Prolonged Preservation of up to 24 Hours at 10 °C Does Not Impact Outcomes after Lung Transplantation.

Objective: To determine the impact of prolonged storage of donor lungs at 10 °C for up to 24 hours on outcome after lung transplantation.

Background: An increasing body of evidence suggests 10 °C as the optimal storage temperature for donor lungs. A recent study showed that cold ischemic times can be safely expanded to >12 hours when lungs are stored at 10 °C.

The combination of postmortem sevoflurane ventilation and in situ topical cooling provides improved 6 hours lung preservation in an uncontrolled DCD porcine model.

Background: Recent clinical series on donation after uncontrolled cardiovascular death (uDCD) reported successful transplantation of lungs preserved by pulmonary inflation up to 3 hours postmortem. This study aims to investigate the additive effects of in situ lowering of intrathoracic temperature and sevoflurane preconditioning on lung grafts in a porcine uDCD model.

Methods: After uDCD induction, donor pigs were allocated to one of the following groups: control-static lung inflation only (SLI); TC - SLI + continuous intrapleural topical cooling (TC); or TC+Sevo - SLI + TC + sevoflurane.

Metabolomic studies reveal an organ-protective hibernation state in donor lungs preserved at 10 °C.

Objective: Previous reports showed enhanced graft function in both healthy and injured porcine lungs after preservation at 10 °C. The objective of the study is to elucidate the mechanism of lung protection by 10 °C and identify potential therapeutic targets to improve organ preservation.

Methods: Metabolomics data were analyzed from healthy and injured porcine lungs that underwent extended hypothermic preservation on ice and at 10 °C.

Lung Transplant Immunomodulation with Genetically Engineered Mesenchymal Stromal Cells-Therapeutic Window for Interleukin-10.

Lung transplantation results are compromised by ischemia-reperfusion injury and alloimmune responses. Ex vivo lung perfusion (EVLP) is used to assess marginal donor lungs before transplantation but is also an excellent platform to apply novel therapeutics. We investigated donor lung immunomodulation using genetically engineered mesenchymal stromal cells with augmented production of human anti-inflammatory hIL-10 (MSCs).

Extension of Cold Static Donor Lung Preservation at 10°C.

BACKGROUND: Lung transplantation is performed on a 24/7 schedule to minimize organ ischemic time. Recent preclinical studies demonstrated superior graft preservation at 10°C compared with storage in an ice cooler (gold standard). METHODS: In this prospective, multicenter, nonrandomized clinical trial, we studied transplants from donors with overnight cross-clamp times (6:00 p.

A machine-learning approach to human ex vivo lung perfusion predicts transplantation outcomes and promotes organ utilization.

Ex vivo lung perfusion (EVLP) is a data-intensive platform used for the assessment of isolated lungs outside the body for transplantation; however, the integration of artificial intelligence to rapidly interpret the large constellation of clinical data generated during ex vivo assessment remains an unmet need. We developed a machine-learning model, termed InsighTx, to predict post-transplant outcomes using n = 725 EVLP cases. InsighTx model AUROC (area under the receiver operating characteristic curve) was 79 ± 3%, 75 ± 4%, and 85 ± 3% in training and independent test datasets, respectively.

Evaluation of 10°C as the optimal storage temperature for aspiration-injured donor lungs in a large animal transplant model.

Background: Our recent work has challenged 4°C as an optimal lung preservation temperature by showing storage at 10°C to allow for the extension of preservation periods. Despite these findings, the impact of 10°C storage has not been evaluated in the setting of injured donor lungs.

Methods: Aspiration injury was created through bronchoscopic delivery of gastric juice (pH: 1.

Metabolomic fingerprinting of porcine lung tissue during pre-clinical prolonged lung perfusion using SPME coupled with LC-HRMS.

Normothermic ex vivo lung perfusion (NEVLP) has emerged as a modernized organ preservation technique that allows for detailed assessment of donor lung function prior to transplantation. The main goal of this study was to identify potential biomarkers of lung function and/or injury during a prolonged (19 h) NEVLP procedure using in vivo solid-phase microextraction (SPME) technology followed by liquid chromatography-high resolution mass spectrometry (LC-HRMS). The use of minimally invasive in vivo SPME fibers for repeated sampling of biological tissue permits the monitoring and evaluation of biochemical changes and alterations in the metabolomic profile of the lung.

Successful 3-day lung preservation using a cyclic normothermic ex vivo lung perfusion strategy.

Background: Cold static preservation (CSP) at higher temperatures (10°C) has been recently shown as an optimal strategy up to 24-36h of preservation. Here, we hypothesized that alternating 10°C static storage with cycles of normothermic ex vivo lung perfusion (EVLP) would provide conditions for cellular "recharge", allowing for multi-day lung preservation.

Methods: Donor lungs from male Yorkshire pigs were preserved using 10°C CSP with two cycles of 4h EVLP.

High Doses of Inhaled Nitric Oxide as an Innovative Antimicrobial Strategy for Lung Infections.

Since the designation of nitric oxide as "Molecule of the Year" in 1992, the scientific and clinical discoveries concerning this biomolecule have been greatly expanding. Currently, therapies enhancing the release of endogenous nitric oxide or the direct delivery of the exogenous compound are recognized as valuable pharmacological treatments in several disorders. In particular, the administration of inhaled nitric oxide is routinely used to treat patients with pulmonary hypertension or refractory hypoxemia.

Centralized Organ Recovery and Reconditioning Centers.

An increased focus on improving efficiency and decreasing costs has resulted in alternative models of donor management and organ recovery. The specialized donor care facility model provides highly efficient and cost-effective donor care at a free-standing facility, resulting in improved organ yield, shorter ischemic times, decreased travel, and fewer nighttime operations. Ex vivo lung perfusion (EVLP) improves utilization of extended criteria donor lungs, and centralized EVLP facilities have the potential to increase transplant volumes for smaller transplant programs in specified geographic regions.

Near-infrared fluorescence imaging during ex vivo lung perfusion: Noninvasive real-time evaluation of regional lung perfusion and edema.

Objective: Ex vivo lung perfusion (EVLP) is an excellent platform to evaluate donor lung function before transplantation, but novel methods are needed to accurately confirm transplant quality. Near-infrared fluorescence (NIRF) imaging with indocyanine green (ICG) has been used in various clinical perioperative applications to evaluate tissue perfusion. We used NIRF imaging during pig and human EVLP to evaluate donor lung perfusion and edema.

Ex vivo enzymatic treatment converts blood type A donor lungs into universal blood type lungs.

Donor organ allocation is dependent on ABO matching, restricting the opportunity for some patients to receive a life-saving transplant. The enzymes FpGalNAc deacetylase and FpGalactosaminidase, used in combination, have been described to effectively convert group A (ABO-A) red blood cells (RBCs) to group O (ABO-O). Here, we study the safety and preclinical efficacy of using these enzymes to remove A antigen (A-Ag) from human donor lungs using ex vivo lung perfusion (EVLP).

Ex vivo treatment of cytomegalovirus in human donor lungs using a novel chemokine-based immunotoxin.

Background: Transmission of latent human cytomegalovirus (HCMV) via organ transplantation with post-transplant viral reactivation is extremely prevalent and results in substantial adverse impact on outcomes. Therapies targeting the latent reservoir within the allograft to mitigate viral transmission would represent a major advance. Here, we delivered an immunotoxin (F49A-FTP) that targets and kills latent HCMV aiming at reducing the HCMV reservoir from donor lungs using ex-vivo lung perfusion (EVLP).

Engineered mesenchymal stromal cell therapy during human lung lung perfusion is compromised by acidic lung microenvironment.

lung perfusion (EVLP) is an excellent platform to apply novel therapeutics, such as gene and cell therapies, before lung transplantation. We investigated the concept of human donor lung engineering during EVLP by combining gene and cell therapies. Premodified cryopreserved mesenchymal stromal cells with augmented anti-inflammatory interleukin-10 production (MSC) were administered during EVLP to human lungs that had various degrees of underlying lung injury.

A novel pre-clinical strategy to deliver antimicrobial doses of inhaled nitric oxide.

Effective treatment of respiratory infections continues to be a major challenge. In high doses (≥160 ppm), inhaled Nitric Oxide (iNO) has been shown to act as a broad-spectrum antimicrobial agent, including its efficacy in vitro for coronavirus family. However, the safety of prolonged in vivo implementation of high-dose iNO therapy has not been studied.

Static lung storage at 10°C maintains mitochondrial health and preserves donor organ function.

Cold static preservation on ice (~4°C) remains the clinical standard of donor organ preservation. However, mitochondrial injury develops during prolonged storage, which limits the extent of time that organs can maintain viability. We explored the feasibility of prolonged donor lung storage at 10°C using a large animal model and investigated mechanisms related to mitochondrial protection.

Surfactant therapy in lung transplantation: A systematic review and meta-analysis.

Background: Despite numerous reports demonstrating the efficacy of exogenous surfactant therapy during lung transplantation, this strategy remains absent in routine clinical use. Here, we systematically review and meta-analyze the effect of exogenous surfactant on respiratory pathophysiological variables during lung transplantation.

Methods: To identify relevant clinical and pre-clinical studies, we performed an electronic search of MEDLINE, EMBASE, and Cochrane CENTRAL from inception to June 11, 2021.

Pushing the Envelope for Donor Lungs.

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.

Prediction of donor related lung injury in clinical lung transplantation using a validated ex vivo lung perfusion inflammation score.

Background: Ex vivo lung perfusion (EVLP) is an isolated organ assessment technique that has revolutionized the field of lung transplantation and enabled a safe increase in the number of organs transplanted. The objective of this study was to develop a protein-based assay that would provide a precision medicine approach to lung injury assessment during EVLP.

Methods: Perfusate samples collected from clinical EVLP cases performed from 2009 to 2019 were separated into development (n = 281) and validation (n = 57) sets to derive and validate an inflammation score based on IL-6 and IL-8 protein levels in perfusate.

Safety of continuous 12-hour delivery of antimicrobial doses of inhaled nitric oxide during ex vivo lung perfusion.

Introduction: High-dose nitric oxide (NO) has been shown effective against a variety of micro-organisms in vitro, including common bacteria found in donor organs. However, clinical obstacles related to its implementation in vivo are the formation of methemoglobin and the accumulation of toxic nitrogen compounds. Ex vivo lung perfusion (EVLP) is a platform that allows for organ maintenance with an acellular perfusion solution, thus overcoming these limitations.

Ex vivo lung perfusion for donor lung assessment and repair: a review of translational interspecies models.

For patients with end-stage lung disease, lung transplantation is a lifesaving therapy. Currently however, the number of patients who require a transplant exceeds the number of donor lungs available. One of the contributing factors to this is the conservative mindset of physicians who are concerned about transplanting marginal lungs due to the potential risk of primary graft dysfunction.