Primary lung graft dysfunction

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 P/F ratio. If the PaO₂ is not available, 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 contribute to end-organ damage. Additionally, aspiration, pulmonary embolism, fat emboli, traumatic injury, and cardiac dysfunction may also cause 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 may also contribute to 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 risk of developing organ damage [11,16-19]. For example, levels of the pro-inflammatory cytokine interleukin (IL)-8 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 preservation fluid at 4 to 8ºC during organ retrieval. While cold storage helps preserve lung allograft integrity, a number of injurious events may occur during this phase, especially if 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, types, and composition of preservation solutions, is discussed 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 activated or amplified that then activate the innate immune system and trigger 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 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 in several studies to be an important risk factor for PGD [6,7,27,28]. In fact, any donor smoking history was found to be independently associated with PGD in a large multicenter United States-based prospective cohort study of 1255 patients [6]. In a study of 1295 lung transplants performed in the UK, donor smoking history was 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 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 or not there is a dose effect, and if there are certain recipients who would be at prohibitively high risk for developing PGD or poor outcome from 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].

●Donor alcohol use – High alcohol consumption increases the risk for acute respiratory distress syndrome (ARDS) [31,32]. Thus, it's not surprising that a donor history of heavy alcohol use has been associated with PGD grade 3 [33]. In one study, this risk was almost ninefold higher compared with donors without alcohol use [34].

●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) of 1212 patients, donor age between 18 and 64 was not significantly associated with PGD risk [35]. The risk of using donors at the extremes of age is uncertain and may confer greater risk [7]. 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 [36].

●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 [6,37]. The impact of donor sex or donor–recipient sex mismatch is uncertain, with published reports yielding conflicting results [7,38]. 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 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 [39]. 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 [40].

●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 [41].

Both aspiration and trauma may contribute to extravascular lung water accumulation and increase donor lung weight, which has also been suggested as a risk factor [42,43]. 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) [43]. 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 a risk factors for PGD [44]. 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 and thromboemboli, respectively, compared with patients who obtained lungs without these abnormalities [45].

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 [6,7,25,46-48]. 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 identified elevated recipient body mass index (BMI; ≥25 kg/m²) as a risk factor for PGD [6,7,46,49]. In the multicenter LTOG study of 1255 recipients, 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, has been associated with PGD risk [50]. 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 [51].

●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 and involving more than 10,000 patients, both female sex and African-American descent were associated with higher rates of PGD. Limitations of this study included significant heterogeneity of patient populations, era of transplantation, and PGD definition [46]. 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 as 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) [52-54].

●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 [55]. Elevated left-ventricular end-diastolic pressure (LVEDP >15 mmHg) on pretransplant cardiac catheterization was also associated with PGD grade 3 [56,57].

●Preformed autoantibodies – The presence of preformed antibodies to lung-restricted self-antigens (k-alpha-1 tubulin and collagen type V) have been identified as risk factors for PGD [58-60].

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) [6,7,46]. The need for CPB may be 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 [61-63]. 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, renal failure) were increased in patients receiving CPB when compared with those who had received V-A ECMO intraoperatively [64].

●Transfusion – Large-volume intraoperative blood product transfusion is an independent risk factor for PGD [7,65-67]. Transfusion-related acute lung injury (TRALI) mediated by transfused human leukocyte antigen (HLA)-antibodies or anti-granulocyte antibodies in the inflamed allograft has been reported in the setting of PGD [14]. (See "Transfusion-related acute lung injury (TRALI)".)

●Ischemic time – Multiple observational studies have found prolonged ischemic time to be a risk factor for PGD in adult recipients. However, a multicenter observational study reported that the incidence of PGD grade 3 at 48 and 72 hours was not associated with ischemic time [6,7]. While the upper limit of safe ischemic times is unknown, standard practice is to limit cold ischemic times to <8 hours. The continued development of ex vivo lung perfusion (EVLP) technologies may expand the duration of safe ischemic times beyond 12 hours [68]. (See "Lung transplantation: Donor lung procurement and preservation", section on 'Normothermic ex-vivo perfusion (after cold static preservation)'.)

●Anastomosis time – Warm ischemia during the implantation process may contribute to reperfusion injury. One retrospective cohort study of 427 patients examined the association between PGD grade 3 and anastomosis time, defined as the time from the end of the ice-cold preservation period to the removal of vascular clamps [69]. One hundred thirty patients (30 percent) developed PGD grade 3 at 72 hours after transplant. Anastomosis time was an independent predictor of PGD grade 3 at 72 hours (OR 1.2 per 10 minutes, 95% CI 1.02-1.4) after controlling for other factors, including age, BMI, intraoperative extracorporeal lung support (ECLS), cold ischemic time, transplant type, and transfusions.

●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 [70].

●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, as delayed chest closure is associated with use of CPB, high transfusion requirement, increased oxygen requirement, and elevated pulmonary artery pressure [71,72].

●Type of transplant procedure – In some studies, single lung transplant 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 [46].

Post-transplant factors — A number of 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 that may have a similar clinical and radiographic presentation. These conditions include pulmonary edema secondary to volume overload, left ventricular dysfunction or pulmonary venous outflow obstruction secondary to left atrial thrombus or mechanical issue. 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 [12,73] (see "Noninfectious complications following lung transplantation" and "Bacterial infections following lung transplantation"):

Retrospective crossmatch and HLA antibody testing — Laboratory assessment to evaluate for the possibility of hyperacute rejection includes review of 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, renal function, lactic acidosis, and hemodynamic status. In general, a conservative fluid management strategy that maintains adequate urine output, oxygen delivery, and systemic blood pressure is recommended [74].

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 [75-77].

Radiographic imaging — Review of a conventional chest radiograph can identify new opacities in the lung allograft(s), pleural effusions, hemothorax, and pneumothorax [47]. 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 [78].

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 [79]. (See "Viral infections following lung transplantation".)

Bronchoscopy is also useful for 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 [80]. (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 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) [81] may also increase PGD risk. Initial evaluation includes review of pre-transplant testing for presence of donor-specific antibodies (DSA) and results of the direct crossmatch. (See 'Retrospective crossmatch and HLA antibody testing' above.)

●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 – Bacteria are the most common infectious agents in the immediate post-transplant period despite prophylactic antibiotics. 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 useful 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 [9,25,82]. 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 [9,74].

●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 [70]. (See "Acute respiratory distress syndrome: Ventilator management strategies for adults", section on '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, renal failure, encephalopathy, or other complications that require consideration of alternative immunosuppressive agents or dose adjustment. (See "Maintenance immunosuppression following lung transplantation".)

Refractory hypoxemia — For patients with refractory hypoxemia despite optimization of fluid status and ventilator settings, the next step is usually a trial of inhaled nitric oxide (iNO) and/or inhaled prostaglandin (eg, epoprostenol [off-label]). Extracorporeal membrane oxygenation (ECMO) is reserved for patients who do not respond to these measures. Retransplantation is generally avoided due to poor outcomes.

●Pulmonary vasodilators – iNO or inhaled epoprostenol reduce pulmonary vasoconstriction/pulmonary artery pressure and improve ventilation-perfusion matching, and thereby improve oxygenation [9,83], although evidence demonstrating clinical benefit is limited [9,84,85]. A range of dosing concentrations of iNO has been reported for PGD, but 10 to 20 parts per million (ppm) is most commonly utilized [86]. 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, ECMO initiation is recommended [9]. Outcomes are generally better if ECMO is initiated early, preferably within 24 to 48 hours of transplantation [9,87,88].

Venovenous (V-V) ECMO is preferred over venoarterial (V-A) ECMO unless hemodynamic support is required. In general, most patients will stabilize on V-V ECMO and it is associated with fewer complications [9]. In a report reviewing a single center’s experience, 96 lung transplant recipients required ECMO support over a 10-year period. All but seven patients were managed with V-V ECMO. Overall, one-year survival was 50 percent. Initiation of ECMO within 48 hours was associated with better outcome [89]. Another study described better survival in patients supported with V-V ECMO: 82 percent at 30 days; 64 percent at one year; and 49 percent survival at five years. By comparison, reported survival with V-A ECMO support was poorer: 56 percent, 40 percent, and 25 percent at 30 days, one year, and five years, respectively [90,91].

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 [92,93].

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 [94]. 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 1-year survival of only 31 percent [95]. While overall survival following retransplantation has improved [96-98], 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, although reported data are conflicting regarding whether longer cold ischemic times are associated with increased PGD risk [22,99] (see 'Risk factors' above). The decision to use lungs with ischemic times anticipated to exceed eight hours should be made based on the evaluation of other risk factors while also considering the overall status of the recipient/urgency of transplantation.

The introduction of normothermic ex vivo lung perfusion (EVLP) techniques may allow for safer evaluation of lungs with extended cold ischemic times [68,100,101]. However, evidence regarding the potential to successfully and safely recondition lungs with prolonged cold ischemic times prior to EVLP is conflicting [102,103]. 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 [104]. (See "Lung transplantation: Donor lung procurement and preservation", section on 'Normothermic ex-vivo perfusion (after cold static 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 [105-107]. Rapid reperfusion of the allograft may increase shear stress and augment injury to the vulnerable alveolar capillary barrier, resulting in severe pulmonary edema [105]. Severity of lung injury may be mitigated with gradual reperfusion over a 10-minute period by slowly releasing the pulmonary artery clamp [108]. This approach has been adopted into clinical practice at many centers [9].

●Reperfusion FiO₂ – 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].

●Inhaled nitric oxide (iNO) – Inhaled nitric oxide (iNO) does not prevent PGD. Available evidence from three small, randomized studies did not show benefit in preventing PGD when administered at the time of graft reperfusion or shortly afterwards [109-111]. It is not known whether administration of iNO at earlier time points would be beneficial [112].

●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 [113,114]. 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").

The role of the pulmonary vasodilator iloprost (ILO), a synthetic analogue of prostacyclin PGI2, was evaluated in 84 consecutive patients who were transplanted with intraoperative ECMO support. 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 [115]. Separately, 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 [116].

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 [117-120].

Below, a few experimental approaches are briefly highlighted:

●Adenosine 2A receptor agonists – Preclinical studies have shown that adenosine 2A receptor (A_2AR) 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 A_2AR agonist, regadenoson, was administered to 14 lung transplant recipients as a 12 hour continuous infusion starting at the time of skin incision [121]. 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 [122]. Experimental studies in pigs have found that exogenous surfactant therapy improves pulmonary compliance and alveolar-arterial oxygen gradient after lung transplantation [123,124]. Clinical case reports and an open label trial have also shown promising results using surfactant in patients with PGD [125,126]. In addition, a randomized trial of 15 lung transplant recipients showed a benefit when exogenous surfactant was instilled into donor lungs before retrieval; post-transplant surfactant function and forced expiratory volume in one second (FEV₁) were both improved relative to control [127]. A meta-analysis of preclinical and clinical studies suggested that exogenous surfactant therapy during lung transplantation improved oxygenation; however, clinical benefit was not established [128]. Larger studies are needed to confirm these preliminary findings. In particular, questions remain about the optimal timing and dosing of therapy [9].

●Complement inhibition – Complement activation is thought to have a significant role in ischemia reperfusion injury [129]. 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 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 [130]. 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 [131]. Randomized trials are required 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 [132]. Other studies in lung transplantation have not been reported.

●Inhibition of neutrophil recruitment – Recruitment of neutrophils following ischemia-reperfusion injury contributes to primary graft dysfunction. Repertaxin is an investigational inhibitor of the chemokine CXCL8 (also called interleukin [IL]-8). CXCL8 has a central role in neutrophil chemotaxis, and it has been hypothesized that repertaxin might prevent neutrophil infiltration and tissue damage and thereby reduce the occurrence of PGD [133]. A clinical in lung transplantation has been completed, however, results have not yet been reported [134].

●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 [135]. 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 [136]. Use of nonviral vectors for gene delivery may be safer alternatives [119].

●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, administration of MSCs increased parenchymal concentrations of vascular endothelial growth factor (VEGF) and significantly decreased levels of the pro-inflammatory cytokine IL-8 [137]. Additional studies are underway exploring the role of MSCs, including use of genetically modified MSCs in reducing lung injury [138,139].

●Pirfenidone – Pirfenidone is a drug with anti-inflammatory, antifibrotic, and antioxidant properties. It has been approved for the treatment pf idiopathic pulmonary fibrosis (IPF) [140]. In a rat model of warm ischemia-reperfusion injury, pirfenidone administered before ischemia attenuated lung injury [141]. 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 will likely be forthcoming to evaluate the therapeutic role of pirfenidone [142].

PROGNOSIS

Survival — Mortality after lung transplant is improving despite an increase in the incidence of PGD [4-6], suggesting that current critical care management better addresses PGD-associated morbidity. For example, in a single-center study of more than 1500 lung transplant recipients, transplantation in the post-lung allocation score (LAS) era (since May 2005) had higher rates of PGD 3 (31.6 percent) [4]. However, this was not associated with increased short-term or long-term mortality compared with the earlier cohort.

Nevertheless, advances in organ preservation, surgical technique, and perioperative care have not prevented a strong association between PGD and posttransplant morbidity and mortality [7]. In particular, PGD severity at 48 to 72 hours after transplantation correlates with short- and long-term outcomes [143]. 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).

The role of early extracorporeal membrane oxygenation (ECMO) support in preventing or improving severe PGD is not clear. Nonemergent use of ECMO in the posttransplant setting ("bridging") was not associated with grade 3 PGD at 48 or 72 hours or worsening survival in the LTOG cohort [5]. However, in patients with grade 3 PGD, those who initiated ECMO as a salvage strategy experienced slightly worse short-term and significantly worse long-term outcomes compared with those who did not. In addition, patients requiring venoarterial ECMO salvage had much higher mortality over the course of the study than those requiring venovenous ECMO salvage (37 versus 24 percent). Whether the mortality risk in patients with PGD requiring ECMO rescue is due to the severity of PGD (within grade 3), recipient severity of illness pretransplant, or deleterious effects of ECMO itself remains highly uncertain.

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) [4,25,144-147]. In a retrospective cohort study of 334 lung transplant recipients, the severity of initial PGD correlated with the risk of bronchiolitis obliterans syndrome. (See "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome".)

The link between PGD and CLAD is not fully understood. Data suggest that severe early lung inflammation during PGD promotes the development of alloimmune responses. Additionally, lung injury exposes sequestered lung antigens such as collagen type V and subsequently promotes development of autoimmune responses that have been implicated in the pathogenesis of CLAD [148,149]. Plasma donor-derived cell free DNA, a biomarker for severity of lung injury, was shown to be associated with subsequent development of CLAD [150]. Thus, approaches to prevent PGD or attenuate severity may be important for improving long-term outcomes after transplantation.

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

●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. (See 'Introduction' above and 'Risk factors' above.)

●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.)

●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.)

●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.).

●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.)

●For patients with more severe PGD grade 3 (ie, persistent difficulty with oxygenation and 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.)

●For patients with severe PGD grade 3 and an inadequate response to optimal ventilator and fluid management and iNO/epoprostenol, we recommend initiating extracorporeal membrane oxygenation (ECMO) (Grade 1B). Some patients will stabilize with venovenous ECMO, although some patients will require venoarterial ECMO. Early initiation of ECMO support (within 24 hours) has a greater likelihood of success. (See 'Refractory hypoxemia' above.)

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

●PGD appears to be a risk factor for subsequent development of chronic lung allograft dysfunction. (See 'Chronic lung allograft dysfunction' above.)

●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".)

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.