Immediate post-operative broncho-alveolar lavage IL-6 and IL-8 are associated with early outcomes after lung transplantation.

INTRODUCTION: Previous studies demonstrated that increased cytokine and chemokine levels, either shortly before or after lung transplantation, were associated with post-transplant outcome. However, small patient cohorts were mostly used, focusing on 1 molecule and 1 outcome. In a large single-center cohort, we investigated the predictive value of immediate post-operative broncho-alveolar lavage (BAL) expression of IL-6 and IL-8 on multiple key outcomes, including PGD, CLAD, graft survival, as well as several secondary outcomes. MATERIAL AND METHODS: All patients undergoing a first lung transplant in whom routine bronchoscopy with BAL was performed during the first 48 hours post-transplantation were included. IL-6 and IL-8 protein levels were measured in BAL via ELISA. RESULTS: A total of 336 patients were included. High IL-6 levels measured within 24 hours of transplantation were associated with longer time on ICU and time to hospital discharge; and increased prevalence of PGD grade 3. Increased IL-8 levels, measured within 24 hours, were associated with PGD3, more ECMO use, higher donor paO2 , younger donor age, but not with other short-or long-term outcome. IL-6 and IL-8 measured between 24 and 48 hours of transplantation were not associated with any outcome parameters. CONCLUSION: Recipient BAL IL-6 and IL-8 within 24 hours post-transplant were associated with an increased incidence of PGD3.

A retrospective database analysis to evaluate the potential of ex vivo lung perfusion to recruit declined lung donors.

Ex vivo lung perfusion (EVLP) is currently used for both standard and extended-criteria donor (ECD) lungs. To enlarge the donor pool, we might have to extend the threshold for ECD donation. The purpose of this study was to estimate how many additional ECD lungs could be recruited by EVLP. We reviewed all multi-organ donors (MODs) from our collaborative donor hospitals (January 2010-June 2015). All unused lung donors were categorized using registered donor data and evaluated by two independent investigators to identify which lungs could be transplanted after EVLP. 584 MODs were registered at our transplant center. 268 (45.9%) were declined as lung donor at the moment of registration, and 316 (54.1%) were considered as a donor for lung transplantation. In the latter, lungs from 220 (37.7%) donors were transplanted and 96 donors (16.4%) were not. We identified 78 of 364 declined donors (21.4%) whose lungs could potentially become transplantable after EVLP. With this retrospective database analysis of unused lung donors, we identified a large potential for EVLP to further increase the donor pool in transplant centers where the majority of donor lungs are already extended.

Argon and xenon ventilation during prolonged ex vivo lung perfusion.

BACKGROUND: Evidence supports the use of ex vivo lung perfusion (EVLP) as a platform for active reconditioning before transplantation to increase the potential donor pool and to reduce the incidence of primary graft dysfunction. A promising reconditioning strategy is the administration of inhaled noble gases based on their organoprotective effects. Our aim was to validate a porcine warm ischemic lung injury model and investigate postconditioning with argon (Ar) or xenon (Xe) during prolonged EVLP. METHODS: Domestic pigs were divided in four groups (n = 5 per group). In the negative control group, lungs were flushed immediately. In the positive control (PC) and treatment (Ar, Xe) groups, lungs were flushed after a warm ischemic interval of 2-h in situ. All grafts were evaluated and treated during normothermic EVLP for 6 h. In the control groups, lungs were ventilated with 70% N2/30% O2 and in the treatment groups with 70% Ar/30% O2 or 70% Xe/30% O2, respectively. Outcome parameters were physiological variables (pulmonary vascular resistance, peak airway pressures, and PaO2/FiO2), histology, wet-to-dry weight ratio, bronchoalveolar lavage, and computed tomography scan. RESULTS: A significant difference between negative control and PC for pulmonary vascular resistance, peak airway pressures, PaO2/FiO2, wet-to-dry weight ratio, histology, and computed tomography-imaging was observed. No significant differences between the injury group (PC) and the treatment groups (Ar, Xe) were found. CONCLUSIONS: We validated a reproducible prolonged 6-h EVLP model with 2 h of warm ischemia and described the physiological changes over time. In this model, ventilation during EVLP with Ar or Xe administered postinjury did not improve graft function.

Steroids can reduce warm ischemic reperfusion injury in a porcine donation after circulatory death model with ex vivo lung perfusion evaluation.

Donation after circulatory death (DCD) is being used to increase the number of transplantable organs. The role and timing of steroids in DCD donation and ex vivo lung perfusion (EVLP) has not been thoroughly investigated. In this study, we investigated the effect of steroids on warm ischemic injury in a porcine model (n = 6/group). Following cardiac arrest, grafts were left untouched in the donor (90-min warm ischemia). Graft function was assessed after 6 h of EVLP. In the MP group, 500 mg methylprednisolone was given prior to cardiac arrest and during EVLP. In the CONTR group, no steroids were added. Median lung compliance (13 ml/cmH2 0) was significantly better preserved in the CONTR group than in the MP group (30.5 ml/cmH2 0). Also, median wet-to-dry weight (6.11 vs. 6.94) and CT density (182.5 vs. 352.9 g/l) were significantly better in the MP group than in the CONTR group, respectively. There was no difference in oxygenation and pulmonary vascular resistance. Perfusate cytokine analysis showed a significant reduction in IL-1ß, IL-8, IFN-α, IL-10, TNF-α, and IFN-γ in MP. Cytokines in bronchoalveolar lavage were not decreased except for IFN-gamma. We demonstrated that warm ischemic injury in DCD donation can be attenuated by steroids when given prior to warm ischemia and during EVLP. Ethical context of donor preconditioning should be discussed further.

Short- and Long-term Outcomes After Lung Transplantation From Circulatory-Dead Donors: A Single-Center Experience.

BACKGROUND: Donation after cardiac death (DCD) to overcome the donor organ shortage is well accepted in the clinical setting, although long-term outcome after DCD lung transplantation (LTx) remains largely unknown. METHODS: In this retrospective study, DCD LTx recipients (n = 59) were compared with a cohort of donation after brain death (DBD) LTx recipients (n = 331) transplanted between February 2007 and September 2013; follow-up was until January 1, 2016. Short-term (duration of mechanical ventilation, intensive care unit stay, hospital stay, and highest primary graft dysfunction score within 72 hours) and long-term (chronic lung allograft dysfunction-free and overall survival) follow-up were compared over a median follow-up of 50.5 (±3.7) months for DCD and 66.8 (±1.5) months for DBD. RESULTS: There were no differences between groups with regard to patient characteristics: age (P = 0.78), underlying disease (P = 0.30) and type of type of LTx (P = 0.10), except sex where more males were transplanted with a DCD donor (62.7%) vs (48.3%, P = 0.048). There was no difference in time on mechanical ventilation (P = 0.59), intensive care unit stay (P = 0.74), highest primary graft dysfunction score (P = 0.67) and hospital stay (P = 0.99). Moreover, chronic lung allograft dysfunction-free (P = 0.86) and overall survival (P = 0.15) did not differ between the DBD and DCD groups. CONCLUSIONS: In our experience, both short- and long-term outcomes in DCD lung recipients are comparable to that of DBD lung recipients. Therefore, DCD LTx can be considered a safe strategy that significantly increased our transplant activity.

A porcine ex vivo lung perfusion model with maximal argon exposure to attenuate ischemia-reperfusion injury.

Argon (Ar) is a noble gas with known organoprotective effects in rodents and in vitro models. In a previous study we failed to find a postconditioning effect of Ar during ex vivo lung perfusion (EVLP) on warm-ischemic injury in a porcine model. In this study, we further investigated a prolonged exposure to Ar to decrease cold ischemia-reperfusion injury after lung transplantation in a porcine model with EVLP assessment. Domestic pigs (n = 6/group) were pre-conditioned for 6 hours with 21% O2 and 79% N2 (CONTR) or 79% Ar (ARG). Subsequently, lungs were cold flushed and stored inflated on ice for 18 hours inflated with the same gas mixtures. Next, lungs were perfused for 4 hours on EVLP (acellular) while ventilated with 12% O2 and 88% N2 (CONTR group) or 88% Ar (ARG group). The perfusate was saturated with the same gas mixture but with the addition of CO2 to an end-tidal CO2 of 35-45 mmHg. The saturated perfusate was drained and lungs were perfused with whole blood for an additional 2 hours on EVLP. Evaluation at the end of EVLP did not show significant effects on physiologic parameters by prolonged exposure to Ar. Also wet-to-dry weight ratio did not improve in the ARG group. Although in other organ systems protective effects of Ar have been shown, we did not detect beneficial effects of a high concentration of Ar on cold pulmonary ischemia-reperfusion injury in a porcine lung model after prolonged exposure to Ar in this porcine model with EVLP assessment.

Immunoregulatory effects of multipotent adult progenitor cells in a porcine ex vivo lung perfusion model.

BACKGROUND: Primary graft dysfunction (PGD) is considered to be the end result of an inflammatory response targeting the new lung allograft after transplant. Previous research has indicated that MAPC cell therapy might attenuate this injury by its paracrine effects on the pro-/anti-inflammatory balance. This study aims to investigate the immunoregulatory capacities of MAPC cells in PGD when administered in the airways. METHODS: Lungs of domestic pigs (n = 6/group) were subjected to 90 minutes of warm ischemia. Lungs were cold flushed, cannulated on ice and placed on EVLP for 6 hours. At the start of EVLP, 40 ml of an albumin-plasmalyte mixture was distributed in the airways (CONTR group). In the MAPC cell group, 150 million MAPC cells (ReGenesys/Athersys, Cleveland, OH, USA) were added to this mixture. At the end of EVLP, a physiological evaluation (pulmonary vascular resistance, lung compliance, PaO2/FiO2), wet-to-dry weight ratio (W/D) sampling and a multiplex analysis of bronchoalveolar lavage (BAL) (2 × 30 ml) was performed. RESULTS: Pulmonary vascular resistance, lung compliance, PaO2/FiO2 and W/D were not statistically different at the end of EVLP between both groups. BAL neutrophilia was significantly reduced in the MAPC cell group. Moreover, there was a significant decrease in TNF-α, IL-1ß and IFN-γ in the BAL, but not in IFN-α; whereas IL-4, IL-10 and IL-8 were below the detection limit. CONCLUSIONS: Although no physiologic effect of MAPC cell distribution in the airways was detected during EVLP, we observed a reduction in pro-inflammatory cytokines and neutrophils in BAL in the MAPC cell group. This effect on the innate immune system might play an important role in critically modifying the process of PGD after transplantation. Further experiments will have to elucidate the immunoregulatory effect of MAPC cell administration on graft function after transplantation.