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Platelets have multiple functions beyond their roles in thrombosis and hemostasis. Platelets support liver regeneration, which is required after partial hepatectomy and acute or chronic liver injury. Although it is widely assumed that platelets stimulate liver regeneration by local excretion of mitogens stored within platelet granules, definitive evidence for this is lacking, and alternative mechanisms deserve consideration. In-depth knowledge of mechanisms of plateletmediated liver regeneration may lead to new therapeutic strategies to treat patients with failing regenerative responses. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that levels of angiogenic proteins within blood platelets change at the earliest stages of cancer development and may thus provide a promising diagnostic and prognostic tool. Patients with cirrhosis have increased risk of developing hepatocellular carcinoma (HCC). We aimed to study whether development of HCC in hepatitis-related cirrhosis results in changes in platelet levels of angiogenic proteins. We studied the intraplatelet levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), endostatin, platelet factor 4 (PF4) and thrombospondin type 1 (TSP-1) in 38 consecutive patients with hepatitis B- or C-related liver cirrhosis with or without HCC in addition to plasma levels of the same proteins. Twenty healthy volunteers were included to establish reference values for the various tests. Intraplatelet levels of VEGF, bFGF, HGF and endostatin were significantly higher in patients compared to controls. Intraplatelet levels of PDGF, PF4 and TSP-1 were comparable between patients and controls. Plasma levels of VEGF, bFGF and endostatin were comparable between patients and controls. Plasma levels of PDGF, PF4 and TSP-1 were decreased in patients, but this difference disappeared when levels were corrected for platelet count. Intraplatelet and plasma levels of all proteins assessed were comparable between patients with and without HCC. In conclusion, the intraplatelet levels of some angiogenic proteins are elevated in cirrhosis, but do not discriminate between patients with and without HCC. Thus, intraplatelet levels of angiogenic proteins do not seem useful as diagnostic or prognostic biomarker of HCC in cirrhotic patients. [ABSTRACT FROM PUBLISHER]

Cancer is a major risk factor for developing venous thromboembolism (VTE). Plasma hypercoagulability is an established risk factor for cancer-related VTE. In addition, thrombocytosis and hyperreactive platelets have been implicated in VTE and cancer progression. Cirrhosis is associated with changes in platelet number and function. The platelet activation status of patients with cirrhosis and hepatocellular carcinoma has not yet been established. Here we assessed the platelet activation status in patients with hepatitis-related cirrhosis in presence or absence of HCC. Materials and methods We performed a cross-sectional study including thirty-eight consecutive patients with hepatitis B- or C- related liver cirrhosis in presence or absence of HCC. We studied basal and agonist-induced platelet activation using flow cytometry. In addition, we studied the plasma levels of von Willebrand factor (VWF) and the VWF-cleaving protease ADAMTS13. Twenty healthy volunteers served as controls. Results We found no evidence of basal platelet activation in patients with cirrhosis compared to controls. However, we found reduced agonist-induced platelet activation in patients. No differences in the basal and agonist-induced platelets activation status between patients with or without HCC were detected. Plasma levels of VWF were increased and the levels of ADAMTS13 activity were decreased in patients compared to controls. No differences between the levels of VWF and ADAMTS13 in patients with or without HCC were detected. Conclusions HCC development or recurrence in patients with hepatitis B- or C-related cirrhosis does not appear to be associated with platelet activation and changes in pivotal proteins in primary hemostasis. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) arising in noncirrhotic and nonfibrotic liver (NC-HCC) is a rare type of malignancy frequently found in healthy young individuals. Partial liver resection is the treatment of choice with expected 5-year survival rates between 40% and 70%. As a result of absence of any symptom, a considerable number of patients are diagnosed when the malignancy has progressed to an advanced stage and the tumor has turned already unresectable. Some other patients suffer from intrahepatic recurrence after previous liver resection that cannot be re-resected or locally ablated. In these situations, liver transplantation (LT) may be the only potentially curative treatment. The indication for LT in NC-HCC patients, however, is not well established. The preliminary results of recent analysis of the European Liver Transplant Registry (ELTR) together with a literature review identified over 150 patients transplanted for NC-HCC during the last 15 years. In contrast to the historical data, these studies showed 5-year survival rates at 50–70% in well-selected patients. Important determinants of poor outcome are macrovascular invasion, lymph node involvement, and time interval of <12 months when LT is used as rescue therapy for intrahepatic recurrence after a previous partial liver resection. Interestingly, outcomes after both liver resection and LT for NC-HCC are much less influenced by tumor size than is the case with cirrhotic HCC. A large tumor size per se should, therefore, not to be seen as a strict contraindication for performing LT in patients with NC-HCC. [ABSTRACT FROM AUTHOR]

Background: Intraoperative hyperfibrinolysis contributes to bleeding during adult orthotopic liver transplantation. We aimed to find out whether aprotinin, a potent antifibrinolytic agent, reduces blood loss and transfusion requirements.Methods: We did a randomised, double-blind, placebo-controlled trial in which six liver-transplant centres participated. Patients undergoing primary liver transplantation were randomly assigned intraoperative high-dose aprotinin, regular-dose aprotinin, or placebo. Primary endpoints were intraoperative blood loss and transfusion requirements. Secondary endpoints were perioperative fluid requirements, postoperative blood transfusions, complications, and mortality.Findings: 137 patients received high-dose aprotinin (n=46), regular-dose aprotinin (n=43), or placebo (n=48). Intraoperative blood loss was significantly lower in the aprotinin-treated patients, with a reduction of 60% in the high-dose group and 44% in the regular-dose group, compared with the placebo group (p=0.03). Total amount of red blood cell (homologous and autologous) transfusion requirements was 37% lower in the high-dose group and 20% lower in the regular-dose group, than in the placebo group (p=0.02). Thromboembolic events occurred in two patients in the high-dose group, none in the regular-dose group, and in two patients in the placebo group (p=0.39). Mortality at 30 days did not differ between the three groups (6.5%, 4.7%, and 8.3%; p=0.79).Interpretation: Intraoperative use of aprotinin in adult patients undergoing orthotopic liver transplantation significantly reduces blood-transfusion requirements and should be routinely used in patients without contraindications. [ABSTRACT FROM AUTHOR]

Background: Recent evidence supports the use of machine perfusion technologies (MP) for marginal liver grafts. Their effect on enhanced recovery, however, remains uncertain. Objectives: To identify areas in which MP might contribute to an ERAS program and to provide expert panel recommendations. Data sources: Ovid MEDLINE, Embase, Scopus, Google Scholar, and Cochrane Central. Methods: Systematic review and meta‐analysis following PRISMA guidelines and recommendations using the GRADE approach. CRD42021237713 Results: Both hypothermic (HMP) and normothermic (NMP) machine perfusion demonstrated significant benefits in preventing postreperfusion syndrome (PRS) (HMP OR.33,.15‐.75 CI; NMP OR.51,.29‐.90 CI) and early allograft dysfunction (EAD) (HMP OR.51,.35‐.75 CI; NMP OR.66,.45‐.97 CI), while shortening LOS (HMP MD ‐3.9; NMP MD ‐12.41). Only NMP showed a significant decrease in the length of ICU stay (L‐ICU) (MD ‐7.07, ‐8.76; ‐5.38 CI), while only HMP diminishes the likelihood of major complications. Normothermic regional perfusion (NRP) reduces EAD (OR.52,.38–.70 CI) and primary nonfunction (PNF) (OR.51,.27‐.98 CI) without effect on L‐ICU and LOS. Conclusions: The use of HMP decreases PRS and EAD, specifically for marginal grafts. This is supported by a shorter LOS and a lower rate of major postoperative complications (QOE; moderate | Recommendation; Strong). NMP reduces the incidence of PRS and EAD with associated shortening in L‐ICU for both DBD and DCD grafts (QOE; moderate | Recommendation; High) This technology also shortens the length of hospital stay (QOE; low | Recommendation; Strong). NRP decreases the likelihood of EAD (QOE; moderate) and the risk of PNF (QOE; low) when compared to both DBD and SRR‐DCD grafts preserved in SCS. (Recommendation; Strong). [ABSTRACT FROM AUTHOR]

Liver transplantation has become an immense success; nevertheless, far more recipients are registered on waiting lists than there are available donor livers for transplantation. High-risk, extended criteria donor livers are increasingly used to reduce the discrepancy between organ demand and supply. Especially for high-risk livers, dynamic preservation using machine perfusion can decrease post-transplantation complications and may increase donor liver utilisation by improving graft quality and enabling viability testing before transplantation. To further increase the availability of donor livers suitable for transplantation, new strategies are required that make it possible to use organs that are initially too damaged to be transplanted. With the current progress in experimental liver transplantation research, (long-term) normothermic machine perfusion may be used in the future as a dynamic platform for regenerative medicine approaches, enabling repair and regeneration of injured donor livers. Currently explored therapeutics such as defatting cocktails, RNA interference, senolytics, and stem cell therapy may assist in the repair and/or regeneration of injured livers before transplantation. This review will provide a forecast of the future utility of normothermic machine perfusion in decreasing the imbalance between donor liver demand and supply by enabling the repair and regeneration of damaged donor livers. [ABSTRACT FROM AUTHOR]

Introduction: Cold ischemia time is a well‐known risk factor for the development of non‐anastomotic biliary strictures (NAS) after liver transplantation. End‐ischemic hypothermic oxygenated machine perfusion (HOPE) of DCD liver grafts reduces the incidence of NAS, and has the potential to reduce cold ischemia times. We hypothesized that if a part of the back‐table procedure could be performed under continuous HOPE, cold ischemia times would be reduced. Methods: In this prospective observational cohort study, all nationwide declined livers that underwent DHOPE‐NMP between July 1st 2021 and January 1st 2022 were included. The back‐table of ten consecutive high‐risk donor livers was performed with ongoing HOPE. Sixty DHOPE‐NMP procedures (August 1st 2017–July 1st 2021) with a conventional back‐table procedure functioned as a control group. Results: Compared to the control group, this technique led to a decrease in non‐oxygenated back‐table time from median 74 min (IQR 58–92 min) to median 25 min (IQR 21–31 min), p <.01. Median total cold preservation times were reduced from 279 min (IQR 254–297) to 214 min (IQR 132–254), p <.01. Conclusion: Cold ischemia time of liver grafts can be successfully reduced by over one hour by using portal vein only HOPE during back‐table preparation. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Liver transplantation is used for treating end‐stage liver disease, fulminant hepatitis, and oncological malignancies and organ shortage is a major limiting factor worldwide. The use of grafts based on extended donor criteria have become internationally accepted. Oxygenated machine perfusion technologies are the most recent advances in organ transplantation; however, it is only applied after a period of cold ischemia. Due to its high cost, we aimed to use a novel device, OxyFlush®, based on oxygenation of the preservation solution, applied during liver procurement targeting the maintenance of ATP during static cold storage (SCS).Twenty patients were randomly assigned to the OxyFlush or control group based on a 1:1 ratio. In the OxyFlush group, the perfusion solution was oxygenated with OxyFlush® device while the control group received a non‐oxygenated solution. Liver and the common bile duct (CBD) biopsies were obtained at three different time points. The first was at the beginning of the procedure, the second during organ preparation, and the third after total liver reperfusion. Biopsies were analyzed, and adenosine triphosphate (ATP) levels and histological scores of the liver parenchyma and CBD were assessed. Postoperative laboratory tests were performed.OxyFlush® was able to maintain ATP levels during SCS and improved the damage caused by the lack of oxygen in the CBD. However, OxyFlush® did not affect laboratory test results and histological findings of the parenchyma.We present a novel low‐cost device that is feasible and could represent a valuable tool in organ preservation during SCS. [ABSTRACT FROM AUTHOR]

Intraoperative blood loss and postoperative hemorrhage affect outcomes after liver resection. GATT-Patch is a new flexible, pliable hemostatic sealant patch comprising fibrous gelatin carrier impregnated with N-hydroxy-succinimide polyoxazoline. We evaluated safety and performance of the GATT-Patch for hemostasis at the liver resection plane. Adult patients undergoing elective open liver surgery were recruited in three centers. GATT-Patch was used for minimal to moderate bleeding at the liver resection plane. The primary endpoint was hemostasis of the first-treated bleeding site at 3 min versus a prespecified performance goal of 65.4%. Two trial stages were performed: I (n = 8) for initial safety and II (n = 39) as the primary outcome cohort. GATT-Patch was applied in 47 patients on 63 bleeding sites. Median age was 60.0 (range 25-80) years and 70% were male. Most (66%) surgeries were for colorectal cancer metastases. The primary endpoint was met in 38 out of 39 patients (97.4%; 95% confidence interval: 84.6%-99.9%) versus 65.4% (P < 0.001). Of all the 63 bleeding sites, hemostasis was 82.7% at 30, 93.7% at 60, and 96.8% at 180 s. No reoperations for rebleeding or device-related issues occurred. When compared to a performance goal derived from state-of-the-art hemostatic agents, GATT-Patch for the treatment of minimal to moderate bleeding during liver surgery successfully and quickly achieved hemostasis with acceptable safety outcomes. (ClinicalTrials.gov Identifier: NCT04819945). [ABSTRACT FROM AUTHOR]

The article presents the author's comments on the thrombosis of the hepatic artery as one of the major complications after liver transplantation and its association with morbidity and graft loss. The author says although a patient with liver disease is generally considered to have a defective hemostatic system, evidences are increasing that bleeding tendency might not be reflected by these coagulation. He has also discussed a number of cases.

Biliary atresia (BA) is an obstructive cholangiopathy that initially affects the extrahepatic bile ducts (EHBDs) of neonates. The etiology is uncertain, but evidence points to a prenatal cause. Fetal tissues have increased levels of hyaluronic acid (HA), which plays an integral role in fetal wound healing. The objective of this study was to determine whether a program of fetal wound healing is part of the response to fetal EHBD injury. Mouse, rat, sheep, and human EHBD samples were studied at different developmental time points. Models included a fetal sheep model of prenatal hypoxia, human BA EHBD remnants and liver samples taken at the time of the Kasai procedure, EHBDs isolated from neonatal rats and mice, and spheroids and other models generated from primary neonatal mouse cholangiocytes. A wide layer of high molecular weight HA encircling the lumen was characteristic of the normal perinatal but not adult EHBD. This layer, which was surrounded by collagen, expanded in injured ducts in parallel with extensive peribiliary gland hyperplasia, increased mucus production and elevated serum bilirubin levels. BA EHBD remnants similarly showed increased HA centered around ductular structures compared with age-appropriate controls. High molecular weight HA typical of the fetal/neonatal ducts caused increased cholangiocyte spheroid growth, whereas low molecular weight HA induced abnormal epithelial morphology; low molecular weight HA caused matrix swelling in a bile duct-on-a-chip device. The fetal/neonatal EHBD, including in human EHBD remnants from Kasai surgeries, demonstrated an injury response with prolonged high levels of HA typical of fetal wound healing. The expanded peri-luminal HA layer may swell and lead to elevated bilirubin levels and obstruction of the EHBD. Biliary atresia is a pediatric cholangiopathy associated with high morbidity and mortality rates; although multiple etiologies have been proposed, the fetal response to bile duct damage is largely unknown. This study explores the fetal pathogenesis after extrahepatic bile duct damage, thereby opening a completely new avenue to study therapeutic targets in the context of biliary atresia. [Display omitted] • Fetal and neonatal extrahepatic bile ducts have high levels of hyaluronic acid, located directly around the lumen. • Damage to the fetal extrahepatic bile duct is followed by increased hyaluronic acid deposition. • Biliary atresia remnants show increased hyaluronic acid deposition around epithelial structures compared to controls. • Hyaluronic acid in neonatal extrahepatic bile ducts is degraded after injury. • Hyaluronic acid polymers of different sizes have distinct biological effects on cholangiocytes. [ABSTRACT FROM AUTHOR]

Liver transplantation remains the only curative treatment for patients with end-stage liver disease. Despite a steadily increasing demand for suitable donor livers, the current pool of donor organs fails to meet this demand. To resolve this discrepancy, livers traditionally considered to be of suboptimal quality and function are increasingly utilized. These marginal livers, however, are less tolerant to the current standard cold preservation of donor organs. Therefore, alternative preservation methods have been sought and are progressively applied into clinical practice. Ex situ machine perfusion is a promising alternative preservation modality particularly for suboptimal donor livers as it provides the ability to resuscitate, recondition, and test the viability of an organ prior to transplantation. This review addresses the modalities of machine perfusion currently being applied, and particularly focuses on the hemostatic management employed during machine perfusion. We discuss the anticoagulant agents used, the variation in dosage, and administration, as well as the implications of perfusion for extended periods of time in terms of coagulation activation associated with production of coagulation factors during perfusion. Furthermore, in regard to viability testing of an organ prior to transplantation, we discuss the possibilities and limitations of utilizing the synthesis of liver-derived coagulation factors as potential viability markers. [ABSTRACT FROM AUTHOR]

There is increasing evidence that portal hypertension plays a major role in bleeding risk during orthotopic liver transplantation (OLT). We investigated the association between preoperative blood levels of von Willebrand factor (VWF) and soluble CD163 (sCD163), which are established markers of portal hypertension, and blood loss and transfusion requirements during OLT. We measured levels of VWF and sCD163 in preoperative serum samples of 168 adult patients undergoing a primary OLT between 1998 and 2012. Preoperative levels of VWF and sCD163 correlated with the model of end-stage liver disease (MELD) score ( r  = 0.414, p  < 0.001 and r  = 0.382, p  < 0.001, respectively). Patients with high VWF or sCD163 levels (VWF and sCD163 levels above the median) had a substantially increased risk of needing red blood cell transfusion compared with patients with low VWF or sCD163 levels (VWF and sCD163 levels below the median) (odds ratio 3.5 [95% confidence interval, CI 1.7–7.0] and 2.3 [95% CI 1.1–4.5], respectively). Blood loss was highest in patients with both high VWF or sCD163 levels and a high preoperative international normalized ratio. Elevated blood levels of markers of portal hypertension are associated with increased blood loss and transfusion requirements during OLT and support the notion that portal hypertension is an important contributor to perioperative blood loss. [ABSTRACT FROM AUTHOR]

Normothermic machine perfusion (NMP) of donor livers allows for new diagnostic and therapeutic strategies. As the liver produces most of the haemostatic proteins, coagulation assays such as the International Normalised Ratio (INR) performed in perfusate may be useful to assess hepatocellular function of donor livers undergoing NMP. However, high concentrations of heparin and low levels of fibrinogen may affect coagulation assays. Thirty donor livers that underwent NMP were retrospectively included in this study, of which 18 were subsequently transplanted. We measured INRs in perfusate in presence or absence of exogenously added fibrinogen and/or polybrene. Additionally, we prospectively included 14 donor livers that underwent NMP (of which 11 were transplanted) and measured INR using both a laboratory coagulation analyser and a point-of-care device. In untreated perfusate samples, the INR was above the detection limit in all donor livers. Addition of both fibrinogen and polybrene was required for adequate INR assessment. INRs decreased over time and detectable perfusate INR values were found in 17/18 donor livers at the end of NMP. INR results were similar between the coagulation analyser and the point-of-care device, but did not correlate with established hepatocellular viability criteria. Most of the donor livers that were transplanted showed a detectable perfusate INR at the end of NMP, but samples require processing to allow for INR measurements using laboratory coagulation analysers. Point-of-care devices bypass this need for processing. The INR does not correlate with established viability criteria and might therefore have additional predictive value. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "A Comparison of Aprotinin and Lysine Analogues in High Risk Cardiac Surgery" by D. A. Fergusson, P. C. Hebert and C. D. Mazer in the May 29, 2008 issue.

With the increasing number of accepted candidates on waiting lists worldwide, there is an urgent need to expand the number and the quality of donor livers. Dynamic preservation approaches have demonstrated various benefits, including improving liver function and graft survival, and reducing liver injury and post-transplant complications. Consequently, organ perfusion techniques are being used in clinical practice in many countries. Despite this success, a proportion of livers do not meet current viability tests required for transplantation, even with the use of modern perfusion techniques. Therefore, devices are needed to further optimise machine liver perfusion – one promising option is to prolong machine liver perfusion for several days, with ex situ treatment of perfused livers. For example, stem cells, senolytics, or molecules targeting mitochondria or downstream signalling can be administered during long-term liver perfusion to modulate repair mechanisms and regeneration. Besides, today's perfusion equipment is also designed to enable the use of various liver bioengineering techniques, to develop scaffolds or for their re-cellularisation. Cells or entire livers can also undergo gene modulation to modify animal livers for xenotransplantation, to directly treat injured organs or to repopulate such scaffolds with "repaired" autologous cells. This review first discusses current strategies to improve the quality of donor livers, and secondly reports on bioengineering techniques to design optimised organs during machine perfusion. Current practice, as well as the benefits and challenges associated with these different perfusion strategies are discussed. [ABSTRACT FROM AUTHOR]

Hepatobiliary surgery is a well-known risk factor for thrombotic complications but is also associated with substantial perioperative blood loss. Given the central role of the liver in hemostasis, hepatobiliary surgery is frequently accompanied by complex changes in the hemostatic system. Increasing knowledge of these changes has resulted in an improved understanding of the etiology of some of the hemostatic complications. In the early postoperative period a prolongation of conventional coagulation test times, such as the prothrombin time, is frequently seen. Together with a decreased platelet count, this suggests a hypocoagulable state. The concomitant decline of anticoagulant factors and development of a von Willebrand factor/ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) imbalance, however, suggest a hypercoagulable state, potentially contributing to the risk of thromboembolism. Postoperative thromboprophylaxis should be initiated early to avoid thrombosis, and intensified prophylaxis might benefit highrisk patients. The risk of hemorrhagic complications during hepatobiliary surgery has diminished over time, mainly due to improved surgical and anesthesiological techniques. However, bleeding can still be profound in individual patients and is difficult to predict using (global) hemostasis tests. A restrictive transfusion and fluid infusion policy tomaintain a low central venous pressure is crucial in prevention of perioperative bleeding. However, when active bleeding occurs, proactive prohemostatic management is required. [ABSTRACT FROM AUTHOR]

Machine perfusion is a novel method intended to optimize livers before transplantation. However, its effect on morbidity within a 1-year period after transplantation has remained unclear. In this multicenter controlled trial, we randomly assigned livers donated after brain death (DBD) for liver transplantation (LT). Livers were either conventionally cold stored (control group), or cold stored and subsequently treated by 1-2 h hypothermic oxygenated perfusion (HOPE) before implantation (HOPE group). The primary endpoint was the occurrence of at least one post-transplant complication per patient, graded by the Clavien score of ≥III, within 1-year after LT. The comprehensive complication index (CCI), laboratory parameters, as well as duration of hospital and intensive care unit stay, graft survival, patient survival, and biliary complications served as secondary endpoints. Between April 2015 and August 2019, we randomized 177 livers, resulting in 170 liver transplantations (85 in the HOPE group and 85 in the control group). The number of patients with at least one Clavien ≥III complication was 46/85 (54.1%) in the control group and 44/85 (51.8%) in the HOPE group (odds ratio 0.91; 95% CI 0.50-1.66; p = 0.76). Secondary endpoints were also not significantly different between groups. A post hoc analysis revealed that liver-related Clavien ≥IIIb complications occurred less frequently in the HOPE group compared to the control group (risk ratio 0.26; 95% CI 0.07-0.77; p = 0.027). Likewise, graft failure due to liver-related complications did not occur in the HOPE group, but occurred in 7% (6 of 85) of the control group (log-rank test, p = 0.004, Gray test, p = 0.015). HOPE after cold storage of DBD livers resulted in similar proportions of patients with at least one Clavien ≥III complication compared to controls. Exploratory findings suggest that HOPE decreases the risk of severe liver graft-related events. This randomized controlled phase III trial is the first to investigate the impact of hypothermic oxygenated perfusion (HOPE) on cumulative complications within a 12-month period after liver transplantation. Compared to conventional cold storage, HOPE did not have a significant effect on the number of patients with at least one Clavien ≥III complication. However, we believe that HOPE may have a beneficial effect on the quantity of complications per patient, based on its application leading to fewer severe liver graft-related complications, and to a lower risk of liver-related graft loss. The HOPE approach can be applied easily after organ transport during recipient hepatectomy. This appears fundamental for wide acceptance since concurring perfusion technologies need either perfusion at donor sites or continuous perfusion during organ transport, which are much costlier and more laborious. We conclude therefore that the post hoc findings of this trial should be further validated in future studies. [Display omitted] • The number of patients with at least one Clavien ≥III complication was not significantly different between groups. • Severe post-transplant complications (Clavien grade IIIb or more), occurred less frequently in the HOPE-group. • This was caused by a 3.7-fold lower number of liver-related Clavien ≥IIIb complications per patient in the HOPE-group. • Graft failure due to liver-related complications did not occur in the HOPE-group but occurred in 7% in the control-group. [ABSTRACT FROM AUTHOR]

The DRAINAGE trial was a randomized controlled trial comparing preoperative endoscopic (EBD) and percutaneous biliary drainage (PTBD) in patients with potentially resectable, perihilar cholangiocarcinoma (pCCA). The aim of this study was to compare the long-term outcomes. Patients were randomized in four tertiary referral centers. Follow-up data were available for all included patients. Primary outcome was overall survival (OS). Secondary outcomes were readmissions, and re-interventions not including in-trial interventions. A total of 54 patients were randomized; 27 in both groups. Median follow-up for both groups was 62 months (95% CI 54–70). The median OS was 13 months (95% CI 7.9–18.1) in the EBD and 7 months (95% CI 0.0–17.2) in the PTBD group (P = 0.28). Twenty (37%, n = 8 EBD vs n = 12 PTBD, P = 0.43) of 54 patients were readmitted at least once, mostly due to drainage-related complications (n = 13, 24%). Of note, 14 out of the 54 patients died within the trial. A total of 76 drainage procedures (32 EBD and 44 PTBD) were performed in 28 patients. The median number of stent or drain placements was 2 (2–4) for the EBD group and 2 (1–3) for the PTBD group (P = 0.77). Although this follow-up study represented a small cohort, no long-term differences in survival, readmissions, and drainage procedures for EBD and PTBD were found, even when comparing the resected and unresected group. However, this study demonstrates the complexity of biliary drainage for patients with potentially resectable pCCA, even in tertiary referral centers. [Display omitted] [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article on the status of platelet activation in patients with liver disease in the 2011 issue.

A letter to the editor is presented in response to the article "Low-molecular-weight heparin in patients with advanced cirrhosis," by L. P. Bechmann and colleagues in a 2011 issue.

Background: Trichosporon species are ubiquitously spread and known to be part of the normal human flora of the skin and gastrointestinal tract. Trichosporon spp. normally cause superficial infections. However, in the past decade Trichosporon spp. are emerging as opportunistic agents of invasive fungal infections, particularly in severely immunocompromised patients. Clinical isolates are usually sensitive to triazoles, but strains resistant to multiple triazoles have been reported.Case Presentation: We report a high-level pan-azole resistant Trichosporon dermatis isolate causing an invasive cholangitis in a patient after liver re-transplantation. This infection occurred despite of fluconazole and low dose amphotericin B prophylaxis, and treatment with combined liposomal amphotericin B and voriconazole failed.Conclusion: This case and recent reports in literature show that not only bacteria are evolving towards pan-resistance, but also pathogenic yeasts. Prudent use of antifungals is important to withstand emerging antifungal resistance. [ABSTRACT FROM AUTHOR]

Summary The high incidence of non-anastomotic biliary strictures (NAS) after transplantation of livers from extended criteria donors is currently a major barrier to widespread use of these organs. This review provides an update on the most recent advances in the understanding of the etiology of NAS. These new insights give reason to believe that machine perfusion can reduce the incidence of NAS after transplantation by providing more protective effects on the biliary tree during preservation of the donor liver. An overview is presented regarding the different endpoints that have been used for assessment of biliary injury and function before and after transplantation, emphasizing on methods used during machine perfusion. The wide spectrum of different approaches to machine perfusion is discussed, including the many different combinations of techniques, temperatures and perfusates at varying time points. In addition, the current understanding of the effect of machine perfusion in relation to biliary injury is reviewed. Finally, we explore directions for future research such as the application of (pharmacological) strategies during machine perfusion to further improve preservation. We stress the great potential of machine perfusion to possibly expand the donor pool by reducing the incidence of NAS in extended criteria organs. [ABSTRACT FROM AUTHOR]

Introduction Patients with cirrhosis have substantial alterations in their hemostatic system, which are paradoxically associated with the risk of both bleeding and thrombotic complications. However, it still remains difficult to predict those risks, because results from conventional coagulation tests, such as the prothrombin time (PT) and activated partial thromboplastin time (APTT), do not reflect the complex hemostatic changes in these patients. More sophisticated global hemostasis tests, such as thrombin generation assays, are not standardized for routine use yet. Here we examined the spatial clot growth in plasma from patients with cirrhosis using the novel Thrombodynamics assay, which uses a fundamentally new approach to test plasma hemostatic capacity. Materials and Methods Thrombodynamics assays were performed in plasma from thirty-one patients with cirrhosis and twenty-five healthy controls. Results were compared to results with thrombin generation testing and PT/APTT test results. Results Rates of clot growth, clot size, and clot density from the Thrombodynamics assay were comparable between patients and controls. Thrombin generation in the presence of thrombomodulin was increased in the patients, despite prolonged PT and APTT test results. There was little correlation between parameters derived from the Thrombodynamics assay and the PT, APTT, or thrombin generation data. Conclusions The Thrombodynamics assay showed preserved clot formation in plasma from patients with cirrhosis, which is in line with the results of the thrombin generation assay in this study and previously reported by others. [ABSTRACT FROM AUTHOR]

• Six hours of ex vivo subnormothermic machine perfusion (SNMP) of rodent vascularized composite allografts (VCA) is feasible using acellular oxygen carrier HBOC-201 • SNMP results in superior tissue preservation compared to conventional static cold storage (SCS) preservation • Successful transplantation of VCA grafts preserved with 6 h of SNMP is feasible and 30-d • survival rates are comparable to SCS preserved graft Machine perfusion is gaining interest as an efficient method of tissue preservation of Vascularized Composite Allografts (VCA). The aim of this study was to develop a protocol for ex vivo subnormothermic oxygenated machine perfusion (SNMP) on rodent hindlimbs and to validate our protocol in a heterotopic hindlimb transplant model. In this optimization study we compared three different solutions during 6 h of SNMP (n = 4 per group). Ten control limbs were stored in a preservation solution on Static Cold Storage [SCS]). During SNMP we monitored arterial flowrate, lactate levels, and edema. After SNMP, muscle biopsies were taken for histology examination, and energy charge analysis. We validated the best perfusion protocol in a heterotopic limb transplantation model with 30-d follow up (n = 13). As controls, we transplanted untreated limbs (n = 5) and hindlimbs preserved with either 6 or 24 h of SCS (n = 4 and n = 5). During SNMP, arterial outflow increased, and lactate clearance decreased in all groups. Total edema was significantly lower in the HBOC-201 group compared to the BSA group (P = 0.005), 4.9 (4.3-6.1) versus 48.8 (39.1-53.2) percentage, but not to the BSA + PEG group (P = 0.19). Energy charge levels of SCS controls decreased 4-fold compared to limbs perfused with acellular oxygen carrier HBOC-201, 0.10 (0.07-0.17) versus 0.46 (0.42-0.49) respectively (P = 0.002). Six hours ex vivo SNMP of rodent hindlimbs using an acellular oxygen carrier HBOC-201 results in superior tissue preservation compared to conventional SCS. [ABSTRACT FROM AUTHOR]

Background: During donor organ procurement and subsequent static cold storage (SCS), hepatic adenosine triphosphate (ATP) levels are progressively depleted, which contributes to ischemia‐reperfusion injury (IRI). We sought to investigate a simple approach to prevent ATP depletion and IRI using a porcine donation after circulatory death (DCD) liver reperfusion model. Methods: After 30 min warm ischemia, porcine livers were flushed via the portal vein with cold (4°C) non‐oxygenated University of Wisconsin (UW) preservation solution (n = 6, control group) or with oxygenated UW (n = 6, OxyFlush group). Livers were then subjected to 4 h SCS in non‐oxygenated (control) or oxygenated (OxyFlush) UW, followed by 4 h normothermic reperfusion using whole blood. Hepatic ATP levels were compared, and hepatobiliary function and injury were assessed. Results: At the end of SCS, ATP was higher in the OxyFlush group compared to controls (delta ATP of +0.26 vs. −0.68 µmol/g protein, p = 0.04). All livers produced bile and metabolized lactate, and there were no differences between the groups. Grafts in the OxyFlush group had lower blood glucose levels after reperfusion (p = 0.04). Biliary pH, glucose and bicarbonate were not different between the groups. Injury markers including liver transaminases, lactate dehydrogenase, malondialdehyde, cell‐free DNA and flavin mononucleotide in the SCS solution and during reperfusion were also similar. Histological assessment of the parenchyma and bile ducts did not reveal differences between the groups. Conclusion: Oxygenated flush out and storage of DCD porcine livers prevents ATP depletion during ischemia, but this does not seem sufficient to mitigate early signs of IRI. [ABSTRACT FROM AUTHOR]

Introduction: Several clinical studies have demonstrated the safety, feasibility, and efficacy of machine perfusion in liver transplantation, although its economic outcomes are still underexplored. This review aimed to examine the costs related to machine perfusion and its associated outcomes. Methods: Expert opinion of several groups representing different machine perfusion modalities. Critical analysis of the published literature reporting the economic outcomes of the most used techniques of machine perfusion in liver transplantation (normothermic and hypothermic ex situ machine perfusion and in situ normothermic regional perfusion). Results: Machine perfusion costs include disposable components of the perfusion device, perfusate components, personnel and facility fees, and depreciation of the perfusion device or device lease fee. The limited current literature suggests that although this upfront cost varies between perfusion modalities, its use is highly likely to be cost‐effective. Optimization of the donor liver utilization rate, local conditions of transplant programs (long waiting list times and higher MELD scores), a decreased rate of complications, changes in logistics, and length of hospital stay are potential cost savings points that must highlight the expected benefits of this intervention. An additional unaccounted factor is that machine perfusion optimizing donor organ utilization allows patients to be transplanted earlier, avoiding clinical deterioration while on the waiting list and the costs associated with hospital admissions and other required procedures. Conclusion: So far, the clinical benefits have guided machine perfusion implementation in liver transplantation. Albeit there is data suggesting the economic benefit of the technique, further investigation of its costs to healthcare systems and society and associated outcomes is needed. [ABSTRACT FROM AUTHOR]

Although short-term machine perfusion (-24 h) allows for resuscitation and viability assessment of high-risk donor livers, the donor organ shortage might be further remedied by long-term perfusion machines. Extended preservation of injured donor livers may allow reconditioning, repairing, and regeneration. This review summarizes the necessary requirements and challenges for long-term liver machine preservation, which requires integrating multiple core physiological functions to mimic the physiological environment inside the body. A pump simulates the heart in the perfusion system, including automatically controlled adjustment of flow and pressure settings. Oxygenation and ventilation are required to account for the absence of the lungs combined with continuous blood gas analysis. To avoid pressure necrosis and achieve heterogenic tissue perfusion during preservation, diaphragm movement should be simulated. An artificial kidney is required to remove waste products and control the perfusion solution's composition. The perfusate requires an oxygen carrier, but will also be challenged by coagulation and activation of the immune system. The role of the pancreas can be mimicked through closed-loop control of glucose concentrations by automatic injection of insulin or glucagon. Nutrients and bile salts, generally transported from the intestine to the liver, have to be supplemented when preserving livers long term. Especially for long-term perfusion, the container should allow maintenance of sterility. In summary, the main challenge to develop a long-term perfusion machine is to maintain the liver's homeostasis in a sterile, carefully controlled environment. Long-term machine preservation of human livers may allow organ regeneration and repair, thereby ultimately solving the shortage of donor livers. [ABSTRACT FROM AUTHOR]

Background: The German anatomist Hubert von Luschka gave name to several structures in the human body. One of great discussion is the duct of Luschka, part of the biliary system. There are different descriptions of the duct of Luschka. This might lead to confusion in the debate and as to what therapy should best be provided in case of an injured duct of Luschka. Methods: We reviewed the literature on descriptions of Luschka's duct and studied the original German descriptions by Hubert von Luschka. Results: While reading the original work by von Luschka on the hepatobiliary system, we were not able to find a description of either one of the two structures that are nowadays referred to as 'the duct of Luschka'. Conclusions: von Luschka maybe never described the so-called duct of Luschka. He did, however, describe the peribiliary glands in the intra- and extrahepatic bile ducts and gallbladder wall. These might have been misinterpreted as a duct running along the gallbladder fossa. The lack of a clear definition is the reason for the development of rather confusing and sometimes misleading eponyms as the duct of Luschka. The eponym 'duct of Luschka' should, therefore, better not be used. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Traditionally, perioperative bleeding complications were a major concern during orthotopic liver transplantation, but a tremendous decline in transfusion requirements has been reported over the last decade. In recent years, there has been an increasing awareness towards perioperative thrombotic complications, including liver vessel thrombosis, and systemic venous and arterial thromboembolic events. Whereas a number of these thrombotic complications were previously categorized as surgical complications, increasing clinical and laboratory evidence suggest a role for the haemostatic system in thrombotic complications occurring during and after transplantation. High levels of the platelet adhesive protein von Willebrand factor with low levels of its regulator ADAMTS13, an increased potential to generate thrombin, and temporary hypofibrinolysis are all indicative of increased haemostatic potential after transplantation. Clinical evidence for a role of the haemostatic system in post-operative thromboses includes a higher thrombotic risk in patients with various acquired thrombotic risk factors. Although data on efficacy of anticoagulant therapy after liver transplantation are scarce, one study has shown a significant decrease in the risk for late hepatic artery thrombosis by antithrombotic therapy with aspirin. These findings suggest that antihaemostatic therapy in prevention or treatment of thromboembolic complications after liver transplantation may be relevant. Studies on efficacy and safety of these interventions are required as many of the thrombotic complications have a pronounced negative impact on graft and patient survival. [ABSTRACT FROM AUTHOR]

Abstract: The effects of the secondary bile acid, lithocholic acid (LCA), a VDR, FXR and PXR ligand, on the regulation of bile acid metabolism (CYP3A isozymes), synthesis (CYP7A1), and transporter proteins (MRP3, MRP2, BSEP, NTCP) as well as nuclear receptors (FXR, PXR, LXRα, HNF1α, HNF4α and SHP) were studied in rat and human precision-cut intestine and liver slices at the mRNA level. Changes due to 5 to 10μM of LCA were compared to those of other prototype ligands for VDR, FXR, PXR and GR. LCA induced rCYP3A1 and rCYP3A9 in the rat jejunum, ileum and colon, rCYP3A2 only in the ileum, rCYP3A9 expression in the liver, and CYP3A4 in the human ileum but not in liver. LCA induced the expression of rMRP2 in the colon but not in the jejunum and ileum but did not affect rMRP3 expression along the length of the rat intestine. In human ileum slices, LCA induced hMRP3 and hMRP2 expression. In rat liver slices, LCA decreased rCYP7A1, rLXRα and rHNF4α expression, induced rSHP expression, but did not affect rBSEP or rNTCP expression; whereas in the human liver, a small but significant decrease was found for hHNF1α expression. These data suggests profound species differences in the effects of LCA on bile acid transport, synthesis and detoxification. An examination of the effects of prototype VDR, PXR, GR and FXR ligands showed that these pathways are all intact in precision cut slices and that LCA exerted VDR, PXR and FXR effects. The LCA-induced altered enzymes and transporter expressions in the intestine and liver would affect the disposition of drugs. [ABSTRACT FROM AUTHOR]

Abstract: The vitamin D receptor (VDR) regulates the expression of drug metabolizing enzymes and transporters in intestine and liver, but the regulation of VDR expression in intestine and liver is incompletely understood. We studied the regulation of VDR mRNA expression by ligands for VDR, farnesoid X receptor (FXR), glucocorticoid receptor (GR) and protein kinase C α (PKCα) in rat and human ileum and liver using precision-cut slices. 1,25(OH)2D3 induced VDR expression in rat ileum and liver, and human ileum but not in liver. Chenodeoxycholic acid (CDCA), but not lithocholic acid (LCA) and GW4064 induced VDR mRNA expression in rat ileum and liver. The PKCα activator, phorbol-12-myristate-13-acetate (PMA) induced the expression of VDR in the rat liver, and the induction of VDR by 1,25(OH)2D3 and CDCA was inhibited by the PKCα inhibitor, bisindolyl maleimide I (Bis I). These results show that the expression of VDR is likely to be regulated by PKC but not by FXR or VDR activation at least in the rat liver. The VDR mediated induction of its target genes CYP3A1 and CYP3A2 by 1,25(OH)2D3 or LCA in the rat ileum was strongly reduced in the presence of CDCA despite the higher VDR expression. Thus, CDCA might potentiate the toxicity of LCA by inhibiting its metabolism. [Copyright &y& Elsevier]

Patients with liver disease frequently have substantial changes in their haemostatic system. This is reflected in abnormal test results on routine coagulation screening assays such as the prothrombin time (PT), activated thromboplastin time (APTT) and platelet count. Traditionally, attempts were made to correct abnormalities in the haemostatic system as measured by routine coagulation assays prior to invasive procedures by infusion of platelets or fresh frozen plasma (FFP). Recent laboratory and clinical data have indicated that the haemostatic reserve in cirrhotic patients is relatively well maintained although the coagulation screening assays suggest otherwise. Pre-procedural correction of coagulation tests with blood products may therefore not be necessary, and may even have harmful side-effects. In particular, fluid overload resulting in exacerbation of portal hypertension by infusion of blood products may in fact promote bleeding. In recent years, it has become clear that reduction of the central and portal venous pressure by fluid restriction and avoidance of blood product transfusion is a beneficial strategy in minimizing bleeding during liver surgery in cirrhotic patients. Some investigators have even taken this a step further and suggested pre-procedural phlebotomy in liver transplant recipients. The aim of this review is to provide an overview of recent studies and developments which have changed our understanding of the clinical relevance of abnormal coagulation tests in patients with cirrhosis, and which have contributed to a reduction in blood loss and transfusion requirements when liver surgery is needed in these patients. [ABSTRACT FROM AUTHOR]

Partial liver resections are the treatment of choice for patients with a malignant liver or bile duct tumor. The most frequent indications for partial liver resections are colorectal metastasis, hepatocellular carcinoma (HCC) and cholangiocarcinoma. Liver resection is the only therapy with a chance for cure in these patients. Refinements in surgical technique and increasing experience have contributed to a reduction in perioperative morbidity and mortality in recent years. Despite these improvements, partial liver resections remain a major surgical procedure and carry the risk for excessive blood loss and a subsequent need for blood transfusion. Blood transfusions have been associated with systemic side effects, such as depression of the immune system. Several studies have suggested that perioperative blood loss or transfusions have a negative impact on postoperative outcome. However, it has been debated whether this is due to a real cause-effect relationship or merely the result of more complicated surgery. We have reviewed the literature concerning studies focusing on the relationship between blood loss and blood transfusion during liver surgery for malignant tumors and postoperative outcome. Most studies were based on a retrospective analysis of single center experiences, using uni- and multivariate statistical methods. Most studies have demonstrated a significant and clinically relevant association between blood transfusion and postoperative mortality and morbidity, especially postoperative infectious complications. The effect of blood transfusions on tumor recurrence and more long-term mortality is much less clear and evidence varies depending on the type of malignancy. The strongest indication that blood transfusion may have an impact on tumor recurrence has been found for patients with early stages of HCC. However, overall, no such effect could be demonstrated for patients undergoing partial liver resection for late stages of HCC, colorectal liver metastasis or cholangiocarcinoma. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The origin of blood loss during liver surgery is multifactorial. Surgical skill, technique, anesthesiological care, but also hyperfibrinolysis have been shown to play a role in the origin of bleeding during partial hepatectomy and liver transplantation. The latter has provided the scientific basis for the prophylactic use of antifibrinolytic drugs, such as aprotinin and nafamostat mesilate in liver surgery. Recently however, concern has been voiced about potential risks associated with aprotinin, including renal failure and thromboembolic events. In this review we discuss the efficacy and safety issues of aprotinin and nafamostat mesilate in liver surgery. We identified a total of 19 studies on the use of either aprotinin or nafamostat mesilate in liver surgery reported in the time period between 1966 and July 2006. The use of aprotinin or nafamostat mesilate in partial hepatectomies was studied in three studies. In 16 studies the use of aprotinin in liver transplantation was investigated. With respect to partial hepatectomy, improvements in surgical technique and anesthesiological care seem to be more important in reducing blood loss than the use of the antifibrinolytic drugs. Aprotinin may be indicated in a selected group of patients with cirrhosis undergoing liver resection, but further studies in this specific group of patients will be needed. In liver transplantation, the use of aprotinin is associated with a significant reduction in blood loss and transfusion requirements of around 30–40%. Results of prospective studies do not provide support for safety concerns as no increased risk for thromboembolic events or renal dysfunction has been observed in liver transplant patients treated with aprotinin. In conclusion, there is currently no scientific support for the routine use of aprotinin or nafamostat mesilate in patients undergoing partial hepatectomy, whereas the efficacy of aprotinin in liver transplantation is well established. More studies will be needed to address the safety aspects of aprotinin in patients undergoing liver surgery in more detail. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

After liver transplantation, the prevalence of complications related to the biliary system is 6–35%. In recent years, the diagnosis and treatment of biliary problems has changed markedly. The two standard methods of biliary reconstruction in liver transplant recipients are the duct-to-duct choledochocholedochostomy and the Roux-en-Y-hepaticojejunostomy. Biliary leakage occurs in approximately 5–7% of transplant cases. Leakage from the site of anastomosis, the T-tube exit site and donor or recipient remnant cystic duct is well described. Symptomatic bile leakage should be treated by stenting of the duct by endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTCD). Biliary strictures can occur at the site of the anastomosis (anastomotic stricture; AS) or at other locations in the biliary tree (non-anastomotic strictures; NAS). AS occur in 5–10% of cases and are due to fibrotic healing. Treatment by ERCP or PTCD with dilatation and progressive stenting is successful in the majority of cases. NAS can occur in the context of a hepatic artery thrombosis, or with an open hepatic artery (ischaemic type biliary lesions or ITBL). The incidence is 5–10%. NAS has been associated with various types of injury, e.g. macrovascular, microvascular, immunological and cytotoxic injury by bile salts. Treatment can be attempted with multiple sessions of dilatation and stenting of stenotic areas by ERCP or PTCD. In cases of localized diseased and good graft function, biliary reconstructive surgery is useful. However, a significant number of patients will need a re-transplant. When biliary strictures or ischaemia of the graft are present, stones, casts and sludge can develop. [ABSTRACT FROM AUTHOR]

Summary: High‐risk combinations of recipient and graft characteristics are poorly defined for liver retransplantation (reLT) in the current era. We aimed to develop a risk model for survival after reLT using data from the European Liver Transplantation Registry, followed by internal and external validation. From 2006 to 2016, 85 067 liver transplants were recorded, including 5581 reLTs (6.6%). The final model included seven predictors of graft survival: recipient age, model for end‐stage liver disease score, indication for reLT, recipient hospitalization, time between primary liver transplantation and reLT, donor age, and cold ischemia time. By assigning points to each variable in proportion to their hazard ratio, a simplified risk score was created ranging 0–10. Low‐risk (0–3), medium‐risk (4–5), and high‐risk (6–10) groups were identified with significantly different 5‐year survival rates ranging 56.9% (95% CI 52.8–60.7%), 46.3% (95% CI 41.1–51.4%), and 32.1% (95% CI 23.5–41.0%), respectively (P < 0.001). External validation showed that the expected survival rates were closely aligned with the observed mortality probabilities. The Retransplantation Risk Score identifies high‐risk combinations of recipient‐ and graft‐related factors prognostic for long‐term graft survival after reLT. This tool may serve as a guidance for clinical decision‐making on liver acceptance for reLT. [ABSTRACT FROM AUTHOR]

A decision to withdraw life-sustaining treatment (WLST) is derived by a conclusion that further treatment will not enable a patient to survive or will not produce a functional outcome with acceptable quality of life that the patient and the treating team regard as beneficial. Although many hospitalized patients die under such circumstances, controlled donation after the circulatory determination of death (cDCDD) programs have been developed only in a reduced number of countries. This International Collaborative Statement aims at expanding cDCDD in the world to help countries progress towards self-sufficiency in transplantation and offer more patients the opportunity of organ donation. The Statement addresses three fundamental aspects of the cDCDD pathway. First, it describes the process of determining a prognosis that justifies the WLST, a decision that should be prior to and independent of any consideration of organ donation and in which transplant professionals must not participate. Second, the Statement establishes the permanent cessation of circulation to the brain as the standard to determine death by circulatory criteria. Death may be declared after an elapsed observation period of 5 min without circulation to the brain, which confirms that the absence of circulation to the brain is permanent. Finally, the Statement highlights the value of perfusion repair for increasing the success of cDCDD organ transplantation. cDCDD protocols may utilize either in situ or ex situ perfusion consistent with the practice of each country. Methods to accomplish the in situ normothermic reperfusion of organs must preclude the restoration of brain perfusion to not invalidate the determination of death. [ABSTRACT FROM AUTHOR]