OBJECTIVE: The aim of this study was to evaluate peak serum alanine aminotransferase (ALT) and postoperative clinical outcomes after hypothermic oxygenated machine perfusion (HOPE) versus static cold storage (SCS) in extended criteria donation (ECD) liver transplantation (LT) from donation after brain death (DBD). BACKGROUND: HOPE might improve outcomes in LT, particularly in high-risk settings such as ECD organs after DBD, but this hypothesis has not yet been tested in a randomized controlled clinical trial (RCT). METHODS: Between September 2017 and September 2020, 46 patients undergoing ECD-DBD LT from four centers were randomly assigned to HOPE (n = 23) or SCS (n = 23). Peak-ALT levels within 7 days following LT constituted the primary endpoint. Secondary endpoints included incidence of postoperative complications [Clavien-Dindo classification (CD), Comprehensive Complication Index (CCI)], length of intensive care- (ICU) and hospital-stay, and incidence of early allograft dysfunction (EAD). RESULTS: Demographics were equally distributed between both groups [donor age: 72 (IQR: 59-78) years, recipient age: 62 (IQR: 55-65) years, labMELD: 15 (IQR: 9-25), 38 male and 8 female recipients]. HOPE resulted in a 47% decrease in serum peak ALT [418 (IQR: 221-828) vs 796 (IQR: 477-1195) IU/L, P = 0.030], a significant reduction in 90-day complications [44% vs 74% CD grade ≥3, P = 0.036; 32 (IQR: 12-56) vs 52 (IQR: 35-98) CCI, P = 0.021], and shorter ICU- and hospital-stays [5 (IQR: 4-8) vs 8 (IQR: 5-18) days, P = 0.045; 20 (IQR: 16-27) vs 36 (IQR: 23-62) days, P = 0.002] compared to SCS. A trend toward reduced EAD was observed for HOPE (17% vs 35%; P = 0.314). CONCLUSION: This multicenter RCT demonstrates that HOPE, in comparison to SCS, significantly reduces early allograft injury and improves post-transplant outcomes in ECD-DBD liver transplantation.

Department for General Visceral and Transplant Surgery Hannover Medical School Hannover Germany

Department of Anesthesiology McGovern Medical School University of Texas Health Science Center at Houston Houston TX

Department of General Surgery and Liver transplantation Fundeni Clinical Institute Bucharest Romania

Department of General Visceral and Transplant Surgery Ludwig Maximilians University Munich Munich Germany

Department of General Visceral and Transplantation Surgery University of Heidelberg Germany

Department of Hepatology and Gastroenterology Campus Charité Mitte | Campus Virchow Klinikum Charité Universitätsmedizin Berlin Germany

Department of Hepatology Maastricht University Medical Center Maastricht The Netherlands

Department of HPB Surgery and Liver Transplantation Royal Free Hospital London UK

Department of Internal Medicine 3 University Hospital RWTH Aachen Aachen Germany

Department of Surgery and Transplantation University Hospital RWTH Aachen Aachen Germany

Department of Surgery Campus Charité Mitte | Campus Virchow Klinikum Charité Universitätsmedizin Berlin Germany

Department of Transplantation Surgery Institute for Clinical and Experimental Medicine Prague Czech Republic

Institute for Biometry and Clinical Epidemiology Charité Universitätsmedizin Berlin Campus Charité Mitte Berlin Germany

Institute for Laboratory Animal Science and Experimental Surgery University Hospital RWTH Aachen Aachen Germany

University College London London UK

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Czigany Z, Lurje I, Tolba RH, et al. Machine perfusion for liver transplantation in the era of marginal organs—new kids on the block. Liver Int 2019; 39:228–249.

Nasralla D, Coussios CC, Mergental H, et al. A randomized trial of normothermic preservation in liver transplantation. Nature 2018; 557:50–56.

van Leeuwen OB, de Vries Y, Fujiyoshi M, et al. Transplantation of high-risk donor livers after ex situ resuscitation and assessment using combined hypo- and normothermic machine perfusion: a prospective clinical trial. Ann Surg 2019; 270:906–914.

Schlegel A, de Rougemont O, Graf R, et al. Protective mechanisms of end-ischemic cold machine perfusion in DCD liver grafts. J Hepatol 2013; 58:278–286.

Patrono D, Surra A, Catalano G, et al. Hypothermic oxygenated machine perfusion of liver grafts from brain-dead donors. Sci Rep 2019; 9:9337.

Schlegel A, Muller X, Kalisvaart M, et al. Outcomes of DCD liver transplantation using organs treated by hypothermic oxygenated perfusion before implantation. J Hepatol 2019; 70:50–57.

Burlage LC, Hessels L, van Rijn R, et al. Opposite acute potassium and sodium shifts during transplantation of hypothermic machine perfused donor livers. Am J Transplant 2019; 19:1061–1071.

de Vries Y, Berendsen TA, Fujiyoshi M, et al. Transplantation of high-risk donor livers after resuscitation and viability assessment using a combined protocol of oxygenated hypothermic, rewarming and normothermic machine perfusion: study protocol for a prospective, single-arm study (DHOPE-COR-NMP trial). BMJ Open 2019; 9:e028596.

Rhodes KE, Zhang W, Yang D, et al. ABCB1, SLCO1B1 and UGT1A1 gene polymorphisms are associated with toxicity in metastatic colorectal cancer patients treated with first-line irinotecan. Drug Metab Lett 2007; 1:23–30.

Boutron I, Moher D, Altman DG, et al. Extending the CONSORT statement to randomized trials of nonpharmacologic treatment: explanation and elaboration. Ann Intern Med 2008; 148:295–309.

Czigany Z, Schoning W, Ulmer TF, et al. Hypothermic oxygenated machine perfusion (HOPE) for orthotopic liver transplantation of human liver allografts from extended criteria donors (ECD) in donation after brain death (DBD): a prospective multicentre randomised controlled trial (HOPE ECD-DBD). BMJ Open 2017; 7:e017558.

Dutkowski P, Polak WG, Muiesan P, et al. First comparison of hypothermic oxygenated perfusion versus static cold storage of human donation after cardiac death liver transplants: an international-matched case analysis. Ann Surg 2015; 262:764–770. discussion 770-1.

Op den Dries S, Sutton ME, Karimian N, et al. Hypothermic oxygenated machine perfusion prevents arteriolonecrosis of the peribiliary plexus in pig livers donated after circulatory death. PLoS One 2014; 9:e88521.

Clavien PA, Barkun J, de Oliveira ML, et al. The Clavien-Dindo classification of surgical complications: five-year experience. Ann Surg 2009; 250:187–196.

Slankamenac K, Graf R, Barkun J, et al. The comprehensive complication index: a novel continuous scale to measure surgical morbidity. Ann Surg 2013; 258:1–7.

van den Brand JA, van Boekel GA, Willems HL, et al. Introduction of the CKD-EPI equation to estimate glomerular filtration rate in a Caucasian population. Nephrol Dial Transplant 2011; 26:3176–3181.

Olthoff KM, Kulik L, Samstein B, et al. Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors. Liver Transpl 2010; 16:943–949.

Guarrera JV, Henry SD, Samstein B, et al. Hypothermic machine preservation in human liver transplantation: the first clinical series. Am J Transplant 2010; 10:372–381.

Lurje G, Raptis DA, Steinemann DC, et al. Cosmesis and body image in patients undergoing single-port versus conventional laparoscopic cholecystectomy: a multicenter double-blinded randomized controlled trial (SPOCC-trial). Ann Surg 2015; 262:728–734. discussion 734-5.

Bellini MI, Nozdrin M, Yiu J, et al. Machine perfusion for abdominal organ preservation: a systematic review of kidney and liver human grafts. J Clin Med 2019; 8:8.

Richtlinien für die Wartelistenführung und Organvermittlung zur Lebertransplantation gem. § 16 Abs. 1 S. 1 Nrn. 2 u. 5 TPG. In Bundesärztekammer, ed. pp. 29.

McCormack L, Dutkowski P, El-Badry AM, et al. Liver transplantation using fatty livers: always feasible? J Hepatol 2011; 54:1055–1062.

Staiger RD, Cimino M, Javed A, et al. The Comprehensive Complication Index (CCI(R)) is a novel cost assessment tool for surgical procedures. Ann Surg 2018; 268:784–791.

Braat AE, Blok JJ, Putter H, et al. The Eurotransplant donor risk index in liver transplantation: ET-DRI. Am J Transplant 2012; 12:2789–2796.

Dutkowski P, Oberkofler CE, Slankamenac K, et al. Are there better guidelines for allocation in liver transplantation?A novel score targeting justice and utility in the model for end-stage liver disease era. Ann Surg 2011; 254:745–753. discussion 753.

Dutkowski P, Schlegel A, de Oliveira M, et al. HOPE for human liver grafts obtained from donors after cardiac death. J Hepatol 2014; 60:765–772.

van Rijn R, van den Berg AP, Erdmann JI, et al. Study protocol for a multicenter randomized controlled trial to compare the efficacy of end-ischemic dual hypothermic oxygenated machine perfusion with static cold storage in preventing non-anastomotic biliary strictures after transplantation of liver grafts donated after circulatory death: DHOPE-DCD trial. BMC Gastroenterol 2019; 19:40.

de Vries Y, Matton APM, Nijsten MWN, et al. Pretransplant sequential hypo- and normothermic machine perfusion of suboptimal livers donated after circulatory death using a hemoglobin-based oxygen carrier perfusion solution. Am J Transplant 2019; 19:1202–1211.

Muller X, Schlegel A, Kron P, et al. Novel real-time prediction of liver graft function during hypothermic oxygenated machine perfusion before liver transplantation. Ann Surg 2019; 270:783–790.

Czigany Z, Lurje I, Schmelzle M, et al. Ischemia-reperfusion injury in marginal liver grafts and the role of hypothermic machine perfusion: molecular mechanisms and clinical implications. J Clin Med 2020; 9:3.

Schlegel A, Graf R, Clavien PA, et al. Hypothermic oxygenated perfusion (HOPE) protects from biliary injury in a rodent model of DCD liver transplantation. J Hepatol 2013; 59:984–991.

Schlegel A, Kron P, Graf R, et al. Hypothermic Oxygenated Perfusion (HOPE) downregulates the immune response in a rat model of liver transplantation. Ann Surg 2014; 260:931–937. discussion 937-8.

op den Dries S, Karimian N, Weeder PD, et al. Normothermic acellular machine perfusion and bile duct injury in pig livers retrieved after cardiac death. Am J Transplant 2013; 13:3289.

Westerkamp AC, Karimian N, Matton AP, et al. Oxygenated hypothermic machine perfusion after static cold storage improves hepatobiliary function of extended criteria donor livers. Transplantation 2016; 100:825–835.

Ravaioli M, De Pace V, Angeletti A, et al. Hypothermic oxygenated new machine perfusion system in liver and kidney transplantation of extended criteria donors: first Italian clinical trial. Sci Rep 2020; 10:6063.

Czigany Z, Tacke F, Lurje G. Evolving trends in machine liver perfusion: comments on clinical end points and selection criteria. Gastroenterology 2019; 157:1166–1167.

Dutkowski P, Guarrera JV, de Jonge J, et al. Evolving trends in machine perfusion for liver transplantation. Gastroenterology 2019; 156:1542–1547.

Loosen SH, Roderburg C, Kauertz KL, et al. CEA but not CA19-9 is an independent prognostic factor in patients undergoing resection of cholangiocarcinoma. Sci Rep 2017; 7:16975.

Muller X, Marcon F, Sapisochin G, et al. Defining benchmarks in liver transplantation: a multicenter outcome analysis determining best achievable results. Ann Surg 2018; 267:419–425.

van Rijn R, Schurink IJ, de Vries Y, et al. Hypothermic machine perfusion in liver transplantation—a randomized trial. N Engl J Med 2021; 384:1391–1401.

Jochmans I, Brat A, Davies L, et al. Oxygenated versus standard cold perfusion preservation in kidney transplantation (COMPARE): a randomised, double-blind, paired, phase 3 trial. Lancet 2020; 396:1653–1662.

Ergina PL, Cook JA, Blazeby JM, et al. Challenges in evaluating surgical innovation. Lancet 2009; 374:1097–1104.

Martins PN, Rizzari MD, Ghinolfi D, et al. Design, analysis, and pitfalls of clinical trials using ex situ liver machine perfusion: the international liver transplantation society consensus guidelines. Transplantation 2021; 105:796–815.

Lomero M, Gardiner D, Coll E, et al. Donation after circulatory death today: an updated overview of the European landscape. Transpl Int 2020; 33:76–88.

Improved outcomes after hypothermic oxygenated machine perfusion in liver transplantation-Long-term follow-up of a multicenter randomized controlled trial

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ClinicalTrials.gov
NCT03124641