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Primary graft dysfunction

lessons learned about the first 72 h after lung transplantation

Porteous, Mary K.a; Diamond, Joshua M.a,b; Christie, Jason D.a,b

Current Opinion in Organ Transplantation: October 2015 - Volume 20 - Issue 5 - p 506–514
doi: 10.1097/MOT.0000000000000232
LUNG TRANSPLANTATION: Edited by Stephanie G. Norfolk
Free

Purpose of review In 2005, the International Society for Heart and Lung Transplantation published a standardized definition of primary graft dysfunction (PGD), facilitating new knowledge on this form of acute lung injury that occurs within 72 h of lung transplantation. PGD continues to be associated with significant morbidity and mortality. This article will summarize the current literature on the epidemiology of PGD, pathogenesis, risk factors, and preventive and treatment strategies.

Recent findings Since 2011, several manuscripts have been published that provide insight into the clinical risk factors and pathogenesis of PGD. In addition, several transplant centers have explored preventive and treatment strategies for PGD, including the use of extracorporeal strategies. More recently, results from several trials assessing the role of extracorporeal lung perfusion may allow for much-needed expansion of the donor pool, without raising PGD rates.

Summary This article will highlight the current state of the science regarding PGD, focusing on recent advances, and set a framework for future preventive and treatment strategies.

aDepartment of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

bCenter for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

Correspondence to Mary K. Porteous, MD, Department of Medicine, University of Pennsylvania, 839 West Gates, 3400 Spruce Street, Philadelphia, PA 19104, USA. E-mail: mary.porteous@uphs.upenn.edu

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INTRODUCTION

Primary graft dysfunction (PGD) after lung transplantation is a significant source of early morbidity and mortality [1–7]. We will review recently published literature on the epidemiology, pathogenesis, risk factors, prevention, and treatment of PGD.

Box 1

Box 1

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DEFINITION

PGD, a form of acute lung injury occurring within 72 h of lung transplantation, is characterized by hypoxemia and alveolar infiltrates in the allograft [2]. Early case reports of postoperative allograft dysfunction used different criteria to define the syndrome and referred to it by various names [4,8–12]. In 2005, the International Society for Heart and Lung Transplantation (ISHLT) standardized the definition of PGD, permitting consistent classification of this clinical syndrome [2]. PGD is now graded based on PaO2/FiO2 (P/F) and the presence of radiographic infiltrates in the allograft consistent with pulmonary edema. The definition also requires exclusion of contributing factors, including hyperacute rejection, pulmonary venous anastomotic obstruction, cardiogenic edema, and pneumonia [2]. The severity of PGD is reassessed daily up to 72 h after reperfusion (Table 1). Grade 3 PGD (PGD3) corresponds to a P/F of less than 200 with allograft infiltrates, on extracorporeal membrane oxygenation (ECMO) or ventilated with FiO2 above 0.5 and on iNO [2].

Table 1

Table 1

PGD3 occurring at any time point after reperfusion is associated with greater alteration in plasma markers of lung injury and higher 30-day mortality compared to those with lower grades [1]. However, even among patients with PGD3, there is variability in the duration of pulmonary edema and patient mortality [13], leading to a belief that separate endotypes may be indicative of differences in injury response. In 2015, the ISHLT began a second consensus effort to update and refine the PGD definition; therefore, updated criteria should be forthcoming addressing issues including timing of PGD onset and resolution, precision of the P/F at different levels of FiO2, single versus bilateral transplants, and differences in grading fibrotic lung disease patients.

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EPIDEMIOLOGY AND OUTCOMES

Since 2005, the incidence of PGD3 at a single time point has been reported to be 7.9% and 25%, whereas the incidence of PGD3 at any time point during the first 3 days is approximately 30% [1,5,7,14–17]. The variability is likely attributable to differences in institutional practices and risk factor distributions.

PGD is associated with significant early and late posttransplant morbidity. Regardless of the time point of grading, PGD3 has been associated with significantly longer hospital length of stay, duration of mechanical ventilation, and 90-day mortality than those with lower grades of PGD [1,4,5,14,16,17]. PGD3 present at 48 or 72 h after transplantation was associated with an 18% increased absolute risk of 90-day mortality [14], with increased mortality persisting at 1, 5, and 10 years after transplantation [5,7,14–17]. In addition, all PGD is associated with elevated risk of bronchiolitis obliterans syndrome (BOS), a form of chronic allograft dysfunction [5,7,15,16]. Future mechanistic trials are needed to understand the relationship between PGD and the development of BOS.

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PATHOGENESIS

PGD represents the end result of multiple deleterious mechanisms provoked by donor brain death, mechanical ventilation, procurement, storage, and ischemia reperfusion injury (IRI). IRI refers to sterile inflammation that occurs after substrate supply is restored following a period of absent blood flow [18▪]. Although many mechanisms are at play, recent studies highlight the importance of the interplay between innate immune activation, epithelial cell injury, endothelial cell dysfunction, and cytokine release [19] (Table 2).

Table 2

Table 2

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INNATE IMMUNE ACTIVATION

Upregulation of innate immune pathways, including toll-like receptors (TLR) and nucleotide-binding oligomerization-like receptor inflammasome signaling, has been demonstrated in-vivo animal models following IRI and in human patients with PGD [35–38,40–47]. Animal models suggests that IRI occurs in two phases mediated in part by a bimodal response by the innate immune system with donor macrophages and lymphocytes inducing the early phase and recipient monocytes, T-cells, and neutrophils inducing the late phase [40–47].

A family of innate immune cells, innate lymphoid cells (ILCs) have recently been recognized for their role in inflammation regulation, barrier protection and repair, and host defense. Although ILCs have lymphoid morphology, they lack antigen receptors and can be subdivided based on cytokine expression and function [39,48▪,49]. Group 2 ILCs (ILC2) produce type 2 T-helper cell-associated cytokines and have been isolated in both human blood and lung, suggesting a trafficking ability. In animal models, ILC2 cells appear to play an important role in airway epithelial integrity and airway remodeling [39]. Isolation of ILC2 cells in bronchoalveolar lavage of transplant recipients warrants further exploration of the role of ILCs and other innate immune cells in PGD [39].

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EPITHELIAL CELL INJURY

Numerous markers of epithelial cell injury have also been associated with PGD in both animal and human studies, including receptor for advanced glycation end products (RAGE), type V collagen, and plasma clara cell secretory protein [20–25,50–52]. The role of traumatic brain injury (TBI) in the development of epithelial cell injury and IRI has been of increasing interest as the majority of lungs used for transplantation are procured from patients who have suffered TBI. High-mobility group box protein 1 (HMGB1) is a danger-associated molecular pattern released from necrotic neurons after TBI as well as alveolar macrophages after IRI. HMGB1 binds TLR4 and RAGE, inducing cytokine release and tissue damage [26▪▪,45]. Animal models suggest that HMGB1-induced RAGE activation may contribute to IRI via activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in epithelial cells and production of interleukin (IL)-17 by natural killer T cells [26▪▪,45]. Elevated levels of HMGB1 from brain-dead donors were associated with lower P/F before and after human lung transplantation [26▪▪,53▪]. Therapeutic strategies to block RAGE and decrease epithelial cell injury should be explored in recipients of lungs from brain-dead donors post-TBI.

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ENDOTHELIAL DYSFUNCTION

Endothelial dysfunction in lung IRI typically results mostly from disruption and restoration of blood flow with minimal contribution from tissue hypoxia and reoxygenation as the lung does not rely on perfusion for oxygenation [18▪]. Changes in blood flow during ischemia lead to closure of inward-rectifying potassium channels and subsequent endothelial cell depolarization [54–56]. This depolarization results in production of reactive oxygen species (ROS) and nitric oxide [57–60], increasing cell adhesion molecules for leukocyte adhesion and extravasation and activating NF-KB and other transcription factors [18▪,59,61▪▪]. Subsequent reperfusion results in hyperpolarization of endothelial cells and activation of a similar cascade as ischemia, the end result of which is further oxidative injury [62]. Future potential targets to modify endothelial activation and decrease PGD may include maintenance of lung perfusion with extracorporeal lung perfusion, administration of potassium channel agonists, and inhibition of ROS production [18▪,63].

In addition to inducing oxidative injury, disruption in blood flow to the lung may disrupt the endothelial cell barrier and induce vascular remodeling. Sphingosine 1-phosphate (S1P) controls endothelial cell tight junction formation and prevents chemotaxis. S1P supplementation prior to reperfusion decreased inflammatory cytokines and improved oxygenation in animal models [64,65▪]. Several animal and human studies have demonstrated an association between IRI and mediators of vascular permeability and angiogenesis including vascular endothelial growth factor and angiopoietin-2 [27–30,66–68]. Further trials are needed to explore the role of IRI on endothelial integrity and vascular remodeling.

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CHEMOTAXIS AND CYTOKINES

In many solid organ models, IRI has been shown to stimulate the release of proinflammatory cytokines as well as chemokines involved in migration of recipient immune cells including IL-1β, IL-6, IL-8, IL-11, interferon-gamma, and tumor necrosis factor (TNF)-α [44,69–73,74▪,75–78]. These findings have been confirmed in human lung observational studies and may represent future therapeutic targets [31–34].

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CLINICAL RISK FACTORS

Many groups have studied PGD risk factors (Table 3) [6,11,12,14,27,79–82,83▪,84▪,85–94]. Variability in reported risk factors may be attributed to single center studies, differences in perioperative management between centers, and use of nonstandardized PGD definitions; however, several donor, recipient, and procedural risk factors have consistently emerged.

Table 3

Table 3

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DONOR-RELATED CLINICAL RISK FACTORS

Reported donor risk factors include age, African American race, female sex, and history of tobacco exposure (Table 3) [6,14,80–82,83▪,99]. Smoke exposure is hypothesized to increase oxidative injury and thus IRI [101]. In donor lungs deemed unsuitable for transplantation, pulmonary edema and IL-8 were higher in donors who currently smoked although alveolar fluid clearance was lower in donors with greater than 20-pack year history compared to those with a less than 20-pack year history, suggesting a possible dose-related effect [102▪▪]. The impact of donor smoke exposure on PGD risk is difficult to ascertain as individual studies use different smoking cut-offs, and smoking status is obtained from surrogates. Further studies are needed to clarify the role of donor smoke exposure on PGD. A recent study using registry data suggested that although donor smoke exposure was associated with worse recipient outcomes, the survival probability after receiving such an allograft still exceeded that of remaining on the waiting list [103].

Donor-acquired risk factors, including prolonged mechanical ventilation, aspiration, and trauma, are potential risk factors without definitive studies demonstrating consistent associations with PGD [81]. Efforts are needed to standardize donor management and to optimize donor–recipient matching.

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RECIPIENT-RELATED RISK FACTORS

Reported recipient risk factors for PGD include obesity, pulmonary hypertension, and diagnoses of idiopathic pulmonary fibrosis or sarcoidosis (Table 3) [6,11,14,79,80,82,89,97,98,100]. After adjustment for multiple risk factors, obese and overweight recipient BMI were independent predictors of PGD. Higher levels of leptin, which regulates adipose tissue mass and has inflammatory properties, were also associated with increased PGD risk and mortality [97]. This supports previous studies showing obesity increases the risk of acute lung injury [104,105]. Although increasing adiposity is associated with PGD, it is unclear how best to assess body composition given a recent study demonstrating that BMI is a poor measure of adiposity [106▪▪]. Following identification of a reliable measure of body composition, future studies should evaluate the role of adipokines in cytokine release and PGD.

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PERIOPERATIVE RISK FACTORS

The operative risk factors for PGD reported in multicenter cohort studies are single lung transplant procedure type, prolonged ischemic time, cardiopulmonary bypass (CPB) use, greater than 1L packed red blood cell transfusion volume, use of Euro-Collins preservation solution, and reperfusion FiO2 greater than 0.4 (Table 3) [12,14,82,87,89,90,95,96]. Oversized allografts have been associated with a decreased risk of PGD3 and improved survival in bilateral lung transplant recipients, especially in recipients without chronic obstructive pulmonary disease [107,108▪▪].

Significant operative variability exists across transplant centers making it difficult to identify consistent operative risk factors. Confounding by disease severity or treatment indication further complicates the study of operative risk factors. Future trials should distinguish between emergent and planned use of CPB, evaluate the effect of lower reperfusion FiO2 on PGD, and explore the mechanisms by which the above operative factors increase PGD risk.

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PREVENTION AND TREATMENT

Several agents have been investigated to prevent PGD [109]. Although some observational trials of inhaled nitric oxide (iNO) suggest improved clinical outcomes, randomized control trials failed to show a definitive effect of iNO on PGD prevention when used routinely [110–116]. Soluble complement receptor 1 inhibitor, plasminogen-activating factor antagonist, and exogenous surfactant demonstrated beneficial effects on surrogates of PGD including A-a gradient [117–120]. A trial of aprotinin failed to detect an effect on PGD risk and was stopped early out of concern for potential renal toxicity [121]. Clearly, additional trials on PGD prevention are needed.

Therapy for PGD remains largely supportive and is heavily influenced by acute respiratory distress syndrome management strategies. Although most centers use low-stretch ventilation, tidal volumes are frequently selected based on recipient characteristics with little consideration given to donor characteristics [122▪,123▪,124]. Although there is no proven role for iNO in the prevention of PGD, it has been used as salvage therapy for severe allograft dysfunction following transplant and may be useful in patients with refractory hypoxemia posttransplant [125–127].

Veno-arterial ECMO has been studied for refractory hypoxemia and hemodynamic instability after lung transplant [128–134]. Given the link between CPB use and PGD, several groups have evaluated replacing CPB intraoperatively with veno-arterial ECMO with mixed results [135,136,137▪▪]. Veno-arterial ECMO has been associated with shorter duration of mechanical ventilation and ICU/hospital length of stay, and lower transfusion requirements, but no statistically significant difference in 90-day mortality [137▪▪]. With improvement in ECMO technology, including high performance membranes and coated circuits, veno-venous ECMO has been increasingly used with similar posttransplant outcomes and survival as veno-arterial ECMO [131,135]. Several groups have evaluated the use of extracorporeal life support (ECLS) with veno-venous, veno-arterial, and arterio-venous ECMO as a bridge to lung transplantation. Future research is needed to identify optimal candidates, standardize management strategies, and understand the impact of ECLS on PGD risk [138▪,139,140▪–146▪].

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FUTURE DIRECTIONS

Several commercial devices using extracorporeal lung perfusion technology have been created and differ by pump type, flow type, mobility, perfusate, and presence of an internal ventilator. Extracorporeal lung perfusion has been associated with increased lung utilization, similar or lower risk of PGD, and equivalent 30-day, 1-year, and 3-year survival compared with standard criteria donors [147,148▪,149,150▪–154▪,155,156▪,157▪,158,159]. Small case series have described similar incidence of acute rejection and respiratory infection up to 1 year after transplant [150▪,153▪]. The use of these technologies for donation after circulatory determination of death has demonstrated similar survival as donation after neurological determination of death [151▪]. A portable extracorporeal lung perfusion device was created to minimize ischemic time. Although case reports of this portable extracorporeal perfusion system are promising [160,161], the results of randomized control trials are pending [162,163]. Extracorporeal lung perfusion may eventually allow well tolerated expansion of the donor pool and serve as a vehicle for testing targeted therapeutics to improve organ quality and decrease PGD risk. Several multicenter prospective trials are underway to further evaluate this technology, with PGD as an endpoint.

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CONCLUSION

PGD is associated with poor short-term and long-term outcomes. The ISHLT definition has improved our ability to study this clinical syndrome, but further refinement of the definition is still needed and should be forthcoming. Improved understanding of risk factors and pathogenesis will identify potential therapeutic targets to modify the risk of PGD. As the acceptable recipient pool likely expands secondary to increasing ECLS use, continued well tolerated expansion of the donor pool must follow and may be possible given the promising results seen with extracorporeal lung perfusion.

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Acknowledgements

None.

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Financial support and sponsorship

National Institutes of Health [Grants: T32 HL-007891, K23 HL-121406] and Actelion Entelligence Grant.

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Conflicts of interest

There are no conflicts of interest to declare.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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72. Serrick C, Adoumie R, Giaid A, et al. The early release of interleukin-2, tumor necrosis factor-alpha and interferon-gamma after ischemia reperfusion injury in the lung allograft. Transplantation 1994; 58:1158–1162.
73. Zhao M, Fernandez LG, Doctor A, et al. Alveolar macrophage activation is a key initiation signal for acute lung ischemia-reperfusion injury. Am J Physiol Lung Cell Mol Physiol 2006; 291:L1018–L1026.
74▪. Spahn JH, Li W, Bribriesco AC, et al. DAP12 expression in lung macrophages mediates ischemia/reperfusion injury by promoting neutrophil extravasation. J Immunol 2015; 194:4039–4048.

This study demonstrated the role of alveolar macrophage in production of chemokines involved in leukocyte attraction and extravasation.

75. Krishnadasan B, Naidu BV, Byrne K, et al. The role of proinflammatory cytokines in lung ischemia-reperfusion injury. J Thorac Cardiovasc Surg 2003; 125:261–272.
76. Naidu BV, Woolley SM, Farivar AS, et al. Early tumor necrosis factor-alpha release from the pulmonary macrophage in lung ischemia-reperfusion injury. J Thorac Cardiovasc Surg 2004; 127:1502–1508.
77. Gelman AE, Okazaki M, Sugimoto S, et al. CCR2 regulates monocyte recruitment as well as CD4 T1 allorecognition after lung transplantation. Am J Transplant 2010; 10:1189–1199.
78. Kreisel D, Nava RG, Li W, et al. In vivo two-photon imaging reveals monocyte-dependent neutrophil extravasation during pulmonary inflammation. Proc Natl Acad Sci U S A 2010; 107:18073–18078.
79. Barr ML, Kawut SM, Whelan TP, et al. Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part IV: recipient-related risk factors and markers. J Heart Lung Transplant 2005; 24:1468–1482.
80. Christie JD, Kotloff RM, Pochettino A, et al. Clinical risk factors for primary graft failure following lung transplantation. Chest 2003; 124:1232–1241.
81. de Perrot M, Bonser RS, Dark J, et al. Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part III: donor-related risk factors and markers. J Heart Lung Transplant 2005; 24:1460–1467.
82. Kuntz CL, Hadjiliadis D, Ahya VN, et al. Risk factors for early primary graft dysfunction after lung transplantation: a registry study. Clin Transplant 2009; 23:819–830.
83▪. Liu Y, Liu Y, Su L, et al. Recipient-related clinical risk factors for primary graft dysfunction after lung transplantation: a systematic review and meta-analysis. PLoS One 2014; 9:e92773.

This metaanalysis identified recipient risk factors associated with the development of PGD.

84▪. Nosotti M, Palleschi A, Rosso L, et al. Clinical risk factors for primary graft dysfunction in a low-volume lung transplantation center. Transplant Proc 2014; 46:2329–2333.

This retrospective study identified clinical risk factors associated with the development of PGD3 in a low-volume center.

85. Novick RJ, Bennett LE, Meyer DM, et al. Influence of graft ischemic time and donor age on survival after lung transplantation. J Heart Lung Transplant 1999; 18:425–431.
86. Samano MN, Fernandes LM, Baranauskas JC, et al. Risk factors and survival impact of primary graft dysfunction after lung transplantation in a single institution. Transplant Proc 2012; 44:2462–2468.
87. Allen JG, Lee MT, Weiss ES, et al. Preoperative recipient cytokine levels are associated with early lung allograft dysfunction. Ann Thorac Surg 2012; 93:1843–1849.
88. Burton CM, Iversen M, Milman N, et al. Outcome of lung transplanted patients with primary graft dysfunction. Eur J Cardiothorac Surg 2007; 31:75–82.
89. Fang A, Studer S, Kawut SM, et al. Elevated pulmonary artery pressure is a risk factor for primary graft dysfunction following lung transplantation for idiopathic pulmonary fibrosis. Chest 2011; 139:782–787.
90. Felten ML, Sinaceur M, Treilhaud M, et al. Factors associated with early graft dysfunction in cystic fibrosis patients receiving primary bilateral lung transplantation. Eur J Cardiothorac Surg 2012; 41:686–690.
91. Shah RJ, Diamond JM, Lederer DJ, et al. Plasma monocyte chemotactic protein-1 levels at 24 h are a biomarker of primary graft dysfunction after lung transplantation. Transl Res 2012; 160:435–442.
92. Lee JC, Christie JD, Keshavjee S. Primary graft dysfunction: definition, risk factors, short- and long-term outcomes. Semin Respir Crit Care Med 2010; 31:161–171.
93. Suzuki Y, Cantu E, Christie JD. Primary graft dysfunction. Semin Respir Crit Care Med 2013; 34:305–319.
94. Lee JC, Christie JD. Primary graft dysfunction. Proc Am Thorac Soc 2009; 6:39–46.
95. Nagendran M, Maruthappu M, Sugand K. Should double lung transplant be performed with or without cardiopulmonary bypass? Interact Cardiovasc Thorac Surg 2011; 12:799–804.
96. Szeto WY, Kreisel D, Karakousis GC, et al. Cardiopulmonary bypass for bilateral sequential lung transplantation in patients with chronic obstructive pulmonary disease without adverse effect on lung function or clinical outcome. J Thorac Cardiovasc Surg 2002; 124:241–249.
97. Lederer DJ, Kawut SM, Wickersham N, et al. Obesity and primary graft dysfunction after lung transplantation: the Lung Transplant Outcomes Group Obesity Study. Am J Respir Crit Care Med 2011; 184:1055–1061.
98. Lederer DJ, Wilt JS, D’Ovidio F, et al. Obesity and underweight are associated with an increased risk of death after lung transplantation. Am J Respir Crit Care Med 2009; 180:887–895.
99. Oto T, Griffiths AP, Levvey B, et al. A donor history of smoking affects early but not late outcome in lung transplantation. Transplantation 2004; 78:599–606.
100. Sommers KE, Griffith BP, Hardesty RL, et al. Early lung allograft function in twin recipients from the same donor: risk factor analysis. Ann Thorac Surg 1996; 62:784–790.
101. Lawrence J, Xiao D, Xue Q, et al. Prenatal nicotine exposure increases heart susceptibility to ischemia/reperfusion injury in adult offspring. J Pharmacol Exp Ther 2008; 324:331–341.
102▪▪. Ware LB, Lee JW, Wickersham N, et al. Donor smoking is associated with pulmonary edema, inflammation and epithelial dysfunction in ex vivo human donor lungs. Am J Transplant 2014; 14:2295–2302.

This study demonstrated higher levels of IL-8 and lower rates of alveolar fluid clearance in donor lungs with smoke exposure compared with those without smoke exposure suggesting that exposure to cigarette smoker may affect gas exchange, lung epithelial function, and fluid balance.

103. Bonser RS, Taylor R, Collett D, et al. Effect of donor smoking on survival after lung transplantation: a cohort study of a prospective registry. Lancet 2012; 380:747–755.
104. Gong MN, Bajwa EK, Thompson BT, et al. Body mass index is associated with the development of acute respiratory distress syndrome. Thorax 2010; 65:44–50.
105. Anzueto A, Frutos-Vivar F, Esteban A, et al. Influence of body mass index on outcome of the mechanically ventilated patients. Thorax 2011; 66:66–73.
106▪▪. Singer JP, Peterson ER, Snyder ME, et al. Body composition and mortality after adult lung transplantation in the United States. Am J Respir Crit Care Med 2014; 190:1012–1021.

This study determined that leptin levels were associated with 1-year mortality after lung transplantation, whereas a BMI of 30–35 was not. BMI had poor sensitivity to measure total body fat-defined obesity, suggesting the need to identify a better measure of adiposity.

107. Eberlein M, Diehl E, Bolukbas S, et al. An oversized allograft is associated with improved survival after lung transplantation for idiopathic pulmonary arterial hypertension. J Heart Lung Transplant 2013; 32:1172–1178.
108▪▪. Eberlein M, Reed RM, Bolukbas S, et al. Lung size mismatch and primary graft dysfunction after bilateral lung transplantation. J Heart Lung Transplant 2015; 34:233–240.

This study demonstrated that oversized allografts were associated with a lower risk of PGD3 after bilateral lung transplantation, especially among non-COPD patients. This may have important implications for organ allocation.

109. 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; 24:1489–1500.
110. Bacha EA, Herve P, Murakami S, et al. Lasting beneficial effect of short-term inhaled nitric oxide on graft function after lung transplantation. Paris-Sud University Lung Transplantation Group. J Thorac Cardiovasc Surg 1996; 112:590–598.
111. 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; 26:1199–1205.
112. 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; 167:1483–1489.
113. Moreno I, Vicente R, Mir A, et al. Effects of inhaled nitric oxide on primary graft dysfunction in lung transplantation. Transplant Proc 2009; 41:2210–2212.
114. Tavare AN, Tsakok T. Does prophylactic inhaled nitric oxide reduce morbidity and mortality after lung transplantation? Interact Cardiovasc Thorac Surg 2011; 13:516–520.
115. Thabut G, Brugiere O, Leseche G, et al. Preventive effect of inhaled nitric oxide and pentoxifylline on ischemia/reperfusion injury after lung transplantation. Transplantation 2001; 71:1295–1300.
116. Yerebakan C, Ugurlucan M, Bayraktar S, et al. Effects of inhaled nitric oxide following lung transplantation. J Cardiac Surg 2009; 24:269–274.
117. 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; 129:423–428.
118. Struber 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; 133:1620–1625.
119. Wittwer T, Grote M, Oppelt P, et al. Impact of PAF antagonist BN 52021 (Ginkolide B) on postischemic graft function in clinical lung transplantation. J Heart Lung Transplant 2001; 20:358–363.
120. Zamora MR, Davis RD, Keshavjee SH, et al. Complement inhibition attenuates human lung transplant reperfusion injury: a multicenter trial. Chest 1999; 116 (1 Suppl):46S.
121. Herrington CS, Prekker ME, Arrington AK, et al. A randomized, placebo-controlled trial of aprotinin to reduce primary graft dysfunction following lung transplantation. Clin Transplant 2011; 25:90–96.
122▪. Beer A, Reed RM, Bolukbas S, et al. Mechanical ventilation after lung transplantation. An international survey of practices and preferences. Ann Am Thorac Soc 2014; 11:546–553.

This study outlines the variability in mechanical ventilation practices after lung transplantation across centers and highlights the lack of consideration of donor characteristics when selecting tidal volumes.

123▪. Diamond JM, Ahya VN. Mechanical ventilation after lung transplantation. It's time for a trial. Ann Am Thorac Soc 2014; 11:598–599.

This article stresses the need for a multicenter trial to standardize mechanical ventilation management after lung transplantation.

124. Currey J, Pilcher DV, Davies A, et al. Implementation of a management guideline aimed at minimizing the severity of primary graft dysfunction after lung transplant. J Thorac Cardiovasc Surg 2010; 139:154–161.
125. Adatia I, Lillehei C, Arnold JH, et al. Inhaled nitric oxide in the treatment of postoperative graft dysfunction after lung transplantation. Ann Thorac Surg 1994; 57:1311–1318.
126. Date H, Triantafillou AN, Trulock EP, et al. Inhaled nitric oxide reduces human lung allograft dysfunction. J Thorac Cardiovasc Surg 1996; 111:913–919.
127. Macdonald P, Mundy J, Rogers P, et al. Successful treatment of life-threatening acute reperfusion injury after lung transplantation with inhaled nitric oxide. J Thorac Cardiovasc Surg 1995; 110:861–863.
128. Aigner C, Wisser W, Taghavi S, et al. Institutional experience with extracorporeal membrane oxygenation in lung transplantation. Eur J Cardiothorac Surg 2007; 31:468–473.discussion 73–74.
129. 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; 87:854–860.
130. Glassman LR, Keenan RJ, Fabrizio MC, et al. Extracorporeal membrane oxygenation as an adjunct treatment for primary graft failure in adult lung transplant recipients. J Thorac Cardiovasc Surg 1995; 110:723–726.discussion 6–7.
131. Hartwig MG, Walczak R, Lin SS, et al. Improved survival but marginal allograft function in patients treated with extracorporeal membrane oxygenation after lung transplantation. Ann Thorac Surg 2012; 93:366–371.
132. 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; 120:20–26.
133. 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; 26:331–338.
134. Xu LF, Li X, Guo Z, et al. Extracorporeal membrane oxygenation during double-lung transplantation: single center experience. Chin Med J 2010; 123:269–273.
135. Bittner HB, Binner C, Lehmann S, et al. Replacing cardiopulmonary bypass with extracorporeal membrane oxygenation in lung transplantation operations. Eur J Cardiothorac Surg 2007; 31:462–467.discussion 7.
136. Ko WJ, Chen YS, Lee YC. Replacing cardiopulmonary bypass with extracorporeal membrane oxygenation in lung transplantation operations. Artif Organs 2001; 25:607–612.
137▪▪. Machuca TN, Collaud S, Mercier O, et al. Outcomes of intraoperative extracorporeal membrane oxygenation versus cardiopulmonary bypass for lung transplantation. J Thorac Cardiovasc Surg 2015; 149:1152–1157.

Patients receiving lung transplantation using extracorporeal membrane oxygenation had a shorter hospital length of stay, lower blood product transfusion requirement, and similar 90-day mortality compared with those on CPB after matching for age, transplant indication, and procedure type. This has important implications for perioperative management of lung transplant recipients.

138▪. Bozso S, Sidhu S, Garg M, et al. Canada's longest experience with extracorporeal membrane oxygenation as a bridge to lung transplantation: a case report. Transplant Proc 2015; 47:186–189.

This case report describes the successful use of extracorporeal membrane oxygenation as a bridge to lung transplantation in a patient with stage IV pulmonary sarcoidosis.

139. de Perrot M, Granton JT, McRae K, et al. Impact of extracorporeal life support on outcome in patients with idiopathic pulmonary arterial hypertension awaiting lung transplantation. J Heart Lung Transplant 2011; 30:997–1002.
140▪. Kon ZN, Wehman PB, Gibber M, et al. Venovenous extracorporeal membrane oxygenation as a bridge to lung transplantation: successful transplantation after 155 days of support. Ann Thorac Surg 2015; 99:704–707.

This case report describes the use of venovenous extracorporeal membrane oxygenation as a bridge to lung transplantation in a patient recovering from acute respiratory distress syndrome.

141▪. Lehr CJ, Zaas DW, Cheifetz IM, et al. Ambulatory extracorporeal membrane oxygenation as a bridge to lung transplantation: walking while waiting. Chest 2015; 147:1213–1218.

This article reviews the studies using extracorporeal membrane oxygenation as a bridge to lung transplantation and identifies the need for future trials to understand the optimal use of this technology.

142▪. Mohite PN, Sabashnikov A, Reed A, et al. Extracorporeal Life Support in ‘Awake’ Patients as a Bridge to Lung Transplant. Thoracic Cardiovasc Surg 2015.

This observational study describes similar 1-year survival among those bridged to lung transplantation using extracorporeal membrane oxygenation placed while awake and those placed while sedated.

143▪. Patil NP, Mohite PN, Reed A, et al. Modified technique using Novalung as bridge to transplant in pulmonary hypertension. Ann Thorac Surg 2015; 99:719–721.

This case report describes the use of Novalung as a bridge to lung transplantation in a patient with pulmonary hypertension.

144▪. Patil NP, Popov AF, Lees NJ, et al. Novel sequential bridge to lung transplant in an awake patient. J Thorac Cardiovasc Surg 2015; 149:e2–e4.

This case report describes the use of Novalung as a bridge to lung transplantation in a patient with pulmonary hypertension.

145▪. Schellongowski P, Riss K, Staudinger T, et al. Extracorporeal CO2 removal as bridge to lung transplantation in life-threatening hypercapnia. Transplant Int 2015; 28:297–304.

This case series describes the use of extracorporeal CO2 removal through Novalung for life-threatening hypercapnia as a bridge to lung transplantation.

146▪. Wiktor AJ, Haft JW, Bartlett RH, et al. Prolonged VV ECMO (265 Days) for ARDS without technical complications. ASAIO J 2015; 61:205–206.

This case report explains the use of extracorporeal membrane oxygenation in a patient with acute respiratory distress syndrome undergoing lung transplantation.

147. Aigner C, Slama A, Hotzenecker K, et al. Clinical ex vivo lung perfusion – pushing the limits. Am J Transplant 2012; 12:1839–1847.
148▪. Boffini M, Ricci D, Bonato R, et al. Incidence and severity of primary graft dysfunction after lung transplantation using rejected grafts reconditioned with ex vivo lung perfusion. Eur J Cardiothorac Surg 2014; 46:789–793.

This study demonstrated that grafts reconditioned with extracorporeal lung perfusion had similar rates and severity of PGD as standard grafts.

149. Cypel M, Yeung JC, Liu M, et al. Normothermic ex vivo lung perfusion in clinical lung transplantation. N Engl J Med 2011; 364:1431–1440.
150▪. Fildes JE, Archer LD, Blaikley J, et al. Clinical outcome of patients transplanted with marginal donor lungs via ex vivo lung perfusion compared to standard lung transplantation. Transplantation 2015; 99:1078–1083.

This study concluded that lungs reconditioned using extracorporeal lung perfusion reconditioned had similar rates of acute rejection, infection, hospital length of stay, and 1-year mortality as lungs deemed acceptable at initial evaluation.

151▪. Machuca TN, Mercier O, Collaud S, et al. Lung transplantation with donation after circulatory determination of death donors and the impact of ex vivo lung perfusion. Am J Transplant 2015; 15:993–1002.

This study demonstrated similar outcomes between lung transplantation after donation after circulatory determination of death and donation after neurologic determination of death. Among lungs transplanted from donation after circulatory determination of death donors, there was a nonstatistically significant trend toward shorter hospital length of stay and shorter length of mechanical ventilation if selective extracorporeal lung perfusion was used.

152▪. Sage E, Mussot S, Trebbia G, et al. Lung transplantation from initially rejected donors after ex vivo lung reconditioning: the French experience. Eur J Cardiothorac Surg 2014; 46:794–799.

This study evaluated the use of extracorporeal lung reconditioning on initially rejected donors and demonstrated that transplantation with these lungs had similar rates of primary graft dysfunction, hospital length of stay, and 1-year mortality compared with conventional donors.

153▪. Tikkanen JM, Cypel M, Machuca TN, et al. Functional outcomes and quality of life after normothermic ex vivo lung perfusion lung transplantation. J Heart Lung Transplant 2015; 34:547–556.

This study concluded that transplantation using allografts reconditioned with extracorporeal lung perfusion had similar mortality, freedom from chronic lung allograft dysfunction, and number of acute rejection episodes as those transplanted from conventional donors.

154▪. Valenza F, Rosso L, Coppola S, et al. Ex vivo lung perfusion to improve donor lung function and increase the number of organs available for transplantation. Transplant Int 2014; 27:553–561.

This article demonstrated similar rates of PGD3 at 72 h and survival between allografts reconditioned with extracorporeal lung perfusion and conventional donors and showed that extracorporeal lung perfusion technology could be used to increase the donor pool by 20%.

155. Valenza F, Rosso L, Gatti S, et al. Extracorporeal lung perfusion and ventilation to improve donor lung function and increase the number of organs available for transplantation. Transplant Proc 2012; 44:1826–1829.
156▪. Van Raemdonck D, Neyrinck A, Cypel M, et al. Ex-vivo lung perfusion. Transplant Int 2015; 28:643–656.

This article analyzed the technique, indications, and outcomes of lung transplantation using extracorporeal lung perfusion.

157▪. Wallinder A, Ricksten SE, Silverborn M, et al. Early results in transplantation of initially rejected donor lungs after ex vivo lung perfusion: a case-control study. Eur J Cardiothorac Surg 2014; 45:40–44.discussion 4–5.

Donor lungs initially deemed unsuitable for transplantation were treated with extracorporeal lung perfusion and then compared with conventional donor lungs that did not require extracorporeal lung perfusion. Although lungs treated with extracorporeal lung perfusion demonstrated longer time to extubation and longer median ICU stay, the hospital length of stay was similar.

158. Wigfield CH, Cypel M, Yeung J, et al. Successful emergent lung transplantation after remote ex vivo perfusion optimization and transportation of donor lungs. Am J Transplant 2012; 12:2838–2844.
159. Zych B, Popov AF, Stavri G, et al. Early outcomes of bilateral sequential single lung transplantation after ex-vivo lung evaluation and reconditioning. J Heart Lung Transplant 2012; 31:274–281.
160. Warnecke G, Moradiellos J, Tudorache I, et al. Normothermic perfusion of donor lungs for preservation and assessment with the Organ Care System Lung before bilateral transplantation: a pilot study of 12 patients. Lancet 2012; 380:1851–1858.
161. Souilamas R, Souilamas JI Jr, Saueressig M, et al. Advanced normothermic ex vivo lung maintenance using the mobile Organ Care System. J Heart Lung Transplant 2011; 30:847–848.
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Keywords:

acute lung injury; ischemia-reperfusion injury; lung transplantation; primary graft dysfunction

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