Normothermic Machine Perfusion Is Associated With Improvement in Mortality and Graft Failure in Donation After Cardiac Death Liver Transplant Recipients in the United States
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SUBMITTER: Okumura K
PROVIDER: S-EPMC11230788 | biostudies-literature | 2024 Jul
REPOSITORIES: biostudies-literature
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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.
| S-EPMC11805485 | biostudies-literature
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.
| S-EPMC11833517 | biostudies-literature
Project description: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.
| S-EPMC4117809 | biostudies-literature
Project description:BackgroundA significant proportion of donation after circulatory death (DCD) kidneys are declined for transplantation because of concerns over their quality. Ex vivo normothermic machine perfusion (NMP) provides a unique opportunity to assess the quality of a kidney and determine its suitability for transplantation.MethodsIn phase 1 of this study, declined human DCD kidneys underwent NMP assessment for 60 min. Kidneys were graded 1-5 using a quality assessment score (QAS) based on macroscopic perfusion, renal blood flow and urine output during NMP. In phase 2 of the study, declined DCD kidneys were assessed by NMP with an intention to transplant them.ResultsIn phase 1, 18 of 42 DCD kidneys were declined owing to poor in situ perfusion. After NMP, 28 kidneys had a QAS of 1-3, and were considered suitable for transplantation. In phase 2, ten of 55 declined DCD kidneys underwent assessment by NMP. Eight kidneys had been declined because of poor in situ flushing in the donor and five of these were transplanted successfully. Four of the five kidneys had initial graft function.ConclusionNMP technology can be used to increase the number of DCD kidney transplants by assessing their quality before transplantation.
| S-EPMC5887977 | biostudies-literature
Project description:Kidney transplantation is the optimal treatment for end-stage renal disease, but it is still severely limited by a lack of suitable organ donors. Kidneys from donation after circulatory death (DCD) donors have been used to increase transplant rates, but these organs are susceptible to cold ischemic injury in the storage period before transplantation, the clinical consequence of which is high rates of delayed graft function (DGF). Normothermic machine perfusion (NMP) is an emerging technique that circulates a warmed, oxygenated red-cell-based perfusate through the kidney to maintain near-physiological conditions. We conducted a randomized controlled trial to compare the outcome of DCD kidney transplants after conventional static cold storage (SCS) alone or SCS plus 1-h NMP. A total of 338 kidneys were randomly allocated to SCS (n = 168) or NMP (n = 170), and 277 kidneys were included in the final intention-to-treat analysis. The primary endpoint was DGF, defined as the requirement for dialysis in the first 7 d after transplant. The rate of DGF was 82 of 135 (60.7%) in NMP kidneys versus 83 of 142 (58.5%) in SCS kidneys (adjusted odds ratio (95% confidence interval) 1.13 (0.69-1.84); P = 0.624). NMP was not associated with any increase in transplant thrombosis, infectious complications or any other adverse events. A 1-h period of NMP at the end of SCS did not reduce the rate of DGF in DCD kidneys. NMP was demonstrated to be feasible, safe and suitable for clinical application. Trial registration number: ISRCTN15821205 .
| S-EPMC10287561 | biostudies-literature
Project description:The optimal oxygen concentration is unclear for normothermic machine perfusion (NMP) of livers from donation after circulatory death (DCD). Our purposes were to investigate the effect of air-ventilated NMP on the DCD liver, analyze the underlying mechanism and select the targets to predict liver functional recovery with NMP. NMP was performed using the NMP system with either air ventilation or oxygen ventilation for 2 h in the rat liver following warm ischemia and cold-storage preservation. Proteomics and metabolomics were used to reveal the significant molecular networks. The bioinformation analysis was validated by administering peroxisome proliferator activator receptor-γ (PPARγ) antagonist and agonist via perfusion circuit in the air-ventilated NMP. Results showed that air-ventilated NMP conferred a better functional recovery and a less inflammatory response in the rat DCD liver; integrated proteomics and metabolomics analysis indicated that intrahepatic docosapentaenoic acid downregulation and upregulation of cytochrome P450 2E1 (CYP2E1) expression and activity were associated with DCD liver functional recovery with air-ventilated NMP; PPARγ antagonist worsened liver function under air-oxygenated NMP whereas PPARγ agonist played the opposite role. In conclusion, air-ventilated NMP confers a better liver function from DCD rats through the DAP-PPARγ-CYP2E1 axis; CYP2E1 activity provides a biomarker of liver functional recovery from DCD.
| S-EPMC9076671 | biostudies-literature
Project description:BackgroundDonation after circulatory death (DCD) with cardiopulmonary bypass for thoracoabdominal normothermic regional perfusion (TA-NRP) has led to increased use of donor hearts. Rejection rates and long-term survival outcomes are not known.MethodsA single-center retrospective cohort review of patients who underwent DCD heart transplantation from January 2020 to December 2023 was performed. Donor and recipient characteristics, operative characteristics, and posttransplantation outcomes were analyzed. Subgroup analysis comparing co-localized vs distant donors and recipients was performed. The primary end point was 1-year survival. Secondary end points included incidences of primary graft dysfunction (PGD), cardiac allograft vasculopathy (CAV), rejection rate, and overall mortality. Our TA-NRP protocol has remained the same, consisting of sternotomy, ligation of aortic arch vessels, establishment of cardiopulmonary bypass, reintubation, resuscitation of the heart, and cold static storage during transport.ResultsIn total, 32 recipients underwent DCD heart transplantation, including 26 isolated hearts, 3 heart-lungs, and 3 heart-kidneys. The median age was 56 years for recipients and 39 years for donors; 21 donors and recipients were co-localized, whereas 11 were distant. One-year survival was 100%. Two patients required mechanical circulatory support for PGD. Four patients experienced grade 2R acute cellular rejection. Five patients had grade 1 CAV at 1 year. On subgroup analysis, distant donors and recipients had longer warm (47 vs 30 minutes; P < .005) and cold (213 vs 76 minutes; P < .005) ischemia times, without any other differences.ConclusionsOutcomes after DCD heart transplantation using TA-NRP remain encouraging with acceptable rates of rejection, PGD, CAV, and survival at 1 year.
| S-EPMC11910781 | biostudies-literature
Project description:Normothermic machine perfusion (NMP) is an alternative to hypothermic machine perfusion (HMP) for donor kidney preservation before transplantation. Contrary to HMP, NMP allows for functional assessment of donor kidneys because normothermic conditions allow for metabolic activity. The kidneys are key producers of hormones. Yet, it remains unknown whether donor kidneys during NMP display endocrine functions.MethodsFifteen donor kidneys were subjected to HMP followed by 2 h of NMP before transplantation. NMP perfusate was collected at 3 time points (0, 1, 2 h) for the measurements of prorenin/renin, erythropoietin (EPO), and vitamin D, and urine samples were collected at 1 h and 2 h for urodilatin measurement. Fifteen HMP perfusate samples were collected for the same measurements.ResultsKidneys on NMP secreted significantly more prorenin, renin, EPO, and active vitamin D than during HMP. EPO and vitamin D secretion remained stable during 2 h of NMP, whereas the prorenin release rate increased and renin release rate decreased after 1 h. Donation after brain death kidneys secreted more vitamin D and less EPO during NMP than donation after circulatory death kidneys. Twelve donor kidneys produced urine during NMP and released detectable levels of urodilatin. Kidneys exhibited a large variation in hormone release rates. No significant differences were found in hormone release capacity between delayed graft function (DGF) and non-DGF kidneys, and no significant correlations were found between hormone release rates and the duration of DGF or 1-mo posttransplant serum creatinine levels.ConclusionsHuman transplant kidneys display endocrine activity during NMP. To explore whether correlations exist between hormone release rates and posttransplant kidney function, large numbers of kidneys are required.
| S-EPMC10259641 | biostudies-literature
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.
| S-EPMC6684160 | biostudies-literature
Project description: Not available
| S-EPMC7077939 | biostudies-literature