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The shortage of organ donors remains the major limiting factor in lung transplant, with the number of patients on the waiting list largely exceeding the number of available organ donors. Another issue is the low utilization rate seen in some types of donors. Therefore, novel strategies are continuously being explored to increase the donor pool. Advanced age, smoking history, positive serologies, and size mismatch are common criteria that decrease the rate of use when it comes to organ utilization. Questioning these limitations is one of the purposes of this review. Challenging these limitations by adapting novel donor management strategies could help to increase the rate of suitable lungs for transplantation while still maintaining good outcomes. A second goal is to present the latest advances in organ donation after controlled and uncontrolled cardiac death, and also on how to improve these lungs on ex vivo platforms for assessment and future specific therapies. Finally, pushing the limit of the donor envelope also means reviewing some of the recent improvements made in lung preservation itself, as well as upcoming experimental research fields. In summary, donor lung optimization refers to a global care strategy to increase the total numbers of available allografts, and preserve or improve organ quality without paying the price of early-, mid-, or long-term negative outcomes after transplantation. [ABSTRACT FROM AUTHOR]

Lung-protective ventilation I We recommend a lung-protective ventilation strategy consisting of low tidal volumes (6-8 mL/kg), high positive end-expiratory pressure i ( I PEEP) (at least 8 cm H i I SB 2 sb i I 0) and recruitment manoeuvres after ventilator disconnections in potential lung donors (strong recommendation i , I moderate-certainty evidence) i . All 3 studies showed an improved lung procurement rate with implementation of their comprehensive lung donor management strategies, and 1 of the 3 studies showed increased recipient survival.[28] The committee considered potential drawbacks not explored in these studies. Given that the evidence for a benefit from lung-protective ventilation is greatest for lung donation, we considered narrowing our recommendations to potential lung donors only. Achieving donor management goals before deceased donor procurement is associated with more organs transplanted per donor. [Extracted from the article]

The article presents a study related to the protective mechanical ventilation in organ donors. It mentions that lung-protective mechanical ventilation strategies aiming to avoid ventilator-induced lung injury (VILI) can potentially determine a great impact on lung availability for transplantation; and prone positioning has been demonstrated to be beneficial during mechanical ventilation for patients with acute respiratory distress syndrome in improving oxygenation.

Background Ex vivo lung perfusion (EVLP) allows for the evaluation and treatment of donor lungs before transplant. Different EVLP strategies have been described using either an open left atrium (LA) (pressure of 0 mm Hg) or closed LA (pressure of 5 mm Hg). We hypothesized that maintaining a physiologic positive LA pressure during EVLP is protective to the lung. Methods Pig lungs were flushed with Perfadex, retrieved and stored at 4°C for 4 hours [short cold ischemic time (CIT), n = 10] or 18 hours (prolonged CIT, n = 8). Subsequently, lungs underwent normothermic EVLP for 12 hours using either an open or closed LA technique. A linear mixed effect model was used to compare functional parameters between the 2 groups. Results After short CIT, 12-hour EVLP could not be completed in 4 of 5 open atrium cases due to significant pulmonary edema. Lung injury was evident in this group after 7 hours of EVLP, demonstrating an increase in pulmonary vascular resistance ( p < 0.001) and peak inspiratory pressure ( p = 0.001), and a decrease in lung compliance ( p < 0.001) and perfusate oxygenation ( p = 0.04). In contrast, in the closed atrium group, all lungs completed 12 hours of EVLP with stable functional parameters. At the end of the experiment, the wet/dry ratio ( p = 0.015) and lung edema score ( p = 0.02) were significantly worse in the open LA group compared with the closed LA EVLP group. Similar findings were observed in the prolonged CIT group. Conclusion The use of a closed atrial technique to create a controlled positive LA during EVLP leads to significantly less edema and superior lung physiology. [ABSTRACT FROM AUTHOR]

Lung transplantation is an established life-saving therapy for patients with end-stage lung disease. Unfortunately, greater success in lung transplantation is hindered by a shortage of lung donors and the relatively poor early-, mid-, and long-term outcomes associated with severe primary graft dysfunction. Ex vivo lung perfusion has emerged as a modern preservation technique that allows for a more accurate lung assessment and improvement in lung quality. This review outlines the: (i) rationale behind the method; (ii) techniques and protocols; (iii) Toronto ex vivo lung perfusion method; (iv) devices available; and (v) clinical experience worldwide. We also highlight the potential of ex vivo lung perfusion in leading a new era of lung preservation. [ABSTRACT FROM AUTHOR]

Purpose: The shortage of organs for transplantation is an important medical and societal problem because transplantation is often the best therapeutic option for end-stage organ failure.Methods: We review the potential deceased organ donation pathways in adult ICU practice, i.e. donation after brain death (DBD) and controlled donation after circulatory death (cDCD), which follows the planned withdrawal of life-sustaining treatments (WLST) and subsequent confirmation of death using cardiorespiratory criteria.Results: Strategies in the ICU to increase the number of organs available for transplantation are discussed. These include timely identification of the potential organ donor, optimization of the brain-dead donor by aggressive management of the physiological consequence of brain death, implementation of cDCD protocols, and the potential for ex vivo perfusion techniques.Conclusions: Organ donation should be offered as a routine component of the end-of-life care plan of every patient dying in the ICU where appropriate, and intensivists are the key professional in this process. [ABSTRACT FROM AUTHOR]

Background The objective of this study was to review the international experience in lung transplantation using lung donation after circulatory death (DCD). Methods In this retrospective study, data from the International Society for Heart and Lung Transplantation (ISHLT) DCD Registry were analyzed. The study cohort included DCD lung transplants performed between January 2003 and June 2013, and reported to the ISHLT DCD Registry as of April 2014. The participating institutions included 10 centers in North America, Europe and Australia. The control group was a cohort of lung recipients transplanted using brain-dead donors (DBDs) during the same study period. The primary end-point was survival after lung transplantation. Results There were 306 transplants performed using DCD donors and 3,992 transplants using DBD donors during the study period. Of the DCD transplants, 94.8% were Maastricht Category III, whereas 4% were Category IV and 1.2% Category V (euthanasia). Heparin was given in 54% of the cases, donor extubation occurred in 90% of the cases, and normothermic ex vivo lung perfusion (EVLP) was used in 12%. The median time from withdrawal of life support therapy (WLST) to cardiac arrest was 15 minutes (5th to 95th percentiles of 5 to 55 minutes), and from WLST to cold flush was 33 minutes (5th to 95th percentiles of 19.5 to 79.5 minutes). Recipient age and medical diagnosis were similar in DCD and DBD groups ( p = not significant [NS]). Median hospital length of stay was 18 days in DCD lung transplants and 16 days in DBD transplants ( p = 0.016). Thirty-day survival was 96% in the DCD group and 97% in the DBD group. One-year survival was 89% in the DCD group and 88% in the DBD group ( p = NS). Five-year survival was 61% in both groups ( p = NS). The mechanism of donor death within the DCD group seemed to influence recipient early survival. The survival rates through 30 days were significantly different by donor mechanism of death ( p = 0.0152). There was no significant correlation between the interval of WLST to pulmonary flush with survival ( p = 0.11). Conclusion This large study of international, multi-center experience demonstrates excellent survival after lung transplantation using DCD donors. It should be further evaluated whether the mechanism of donor death influences survival after DCD transplant. [ABSTRACT FROM AUTHOR]

Summary: Although lung transplantation has become a life-saving option for patients with end-stage lung disease, this intervention is hampered by a shortage of lungs in view of the growing number of people on the waiting list. Lungs are retrieved from only a small percentage of multiorgan donors, and the transplantation and intensive-care communities have recognised the need to develop innovative methods to expand the donor pool. Advancements in lung-preservation techniques in the preretrieval and postretrieval periods have increased the pool of available donors, and novel research and discoveries in this area have steadily improved post-transplantation adverse events. This Review summarises current best practice and the latest research on intensive-care management of a potential lung donor. We also discuss lung-preservation techniques, including advancements in normothermic ex-vivo lung perfusion, and the potential for a personalised medicine approach to the organ. [ABSTRACT FROM AUTHOR]

Objective: Normothermic ex vivo lung perfusion is a novel method to evaluate and improve the function of injured donor lungs. We reviewed our experience with 50 consecutive transplants after ex vivo lung perfusion. Methods: A retrospective study using prospectively collected data was performed. High-risk brain death donor lungs (defined as Pao 2/Fio 2 <300 mm Hg or lungs with radiographic or clinical findings of pulmonary edema) and lungs from cardiac death donors were subjected to 4 to 6 hours of ex vivo lung perfusion. Lungs that achieved stable airway and vascular pressures and Pao 2/Fio 2 greater than 400 mm Hg during ex vivo lung perfusion were transplanted. The primary end point was the incidence of primary graft dysfunction grade 3 at 72 hours after transplantation. End points were compared with lung transplants not treated with ex vivo lung perfusion (controls). Results: A total of 317 lung transplants were performed during the study period (39 months). Fifty-eight ex vivo lung perfusion procedures were performed, resulting in 50 transplants (86% use). Of these, 22 were from cardiac death donors and 28 were from brain death donors. The mean donor Pao 2/Fio 2 was 334 mm Hg in the ex vivo lung perfusion group and 452 mm Hg in the control group (P = .0001). The incidence of primary graft dysfunction grade 3 at 72 hours was 2% in the ex vivo lung perfusion group and 8.5% in the control group (P = .14). One patient (2%) in the ex vivo lung perfusion group and 7 patients (2.7%) in the control group required extracorporeal lung support for primary graft dysfunction (P = 1.00). The median time to extubation, intensive care unit stay, and hospital length of stay were 2, 4, and 20 days, respectively, in the ex vivo lung perfusion group and 2, 4, and 23 days, respectively, in the control group (P > .05). Thirty-day mortality (4% in the ex vivo lung perfusion group and 3.5% in the control group, P = 1.00) and 1-year survival (87% in the ex vivo lung perfusion group and 86% in the control group, P = 1.00) were similar in both groups. Conclusions: Transplantation of high-risk donor lungs after 4 to 6 hours of ex vivo lung perfusion is safe, and outcomes are similar to those of conventional transplants. Ex vivo lung perfusion improved our center use of donor lungs, accounting for 20% of our current lung transplant activity. [Copyright &y& Elsevier]

Background: The evaluation of donor lungs by normothermic ex vivo acellular perfusion has improved the safety of organ utilization. However, this strategy requires a critical re-evaluation of the parameters used to assess lungs during ex vivo perfusion compared with those traditionally used to evaluate the donor lung in vivo. Using a porcine model, we studied the physiology of acellular lung perfusion with the aim of improving the accuracy of clinical ex vivo evaluation. Methods: Porcine lungs after 10 hours of brain death and 24 hours of cold ischemia and uninjured control lungs were perfused for 12 hours and then transplanted. PaO2, compliance, airway pressure and pulmonary vascular resistance were measured. Ventilation with 100% nitrogen and addition of red blood cells to the perfusate were used to clarify the physiologic disparities between in vivo blood perfusion and ex vivo acellular perfusion. Results: During 12 hours of ex vivo perfusion, injured lungs developed edema with decreased compliance and increased airway pressure, but ex vivo PO2 remained stable. After transplantation, injured lungs demonstrated high vascular resistance and poor PaO2. A reduced effect of shunt on ex vivo lung perfusion PO2 was found to be attributable to the linearization of the relationship between oxygen content and PO2, which occurs with acellular perfusate. Conclusions: Ex vivo PO2 may not be the first indication of lung injury and, taken alone, may be misleading in assessing the ex vivo lung. Thus, evaluation of other physiologic parameters takes on greater importance. [ABSTRACT FROM AUTHOR]

Background: More than 80% of donor lungs are potentially injured and therefore not considered suitable for transplantation. With the use of normothermic ex vivo lung perfusion (EVLP), the retrieved donor lung can be perfused in an ex vivo circuit, providing an opportunity to reassess its function before transplantation. In this study, we examined the feasibility of transplanting high-risk donor lungs that have undergone EVLP. Methods: In this prospective, nonrandomized clinical trial, we subjected lungs considered to be high risk for transplantation to 4 hours of EVLP. High-risk donor lungs were defined by specific criteria, including pulmonary edema and a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (PO2:FIO2) less than 300 mm Hg. Lungs with acceptable function were subsequently transplanted. Lungs that were transplanted without EVLP during the same period were used as controls. The primary end point was primary graft dysfunction 72 hours after transplantation. Secondary end points were 30-day mortality, bronchial complications, duration of mechanical ventilation, and length of stay in the intensive care unit and hospital. Results: During the study period, 136 lungs were transplanted. Lungs from 23 donors met the inclusion criteria for EVLP; in 20 of these lungs, physiological function remained stable during EVLP and the median PO2:FIO2 ratio increased from 335 mm Hg in the donor lung to 414 and 443 mm Hg at 1 hour and 4 hours of perfusion, respectively (P<0.001). These 20 lungs were transplanted; the other 116 lungs constituted the control group. The incidence of primary graft dysfunction 72 hours after transplantation was 15% in the EVLP group and 30% in the control group (P=0.11). No significant differences were observed for any secondary end points, and no severe adverse events were directly attributable to EVLP. Conclusions: Transplantation of high-risk donor lungs that were physiologically stable during 4 hours of ex vivo perfusion led to results similar to those obtained with conventionally selected lungs. (Funded by Vitrolife; ClinicalTrials.gov number, NCT01190059.) N Engl J Med 2011;364:1431-40. [ABSTRACT FROM AUTHOR]

Background: Ischemia-reperfusion injury remains the major cause of early morbidity and mortality after lung transplantation. Activated protein C (APC) has been demonstrated to attenuate various acute inflammation-related injuries in the lung and other organs. Methods: The effect of exogenous APC in lung transplantation was examined using a rat orthotopic lung transplantation model of ischemia-reperfusion injury with 24 hours of cold ischemia. APC was administered to the donor airway before cold pulmonary artery flush, or intravenously to the recipient before reperfusion. Results: The levels of APC in the lung tissue were significantly higher in the intra-airway group compared with the intravenous group and the saline control group (p < 0.01). Transplanted lung oxygenation was significantly better in the intra-airway APC group at 2 hours after reperfusion compared with controls (Pao 2, mean ± SD mm Hg: intra-airway APC, 350.9 ± 85.5; intravenous APC, 241.1 ± 59.3; control, 200.2 ± 37.3; p < 0.05). No difference was detected in proinflammatory cytokines or thrombin-anti-thrombin complexes in the lung tissue. Histologic examination of the lung injury score or alveolar fibrin deposition did not demonstrate significant differences among groups. Conclusion: Exogenous APC administered to the donor airway attenuates ischemia-reperfusion injury after lung transplantation. This novel administration route sustains high levels of APC in the lung tissue, which should avoid frequent administration and potential systemic side effects of bleeding. Further investigation is necessary to determine the mechanism of the beneficial effect of APC in this setting. [Copyright &y& Elsevier]

Background: The inhibition of cellular metabolism induced by hypothermia obviates the possibility of substantial reparative processes occurring during organ preservation. The aim of this study was to develop a technique of extended (12-hour) ex vivo lung perfusion (EVLP) at normothermia for assessment and protective maintenance of the donor lung. Methods: Six double-lung blocks from 35-kg pigs and 5 single human lungs were subjected to 12 hours of normothermic EVLP using acellular Steen Solution. In the animal studies, the left lung was transplanted into recipients at the end of EVLP and reperfused for 4 hours to evaluate the impact of prolonged EVLP on post-transplant lung function. A protective mode of mechanical ventilation with controlled perfusion flows and pressures in the pulmonary vasculature were employed during EVLP. Lung oxygenation capacity (ΔPo 2), pulmonary vascular resistance and airway pressures were evaluated in the system. Red blood cells were added to the perfusate to a hematocrit of 20% at the end of human lung EVLP to study lung functional assessment with and without cells. Results: Lung function was stable during 12 hours of EVLP. This stability during prolonged normothermic EVLP translated into excellent post-transplant lung function (Pao 2/Fio 2: 527 ± 22 mm Hg), low edema formation (wet/dry ratio: 5.24 ± 0.38) and preserved lung histology after transplantation. The acellular perfusion assessment of lung function accurately correlated with post-transplant graft function. Conclusions: Twelve hours of EVLP at physiologic temperatures using an acellular perfusate is achievable and maintains the donor lungs without inflicting significant added injury. This system can be used to assess, maintain and treat injured donor lungs. [Copyright &y& Elsevier]

The authors comment on an article by Wallinder et al. published in the journal regarding the use of heparin for grafting in uncontrolled non-heartbeating lung donation (NHBD). They report that an analysis on animal models shows that heparinization is not necessary for setting NHBD. They inform that only 15 percent of organs from brain death donors and less than 10 percent from controlled NHBD are utilized by transplant programmes in North America and Europe.

The number of lung transplant procedures performed internationally is increasing but the donor organ pool is insufficient to meet demand and waiting list mortality is unacceptably high. As survival rates for patients with acute respiratory distress syndrome managed on extracorporeal life support (ECLS) have steadily improved, a potential role for ECLS to support critically ill patients awaiting a donor organ match has emerged. We explore the rapidly evolving landscape of ECLS as a bridge to lung transplantation with review of the patient selection criteria, predictors of survival, modes of pre and peri-transplant support, and the importance of a holistic multidisciplinary approach to care. Finally, we consider innovations that are envisaged to increase the accessibility, safety, and effectiveness of ECLS delivery for future lung transplant candidates. [ABSTRACT FROM AUTHOR]

Background: Lung donation after cardiac death (DCD), in contrast to donation after brain death (DBD), is a promising and increasingly common method to help relieve the shortage of donor organs. We aimed to study the differential gene expression profiles in lungs of DCD and DBD patients and interpreted the differences using functional pathway analysis. Methods: We performed microarray studies on pre- and post-transplant lung tissues from 7 DCD and 12 matched DBD patients. Gene profiling was performed by Affymetrix human gene U-133 plus 2 GeneChip on 35 lung tissues. Principal Component Analysis (PCA), Significance Analysis of Microarray (SAM) and Hierarchical Clustering were performed to identify gross gene expression features and the lists of significantly regulated genes. We used Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) to determine functional significance and the genomic network relationship. Results: Gene expression profiles between DCD and DBD demonstrated a clear distinction by PCA, especially in the pre-transplant period. The gene sets enriched in DBD mapped to innate immunity, intracellular signaling, cytokine interaction, cell communication and apoptosis pathways. The networks produced by IPA showed that pro-inflammatory nodes played major role in pre-transplant DBD networks. However, the number of differentially regulated transcripts or gene sets decreased markedly after transplantation between DBD and DCD. Conclusion: Analysis of gene expression profiles in donor lungs showed significant differences in pathway activation between DBD and DCD lungs. The observation of fewer inflammatory features of DCD donor lungs suggests safe application of lung transplantation in properly preserved DCD donor lungs. [ABSTRACT FROM AUTHOR]

A 19-year-old man with cystic fibrosis, who was on extracorporeal membrane oxygenation, underwent bilateral lung transplantation from a donor with glioblastoma multiforme. Because the risk of tumor transmission from donor-related central nervous system malignancies remains unclear, the use of these extended donors remains controversial. In fact, there are few reports on the outcomes of lung transplantation from donors with central nervous system malignancy. This patient was critically ill with extracorporeal membrane oxygenation support before transplantation, but is well without any sign of malignancy 20 months after transplantation. [Copyright &y& Elsevier]

Background Ex-vivo lung perfusion (EVLP), a technique for donor lung assessment, also represents a platform for donor lung repair and immunomodulation. α 1 -Anti-trypsin (A1AT), a medication used to treat emphysema in A1AT-deficient patients, has anti-inflammatory properties and has been shown to attenuate ischemia–reperfusion injury in rat and pig lung transplants. The objective of this study was to determine whether administration of A1AT during EVLP can improve donor lung quality after prolonged hypothermic preservation. Methods Pig donor lungs were retrieved, preserved at 4°C for 24 hours, and then subjected to normothermic EVLP for 12 hours using the Toronto protocol. The treatment group ( n = 6) received 3 mg/ml A1AT (Zemaira) in the EVLP perfusate, acellular Steen solution. The control group ( n = 6) was perfused with Steen solution only. Physiologic functions and gas exchange were measured hourly. Pulmonary edema, lung injury, apoptosis and inflammatory mediators were evaluated in lung tissues and perfusate. Results A1AT treatment significantly reduced pulmonary arterial pressure, pulmonary vascular resistance and airway pressure changes from the baseline when compared with controls. A1AT treatment significantly improved both dynamic and static pulmonary compliance, and change in partial pressure of oxygen (ΔPO 2 ) between the left atrium and the pulmonary artery. Furthermore, A1AT treatment also significantly reduced pulmonary edema (wet-to-dry ratio), pulmonary cell apoptosis and pro-inflammatory cytokine levels (interleukin-1α and -8) in the perfusate. Conclusion Treatment of 24-hour-preserved pig donor lungs with A1AT during EVLP resulted in improved physiologic function, reduced pulmonary edema and inflammation and decreased cell death. Our findings suggest that treatment of donor lungs during EVLP with A1AT is a promising strategy to attenuate early lung injury and improve donor lung function before lung transplantation. [ABSTRACT FROM AUTHOR]