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Sanguineous normothermic machine perfusion improves hemodynamics and biliary epithelial regeneration in donation after cardiac death porcine livers.

ABSTRACT: The effects of normothermic machine perfusion (NMP) on the postreperfusion hemodynamics and extrahepatic biliary duct histology of donation after cardiac death (DCD) livers after transplantation have not been addressed thoroughly and represent the objective of this study. Ten livers (5 per group) with 60 minutes of warm ischemia were preserved via cold storage (CS) or sanguineous NMP for 10 hours, and then they were reperfused for 24 hours with whole blood in an isolated perfusion system to simulate transplantation. In our experiment, the arterial and portal vein flows were stable in the NMP group during the entire reperfusion simulation, whereas they decreased dramatically in the CS group after 16 hours of reperfusion (P < 0.05); these findings were consistent with severe parenchymal injury. Similarly, significant differences existed between the CS and NMP groups with respect to the release of hepatocellular enzymes, the volume of bile produced, and the levels of enzymes released into bile (P < 0.05). According to histology, CS livers presented with diffuse hepatocyte congestion, necrosis, intraparenchymal hemorrhaging, denudated biliary epithelium, and submucosal bile duct necrosis, whereas NMP livers showed very mild injury to the liver parenchyma and biliary architecture. Most importantly, Ki-67 staining in extrahepatic bile ducts showed biliary epithelial regeneration. In conclusion, our findings advance the knowledge of the postreperfusion events that characterize DCD livers and suggest NMP as a beneficial preservation modality that is able to improve biliary regeneration after a major ischemic event and may prevent the development of ischemic cholangiopathy in the setting of clinical transplantation.

SUBMITTER: Liu Q

PROVIDER: S-EPMC4117809 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Sanguineous normothermic machine perfusion improves hemodynamics and biliary epithelial regeneration in donation after cardiac death porcine livers.

Liu Qiang Q Nassar Ahmed A Farias Kevin K Buccini Laura L Baldwin William W Mangino Martin M Bennett Ana A O'Rourke Colin C Okamoto Toshiro T Uso Teresa Diago TD Fung John J Abu-Elmagd Kareem K Miller Charles C Quintini Cristiano C

Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 20140702 8

The effects of normothermic machine perfusion (NMP) on the postreperfusion hemodynamics and extrahepatic biliary duct histology of donation after cardiac death (DCD) livers after transplantation have not been addressed thoroughly and represent the objective of this study. Ten livers (5 per group) with 60 minutes of warm ischemia were preserved via cold storage (CS) or sanguineous NMP for 10 hours, and then they were reperfused for 24 hours with whole blood in an isolated perfusion system to simu ...[more]

PMID: 24805852

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Project description:ImportanceDonation after circulatory death (DCD) heart procurement has increased, but concerns remain about the effect of simultaneous heart and lung procurement, particularly with thoracoabdominal normothermic regional perfusion (TA-NRP), on the use of DCD lungs. Previous analyses exclude critical donor factors and organ nonuse, and rapidly rising DCD use may bias comparisons to historical controls.ObjectiveTo use validated risk-adjusted models to assess whether DCD heart procurement via TA-NRP and direct procurement is associated with lung use.Design, setting, and participantsThis retrospective cohort study involved adult DCD donors between January 1, 2019, and September 30, 2024, listed in the Scientific Registry of Transplant Recipients (SRTR). The SRTR deceased donor yield model was used to develop an observed to expected (O:E) yield ratio of lung use obtained through DCD among 4 cohorts: cardiac DCD donors vs noncardiac DCD donors and cardiac DCD donors undergoing TA-NRP vs direct procurement. Temporal trends in O:E ratios were analyzed with the Cochran-Armitage test.Main outcomes and measuresThe O:E ratios of DCD lung use.ResultsAmong 24 431 DCD donors (15 878 [65.0%] male; median [IQR] age, 49.0 [37.0-58.0] years), 22 607 were noncardiac DCD (14 375 [63.6%] male; median [IQR] age, 51.0 [39.0-58.0] years) and 1824 were cardiac DCD (1503 [82.4%] male; median [IQR] age, 32.0 [26.0-38.0] years) donors; noncardiac DCD donors were more likely to be smokers (6873 [30.4%] vs 227 [12.4%]; P < .001). Among cardiac DCD donors, 325 underwent TA-NRP, while 712 underwent direct procurement. TA-NRP donors had shorter median (IQR) lung ischemic times (6.07 [4.38-9.56] hours vs 8.12 [6.16-12.00] hours; P < .001) and distances to recipient hospitals (222 [9-626] nautical miles vs 331 [159-521] nautical miles; P = .050) than direct procurement donors. Lung use was higher among cardiac DCD donations compared with noncardiac DCD donations (16.7% vs 4.4%, P < .001). Within the cardiac DCD cohort, lung use was similar between TA-NRP and direct procurement (19.1% vs 18.7%; P = .88) cohorts. Both noncardiac DCD and cardiac DCD donors had observed lung yields greater than expected (O:E, 1.29 [95% CI, 1.21-1.35] and 1.79 [95% CI, 1.62-1.96]; both P < .001), although cardiac DCD yield was significantly higher than noncardiac DCD yield (P < .001). Both TA-NRP and direct procurement lung yields were greater than expected (O:E, 2.00 [95% CI, 1.60-2.43] and 1.77 [95% CI, 1.52-1.99]; both P < .001) but were not significantly different from each other (P = .83). The O:E ratios did not change significantly over time across all cohorts. Among recipients, the TA-NRP cohort experienced significantly better 90-day mortality (0 of 62 vs 9 of 128 patients [7.0%]; P = .03) and overall survival (4 of 62 patients [6.5%] vs 21 of 128 patients [16.4%]; P = .04) rates compared with the direct procurement cohort.Conclusions and relevanceIn this cohort study of DCD donors, concomitant heart procurement provided better-than-expected rates of lung use as assessed with validated O:E use ratios regardless of procurement technique. The findings also suggest a survival benefit with improved 90-day and overall survival rates for the TA-NRP cohort compared with the direct procurement cohort. Policies should be developed to maximize the benefits of these donations.

Project description:BackgroundNormothermic machine perfusion (NMP) of liver grafts donated after circulatory death (DCD) has shown promise in large animal and clinical trials. Following procurement, initial flush with a cold preservation solution is the standard of care. There is concern that initial cooling followed by warming may exacerbate liver injury, and the optimal initial flush temperature has yet to be identified. We hypothesize that avoidance of the initial cold flush will yield better quality liver grafts.MethodsTwenty-four anaesthetized pigs were withdrawn from mechanical ventilation and allowed to arrest. After 60-minutes of warm ischemia to simulate a DCD procurement, livers were flushed with histidine-tryptophan-ketoglutarate (HTK) at 4°C, 25°C or 35°C (n = 4 per group). For comparison, an adenosine-lidocaine crystalloid solution (AD), shown to have benefit at warm temperatures in heart perfusions, was also used (n = 4 per group). During 12-hours of NMP, adenosine triphosphate (ATP), lactate, transaminase levels, and histological injury were determined. Bile production and hemodynamics were monitored continuously.ResultsATP levels recovered substantially following 1-hour of NMP reaching pre-ischemic levels by the end of NMP with no difference between groups. There was no difference in peak aspartate aminotransferase (AST) or in lactate dehydrogenase (LDH). Portal vein resistance was lowest in the 4°C group reaching significance after 2 hours (0.13 CI -0.01,0.277, p = 0.025). Lactate levels recovered promptly with no difference between groups. Comparison to AD groups showed no statistical difference in the abovementioned parameters. On electron microscopy the HTK4°C group had the least edema with mean cell thickness of 2.92μm (p = 0.41) while also having the least sinusoidal dilatation with a mean diameter of 5.36μm (p = 0.04). For AD, the 25°C group had the lowest mean cell thickness at 3.14μm (p = 0.09).ConclusionsAvoidance of the initial cold flush failed to demonstrate added benefit over standard 4°C HTK in this DCD model of liver perfusion.

Project description:BackgroundDuring orthotopic liver transplantation, allograft reperfusion is a dynamic point in the operation and often requires vasoactive medications and blood transfusions. Normothermic machine perfusion (NMP) of liver allografts has emerged to increase the number of transplantable organs and may have utility during donation after circulatory death (DCD) liver transplantation in reducing transfusion burden and vasoactive medication requirements.MethodsThis is a single-center retrospective study involving 226 DCD liver transplant recipients who received an allograft transported with NMP (DCD-NMP group) or with static cold storage (DCD-SCS group). Veno-venous bypass was not used in any patients. Infusion doses of norepinephrine, epinephrine, and vasopressin as well as bolus doses of vasoactive medications during reperfusion were recorded. Blood component therapy was recorded according to phase of liver transplantation and during the first 24 hours postprocedure.ResultsA total of 103 recipients in the DCD-NMP group and 123 patients in the DCD-SCS group were included. Post-reperfusion syndrome (PRS) incidence was reduced in the DCD-NMP group compared to the DCD-SCS group (10.7% [95% confidence interval, CI, 5.5%-18.3%] vs 42.3% [95% CI, 33.4%-51.5%]; P < .001). During the reperfusion period, patients in the DCD-SCS group required increased bolus doses of epinephrine and vasopressin compared to the DCD-NMP group (24.6 vs 7.5 µg; P < .001) and (5.4 vs 2.4 units; P < .001), respectively. The DCD-SCS group received a higher infusion dose of epinephrine during anhepatic phase, at reperfusion, and up to 90 minutes after reperfusion. In the postreperfusion period, there were significant increases in the transfusion of red blood cells (RBCs; 5.3 vs 3.7 units; P = .006), fresh frozen plasma (FFP; 3.4 vs 1.9 units; P < .001), cryoprecipitate (2.7 vs 1.8 pooled units; P = .015) and platelets (0.9 vs 0.4 units; P = .008) in the DCD-SCS group compared to the DCD-NMP group. During the first 24 hours postprocedure, transfusion of RBCs, FFP, and cryoprecipitate in the DCD-SCS group was increased compared to the DCD-NMP group ([2.6 vs 1.7 units; P = .028], [1.6 vs 0.8 units; P < .001], [1.5 vs 0.9 pooled units; P = .031]) respectively. Administration of tranexamic acid was more frequent in the DCD-SCS group during the post-reperfusion period compared to the DCD-NMP group (13% [95% CI, 5.7%-17.4%] vs 3.9% [95% CI, 1.1%-9.6% 95%]; P = .018).ConclusionsIn DCD liver transplantation, use of NMP was associated with reduced incidence of PRS and decreased vasopressor and inotrope requirements at the time of allograft reperfusion compared to using SCS. Additionally, NMP was associated with reduced transfusion of all blood product components as well as antifibrinolytic agent administration in the post-reperfusion period. Reduced transfusion burden in the DCD-NMP group also occurred during the first 24 hours posttransplant.

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Sanguineous normothermic machine perfusion improves hemodynamics and biliary epithelial regeneration in donation after cardiac death porcine livers.

Publications

Sanguineous normothermic machine perfusion improves hemodynamics and biliary epithelial regeneration in donation after cardiac death porcine livers.

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