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The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.

Report of the ISHLT Working Group on Primary Lung Graft Dysfunction Part III: Donor-Related Risk Factors and Markers

      Primary graft dysfunction is the end result of a series of donor lung injuries before and after the declaration of brain death and during the transplant process, as well as in the recipient after reperfusion.
      • de Perrot M.
      • Liu M.
      • Waddell T.K.
      • Keshavjee S.
      Ischemia–reperfusion induced lung injury.
      Donor factors play an important role in the development of primary graft dysfunction after lung transplantation, but few clinical studies have analyzed their impact. Results have been hindered by variations in donor selection criteria and by use of different definitions of primary graft dysfunction between centers. The impact of donor factors, however, appears predominant during the initial 24 hours of reperfusion, whereas recipient factors seem more important thereafter.
      • Sommers K.E.
      • Griffith B.P.
      • Hardesty R.L.
      • Keenan R.J.
      Early lung allograft function in twin recipients from the same donor risk factor analysis.
      The impact of donor factors can be differentiated into those that are inherent to lung donor characteristics and those that are acquired at the time of death or later. This distinction is important because adequate donor management could potentially influence factors that are acquired at the time of death or subsequent to death.

      Inherent lung donor characteristics

      Age, smoking history, race, gender and underlying lung disease are inherent donor characteristics that may influence the quality of the lungs and potentially impact on recipient outcome. Christie and colleagues analyzed the impact of donor factors in a cohort study of 255 consecutive lung transplants and observed that several donor factors, including female gender, African American ethnicity and age, had an independent impact on the development of primary graft dysfunction.
      • Christie J.D.
      • Kotloff R.M.
      • Pochettino A.
      • et al.
      Clinical risk factors for primary graft failure following lung transplantation.
      The difference seen in graft outcome with donor female gender has been observed in other organ transplantations and may be due to size discrepancies between donor and recipient, although other factors, such as gender-linked antigens, cannot be excluded. Because the mechanisms by which race and gender impact on outcome after lung transplantation remain speculative, they should not be used in the decision to accept or reject a donor lung.
      Christie and colleagues found that donor age had an independent impact on the development of primary graft dysfunction after lung transplantation. Donor ages >45 years and <21 years were associated with a higher risk of primary graft dysfunction. Although the data for the young donors are equivocal, similar findings have been observed in the UNOS/ISHLT registry for older donors.
      • Novick R.J.
      • Bennett L.E.
      • Meyer D.M.
      • Hosenpud J.D.
      Influence of graft ischemic time and donor age on survival after lung transplantation.
      Indeed, the combination of donor age >45 years and ischemic time >7 to 8 hours had a significant impact on 30-day mortality after lung transplantation, according to registry data.
      • Novick R.J.
      • Bennett L.E.
      • Meyer D.M.
      • Hosenpud J.D.
      Influence of graft ischemic time and donor age on survival after lung transplantation.
      Some groups, however, have successfully used older donors if all other selection criteria were ideal.
      • Sundaresan S.
      • Semenkovich J.
      • Ochoa L.
      • et al.
      Successful outcome of lung transplantation is not compromised by the use of marginal donor lungs.
      • Bhorade S.M.
      • Vigneswaran W.
      • McCabe M.A.
      • Garrity E.R.
      Liberalization of donor criteria may expand the donor pool without adverse consequence in lung transplantation.
      • Gabbay E.
      • Williams T.J.
      • Griffiths A.P.
      • et al.
      Maximizing the utilization of donor organs offered for lung transplantation.
      • Pierre A.F.
      • Sekine Y.
      • Hutcheon M.A.
      • Waddell T.K.
      • Keshavjee S.H.
      Marginal donor lungs a reassessment.
      • de Perrot M.
      • Waddell T.K.
      • Shargall Y.
      • et al.
      Lung transplantation with donors 60 years of age and older.
      Hence, use of older donors most likely increases the risk of primary graft dysfunction, but the risk seems limited in the absence of other risk factors.
      The impact of smoking history on primary graft dysfunction remains controversial. Although Oto and colleagues recently reported that a cumulative smoking history of >20 pack-years is associated with prolonged mechanical ventilation and ICU stay after lung transplantation, the incidence of death from non-specific graft failure was not significantly different between donors with a smoking history of >20 vs <20 pack-years.
      • Oto T.
      • Griffiths A.P.
      • Levvey B.
      • et al.
      A donor history of smoking affects early but not late outcome in lung transplantation.
      Unfortunately, these investigators did not directly report the impact of donor smoking history on the incidence of primary graft dysfunction. In their analysis, Christie and colleagues, observed that donor smoking history had no significant impact on primary graft dysfunction after lung transplantation. In the future, analysis in larger groups of patients will be necessary to quantify more precisely the impact that donor smoking history may play on the development of primary graft dysfunction.

      Acquired lung donor factors

      The occurrence of brain death, prolonged mechanical ventilation, bronchoaspiration, pneumonia, trauma, multiple blood transfusions or hemodynamic instability in the donor before the retrieval procedure can potentially contribute to lung injury and primary graft dysfunction.
      • de Perrot M.
      • Weder W.
      • Patterson G.A.
      • Keshavjee S.
      Strategies to increase limited donor resources.
      The deleterious effect of brain death on organ function has been increasingly recognized over the last few years.
      • Avlonitis V.S.
      • Fisher A.J.
      • Kirby J.A.
      • Dark J.H.
      Pulmonary transplantation the role of brain death in donor lung injury.
      Brain death can induce disruption in homeostatic regulation, with profound disturbances in endocrine function, and an intense inflammatory reaction that may reduce the tolerance of the organs to handle a period of ischemia.
      • Bittner H.B.
      • Kendall S.W.
      • Chen E.P.
      • Craig D.
      • Van Trigt P.
      The effects of brain death on cardiopulmonary hemodynamics and pulmonary blood flow characteristics.
      Brain death has also been demonstrated experimentally to increase the risk of acute rejection and chronic graft dysfunction.
      • Wilhelm M.J.
      • Pratschke J.
      • Beato F.
      • et al.
      Activation of the heart by donor brain death accelerates acute rejection after transplantation.
      • Pratschke J.
      • Wilhelm M.J.
      • Laskowski I.
      • et al.
      Influence of donor brain death on chronic rejection of renal transplants in rats.
      Clinically, Sommers and colleagues observed that recipients from donors with closed head injury had significantly lower oxygenation on arrival in the ICU than recipients from donors with other causes of death.
      • Sommers K.E.
      • Griffith B.P.
      • Hardesty R.L.
      • Keenan R.J.
      Early lung allograft function in twin recipients from the same donor risk factor analysis.
      Other groups, however, did not confirm this finding.
      • Christie J.D.
      • Kotloff R.M.
      • Pochettino A.
      • et al.
      Clinical risk factors for primary graft failure following lung transplantation.
      • Waller D.A.
      • Thompson A.M.
      • Wrightson W.N.
      • et al.
      Does the mode of donor death influence the early outcome of lung transplantation? A review of lung transplantation from donors involved in major trauma.
      Biopsies from cadaveric kidney donors have been shown to have higher levels of inflammatory cytokines, adhesion molecules and human leukocyte antigen-DR (HLA-DR) than biopsies from living donors, and the expression of these markers on tubular cells before transplantation was associated with a higher incidence of primary graft dysfunction and early acute rejection.
      • Schwarz C.
      • Regele H.
      • Steininger R.
      • et al.
      The contribution of adhesion molecule expression in donor kidney biopsies to early allograft dysfunction.
      • Koo D.D.
      • Welsh K.I.
      • McLaren A.J.
      • et al.
      Cadaver versus living donor kidneys impact of donor factors on antigen induction before transplantation.
      Fisher and colleagues showed that interleukin-8 (IL-8) in lung bronchoalveolar lavage from 28 non-traumatic brain-dead donors was significantly higher than in healthy controls, and these IL-8 levels correlated with neutrophil infiltration in donor lung tissue.
      • Fisher A.J.
      • Donnelly S.C.
      • Hirani N.
      • et al.
      Enhanced pulmonary inflammation in organ donors following fatal non-traumatic brain injury.
      Several groups have begun to administer a bolus of steroids (methylprednisolone ∼15 mg/kg) after brain-death declaration to all potential lung donors to reduce the inflammatory reaction induced by brain death. The steroid bolus has been shown to improve arterial oxygen tension in the donor and also to be associated with an increased lung donor recovery rate as well as improved lung function in the recipient after transplantation.
      • Follette D.M.
      • Rudich S.M.
      • Babcock W.D.
      Improved oxygenation and increased lung donor recovery with high-dose steroid administration after brain death.
      • McElhinney D.B.
      • Khan J.H.
      • Babcock W.D.
      • Hall T.S.
      Thoracic organ donor characteristics associated with successful lung procurement.
      • Wigfield C.H.
      • Golledge H.D.
      • Shenton B.K.
      • Kirby J.A.
      • Dark J.H.
      Ameliorated reperfusion injury in lung transplantation after reduction of brain death induced inflammatory graft damage in the donor.
      Hemodynamic instability with persistent low blood pressures can increase the risk of post-operative graft dysfunction after kidney and liver transplantation.
      • Lucas B.A.
      • Vaughn W.K.
      • Spees E.K.
      • Sanfilippo F.
      Identification of donor factors predisposing to high discard rates of cadaver kidneys and increased graft loss within one year posttransplantation—SEOPF 1977–1982. South-Eastern Organ Procurement Foundation.
      • Busuttil R.W.
      • Goldstein L.I.
      • Danovitch G.M.
      • Ament M.E.
      • Memsic L.D.
      Liver transplantation today.
      Prolonged hypotension before death has also been shown to be associated with significant deterioration in lung graft function after reperfusion in a rat model of non–heart-beating donor.
      • Tremblay L.N.
      • Yamashiro T.
      • DeCampos K.N.
      • et al.
      Effect of hypotension preceding death on the function of lungs from donors with nonbeating hearts.
      Although not studied in clinical lung transplantation, similar findings are to be expected, because adequate blood pressure and stable hemodynamic parameters are important to maintain optimal oxygen delivery and energy metabolism in organ tissues.
      Optimal filling pressures have not been analyzed in humans after brain-death declaration. However, experiments with brain-dead pigs have shown that the heart dilates rapidly and fails with a central venous pressure (CVP) of >9 mm Hg.
      • Wicomb W.N.
      • Cooper D.K.
      • Lanza R.P.
      • Novitzky D.
      • Isaacs S.
      The effects of brain death and 24 hours’ storage by hypothermic perfusion on donor heart function in the pig.
      A CVP of <10 mm Hg is usually recommended in clinical practice. However, caution must be taken with fluid resuscitation in brain-dead donors because excessive fluid administration can cause rapid deterioration in lung function, even if the CVP remains at <10 mm Hg.
      • Pennefather S.H.
      • Bullock R.E.
      • Dark J.H.
      The effect of fluid therapy on alveolar arterial oxygen gradient in brain-dead organ donors.
      Excessive fluid administration can be detrimental to the lung, particularly if left-heart dysfunction has been demonstrated.
      Persistent hypotension and hemodynamic instability from cardiac dysfunction are best managed with vasopressors. Dopamine is used as a first choice because of its potential vasodilative effect on renal and mesenteric blood flow. In addition, low-dose dopamine has recently been shown to improve lung edema in brain-dead donors.
      • Ware L.B.
      • Fang X.
      • Wang Y.
      • et al.
      Selected contribution mechanisms that may stimulate the resolution of alveolar edema in the transplanted human lung.
      Although the data are limited, there is relatively strong evidence suggesting that epinephrine and norepinephrine should be replaced with vasopressin. Vasopressin has been shown to have a stabilizing effect on systemic blood pressure after brain death while also allowing for reduction or discontinuation of epinephrine and norepinephrine in most cadaveric donors.
      • Pennefather S.H.
      • Bullock R.E.
      • Mantle D.
      • Dark J.H.
      Use of low dose arginine vasopressin to support brain-dead organ donors.
      • Iwai A.
      • Sakano T.
      • Uenishi M.
      • et al.
      Effects of vasopressin and catecholamines on the maintenance of circulatory stability in brain-dead patients.
      • Chen J.M.
      • Cullinane S.
      • Spanier T.B.
      • et al.
      Vasopressin deficiency and pressor hypersensitivity in hemodynamically unstable organ donors.
      In addition, vasopressin improves maintenance of energy metabolism and is effective against diabetes insipidus, which occurs in 80% of brain-dead donors.
      • Washida M.
      • Okamoto R.
      • Manaka D.
      • et al.
      Beneficial effect of combined triiodothyronine and vasopressin administration on hepatic energy status and systemic hemodynamics after brain death.
      Although dopamine and vasopressin are helpful in donor management, their impact on recipient outcome remains to be demonstrated.
      Because pneumonia has been a major cause of early morbidity and mortality in lung transplant recipients, utilization of lungs from donors with a positive gram stain in tracheal secretions has initially been avoided. However, aggressive antibiotic treatment in donors and recipients has significantly reduced the incidence of recipient pneumonia, and recent series have shown that gram stain of donor tracheal aspirates does not correlate with recipient outcome.
      • Weill D.
      • Dey G.C.
      • Hicks R.A.
      • et al.
      A positive donor gram stain does not predict outcome following lung transplantation.
      Positive gram stain of tracheal aspirates most likely does not indicate ongoing pneumonia, but simply a collection of purulent secretions in the upper airways. In contrast, positive cultures from donor bronchoalveolar lavage (BAL) may indicate ongoing pneumonia, be associated with lower oxygenation after reperfusion in the recipient, and lead to longer ICU stay as well as prolonged ventilation when compared to donors with negative BAL bacterial cultures.
      • Avlonitis V.S.
      • Krause A.
      • Luzzi L.
      • et al.
      Bacterial colonization of the donor lower airways is a predictor of poor outcome in lung transplantation.
      BAL cultures should be taken from all donors to aggressively adapt the anti-biotherapy post-operatively.

      Donor selection

      Clinical Markers

      The current criteria used to assess donor lungs are based on donor history, arterial blood gases, chest X-ray appearance, bronchoscopy findings and physical examination of the lung at the time of retrieval. These criteria have been reviewed in detail previously and are not the primary focus of this study.
      • Orens J.B.
      • Boehler A.
      • de Perrot M.
      • et al.
      A review of lung transplant donor acceptability criteria.
      However, their accuracy in determining the risk of primary graft dysfunction after transplantation is not optimal. Primary graft dysfunction occasionally occurs in patients receiving lungs from ideal donors, whereas extended donors have been used without significant impairment in post-operative lung function.
      • Novick R.J.
      • Bennett L.E.
      • Meyer D.M.
      • Hosenpud J.D.
      Influence of graft ischemic time and donor age on survival after lung transplantation.
      • Sundaresan S.
      • Semenkovich J.
      • Ochoa L.
      • et al.
      Successful outcome of lung transplantation is not compromised by the use of marginal donor lungs.
      • Bhorade S.M.
      • Vigneswaran W.
      • McCabe M.A.
      • Garrity E.R.
      Liberalization of donor criteria may expand the donor pool without adverse consequence in lung transplantation.
      • Gabbay E.
      • Williams T.J.
      • Griffiths A.P.
      • et al.
      Maximizing the utilization of donor organs offered for lung transplantation.

      Biologic Markers

      Because clinical factors are not accurate enough in predicting primary graft dysfunction after lung transplantation, some groups have focused on biologic markers as a predictor of outcome. As mentioned previously, kidney biopsies from cadaveric kidney donors appear to have significantly higher levels of inflammatory cytokines, adhesion molecules and HLA-DR than biopsies from living donors, and the expression of these markers on tubular cells before transplantation can be associated with a higher incidence of primary graft dysfunction and early acute rejection after transplantation.
      • Schwarz C.
      • Regele H.
      • Steininger R.
      • et al.
      The contribution of adhesion molecule expression in donor kidney biopsies to early allograft dysfunction.
      • Koo D.D.
      • Welsh K.I.
      • McLaren A.J.
      • et al.
      Cadaver versus living donor kidneys impact of donor factors on antigen induction before transplantation.
      In human lung transplantation, the chemokine IL-8 is upregulated in BAL and lung tissue from brain-dead donors and the level seems to correlate with the incidence of primary graft dysfunction after reperfusion.
      • de Perrot M.
      • Sekine Y.
      • Fischer S.
      • et al.
      Interleukin-8 release during early reperfusion predicts graft function in human lung transplantation.
      • Fisher A.J.
      • Donnelly S.C.
      • Hirani N.
      • et al.
      Elevated levels of interleukin-8 in donor lungs is asociated with early graft failure after lung transplantation.
      Biologic markers should be accurate, provide rapid results, and be readily available for clinical use. Rapid, quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) may provide some of these advantages, such as measurement of cytokine levels within 1 hour after lung biopsy. The demonstration of tumor necrosis factor-alpha by RT-PCR in donor myocardium was found to predict post-operative right-heart dysfunction in recipients after heart transplantation.
      • Birks E.J.
      • Owen V.J.
      • Burton P.B.
      • et al.
      Tumor necrosis factor-alpha is expressed in donor heart and predicts right ventricular failure after human heart transplantation.
      In clinical lung transplantation, the level of IL-6 measured by RT-PCR and the ratio of the pro-inflammatory cytokine, IL-6, to the anti-inflammatory cytokine, IL-10, was found to predict 30-day mortality and mortality from primary graft dysfunction, whereas no clinical factor did so in the same group of patients.
      • Kaneda H.
      • Gutierrez C.
      • de Perrot M.
      • et al.
      Preimplantation multiple cytokine mRNA expression analysis in donor lung grafts predicts survival after lung transplantation in humans.
      In the future, rapid analysis of pro- and anti-inflammatory markers in lung parenchyma may be extremely useful to reduce the incidence of primary graft dysfunction by determining more precisely the type of lung suitable for transplantation or by influencing post-implantation management.

      Lung Preservation

      Ischemia–reperfusion-induced lung injury plays a major role in the development of primary graft dysfunction. It is an inevitable step in the transplant process that may potentially add to other injuries occurring in the donor before the period of ischemia or in the recipient after reperfusion. Much of the experimental work over the past decade has focused on how to optimize the methods of lung preservation to reduce the impact of ischemia–reperfusion injury on post-transplant lung function. The temperature, volume and pressure of the preservation solution as well as inflation, temperature and oxygenation of the lung during storage have all been shown experimentally to impact on the quality of the lung after reperfusion. In addition, the type of lung preservation used and use of a retrograde flush have been shown experimentally and clinically to improve post-operative lung function. Some of these experiments are briefly reviewed in what follows.

      Methods of Preservation

      The current clinical practice of lung preservation is a hypothermic pulmonary artery flush at 50 to 60 ml/kg, coupled with topical cold saline solution while ventilating the lungs.
      • Hopkinson D.N.
      • Bhabra M.S.
      • Hooper T.L.
      Pulmonary graft preservation a worldwide survey of current clinical practice.
      The lungs are then transported inflated, in a hypothermic (4°C) solution. The lungs are perfused via the pulmonary artery to uniformly cool the lung tissue and remove blood from the pulmonary vascular bed. Flushing prevents vessel thrombosis and insures uniform tissue cooling, which then decreases membrane damage from retained macrophages and neutrophils.
      • Veith F.J.
      • Sinha S.B.P.
      • Graves J.S.
      • Boley S.J.
      • Dougherty J.C.
      Ischemic tolerance of the lung the effects of ventilation and inflation.

      Temperature of Preservation Solution

      Historically, hypothermia has been a major component of lung preservation and continues to play an important role.
      • Baldwin J.C.
      • Frist W.H.
      • Starkey T.D.
      • et al.
      Distant graft procurement for combined heart and lung transplantation using pulmonary artery flush and simple topical hypothermia for graft preservation.
      Hypothermia suppresses the activity of cellular degradative enzymes, which would otherwise lead to a rapid loss of cellular viability during ischemia at normothermic temperatures. Preservation of tissues at low temperatures reduces metabolic activity to such a level that cell viability can be maintained in the face of ischemia.
      • Pegg D.E.
      Organ preservation.
      Lung preservation at 4°C decreases the metabolic rate to 5% of the metabolic rate at 37°C.
      Controversy remains regarding the optimal flush temperature for lung preservation. Small animal studies suggest that warmer preservation solution temperature would be better than 4°C.
      • Wang L.S.
      • Nakamol K.
      • Hsieh C.M.
      • Miyoshi S.
      • Copper J.D.
      Influence of temperature of flushing solution on lung preservation.
      • Albes J.M.
      • Fischer F.
      • Bando T.
      • et al.
      Influence of the perfusate temperature on lung preservation is there an optimum?.
      However, ultrastructural analyses of human lung parenchyma at various time-points during the preservation period demonstrate minimal lung injury despite preservation at 4°C.
      • Fehrenbach H.
      • Riemann D.
      • Wahlers T.
      • et al.
      Scanning and transmission electron microscopy of human donor lungs fine structure of the pulmonary parenchyma following preservation and ischemia.
      • Muller C.
      • Hoffman H.
      • Bittmann L.
      • et al.
      Hypothermic storage alone in lung preservation for transplantation a metabolic, light microscopic, and functional analysis after 18 hours of preservation.
      Hence, the known advantage of reduced metabolic activity at 4°C and technical ease of maintaining this temperature keeps the use of hypothermic perfusion flush temperature at 4°C the standard flushing temperature.

      Volume of Preservation Solution

      The amount of flush solution required to adequately clear the blood from the lungs and optimize graft function is dependent on patient size and perfusion flow rates. Haverich and colleagues found that a solution volume of 60 ml/kg given at a high flow rate improved lung cooling and post-operative lung function.
      • Haverich A.
      • Aziz S.
      • Scott W.G.
      • Jamieson S.W.
      • Shumway N.E.
      Improved lung preservation using Euro-Collins solution for flush-perfusion.
      Although Steen and colleagues recommended volumes as high as 150 ml/kg, this has not been widely adopted as a significant improvement over 60 ml/kg.
      • Steen S.
      • Sjoberg T.
      • Massa G.
      • Ericsson L.
      • Lindberg L.
      Safe pulmonary preservation for 12 hours with low-potassium-dextran solution.
      The infusion of 60 ml/kg of perfusate solution is sufficient to clear the lungs of blood and uniformly cool the lungs as well. If infused at a low perfusion pressure, the infusion requires only several minutes to complete.

      Pressure of Preservation Solution Infusion

      The optimal pulmonary artery pressure for infusion is controversial. Sasaki and colleagues observed that flushing pressures of 10 to 15 mm Hg achieved significantly better lung function than infusions at pressures of 20 and 25 mm Hg.
      • Tanaka H.
      • Chiba Y.
      • Sasaki M.
      • Matsukawa S.
      • Muraoka R.
      Relationship between flushing pressure and nitric oxide production in preserved lungs.
      The high pulmonary artery pressures noted during the flush with Euro-Collins solution and the improvement in lung function with the addition of prostaglandins also suggest that the optimal perfusion pressure should be in the lower range to maximize graft function after transplantation.
      • Puskas J.D.
      • Cardoso P.F.
      • Mayer E.
      • et al.
      Equivalent eighteen-hour lung preservation with low-potassium dextran or Euro-Collins solution after prostaglandin E1 infusion.

      Inflation or Ventilation

      Experimental and clinical studies clearly support the importance of ventilation during lung procurement and inflation during storage.
      • Veith F.J.
      • Sinha S.B.P.
      • Graves J.S.
      • Boley S.J.
      • Dougherty J.C.
      Ischemic tolerance of the lung the effects of ventilation and inflation.
      • Badellino M.M.
      • Morganroth M.L.
      • Grum C.M.
      • et al.
      Hypothermia or continuous ventilation decreases ischemia–reperfusion injury in an ex vivo rat lung model.
      However, over-distension of the lung by either static inflation, high tidal volume or high positive end-expiratory pressure (PEEP) can be detrimental to the lungs, and hyperinflation during storage can increase the pulmonary capillary filtration coefficient.
      • Haniuda M.
      • Hasegawa S.
      • Shiraishi T.
      • et al.
      Effects of inflation volume during lung preservation on pulmonary capillary permeability.
      Lung inflation during storage should be limited to 50% of the total lung capacity or to an airway pressure of 10 to 15 cm H2O to avoid barotraumas.
      • DeCampos K.N.
      • Keshavjee S.
      • Liu M.
      • Slutsky A.S.
      Optimal inflation volume for hypothermic preservation of rat lungs.
      • Kayano K.
      • Toda K.
      • Naka Y.
      • Pinsky D.J.
      Identification of optimal conditions for lung graft storage with Euro-Collins solution by use of a rat orthotopic lung transplant model.

      Storage Temperature

      The ideal temperature for lung storage remains unclear. In the process of lung transportation, hypothermia is used to decrease cellular metabolic activity and preserve lung function. However, it can also compound injury due to ischemia–reperfusion. Tissue edema as a result of hypothermia is due to decreased ATPase activity.
      • Martin D.R.
      • Scott D.F.
      • Downes G.L.
      • Belzer F.O.
      Primary cause of unsuccessful liver and heart preservation cold sensitivity of the ATPase system.
      ATPase-dependent ion balance in the cell becomes disrupted, alters cellular function, and leads to membrane disruption, followed by cell death. The ATPase activity is temperature-dependent and tissue-specific.
      • Martin D.R.
      • Scott D.F.
      • Downes G.L.
      • Belzer F.O.
      Primary cause of unsuccessful liver and heart preservation cold sensitivity of the ATPase system.
      In the lung, hypothermia results in increased extravascular fluid and pulmonary vasoconstriction. This contributes to diminished oxygen exchange and increased pulmonary vascular resistance after reperfusion. Several animal studies have shown that pulmonary function after 12 to 24 hours of storage is superior if the lungs are preserved at 10°C instead of 4°C or 15°C.
      • Wang L.S.
      • Yoshikawa K.
      • Miyoshi S.
      • et al.
      The effect of ischemic time and temperature on lung preservation in a simple ex vivo rabbit model used for functional assessment.
      However, in clinical lung transplantation, parenchymal injury is dependent on multiple factors, making it difficult to determine the precise contribution from hypothermia alone. In addition, lungs preserved at 10°C require a greater amount of metabolic substrate and the risk of lung injury can increase extremely rapidly if the temperature rises above 10°C during preservation. Hence, given the logistics of transportation and the inconclusive experimental data regarding optimal storage temperature, 4°C continues to be the most common temperature for lung storage.

      Oxygenation

      The lung has the ability to remain in aerobic conditions during preservation if it is inflated with oxygen.
      • De Leyn P.R.J.
      • Lerut T.E.
      • Scheinemakers H.H.
      • et al.
      Effect of inflation on adenosine triphosphate catabolism and lactate production during normothermic lung ischemia.
      This remains true even under conditions of hypothermia.
      • Date H.
      • Matsumura A.
      • Manchester J.K.
      • et al.
      Changes in alveolar oxygen and carbon dioxide concentration and oxygen consumption during lung preservation.
      However, there is a fine line between oxygen requirements for metabolic purposes, and excessive concentrations leading to free-radical production even before reperfusion. In fact, oxygen-free-radical–mediated injury has been shown to occur before reperfusion when rabbit lungs were stored at 10°C, and inflated with 100% oxygen.
      • Heiniuda M.
      • Dresler C.M.
      • Mizuta T.
      • Cooper J.D.
      • Patterson G.A.
      Free radical–mediated vascular injury in lungs preserved at moderate hypothermia.
      This correlates with the finding in rat lungs that there is an oxygen-dependent injury taking place during the ischemic phase.
      • Fisher A.B.
      • Dodia C.
      • Tan Z.
      • Ayene I.
      • Eckenhoff R.G.
      Oxygen-dependent lipid peroxidation during lung ischemia.
      As a result, the most common clinical practice is ventilation and lung inflation with an Fio2 of 0.30 to 0.50.

      Preservation Solutions

      There has been a recent trend toward the use of low-potassium solutions (extracellular), such as Perfadex (Vitrolife, Goteborg, Sweden), for lung preservation. Low-potassium dextran solution has been introduced in the clinical arena after a significant amount of experimental work illustrated its benefits.
      • Steen S.
      • Sjoberg T.
      • Massa G.
      • Ericsson L.
      • Lindberg L.
      Safe pulmonary preservation for 12 hours with low-potassium-dextran solution.
      • Keshavjee S.H.
      • Yamazaki F.
      • Cardoso P.F.
      • et al.
      A method for safe twelve-hour pulmonary preservation.
      Low-potassium dextran (LPD) is the only preservation solution developed specifically for lung preservation. Other low-potassium solutions include Wallwork’s solution and Celsior. Celsior contains the anti-oxidants mannitol, glutathione, glutamate and histidine as well as lactobionate. A modified cold blood solution as proposed by Wallwork and colleagues includes the addition of heparin and lactated Ringer solution to the blood.
      The key components of LPD are the dextran and low-potassium concentration. Dextran-40 in the LPD solution functions as an oncotic agent, tending to keep water in the intravascular compartment, and thereby decreasing interstitial edema formation. It also reduces the aggregation of erythrocytes and circulating thrombocytes, which may improve the microcirculation and reduce cellular activation. The low-potassium concentration maintains normal pulmonary artery pressures during infusion. A further development is a dextran–glucose-based extracellular solution.
      • Date H.
      • Matsumura A.
      • Manchester J.K.
      • et al.
      Evaluation of lung metabolism during successful twenty-four hour canine lung preservation.
      • Wagner F.M.
      • Jamieson S.W.
      • Fung J.
      • et al.
      A new concept for successful long-term pulmonary preservation in a dog model.
      The addition of glucose is designed to support aerobic metabolism and maintain cell integrity during prolonged ischemia. Perfadex is an LPD–glucose solution that is now clinically available worldwide.
      The addition of glucose to a lung preservation solution takes advantage of the unique aspect of lung physiology in transplantation. That is, the inflated lung has the ability to supply oxygen to its parenchyma even during storage. A lung flushed with 1% glucose added to LPD solution and stored for >24 hours was found to be associated with continued normal glucose metabolism in the lung.
      • Date H.
      • Matsumura A.
      • Manchester J.K.
      • et al.
      Evaluation of lung metabolism during successful twenty-four hour canine lung preservation.
      Analyzing lung tissue, the investigators found that tissue glucose, glucose-6-phosphate and lactate levels rose in a parallel fashion, indicating the presence of glycolysis in response to glucose in the LPD solution.
      Clinical reports from 6 centers have compared the effect of Perfadex with an historical control group of lungs preserved with Euro-Collins.
      • Fischer S.
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      • de Perrot M.
      • et al.
      Low-potassium dextran preservation solution improves lung function after human lung transplantation.
      • Struber M.
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      • Harringer W.
      • et al.
      Flush perfusion with low potassium dextran solution improves early graft function in clinical lung transplantation.
      • Muller C.
      • Furst H.
      • Reichenspurner H.
      • et al.
      Lung procurement by low-potassium dextran and the effect on preservation injury. Munich Lung Transplant Group.
      • Aziz T.M.
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      • et al.
      Perfadex for clinical lung procurement is it an advance?.
      • Rega F.
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      Switch from Euro-Collins to Perfadex for pulmonary graft preservation resulted in superior outcome in transplant recipient.
      • Rabanal J.M.
      • Ibanez A.M.
      • Mons R.
      • et al.
      Influence of preservation solution on early lung function (Euro-Collins vs Perfadex).
      Five centers showed significantly better lung function on arrival in the ICU and a trend toward lower 30-day mortality with Perfadex. An additional report demonstrated that, after adjustment for graft ischemic time, extracellular-type preservation solutions were associated with a decreased incidence of primary graft dysfunction after lung transplantation when compared with intracellular-type preservation solutions.
      • Thabut G.
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      • et al.
      Influence of preservation solution on early graft failure in clinical lung transplantation.

      Retrograde Flush

      Retrograde flush, which refers to the administration of flush solution through the left atrial appendage or the pulmonary veins, and drainage through the pulmonary artery, has been described for lung and heart–lung transplantation. The technique adds the potential advantages of flushing both the bronchial and pulmonary vessels, and of limiting the effect of pulmonary arterial vasoconstriction on the distribution of the flush solution. Experimentally, a retrograde flush has been found to improve lung preservation when compared with an anterograde flush.
      • Struber M.
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      • Kofidis T.
      • et al.
      Surfactant function in lung transplantation after 24 hours of ischemia advantage of retrograde flush perfusion for preservation.
      This effect was attributed to more effective clearance of red blood cells within the capillaries, better distribution of the flush solution along the tracheobronchial tree, and less severe impairment of surfactant function. However, despite the retrograde flush, pre-treatment with prostaglandin E1 was still helpful in improving pulmonary dynamic compliance after reperfusion.
      • Chen C.Z.
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      • Ardery P.
      • et al.
      Retrograde flush and cold storage for twenty-two to twenty-five hours lung preservation with and without prostaglandin E1.
      After these results were published, several groups have adopted a combined procedure with an anterograde flush through the pulmonary artery, followed by a retrograde flush through each of the pulmonary veins in situ with the lungs still ventilated. Venuta and colleagues completed a study of 14 patients demonstrating that the addition of a retrograde flush to an anterograde flush was associated with improved lung function after transplantation when compared with an anterograde-only flush.
      • Venuta F.
      • Rendina E.A.
      • Bufi M.
      • et al.
      Preimplantation retrograde pneumoplegia in clinical lung transplantation.
      A retrograde flush was also shown to help remove blood clots from the distal pulmonary artery bed that are occasionally seen in cadaveric lung donors.
      • Fischer S.
      • Gohrbandt B.
      • Meyer A.
      • et al.
      Should lungs from donors with severe acute pulmonary embolism be accepted for transplantation? The Hannover experience.
      • Nguyen D.Q.
      • Salerno C.T.
      • Bolman R.M.
      • Park S.J.
      Pulmonary thromboembolectomy of donor lungs prior to lung transplantation.

      Ischemic Time

      Although prolonged ischemic time has been shown by some investigators to have an impact on the occurrence of primary graft dysfunction, its role may have become less important with improvement in lung preservation methods.
      • Thabut G.
      • Vinatier I.
      • Stern J.B.
      • et al.
      Primary graft failure following lung transplantation predictive factors of mortality.
      • Fiser S.M.
      • Kron I.L.
      • Long S.M.
      • et al.
      Influence of graft ischemic time on outcomes following lung transplantation.
      • Gammie J.S.
      • Stukus D.R.
      • Pham S.M.
      • et al.
      Effect of ischemic time on survival in clinical lung transplantation.
      Recently, ischemic times of up to 10 or even 12 hours have been successfully reported with optimal donors, and ischemic times of 6 to 8 hours are usually considered reasonable.
      • de Perrot M.
      • Liu M.
      • Waddell T.K.
      • Keshavjee S.
      Ischemia–reperfusion induced lung injury.
      Ueno and colleagues reported a series of 74 patients undergoing bilateral lung transplants for indications other than primary pulmonary hypertension and Eisenmenger syndrome, and observed that ischemic times of >8 hours were associated with lower oxygenation in the recipient during the first 24 hours of reperfusion.
      • Ueno T.
      • Snell G.I.
      • Williams T.J.
      • et al.
      Impact of graft ischemic time on outcomes after bilateral sequential single-lung transplantation.
      A large review from the international registry on 5,052 lung transplant recipients has also shown an increased 30-day mortality with cold ischemic times of >7 to 8 hours and donors >45 years of age.
      • Novick R.J.
      • Bennett L.E.
      • Meyer D.M.
      • Hosenpud J.D.
      Influence of graft ischemic time and donor age on survival after lung transplantation.
      However, most of these studies were performed with intracellular preservation solutions such as Euro-Collins, which have been shown to be less efficient than extracellular preservation solutions. Hence, currently, prolonged ischemia should probably be seen as an additional risk factor, but not as a direct cause of primary graft dysfunction.

      Conclusions

      Donor factors should be differentiated into those that are inherent to lung donor characteristics and those that are acquired at the time of brain death or thereafter. Inherent lung donor characteristics, such as age and smoking history, can potentially increase the risk of post-operative lung dysfunction. However, improvement in donor management and lung preservation techniques over the past decade have helped to expand the number of lungs available for transplantation and to reduce the risk of primary graft dysfunction. Currently, primary graft dysfunction is more likely to be the end result of a series of insults to the lungs than to be due to a single factor only. In the future, the development of a multi-institutional database prospectively collecting demographic data from lung donors, length of ischemic time and recipient’s conditions will help to stratify the impact that each of these factors may have on outcome after lung transplantation. This information as well as the potential development of biologic markers could be extremely helpful to further expand the lung donor pool without increasing the risk of primary graft dysfunction.

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