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

Abstract

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

Abordagens Anestésicas Em Cirurgias De Transplante De Órgãos: Novas Técnicas E Resultados Clínicos

“…A complexidade dessas cirurgias exige técnicas avançadas e uma abordagem individualizada para atender às necessidades específicas de cada paciente. Abaixo, foi citado as principais técnicas anestésicas utilizadas nesses procedimentos 7,8,9 .…”

Optimization of liver graft function using poly-pharmacological drug cocktail CEPT in a simulated transplant model

“…In a 45 min Warm Ischemia Time (WIT) donation after brain death (DBD) porcine model of liver transplantation, a combination of drugs was used for flushing and another combination of drugs was used in the recipient, which decreased the primary non-function of the graft, improved liver function and increased survival [9]. In a recent randomized control trial, following static cold storage, donor’s livers were infused ex-situ with epoprostenol via portal vein; recipients received oral α-tocopherol and melatonin before anesthesia and during the anhepatic and reperfusion phase received intravenous drugs-antithrombin III, infliximab, apotransferrin, recombinant erythropoietin-β, C1-inhibitor, and glutathione [7]. In adult living donor liver transplantation clinical trials, intraoperative dexmedetomidine infusion decreased IRI by suppressing intercellular adhesion molecule-1 (ICAM-1) [8].…”

“…Furthermore, anhepatic phases over 100 minutes have a higher incidence of graft dysfunction and worse 1-year patient survival [3], and increased implantation time is associated with poor transplant outcomes due to a rise in the graft temperature [6]. Preclinical animal studies to randomized clinical trials (RCT) have used drugs to precondition the graft before implantation and have treated the recipient to help the graft recover faster upon reperfusion [7][8][9][10]. Using a drug to target the anhepatic phase of graft implantation and treating the recipient with a drug for faster recovery could be a more straightforward and practical approach.…”

Abdominal Organ Transplantation: Noteworthy Literature in 2023

“…The following 3 articles 11,12,48 concerning the prevention of postreperfusion syndrome (PRS), a relatively common and potentially life-threatening complication during LT, were published in 2023.…”

“…Meurisse et al performed an RCT to investigate the effect of a combined drug approach targeting the preimplantation liver graft and recipient on severity of ischemia-reperfusion injury (IRI) during LT. 48 In the combined drug approach group, following static cold preservation, donor livers were infused with epoprostenol at the back table; 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 phase and at reperfusion. Of 72 randomized patients, 36 were allocated to each group [a combined drug approach (CDA) group and a standard of care-only (control) group].…”