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The Advent of Semi-Elective Lung Transplantation-Prolonged Static Cold Storage at 10°C.

ABSTRACT: Since the early days of clinical lung transplantation the preservation of donor organs has become a fairly standardized procedure and most centers do follow similar processes. This includes the use of low-potassium high dextran flush solutions and static cold storage (SCS) in a cooler filled with ice. Depending on the length of SCS, organs usually arrive at the recipient hospital at a temperature of 0°C-4°C. The question of the optimal storage temperature for donor lung preservation has been revisited as data from large animal experiments demonstrated that organs stored at 10°C experience less mitochondrial damage. Thus, prolonged cold ischemic times can be better tolerated at 10°C-even in pre-damaged organs. The clinical applicability of these findings was demonstrated in an international multi-center observational study including three high-volume lung transplant centers. Total clinical preservation times of up to 24 hrs have been successfully achieved in organs stored at 10°C without hampering primary organ function and short-term outcomes. Currently, a randomized-controlled trial (RCT) is recruiting patients with the aim to compare standard SCS on ice with prolonged SCS protocol at 10°C. If, as anticipated, this RCT confirms data from previous studies, lung transplantation could indeed become a semi-elective procedure.

SUBMITTER: Hoetzenecker K

PROVIDER: S-EPMC10839059 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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The Advent of Semi-Elective Lung Transplantation-Prolonged Static Cold Storage at 10°C.

Hoetzenecker K K Benazzo A A Schwarz S S Keshavjee S S Cypel M M

Transplant international : official journal of the European Society for Organ Transplantation 20240122

Since the early days of clinical lung transplantation the preservation of donor organs has become a fairly standardized procedure and most centers do follow similar processes. This includes the use of low-potassium high dextran flush solutions and static cold storage (SCS) in a cooler filled with ice. Depending on the length of SCS, organs usually arrive at the recipient hospital at a temperature of 0°C-4°C. The question of the optimal storage temperature for donor lung preservation has been rev ...[more]

PMID: 38317690

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Project description:Background For 50 years, static cold storage (SCS) has been the gold standard for solid organ preservation in transplantation. Although logistically convenient, this preservation method presents important constraints in terms of duration and cold ischemia-induced lesions. We aimed to develop a machine perfusion (MP) protocol for recovery of vascularized composite allografts (VCA) after static cold preservation and determine its effects in a rat limb transplantation model.Methods Partial hindlimbs were procured from Lewis rats and subjected to SCS in Histidine-Tryptophan-Ketoglutarate solution for 0, 12, 18, 24, and 48 hours. They were then either transplanted (Txp), subjected to subnormothermic machine perfusion (SNMP) for 3 hours with a modified Steen solution, or to SNMP + Txp. Perfusion parameters were assessed for blood gas and electrolytes measurement, and flow rate and arterial pressures were monitored continuously. Histology was assessed at the end of perfusion. For select SCS durations, graft survival and clinical outcomes after transplantation were compared between groups at 21 days.Results Transplantation of limbs preserved for 0, 12, 18, and 24-hour SCS resulted in similar survival rates at postoperative day 21. Grafts cold-stored for 48 hours presented delayed graft failure (p = 0.0032). SNMP of limbs after 12-hour SCS recovered the vascular resistance, potassium, and lactate levels to values similar to limbs that were not subjected to SCS. However, 18-hour SCS grafts developed significant edema during SNMP recovery. Transplantation of grafts that had undergone a mixed preservation method (12-hour SCS + SNMP + Txp) resulted in better clinical outcomes based on skin clinical scores at day 21 post-transplantation when compared to the SCS + Txp group (p = 0.01613).Conclusion To date, VCA MP is still limited to animal models and no protocols are yet developed for graft recovery. Our study suggests that ex vivo SNMP could help increase the preservation duration and limit cold ischemia-induced injury in VCA transplantation.

Project description:BACKGROUND:Extended criteria donors (ECD) are widely utilized due to organ shortage, but they may increase the risk of graft dysfunction and poorer outcomes. Hypothermic oxygenated perfusion (HOPE) is a recent organ preservation strategy for marginal kidney and liver grafts, allowing a redirect from anaerobic metabolism to aerobic metabolism under hypothermic conditions and protecting grafts from oxidative species-related damage. These mechanisms may improve graft function and survival. OBJECTIVE:With this study, we will evaluate the benefit of end-ischemic HOPE on ECD grafts for livers and kidneys as compared to static cold storage (SCS). The aim of the study is to demonstrate the ability of HOPE to improve graft function and postoperative outcomes of ECD kidney and liver recipients. METHODS:This is an open-label, single-center randomized clinical trial with the aim of comparing HOPE with SCS in ECD kidney and liver transplantation. In the study protocol, which has been approved by the ethics committee, 220 patients (110 liver recipients and 110 kidney recipients) will be enrolled. Livers and kidneys assigned to the HOPE group undergo machine perfusion with cold Belzer solution (4-10°C) and continuous oxygenation (partial pressure of oxygen of 500-600 mm Hg). In the control group, livers and kidneys undergoing SCS are steeped in Celsior solution and stored on ice. Using the same perfusion machine for both liver and kidney grafts, organs are perfused from the start of the back-table procedure until implantation, without increasing the cold ischemia time. For each group, we will evaluate clinical outcomes, graft function tests, histologic findings, perfusate, and the number of allocated organs. Publication of the results is expected to begin in 2021. RESULTS:Dynamic preservation methods for organs from high-risk donors should improve graft dysfunction after transplantation. To date, we have recruited 108 participants. The study is ongoing, and recruitment of participants will continue until January 2020. CONCLUSIONS:The proposed preservation method should improve ECD graft function and consequently the postoperative patient outcomes. TRIAL REGISTRATION:ClinicalTrials.gov NCT03837197; https://clinicaltrials.gov/ct2/show/NCT03837197 ; Archived by WebCite® at http://www.webcitation.org/76fSutT3R. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID):DERR1-10.2196/13922.

Project description:IntroductionThe shortage of available donor hearts and the risk of ischemia/reperfusion injury restrict heart transplantation (HTX). Alpha-1-antitrypsin (AAT), a well-characterized inhibitor of neutrophil serine protease, is used in augmentation therapy to treat emphysema due to severe AAT deficiency. Evidence demonstrates its additional anti-inflammatory and tissue-protective effects. We hypothesized that adding human AAT in a preservation solution reduces graft dysfunction in a rat model of HTX following extended cold ischemic storage.MethodsThe hearts from isogenic Lewis donor rats were explanted, stored for either 1h or 5h in cold Custodiol supplemented with either vehicle (1h ischemia, n=7 or 5h ischemia, n=7 groups) or 1 mg/ml AAT (1h ischemia+AAT, n=7 or 5h ischemia+AAT, n=9 groups) before heterotopic HTX. Left-ventricular (LV) graft function was evaluated in vivo 1.5h after HTX. Immunohistochemical detection of myeloperoxydase (MPO) was performed in myocardial tissue and expression of 88 gene quantified with PCR was analyzed both statistical and with machine-learning methods.ResultsAfter HTX, LV systolic function (dP/dtmax 1h ischemia+AAT 4197 ± 256 vs 1h ischemia 3123 ± 110; 5h ischemia+AAT 2858 ± 154 vs 5h ischemia 1843 ± 104mmHg/s, p<0.05) and diastolic function (dP/dtmin 5h ischemia+AAT 1516 ± 68 vs 5h ischemia 1095 ± 67mmHg/s, p<0.05) at an intraventricular volume of 90µl were improved in the AAT groups compared with the corresponding vehicle groups. In addition, the rate pressure product (1h ischemia+AAT 53 ± 4 vs 1h ischemia 26 ± 1; 5h ischemia+AAT 37 ± 3 vs 5h ischemia 21 ± 1mmHg*beats/min at an intraventricular volume of 90µl; p<0.05) was increased in the AAT groups compared with the corresponding vehicle groups. Moreover, the 5h ischemia+AAT hearts exhibited a significant reduction in MPO-positive cell infiltration in comparison to the 5h ischemia group. Our computational analysis shows that ischemia+AAT network displays higher homogeneity, more positive and fewer negative gene correlations than the ischemia+placebo network.DiscussionWe provided experimental evidence that AAT protects cardiac grafts from prolonged cold ischemia during HTX in rats.

Project description:Primary graft dysfunction (PGD) is a major cause of morbidity and mortality after lung transplantation. Ischemia-reperfusion injury (IRI) is a key event that contributes to PGD, though complex interactions affect donor lungs status, such as preceding brain death (BD), hemorrhagic shock (HS), and pre-engraftment lung management, the latter recognized as important risk factors for PGD. We hypothesized that a multi-hit isogenic mouse model of lung transplantation is more closely linked to PGD than IRI alone. Left lung transplants were performed between inbred C57BL/6 mice. A one-hit model of IRI was established by inducing cold ischemia (CI) of the donor lungs at 0°C for 1, 72, or 96 hours before engraftment. Multi-hit models were established by inducing 24 hours of HS and/or 3 hours of BD before 24 hours of CI. The recipients were killed at 24 hours after transplant and lung graft samples were analyzed. In the one-hit model of IRI, up to 72-hour CI time resulted in minimal cellular infiltration near small arteries after 24-hour reperfusion. Extension of CI time to 96 hours led to increased cellular infiltration and necroptotic pathway activation, without evidence of apoptosis, after 24-hour reperfusion. In a multi-hit model of PGD, "HS + BD + IRI" demonstrated increased lung injury, cellular infiltration, and activation of necroptotic and apoptotic pathways compared with IRI alone. Treatment with an inhibitor of receptor-interacting protein kinase 1 kinase, necrostatin-1, resulted in a significant decrease of downstream necroptotic pathway activation in both single- and multi-hit models of IRI. Thus, activation of necroptosis is a central event in IRI after prolonged CI, though it may not be sufficient to cause PGD alone. Pathological evaluation of donor lungs after CI-induced IRI, in conjunction with pre-engraftment donor lung factors in our multi-hit model, demonstrated early evidence of lung injury consistent with PGD. Our findings support the premise that pre-existing donor lung status is more important than CI time alone for inflammatory pathway activation in PGD, which may have important clinical implications for donor lung retrieval.

Project description:Background: Machine perfusion (MP) and static cold storage (CS) are two prevalent methods for liver allograft preservation. However, the preferred method remains controversial. Aim: To conduct a meta-analysis on the impact of MP preservation on liver transplant outcome. Methods: PubMed, EMBASE, and Cochrane Library databases were systematically searched to identify relevant trials comparing the efficacy of MP vs. CS. Odds ratios (OR) and fixed-effects models were calculated to compare the pooled data. Results: Ten prospective cohort studies and two randomized controlled trials (RCTs) were included (MP livers vs. CS livers = 315:489). Machine perfusion demonstrated superior outcomes in posttransplantation aspartate aminotransferase levels compared to CS (P < 0.05). The overall incidence of early allograft dysfunction (EAD) was significantly reduced with MP preservation than CS [OR = 0.46; 95% confidence interval (CI) = 0.31-0.67; P < 0.0001]. The incidence of total biliary complications (OR = 0.53; 95% CI = 0.34-0.83; P = 0.006) and that of ischemic cholangiopathy (OR = 0.39; 95% CI = 0.18-0.85; P = 0.02) were significantly lower in recipients with MP preservation compared with CS preservation. Hypothermic machine perfusion (HMP) but not normothermic machine perfusion (NMP) was found to significantly protect grafts from total biliary complications and ischemic cholangiopathy (P < 0.05). However, no significant differences could be detected utilizing either HMP or NMP in primary nonfunction, hepatic artery thrombosis, postreperfusion syndrome, 1-year patient survival, or 1-year graft survival (P > 0.05). Conclusions: Machine perfusion is superior to CS on improving short-term outcomes for human liver transplantation, with a less clear effect in the longer term. Hypothermic machine perfusion but not NMP conducted significantly protective effects on EAD and biliary complications. Further RCTs are warranted to confirm MP's superiority and applications.

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The Advent of Semi-Elective Lung Transplantation-Prolonged Static Cold Storage at 10°C.

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The Advent of Semi-Elective Lung Transplantation-Prolonged Static Cold Storage at 10°C.

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