusion. JAMA Surg 2019; 154:1143.
  114. Okamoto T, Wheeler D, Farver CF, McCurry KR. Transplant Suitability of Rejected Human Donor Lungs With Prolonged Cold Ischemia Time in Low-Flow Acellular and High-Flow Cellular Ex Vivo Lung Perfusion Systems. Transplantation 2019; 103:1799.
  115. Leiva-Juárez MM, Urso A, Arango Tomás E, et al. Extended post-ex vivo lung perfusion cold preservation predicts primary graft dysfunction and mortality: Results from a multicentric study. J Heart Lung Transplant 2020; 39:954.
  116. Noda K, Chan EG, Furukawa M, et al. Single-center experience of ex vivo lung perfusion and subsequent lung transplantation. Clin Transplant 2023; 37:e14901.
  117. Gouchoe DA, Cui EY, Satija D, et al. Ex Vivo Lung Perfusion and Primary Graft Dysfunction Following Lung Transplantation: A Contemporary United Network for Organ Sharing Database Analysis. J Clin Med 2024; 13.
  118. Xia Y, Kim ST, Dacey M, et al. Characteristics and outcomes of lung transplants performed with ex-situ lung perfusion. J Heart Lung Transplant 2024; 43:217.
  119. Warnecke G, Van Raemdonck D, Smith MA, et al. Normothermic ex-vivo preservation with the portable Organ Care System Lung device for bilateral lung transplantation (INSPIRE): a randomised, open-label, non-inferiority, phase 3 study. Lancet Respir Med 2018; 6:357.
  120. Pierre AF, DeCampos KN, Liu M, et al. Rapid reperfusion causes stress failure in ischemic rat lungs. J Thorac Cardiovasc Surg 1998; 116:932.
  121. Hidalgo MA, Shah KA, Fuller BJ, Green CJ. Cold ischemia-induced damage to vascular endothelium results in permeability alterations in transplanted lungs. J Thorac Cardiovasc Surg 1996; 112:1027.
  122. Hall SM, Odom N, McGregor CG, Haworth SG. Transient ultrastructural injury and repair of pulmonary capillaries in transplanted rat lung: effect of preservation and reperfusion. Am J Respir Cell Mol Biol 1992; 7:49.
  123. Bhabra MS, Hopkinson DN, Shaw TE, Hooper TL. Critical importance of the first 10 minutes of lung graft reperfusion after hypothermic storage. Ann Thorac Surg 1996; 61:1631.
  124. de Perrot M, Fischer S, Liu M, et al. Prostaglandin E1 protects lung transplants from ischemia-reperfusion injury: a shift from pro- to anti-inflammatory cytokines. Transplantation 2001; 72:1505.
  125. Chiang CH, Wu K, Yu CP, et al. Hypothermia and prostaglandin E(1) produce synergistic attenuation of ischemia-reperfusion lung injury. Am J Respir Crit Care Med 1999; 160:1319.
  126. Hsin M, Au T. Ex vivo lung perfusion: a potential platform for molecular diagnosis and ex vivo organ repair. J Thorac Dis 2018; 10:S1871.
  127. Shaver CM, Ware LB. Primary graft dysfunction: pathophysiology to guide new preventive therapies. Expert Rev Respir Med 2017; 11:119.
  128. Tane S, Noda K, Shigemura N. Ex Vivo Lung Perfusion: A Key Tool for Translational Science in the Lungs. Chest 2017; 151:1220.
  129. Iske J, Hinze CA, Salman J, et al. The potential of ex vivo lung perfusion on improving organ quality and ameliorating ischemia reperfusion injury. Am J Transplant 2021; 21:3831.
  130. Botha P, Jeyakanthan M, Rao JN, et al. Inhaled nitric oxide for modulation of ischemia-reperfusion injury in lung transplantation. J Heart Lung Transplant 2007; 26:1199.
  131. Meade MO, Granton JT, Matte-Martyn A, et al. A randomized trial of inhaled nitric oxide to prevent ischemia-reperfusion injury after lung transplantation. Am J Respir Crit Care Med 2003; 167:1483.
  132. Perrin G, Roch A, Michelet P, et al. Inhaled nitric oxide does not prevent pulmonary edema after lung transplantation measured by lung water content: a randomized clinical study. Chest 2006; 129:1024.
  133. Moreno I, Vicente R, Mir A, et al. Effects of inhaled nitric oxide on primary graft dysfunction in lung transplantation. Transplant Proc 2009; 41:2210.
  134. Lee SH, Lee JG, Lee CY, et al. Effects of intraoperative inhaled iloprost on primary graft dysfunction after lung transplantation: A retrospective single center study. Medicine (Baltimore) 2016; 95:e3975.
  135. Ghadimi K, Cappiello J, Cooter-Wright M, et al. Inhaled Pulmonary Vasodilator Therapy in Adult Lung Transplant: A Randomized Clinical Trial. JAMA Surg 2022; 157:e215856.
  136. Ghaidan H, Stenlo M, Niroomand A, et al. Reduction of primary graft dysfunction using cytokine adsorption during organ preservation and after lung transplantation. Nat Commun 2022; 13:4173.
  137. Lindstedt S, Niroomand A, Mittendorfer M, et al. Nothing but NETs: Cytokine adsorption correlates with lower circulating nucleosomes and is associated with decreased primary graft dysfunction. J Heart Lung Transplant 2023; 42:1358.
  138. Lau CL, Beller JP, Boys JA, et al. Adenosine A2A receptor agonist (regadenoson) in human lung transplantation. J Heart Lung Transplant 2020; 39:563.
  139. Ochs M, Nenadic I, Fehrenbach A, et al. Ultrastructural alterations in intraalveolar surfactant subtypes after experimental ischemia and reperfusion. Am J Respir Crit Care Med 1999; 160:718.
  140. Hohlfeld JM, Strüber M, Ahlf K, et al. Exogenous surfactant improves survival and surfactant function in ischaemia-reperfusion injury in minipigs. Eur Respir J 1999; 13:1037.
  141. Koletsis E, Chatzimichalis A, Fotopoulos V, et al. Donor lung pretreatment with surfactant in experimental transplantation preserves graft hemodynamics and alveolar morphology. Exp Biol Med (Maywood) 2003; 228:540.
  142. Kermeen FD, McNeil KD, Fraser JF, et al. Resolution of severe ischemia-reperfusion injury post-lung transplantation after administration of endobronchial surfactant. J Heart Lung Transplant 2007; 26:850.
  143. Amital A, Shitrit D, Raviv Y, et al. The use of surfactant in lung transplantation. Transplantation 2008; 86:1554.
  144. Strüber M, Fischer S, Niedermeyer J, et al. Effects of exogenous surfactant instillation in clinical lung transplantation: a prospective, randomized trial. J Thorac Cardiovasc Surg 2007; 133:1620.
  145. Ali A, Pettenuzzo T, Ramadan K, et al. Surfactant therapy in lung transplantation: A systematic review and meta-analysis. Transplant Rev (Orlando) 2021; 35:100637.
  146. Kulkarni HS, Ramphal K, Ma L, et al. Local complement activation is associated with primary graft dysfunction after lung transplantation. JCI Insight 2020; 5.
  147. Keshavjee S, Davis RD, Zamora MR, et al. A randomized, placebo-controlled trial of complement inhibition in ischemia-reperfusion injury after lung transplantation in human beings. J Thorac Cardiovasc Surg 2005; 129:423.
  148. Sommer W, Tudorache I, Kühn C, et al. C1-esterase-inhibitor for primary graft dysfunction in lung transplantation. Transplantation 2014; 97:1185.
  149. Aigner C, Slama A, Barta M, et al. Treatment of primary graft dysfunction after lung transplantation with orally inhaled AP301: A prospective, randomized pilot study. J Heart Lung Transplant 2017.
  150. Cypel M, Liu M, Rubacha M, et al. Functional repair of human donor lungs by IL-10 gene therapy. Sci Transl Med 2009; 1:4ra9.
  151. Shirley JL, de Jong YP, Terhorst C, Herzog RW. Immune Responses to Viral Gene Therapy Vectors. Mol Ther 2020; 28:709.
  152. Mendiola Pla M, Bowles DE. Ex Vivo Gene Therapy in Organ Transplantation: Considerations and Clinical Translation. Hum Gene Ther 2024; 35:284.
  153. Mordant P, Nakajima D, Kalaf R, et al. Mesenchymal stem cell treatment is associated with decreased perfusate concentration of interleukin-8 during ex vivo perfusion of donor lungs after 18-hour preservation. J Heart Lung Transplant 2016; 35:1245.
  154. Nakajima D, Watanabe Y, Ohsumi A, et al. Mesenchymal stromal cell therapy during ex vivo lung perfusion ameliorates ischemia-reperfusion injury in lung transplantation. J Heart Lung Transplant 2019; 38:1214.
  155. Nykänen AI, Mariscal A, Duong A, et al. Lung Transplant Immunomodulation with Genetically Engineered Mesenchymal Stromal Cells-Therapeutic Window for Interleukin-10. Cells 2024; 13.
  156. Richeldi L, Baldi F, Pasciuto G, et al. Current and Future Idiopathic Pulmonary Fibrosis Therapy. Am J Med Sci 2019; 357:370.
  157. Saito M, Chen-Yoshikawa TF, Suetsugu K, et al. Pirfenidone alleviates lung ischemia-reperfusion injury in a rat model. J Thorac Cardiovasc Surg 2019; 158:289.
  158. Veit T, Leuschner G, Sisic A, et al. Pirfenidone exerts beneficial effects in patients with IPF undergoing single lung transplantation. Am J Transplant 2019; 19:2358.
  159. Munker D, Arnold P, Leuschner G, et al. Impact of ILD-Specific Therapies on Perioperative Course in Patients with Progressive Interstitial Lung Disease Undergoing Lung Transplantation. J Clin Med 2023; 12.
  160. Prekker ME, Nath DS, Walker AR, et al. Validation of the proposed International Society for Heart and Lung Transplantation grading system for primary graft dysfunction after lung transplantation. J Heart Lung Transplant 2006; 25:371.
  161. Luu HY, Santos J, Isaza E, et al. Management of primary graft dysfunction after lung transplantation with extracorporeal life support: an evidence-based review. J Thorac Dis 2023; 15:4090.
  162. Daud SA, Yusen RD, Meyers BF, et al. Impact of immediate primary lung allograft dysfunction on bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 2007; 175:507.
  163. Whitson BA, Prekker ME, Herrington CS, et al. Primary graft dysfunction and long-term pulmonary function after lung transplantation. J Heart Lung Transplant 2007; 26:1004.
  164. Fiser SM, Tribble CG, Long SM, et al. Ischemia-reperfusion injury after lung transplantation increases risk of late bronchiolitis obliterans syndrome. Ann Thorac Surg 2002; 73:1041.
  165. Fisher AJ, Wardle J, Dark JH, Corris PA. Non-immune acute graft injury after lung transplantation and the risk of subsequent bronchiolitis obliterans syndrome (BOS). J Heart Lung Transplant 2002; 21:1206.
  166. Keller M, Bush E, Diamond JM, et al. Use of donor-derived-cell-free DNA as a marker of early allograft injury in primary graft dysfunction (PGD) to predict the risk of chronic lung allograft dysfunction (CLAD). J Heart Lung Transplant 2021; 40:488.
  167. Hachem RR, Tiriveedhi V, Patterson GA, et al. Antibodies to K-α 1 tubulin and collagen V are associated with chronic rejection after lung transplantation. Am J Transplant 2012; 12:2164.
  168. Agashe VV, Burlingham WJ. Autoimmune Reactivity in Graft Injury: Player or Bystander? Curr Transplant Rep 2015; 2:211.
Topic 4663 Version 34.0

References

1 : Report of the ISHLT Working Group on Primary Lung Graft Dysfunction, part I: Definition and grading-A 2016 Consensus Group statement of the International Society for Heart and Lung Transplantation.

2 : Acute respiratory distress syndrome: the Berlin Definition.

3 : Comparison of the SpO2/FIO2 ratio and the PaO2/FIO2 ratio in patients with acute lung injury or ARDS.

4 : A single-center experience of 1500 lung transplant patients.

5 : Contemporary trends in PGD incidence, outcomes, and therapies.

6 : Clinical risk factors for primary graft dysfunction after lung transplantation.

7 : Report of the International Society for Heart and Lung Transplantation Working Group on Primary Lung Graft Dysfunction, part II: Epidemiology, risk factors, and outcomes-A 2016 Consensus Group statement of the International Society for Heart and Lung Transplantation.

8 : Short- and long-term outcomes of 1000 adult lung transplant recipients at a single center.

9 : Report of the ISHLT Working Group on primary lung graft dysfunction Part IV: Prevention and treatment: A 2016 Consensus Group statement of the International Society for Heart and Lung Transplantation.

10 : Inflammatory signalling associated with brain dead organ donation: from brain injury to brain stem death and posttransplant ischaemia reperfusion injury.

11 : Management of the Potential Organ Donor in the ICU: Society of Critical Care Medicine/American College of Chest Physicians/Association of Organ Procurement Organizations Consensus Statement.

12 : Acute postoperative management after lung transplantation.

13 : Single lung transplantation and fatal fat embolism acquired from the donor: management and literature review.

14 : Transfusion-related acute lung injury (TRALI) in graft by blood donor antibodies against host leukocytes.

15 : Primary Graft Dysfunction.

16 : Systemic inflammation in the brain-dead organ donor.

17 : Activation of hemostasis in brain dead organ donors: an observational study.

18 : Pre-implantation multiple cytokine mRNA expression analysis of donor lung grafts predicts survival after lung transplantation in humans.

19 : Brain Death-Induced Inflammatory Activity is Similar to Sepsis-Induced Cytokine Release.

20 : Elevated levels of interleukin-8 in donor lungs is associated with early graft failure after lung transplantation.

21 : Ex vivo perfusion techniques: state of the art and potential applications.

22 : Graft ischemic time and outcome of lung transplantation: a multicenter analysis.

23 : Report of the ISHLT Working Group on Primary Lung Graft Dysfunction Part III: Mechanisms: A 2016 Consensus Group Statement of the International Society for Heart and Lung Transplantation.

24 : Mechanisms of lung ischemia-reperfusion injury.

25 : Primary Graft Dysfunction After Lung Transplantation.

26 : Mitochondrial damage-associated molecular patterns released by lung transplants are associated with primary graft dysfunction.

27 : Risk factors for primary graft dysfunction after lung transplantation.

28 : The Impact of Donor Smoking on Primary Graft Dysfunction and Mortality after Lung Transplantation.

29 : Effect of donor smoking on survival after lung transplantation: a cohort study of a prospective registry.

30 : Donor smoking is associated with pulmonary edema, inflammation and epithelial dysfunction in ex vivo human donor lungs.

31 : Long-term air pollution exposure and the risk of primary graft dysfunction after lung transplantation.

32 : Influence of the donor history of tobacco and marijuana smoking on early and intermediate lung transplant outcomes.

33 : The Effect of Alcohol Consumption on the Risk of ARDS: A Systematic Review and Meta-Analysis.

34 : Effects of drug abuse, smoking and alcohol on donor hearts and lungs.

35 : The role of donor chronic alcohol abuse in the development of primary graft dysfunction in lung transplant recipients.

36 : Heavy alcohol use in lung donors increases the risk for primary graft dysfunction.

37 : Donor age and early graft failure after lung transplantation: a cohort study.

38 : Donor to recipient age matching in lung transplantation: A European experience.

39 : Outcome of Lung Transplantation Using Grafts From Donors Over 65 Years of Age.

40 : Risk factors for early primary graft dysfunction after lung transplantation: a registry study.

41 : Influence of donor-recipient gender mismatch on graft function and survival following lung transplantation.

42 : Donor to recipient sizing in thoracic organ transplantation.

43 : Lung size mismatch and primary graft dysfunction after bilateral lung transplantation.

44 : Triaging donor lungs based on a microaspiration signature that predicts adverse recipient outcome.

45 : Significance of Lung Weight in Cellular Ex Vivo Lung Perfusion.

46 : Clinical significance of donor lung weight at procurement and during ex vivo lung perfusion.

47 : Donor-acquired fat embolism syndrome after lung transplantation.

48 : Donor-acquired fat embolism syndrome after lung transplantation.

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

50 : Early United States experience with lung donation after circulatory death using thoracoabdominal normothermic regional perfusion.

51 : Controlled donation after circulatory death lung transplantation: Results of the French protocol including in situ abdominal normothermic regional perfusion and ex vivo lung perfusion.

52 : Recipient-related clinical risk factors for primary graft dysfunction after lung transplantation: a systematic review and meta-analysis.

53 : Objective Estimates Improve Risk Stratification for Primary Graft Dysfunction after Lung Transplantation.

54 : Clinical Risk Factors and Prognostic Model for Primary Graft Dysfunction after Lung Transplantation in Patients with Pulmonary Hypertension.

55 : Body Mass Index and Cause-Specific Mortality after Lung Transplantation in the United States.

56 : Impact of recipient and donor pretransplantation body mass index on early postosperative complications after lung transplantation.

57 : Obesity and primary graft dysfunction after lung transplantation: the Lung Transplant Outcomes Group Obesity Study.

58 : Adipose tissue quantification and primary graft dysfunction after lung transplantation: The Lung Transplant Body Composition study.

59 : Variation in PTX3 is associated with primary graft dysfunction after lung transplantation.

60 : Genetic variation in the prostaglandin E2 pathway is associated with primary graft dysfunction.

61 : Protein Quantitative Trait Loci Analysis Identifies Genetic Variation in the Innate Immune Regulator TOLLIP in Post-Lung Transplant Primary Graft Dysfunction Risk.

62 : Diastolic Dysfunction Increases the Risk of Primary Graft Dysfunction after Lung Transplant.

63 : Impact of Pre-Transplant Left Ventricular Diastolic Pressure on Primary Graft Dysfunction after Lung Transplantation: A Narrative Review.

64 : Elevated pre-transplant left ventricular end-diastolic pressure increases primary graft dysfunction risk in double lung transplant recipients.

65 : Left ventricular lusitropy and primary graft dysfunction in lung transplantation.

66 : Prevalence of pre-transplant anti-HLA antibodies and their impact on outcomes in lung transplant recipients.

67 : Clinical relevance of lung-restricted antibodies in lung transplantation.

68 : The role of lung-restricted autoantibodies in the development of primary and chronic graft dysfunction.

69 : Outcomes of intraoperative venoarterial extracorporeal membrane oxygenation versus cardiopulmonary bypass during lung transplantation.

70 : Extracorporeal Circulation During Lung Transplantation Procedures: A Meta-Analysis.

71 : Perioperative circulatory support for lung transplantation.

72 : Extracorporeal membrane oxygenation versus cardiopulmonary bypass during lung transplantation: a meta-analysis.

73 : Effects of Intraoperative Support Strategies on Endothelial Injury and Clinical Lung Transplant Outcomes.

74 : Intraoperative Red Blood Cell Transfusion and Primary Graft Dysfunction After Lung Transplantation.

75 : Plasma levels of receptor for advanced glycation end products, blood transfusion, and risk of primary graft dysfunction.

76 : Massive donor transfusion potentially increases recipient mortality after lung transplantation.

77 : Extended ischemic time (>15 hours) using controlled hypothermic storage in lung transplantation: A multicenter experience.

78 : Extension of Cold Static Donor Lung Preservation at 10°C.

79 : Impact of anastomosis time during lung transplantation on primary graft dysfunction.

80 : Lung protective ventilation based on donor size is associated with a lower risk of severe primary graft dysfunction after lung transplantation.

81 : Outcomes of delayed chest closure after bilateral lung transplantation.

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

83 : Critical Care after Lung Transplantation.

84 : Increased Intraoperative Fluid Administration Is Associated with Severe Primary Graft Dysfunction After Lung Transplantation.

85 : Four-year prospective study of pulmonary venous thrombosis after lung transplantation.

86 : Incidence of pulmonary vein complications after lung transplantation: a prospective transesophageal echocardiographic study.

87 : Diagnosis and interventions of vascular complications in lung transplant.

88 : Imaging the Complications of Lung Transplantation.

89 : Influenza B virus transmission in recipients of kidney and lung transplants from an infected donor.

90 : Whole-lung torsion complicating double lung transplantation: CT features.

91 : Antibodies to self-antigens predispose to primary lung allograft dysfunction and chronic rejection.

92 : Pulmonary, circulatory and renal considerations in the early postoperative management of the lung transplant recipient.

93 : The effects of inhaled nitric oxide after lung transplantation.

94 : Aerosolized prostacyclin (epoprostenol) as an alternative to inhaled nitric oxide for patients with reperfusion injury after lung transplantation.

95 : A prospective, randomized, crossover pilot study of inhaled nitric oxide versus inhaled prostacyclin in heart transplant and lung transplant recipients.

96 : Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part VI: treatment.

97 : Early institution of extracorporeal membrane oxygenation for primary graft dysfunction after lung transplantation improves outcome.

98 : Selective use of extracorporeal membrane oxygenation is warranted after lung transplantation.

99 : Outcomes of Extracorporeal Membrane Oxygenation for Primary Graft Dysfunction After Lung Transplantation.

100 : Extracorporeal Membrane Oxygenation for Primary Graft Dysfunction After Lung Transplantation.

101 : Improved survival but marginal allograft function in patients treated with extracorporeal membrane oxygenation after lung transplantation.

102 : Extracorporeal membrane oxygenation for primary graft dysfunction after lung transplantation: long-term survival.

103 : Extracorporeal membrane oxygenation after lung transplantation: risk factors and outcomes analysis.

104 : Extracorporeal membrane oxygenation for grade 3 primary graft dysfunction after lung transplantation: Long-term outcomes.

105 : Pulmonary retransplantation: is it worth the effort? A long-term analysis of 46 cases.

106 : Outcomes after lung retransplantation in the modern era.

107 : Technique and Outcomes of Less Invasive Lung Retransplantation.

108 : Extracorporeal Life Support as Bridge to Lung Retransplantation: A Multicenter Pooled Data Analysis.

109 : Comprehensive outcomes after lung retransplantation: A single-center review.

110 : Worth a Double Take? An In-Depth Review of Lung Retransplantation.

111 : Outcomes after transplantation of lungs preserved for more than 12 h: a retrospective study.

112 : Normothermic ex vivo lung perfusion in clinical lung transplantation.

113 : Long-term Outcomes of Lung Transplant With Ex Vivo Lung Perfusion.

114 : Transplant Suitability of Rejected Human Donor Lungs With Prolonged Cold Ischemia Time in Low-Flow Acellular and High-Flow Cellular Ex Vivo Lung Perfusion Systems.

115 : Extended post-ex vivo lung perfusion cold preservation predicts primary graft dysfunction and mortality: Results from a multicentric study.

116 : Single-center experience of ex vivo lung perfusion and subsequent lung transplantation.

117 : Ex Vivo Lung Perfusion and Primary Graft Dysfunction Following Lung Transplantation: A Contemporary United Network for Organ Sharing Database Analysis.

118 : Characteristics and outcomes of lung transplants performed with ex-situ lung perfusion.

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

120 : Rapid reperfusion causes stress failure in ischemic rat lungs.

121 : Cold ischemia-induced damage to vascular endothelium results in permeability alterations in transplanted lungs.

122 : Transient ultrastructural injury and repair of pulmonary capillaries in transplanted rat lung: effect of preservation and reperfusion.

123 : Critical importance of the first 10 minutes of lung graft reperfusion after hypothermic storage.

124 : Prostaglandin E1 protects lung transplants from ischemia-reperfusion injury: a shift from pro- to anti-inflammatory cytokines.

125 : Hypothermia and prostaglandin E(1) produce synergistic attenuation of ischemia-reperfusion lung injury.

126 : Ex vivo lung perfusion: a potential platform for molecular diagnosis and ex vivo organ repair.

127 : Primary graft dysfunction: pathophysiology to guide new preventive therapies.

128 : Ex Vivo Lung Perfusion: A Key Tool for Translational Science in the Lungs.

129 : The potential of ex vivo lung perfusion on improving organ quality and ameliorating ischemia reperfusion injury.

130 : Inhaled nitric oxide for modulation of ischemia-reperfusion injury in lung transplantation.

131 : A randomized trial of inhaled nitric oxide to prevent ischemia-reperfusion injury after lung transplantation.

132 : Inhaled nitric oxide does not prevent pulmonary edema after lung transplantation measured by lung water content: a randomized clinical study.

133 : Effects of inhaled nitric oxide on primary graft dysfunction in lung transplantation.

134 : Effects of intraoperative inhaled iloprost on primary graft dysfunction after lung transplantation: A retrospective single center study.

135 : Inhaled Pulmonary Vasodilator Therapy in Adult Lung Transplant: A Randomized Clinical Trial.

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

137 : Nothing but NETs: Cytokine adsorption correlates with lower circulating nucleosomes and is associated with decreased primary graft dysfunction.

138 : Adenosine A2A receptor agonist (regadenoson) in human lung transplantation.

139 : Ultrastructural alterations in intraalveolar surfactant subtypes after experimental ischemia and reperfusion.

140 : Exogenous surfactant improves survival and surfactant function in ischaemia-reperfusion injury in minipigs.

141 : Donor lung pretreatment with surfactant in experimental transplantation preserves graft hemodynamics and alveolar morphology.

142 : Resolution of severe ischemia-reperfusion injury post-lung transplantation after administration of endobronchial surfactant.

143 : The use of surfactant in lung transplantation.

144 : Effects of exogenous surfactant instillation in clinical lung transplantation: a prospective, randomized trial.

145 : Surfactant therapy in lung transplantation: A systematic review and meta-analysis.

146 : Local complement activation is associated with primary graft dysfunction after lung transplantation.

147 : A randomized, placebo-controlled trial of complement inhibition in ischemia-reperfusion injury after lung transplantation in human beings.

148 : C1-esterase-inhibitor for primary graft dysfunction in lung transplantation.

149 : Treatment of primary graft dysfunction after lung transplantation with orally inhaled AP301: A prospective, randomized pilot study.

150 : Functional repair of human donor lungs by IL-10 gene therapy.

151 : Immune Responses to Viral Gene Therapy Vectors.

152 : Ex Vivo Gene Therapy in Organ Transplantation: Considerations and Clinical Translation.

153 : Mesenchymal stem cell treatment is associated with decreased perfusate concentration of interleukin-8 during ex vivo perfusion of donor lungs after 18-hour preservation.

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

155 : Lung Transplant Immunomodulation with Genetically Engineered Mesenchymal Stromal Cells-Therapeutic Window for Interleukin-10.

156 : Current and Future Idiopathic Pulmonary Fibrosis Therapy.

157 : Pirfenidone alleviates lung ischemia-reperfusion injury in a rat model.

158 : Pirfenidone exerts beneficial effects in patients with IPF undergoing single lung transplantation.

159 : Impact of ILD-Specific Therapies on Perioperative Course in Patients with Progressive Interstitial Lung Disease Undergoing Lung Transplantation.

160 : Validation of the proposed International Society for Heart and Lung Transplantation grading system for primary graft dysfunction after lung transplantation.

161 : Management of primary graft dysfunction after lung transplantation with extracorporeal life support: an evidence-based review.

162 : Impact of immediate primary lung allograft dysfunction on bronchiolitis obliterans syndrome.

163 : Primary graft dysfunction and long-term pulmonary function after lung transplantation.

164 : Ischemia-reperfusion injury after lung transplantation increases risk of late bronchiolitis obliterans syndrome.

165 : Non-immune acute graft injury after lung transplantation and the risk of subsequent bronchiolitis obliterans syndrome (BOS).

166 : Use of donor-derived-cell-free DNA as a marker of early allograft injury in primary graft dysfunction (PGD) to predict the risk of chronic lung allograft dysfunction (CLAD).

167 : Antibodies to K-α1 tubulin and collagen V are associated with chronic rejection after lung transplantation.

168 : Autoimmune Reactivity in Graft Injury: Player or Bystander?