Preconditioning of Donor Livers With Prostaglandin I2 Before Retrieval Decreases Hepatocellular Ischemia-Reperfusion Injury

Klein, M.; Geoghegan, Justin; Wangemann, R; Böckler, D.; Schmidt, K.; Scheele, J.

doi:10.1097/00007890-199904270-00007

Cited by 56 publications

(29 citation statements)

References 12 publications

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“…The significantly lower release of transaminases after preconditioning liver grafts with prostaglandins has been described earlier in clinical 5 and experimental studies. 5,7 Furthermore, prostaglandin treatment administered after transplant showed lower levels of aspartate aminotransferase and ALAT in a clinical setting.…”

Section: Discussionsupporting

confidence: 61%

“…5,7 Furthermore, prostaglandin treatment administered after transplant showed lower levels of aspartate aminotransferase and ALAT in a clinical setting. 28 With our IECR model, we could reproduce this finding, and all tested iloprost treatment regimens significantly reduced ischemiareperfusion injury.…”

Section: Discussionmentioning

confidence: 98%

“…The use of prostaglandins is accepted widely after clinical and experimental liver transplant. [1][2][3] However, prostaglandin use as liver donor treatment, although beneficial clinically 5 and experimentally, 6,7 is uncommon, and the recommended dosage and type of application are unknown.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4] However, although beneficial clinically and experimentally, its use in donor pretreatment is uncommon and the exact recommendations about type of application are pending. [5][6][7] The purpose of this study was to compare 4 different iloprost treatment regimens to a control group and to determine their effect on liver injury and function after extended cold ischemia time (CIT) (20 h) in an isolated 8-hour extracorporeal pig liver perfusion model. The following parameters were assessed:…”

Section: Introductionmentioning

confidence: 99%

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2015

Exp Clin Transplant

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Objectives: Iloprost has the potential to protect the liver transplant graft before and during cold ischemia. We studied iloprost administration during organ procurement and reperfusion in an extracorporeal pig liver perfusion model. Materials and Methods: German Landrace pigs (n = 7/group; 22-26 kg each) were used as donors. Preservation was performed by aortic perfusion with 2L Bretschneiders' Histidine-Tryptophan-Ketoglutarate solution HTK and cold ischemia time (4°C) 20 hours followed by normothermic extracorporeal perfusion for 8 hours. Untreated controls (1) were compared to iloprost (2) donor bolus-treatment (1 μg/kg body weight), (3) addition of iloprost to Bretschneiders´ Histidine-Tryptophan-Ketoglutarate solution HTK (0.0125 μg/mL), (4) continuous infusion during reperfusion (2 ng/kg/min), and (5) combined treatment (2) and (4). Results: Iloprost donor treatment led to significantly higher bile production. Addition of iloprost to the preservation solution significantly improved hepatic artery perfusion and was accompanied by improvements of microcirculation and bile production. Iloprost reperfusion treatment alone significantly improved bile production. Enzyme levels were positively affected by all treatment regimens.Combined use of iloprost before and after ischemia improved hepatic artery flow and microcirculation and showed significantly lower hypoxia staining versus controls. Conclusions: Iloprost donor treatment and use of iloprost in the preservation solution significantly improved graft perfusion and function. The effects of graft treatment seemed greater before than after reperfusion. Combined treatment did not reveal a synergistic advantage. Key words: End-stage liver disease, Graft, Prostaglandin, Transplant IntroductionThe use of iloprost clinically and experimentally is widely accepted after liver transplant. 1-4 However, although beneficial clinically and experimentally, its use in donor pretreatment is uncommon and the exact recommendations about type of application are pending. [5][6][7] The purpose of this study was to compare 4 different iloprost treatment regimens to a control group and to determine their effect on liver injury and function after extended cold ischemia time (CIT) (20 h) in an isolated 8-hour extracorporeal pig liver perfusion model. The following parameters were assessed:• Liver perfusion (macro-and microcirculation). Materials and Methods Animals and anesthesiaGerman Landrace pigs aged 10 to 16 weeks with a mean body weight (BW) 23.7 ± 1.56 kg (range, 22-26 kg) were used as organ donors. Animals were purchased (Fa. Sommerfeld, Brandenburg, Germany) and housed in our animal facility located at Charité Campus Virchow Klinikum, Berlin, Germany, approximately 1 week before each experiment. Animals were examined after delivery and kept species-appropriate with free access to water. Twice daily they were fed with standard pig nutrition pellets (Mpig-H, Sniff Spezialitäten GmbH, Soest, Germany) and housed at a day and night cycle of 12 hours and mean temperature ...

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Untitled

2015

Exp Clin Transplant

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“…Thromboxane A 2 induces vasoconstriction and platelet aggregation, whereas prostaglandin I 2 induces vasodilation and inhibition of platelet aggregation. Numerous reports showed beneficial effects of prostaglandin I 2 in protecting from hepatic damage under pathological conditions [117][118][119]. In contrast, thromboxane A 2 was shown to aggravate hepatic damage in ischemia/reperfusion [120,121], trauma-hemorrhage [122], endotoxemia [123], and hepatic cirrhosis induced by CCl 4 [124] or bile duct ligation [125].…”

Section: Effects Of Estrogen On Hepatic Vascular Reactivitymentioning

confidence: 99%

Current Understanding of Gender Dimorphism in Hepatic Pathophysiology1

Yokoyama

Nimura

Nagino

et al. 2005

Journal of Surgical Research

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Effect of a Combined Drug Approach on the Severity of Ischemia-Reperfusion Injury During Liver Transplant

et al. 2023

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ImportanceIn a porcine model of liver transplant, a combined drug approach that targeted the donor graft and graft recipient reduced ischemia-reperfusion injury, a major hurdle to the success of liver transplant.ObjectiveTo assess the effect of a clinical form of a perioperative combined drug approach delivered immediately before implantation to the procured liver and to the liver recipient on the degree of ischemia-reperfusion injury.Design, Setting, and ParticipantsThis unicentric, investigator-driven, open-label randomized clinical trial with 2 parallel arms was conducted in Belgium from September 2013 through February 2018, with 1-year follow-up. Adults wait-listed for a first solitary full-size liver transplant were screened for eligibility. Exclusion criteria were acute liver failure, kidney failure, contraindication to treatment, participation in another trial, refusal, technical issues, and death while awaiting transplant. Included patients were enrolled and randomized at the time of liver offer. Data were analyzed from May 20, 2019, to May 27, 2020.InterventionsParticipants were randomized to a combined drug approach with standard of care (static cold storage) or standard of care only (control group). In the combined drug approach group, following static cold preservation, donor livers were infused with epoprostenol (ex situ, portal vein); recipients were given oral α-tocopherol and melatonin prior to anesthesia and intravenous antithrombin III, infliximab, apotransferrin, recombinant erythropoietin-β, C1-inhibitor, and glutathione during the anhepatic and reperfusion phase.Main Outcomes and MeasuresThe primary outcome was the posttransplant peak serum aspartate aminotransferase (AST) level within the first 72 hours. Secondary end points were the frequencies of postreperfusion syndrome, ischemia-reperfusion injury score, early allograft dysfunction, surgical complications, ischemic cholangiopathy, acute kidney injury, acute cellular rejection, and graft and patient survival.ResultsOf 93 randomized patients, 21 were excluded, resulting in 72 patients (36 per study arm) in the per protocol analysis (median recipient age, 60 years [IQR, 51.7-66.2 years]; 52 [72.2%] men). Peak AST serum levels were not different in the combined drug approach and control groups (geometric mean, 1262.9 U/L [95% CI, 946.3-1685.4 U/L] vs 1451.2 U/L [95% CI, 1087.4-1936.7 U/L]; geometric mean ratio, 0.87 [95% CI, 0.58-1.31]; P = .49) (to convert AST to μkat/L, multiply by 0.0167). There also were no significant differences in the secondary end points between the groups.Conclusions and RelevanceIn this randomized clinical trial, the combined drug approach targeting the post–cold storage graft and the recipient did not decrease ischemic-reperfusion injury. The findings suggest that in addition to a downstream strategy that targets the preimplantation liver graft and the graft recipient, a clinically effective combined drug approach may need to include an upstream strategy that targets the donor graft during preservation. Dynamic preservation strategies may provide an appropriate delivery platform.Trial RegistrationClinicalTrials.gov Identifier: NCT02251041

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Preconditioning of Donor Livers With Prostaglandin I2 Before Retrieval Decreases Hepatocellular Ischemia-Reperfusion Injury

Abstract: Reduction of ischemia-reperfusion injury by administration of epoprostenol before graft retrieval may have important applications in liver transplantation. Further studies are required to establish the mechanism of this effect and to define its precise role in clinical practice.

Cited by 56 publications

References 12 publications

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Current Understanding of Gender Dimorphism in Hepatic Pathophysiology1

Effect of a Combined Drug Approach on the Severity of Ischemia-Reperfusion Injury During Liver Transplant

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