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Dynamic organ preservation is a relatively old technique which has regained significant interest in the last decade. Machine perfusion (MP) techniques are applied in various fields of solid organ transplantation today. The first clinical series of ex situ MP in liver transplantation was presented in 2010. Since then, the number of research and clinical applications has substantially increased. Despite the notable beneficial effect on organ quality and recipient outcome, MP is still not routinely used in liver transplantation. Based on the enormous need to better preserve organs and the subsequent demand to continuously innovate and develop perfusion equipment further, this technology is also beneficial to test and deliver future therapeutic strategies to livers before implantation. This article summarizes the various challenges observed during the current shift from static to dynamic liver preservation in the clinical setting. The different organ perfusion strategies are discussed first, together with ongoing clinical trials and future study design. The current status of research and the impact of costs and regulations is highlighted next. Factors contributing to costs and other required resources for a worldwide successful implementation and reimbursement are presented third. The impact of research on cost-utility and effectivity to guide the tailored decision-making regarding the optimal perfusion strategy is discussed next. Finally, this article provides potential solutions to the challenging field of innovation in healthcare considering the various social and economic factors and the role of clinical, regulatory, and financial stakeholders worldwide., Competing Interests: J.V.G. consults for and received grants from Organ Recovery Systems (Itasca, IL) and consults for GATT Technologies. The other authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: To summarize key studies in liver preservation published over the last 3 years and evaluate benefits and limitations of the different perfusion techniques. Selected experimental applications that may be translated to the clinical use will be also discussed., Recent Findings: Normothermic machine perfusion (NMP) has transitioned into clinical practice. Viability assessment is a reliable tool for clinical decision-making, and safety of the back-to-base approach has facilitated adoption of the technology. Data supporting well tolerated use of declined livers after NMP and new protocols selecting complex recipients aim to improve access to suitable organs. Hypothermic machine perfusion (HMP) is showing promising clinical results by decreasing biliary complications in recipients' receiving organs donated after circulatory death (DCD) and improving early graft function in extended criteria organs. Long-term data of HMP on DCD livers shows improved graft survival over standard SCS. Novel approaches utilizing sequential HMP--NMP or ischaemia-free preservation aim to improve outcomes of extended criteria organs., Summary: Machine perfusion for organ transplantation has become an established technique but the field is rapidly evolving. Ongoing research focuses on evaluation of the intervention efficacy and finding optimal indications to use each perfusion strategy according to graft type and clinical scenario., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Normothermic machine perfusion (NMP) of liver grafts is increasingly being incorporated in clinical practice. Current evidence has shown NMP plays a role in reconditioning the synthetic and energy capabilities of grafts. Intraoperative coagulation profile is a surrogate of graft quality and preservation status; however, to date this aspect has not been documented., Methods: The liver transplantation recipients who received NMP liver grafts in the QEHB between 2013 and 2016 were compared in terms of intraoperative thromboelastography characteristics (R time, K time, α-angle, maximum amplitude, G value, and LY30) to a propensity score-matched control group, where the grafts were preserved by traditional static cold storage (SCS)., Results: After propensity matching, none of the thromboelastography characteristics were found to differ significantly between the 72 pairs of SCS and NMP organs when measured preimplantation. However, postimplantation, NMP organs had significantly shorter K time (median: 2.8 vs 3.6 min, P = 0.010) and R + K time (11.4 vs 13.7 min, P = 0.016), as well as significantly larger α-angle (55.9° vs 44.8°, P = 0.002), maximum amplitude (53.5 vs 49.6 mm, P = 0.044), and G values (5.8 vs 4.9k dynes/cm, P = 0.043) than SCS organs. Hyperfibrinolysis after implantation was also mitigated by NMP, with fewer patients requiring aggressive factor correction during surgery (LY30 = 0, NMP vs SCS: 83% vs 60%, P = 0.004). Consequently, NMP organs required significantly fewer platelet units to be transfused during the transplant procedure (median: 0 vs 5, P = 0.001)., Conclusions: In this study, we have shown that NMP liver grafts return better coagulation profiles intraoperatively, which could be attributed to the preservation of liver grafts under physiological conditions.

Background: Strategies for successful transplantation are much needed in the era of organ shortage, and there has been a resurgence of interest on the impact of revascularization time (RT) on outcomes in liver transplantation (LT)., Methods: All primary LT performed in Birmingham between 2009 and 2014 (n = 678) with portal reperfusion first were stratified according to RT (<44 minutes vs ≥44 minutes) and graft quality (standard liver graft [SLG], Donor Risk Index < 2.3 vs marginal liver graft [MLG], Donor Risk Index ≥ 2.3)., Results: Revascularization time of 44 minutes or longer resulted in significantly greater incidence of early allograft dysfunction (EAD) (29% vs 47%, P < 0.001), posttransplant acute kidney injury (AKI) (39% vs 60%, P < 0.001), and new-onset AKI (37% vs 56%, P < 0.001), along with poor long-term outcome (3-year graft survival 92% vs 83%, P = 0.001; 3-year patient survival 87% vs 79%, P = 0.004). On multivariable analysis, RT ≥ 44 was a significant independent predictor of EAD, renal dysfunction, and overall graft survival, but not patient survival. The cumulative effect of prolonged revascularization in marginal grafts (MLG) resulted in the worst transplant outcome compared with all other groups, which could be mitigated by rapid revascularization (SLG, SLG, MLG vs MLG; EAD 24%, 39%, 39% vs 69%; AKI 32%, 46%, 51% vs 70%; 3-year graft survival 94%, 87%, 88% vs 70%, respectively; each P < 0.001). Factors associated with lack of abdominal space, larger grafts, and surgical skills were predictive of RT ≥ 44., Conclusions: Shorter graft revascularization is a protective factor in LT, particularly in the setting of graft marginality. Careful graft-recipient matching and emphasis on surgical expertise may aid in achieving better outcomes in LT.

Background: Causes of severe cholestasis after liver transplantation (LT) are multi-factorial. Although the etiology is predictable in some, others culminate in graft/patient loss without a definitive cause identified. Severe cholestasis is usually associated with overlapped histological findings of rejection and biliary features, and diagnostic interpretation may pose a challenge., Methods: This is 10-year retrospective analysis of patients with unexplained severe cholestasis resulting in death/graft loss within 90 days of LT. Of 1 583 LT during the study period, 90-day graft failure occurred in 129 (8%) cases; a total of 45 (3%) patients had unresolving severe cholestasis (bilirubin, >100 μmol/L; alkaline phosphatase, >400 UI/L after 15 days from LT), excluding those due to primary nonfunction/sepsis/vascular causes (n = 84). Demographics, allograft biopsies, radiological investigations, and clinical outcome were analyzed., Results: All patients had persistent abnormal liver biochemistry. Doppler ultrasound scan was normal in all cases. Thirty-five (78%) recipients had at least 1 allograft biopsy (2 [1-9]). On the first biopsy, 22 (63%) patients had acute rejection, 4 (18%) early-chronic rejection, 12 (34%) antibody-mediated rejection. In subsequent biopsies chronic rejection was evident in 5 (14%) cases. Donor-specific antibodies were detected in all patients tested. Biliary anatomy was studied in detail in 9 (20%) patients, all presenting biliary strictures. The majority (n = 39; 87%) died within 32 (10-91) days, only survivors were from retransplantation (n = 3;6.5%) and biliary intervention (n = 3;6.5%)., Conclusions: Unresolving severe cholestasis after LT is a key parameter predicting patient/allograft outcome. Histologically, rejection seems to overlap with biliary strictures; hence, allograft biopsy with signs of rejection should not be a reason to overlook biliary problems, in particular when biliary features are present. Only extensive radiological investigation/intervention or retransplantation prevents patient/allograft loss.

Background: In the United Kingdom, up to 20% of liver graft offers are not used for transplantation, and the reasons for graft refusal are multifactorial and not consistent among transplant units., Methods: Liver grafts previously declined by other transplant centers in the United Kingdom but transplanted in our unit in Birmingham between 2011 and 2015 were analyzed. According to the indicated reason for previous declines, liver grafts were categorized into 3 refusal groups: "quality," "logistics," and "other reasons." Results were compared with a matched, low-risk cohort of livers primarily accepted and transplanted at our center., Results: During the study period, 206 livers (donation after brain death: n = 141 (68.4%); donation after circulatory arrest: n = 65 (31.6%) were transplanted, which were previously discarded by a median of 4 other UK centers. The majority of declines were donor quality (n = 102; 49.5%), refusals followed by logistics (n = 45; 21.8%), and other reasons (n = 59; 28.6%). Transplantation from both graft types (donation after brain death and donation after circulatory arrest) and all 3 refusal groups achieved equally good outcomes with an overall low complication rate. The incidence of primary nonfunction (2.4% vs 1.7%; P = 0.5483), in-hospital mortality (6.3% vs 4.1%; P = 0.2293) and 3-year graft (82.5% vs 84.1%; P = 0.6872) and patient (85.4% vs 87.6%; P = 0.8623) survival was comparable between livers previously declined and livers primarily accepted and transplanted at our center., Conclusions: Transplantation of declined livers can achieve comparable outcomes to primary liver low-risk graft offers. Previous refusal should not be taken as a barrier to use the graft, and with appropriate recipient selection, more lives could be saved.

Background: Normothermic machine perfusion of the liver (NMP-L) is a novel technique that preserves liver grafts under near-physiological conditions while maintaining their normal metabolic activity. This process requires an adequate oxygen supply, typically delivered by packed red blood cells (RBC). We present the first experience using an acellular hemoglobin-based oxygen carrier (HBOC) Hemopure in a human model of NMP-L., Methods: Five discarded high-risk human livers were perfused with HBOC-based perfusion fluid and matched to 5 RBC-perfused livers. Perfusion parameters, oxygen extraction, metabolic activity, and histological features were compared during 6 hours of NMP-L. The cytotoxicity of Hemopure was also tested on human hepatic primary cell line cultures using an in vitro model of ischemia reperfusion injury., Results: The vascular flow parameters and the perfusate lactate clearance were similar in both groups. The HBOC-perfused livers extracted more oxygen than those perfused with RBCs (O2 extraction ratio 13.75 vs 9.43 % ×10 per gram of tissue, P = 0.001). In vitro exposure to Hemopure did not alter intracellular levels of reactive oxygen species, and there was no increase in apoptosis or necrosis observed in any of the tested cell lines. Histological findings were comparable between groups. There was no evidence of histological damage caused by Hemopure., Conclusions: Hemopure can be used as an alternative oxygen carrier to packed red cells in NMP-L perfusion fluid.

Purpose of Review: Normothermic machine perfusion of the liver (NMP-L) is a novel technology recently introduced into the practice of liver transplantation. This review recapitulates benefits of normothermic perfusion over conventional static cold storage and summarizes recent publications in this area., Recent Findings: The first clinical trials have demonstrated both safety and feasibility of NMP-L. They have shown that machine perfusion can entirely replace cold storage or be commenced following a period of cold ischaemia. The technology currently allows transplant teams to extend the period of organ preservation for up to 24 h. Results from the first randomized control trial comparing NMP-L with static cold storage will be available soon. One major advantage of NMP-L technology over other parallel technologies is the potential to assess liver function during NMP-L. Several case series have suggested parameters usable for liver viability testing during NMP-L including bile production and clearance of lactic acidosis. NMP-L allows viability testing of high-risk livers. It has shown the potential to increase utilization of donor organs and improve transplant procedure logistics., Summary: NMP-L is likely to become an important technology that will improve organ preservation as well as have the potential to improve utilization of extended criteria donor livers.

Objective: The primary aim of this study is to evaluate the role of split liver transplantation (SLT) in a combined pediatric and adult liver transplant center. The secondary aim is to reflect on our clinical practice and discuss strategies to build a successful split program using an "intention to split policy.", Background: SLT is an established procedure to expand the organ pool and reduce wait list mortality; however, technical and logistic issues are limiting factors., Methods: Prospectively collected data and outcomes of SLT procedures performed between November 1992 and March 2014 were analyzed retrospectively. To assess the effect of standardization and learning curve, the experience was divided into 2 time periods., Results: Out of 3449 liver transplant procedures performed, 516(15%) were SLT. The recipients included 266 children (290 grafts; 56%) and 212 adults (226 grafts; 44%). The median donor age was 25(7-63 years) and the median weight was 70(22-111 kg). The cold and warm ischemic times improved significantly during the second period (SP) (2001-2014). With experience, there was a significant reduction in the biliary complications for both grafts. The introduction of "intention to split policy" resulted in a significantly increased usage of SLT. There was no mortality on the pediatric wait list for last 4 years. Over the last decade 65% of our pediatric transplants were SLT. The overall 1-, 5-, 10-year patient and graft survival of left graft recipients was 91%, 90%, and 89% and 90%, 87%, and 86%. For right grafts it was 87%, 82%, and 81% and 82%, 81%, and 79%, respectively., Conclusions: SLT is an effective surgical strategy to meet the demands in a combined adult and pediatric transplant center. Good outcomes can be achieved with a standardized technique.

Background: Whilst causes of hepatic artery thrombosis (HAT) after liver transplantation (LT) are multifactorial, early HAT (E-HAT) remains pertinent complication impacting on graft and patient survival. Currently there is no screening tool that would identify patients with increased risk of developing E-HAT., Methods: We analyzed the native procoagulant state of LT recipients, identified through pretransplant thromboelastographic (TEG) data among other known risk factors, to identify risk factors for E-HAT., Results: The outcomes of 828 adult patients undergoing LT between 2008 and 2013 were analyzed. Overall, 79 (9.5%) patients experienced HAT, E-HAT was diagnosed in 23, and in the remainder this was "late" HAT. The maximum amplitude (MA) on preoperative TEG was significantly higher in patients diagnosed with E-HAT compared with those who did not (71.2 mm vs 57.9 mm; P < 0.0001). Receiver operating characteristic analysis with the cutoff value for MA of 65 mm or greater returned area under the curve of 0.750 (P < 0.001) predicting E-HAT with a sensitivity of 70%. A total of 7% of patients with an MA of 65 mm or greater went on to develop E-HAT (hazard ratio, 5.28; 95% confidence interval, 2.10-12.29; P < 0.001), whereas only 1.2% patients with an MA less than 65 mm experienced E-HAT., Conclusions: Preoperative TEG may reliably identify group of recipients at greater risk of developing E-HAT, and intense surveillance and anticoagulation prophylaxis may avoid this serious complication after LT.

Objective: The aims of this study were to verify whether the selective use of staging laparoscopy can prevent unnecessary laparotomy and to find a surrogate marker for surgical unresectability in patients with potentially or borderline resectable pancreatic cancer., Methods: Group A consisted of consecutive 33 patients evaluated between 2005 and 2006 and who directly underwent open laparotomy for planned surgical resection. Group B consisted of consecutive 61 patients evaluated between 2007 and 2009 and of whom 16 patients (26%) had a staging laparoscopy due to the presence of high-risk markers of unresectability defined as carbohydrate antigen 19-9 level 150 U/mL or greater and tumor size 30 mm or greater., Results: The frequency of unnecessary laparotomies for occult distant organ metastasis was significantly different between groups A and B (18% and 3%, respectively; P = 0.021). Of 16 patients who underwent staging laparoscopy in group B, 5 patients (31%) had occult metastases. The multivariate analysis showed that the presence of high-risk markers and extrapancreatic plexus invasion on multidetector-row computed tomography were significant independent risk factors for unresectability., Conclusions: The presence of high-risk markers was associated with surgical unresectability in patients with potentially or borderline resectable pancreatic cancer. The selective use of staging laparoscopy decreased the frequency of unnecessary laparotomy by detecting minute metastases.

Objectives: To examine whether pressure-tight reinforcement of pancreaticojejunostomy (PJ) using polyglycolic acid (PGA) mesh and fibrin glue sealant can reduce the incidence of postoperative pancreatic fistula (POPF)., Methods: The study population included 128 consecutive patients who underwent pancreaticoduodenectomy between September 2006 and January 2010. Postoperative mortality and morbidity among 50 patients who underwent reinforcement of PJ anastomosis using PGA mesh and fibrin glue were compared with 78 patients (historical controls)., Results: The 2 groups demonstrated no significant differences in frequencies of overall or septic complications, reoperation, or in-hospital death. No significant difference in the frequency of POPF, delayed gastric emptying, or intra-abdominal abscess was found between groups. There was no difference between the 2 groups in the number of necessary interventions, and no bleeding complications or POPF-related mortality occurred. The median length of postoperative in-hospital stay between the 2 groups was similar: 13 days (range, 8-101 days) versus 14 days (range, 8-61 days). Similar findings were observed in a subgroup analysis consisting of patients with a pancreatic duct diameter smaller than 3 mm., Conclusion: This retrospective single-center study showed that reinforcement of PJ anastomosis using PGA mesh and fibrin glue provided no significant benefit in reducing the frequency of POPF.

Objectives: After standardization of the perioperative management of pancreaticoduodenectomy, we retrospectively compared results in nonstented pancreaticojejunostomy with external-stented pancreaticojejunostomy., Methods: The study population included 129 consecutive patients who underwent pancreaticoduodenectomy between 2004 and 2008. The postoperative mortality and morbidity were compared between 51 patients with restrictive use of external stenting (group A) and 78 patients without external stenting (group B). The patient with a pancreatic duct of less than 3 mm in diameter was 31% in group A and 46% in group B., Results: There were no differences in postoperative morbidity and mortality between the 2 groups. Although the frequency of overall postoperative pancreatic fistula development was significantly higher in group B than in group A (44% vs 27%, P = 0.0004), there was no difference in grade B/C postoperative pancreatic fistula rate (group A: 5.9% vs group B: 14.1%). The length of in-hospital stay in group B was significantly shorter than group A (13 vs 24 days, P < 0.0001). There were no differences in postoperative morbidity and mortality between subgroups that were consisted of patients with small pancreatic duct diameter., Conclusion: This retrospective single-center study showed that nonstented duct-to-mucosa anastomosis was a safe procedure and was associated with a shortened in-hospital stay.

Objectives: The results of surgical therapy alone for pancreatic cancer are disappointing. We explored surgical results after neoadjuvant chemoradiation therapy (NACRT) for patients with pancreatic cancer that extended beyond the pancreas., Methods: Sixty-eight consecutive patients with pancreatic cancer who underwent pancreatic resection were included. Twenty-seven patients underwent surgical resection after NACRT (NACRT group). The other 41 patients were classified as surgery-alone group. Surgical results were compared in patients who underwent curative resection (R0/1) who were followed up for at least 25 months and underwent no adjuvant therapy., Results: A lower frequency of lymph node metastasis was observed in the NACRT group (P < 0.05). The frequency of residual tumor grading in the NACRT group was significantly different from that in surgery-alone (R0/1/2%, 52/15/33 vs 22/51/27; P = 0.0040). In R0/1 cases, overall survival and disease-free survival rates in the NACRT group (n = 18) were significantly longer than in surgery-alone (n = 30, P < 0.05). The rate of local recurrence in the NACRT group was significantly less than in surgery-alone (11% vs 47%, P = 0.0024)., Conclusions: This single-institution experience indicates that NACRT is able to increase the resectability rate with clear margins and to decrease the rate of metastatic lymph nodes, resulting in improved prognosis of curative cases with pancreatic cancer that extended beyond the pancreas.

Objectives: Pancreaticoduodenectomy (PD) is still associated with high morbidity. To reduce the frequency of postoperative complications, we have made revisions in perioperative managements of pancreaticoduodenectomy., Methods: Subjects were 128 consecutive patients who underwent PD between January 2000 and August 2006. In June 2004, the following new departmental guidelines were introduced: (1) modified Kakita method of pancreaticojejunostomy, (2) omental wrapping, (3) early removal of closed-suction drain, and (4) restrictive use of pancreatic and biliary duct stenting. Operative mortality and morbidity between 77 patients managed conventionally (group A) and 51 patients since 2004 (group B) were compared. Risk factors for postoperative complications were determined., Results: Postoperative morbidity in group B (39%) was significantly lower than in group A (64%; P = 0.019). Occurrence of grade B/C pancreatic fistula (PF) in group B (6%) was significantly lower than in group A (19%; P = 0.0376). Delayed gastric emptying was significantly reduced in group B relative to group A (23% vs 6%; P = 0.0133). Logistic regression analyses showed that the modified Kakita method was a negative independent factor for overall complications, PF, and delayed gastric emptying., Conclusions: The incidence of overall postoperative complications, grade B/C PF, and delayed gastric emptying after PD has been reduced because of the introduction of a new guideline.

Objectives: This study was designed to compare multidetector row computed tomography (MDCT) and CT-assisted hepatic arteriography (CTHA)/CT during arterial portography (CTAP)/angiography/contrast-enhanced CT (CECT) findings prospectively for accuracy in the detection of liver metastasis and vascular involvement of the tumor., Methods: The study included 43 patients with pancreatic cancer who were evaluated from September 2002 to December 2003. These patients underwent preoperative evaluation by angiography/CTHA/CTAP/CECT (7-mm thickness) and by MDCT (1.25-mm thickness)., Results: The sensitivity, specificity, positive predictive value, and negative predictive value of liver metastasis diagnosis were all superior using MDCT relative to CTHA/CTAP. The diagnostic accuracy of liver metastasis for patients with tumors less than 10 mm in diameter was particularly superior with MDCT relative to CTHA/CTAP. The surgical and pathological findings of vascular involvement were more accurately diagnosed by MDCT than by CTHA/CTAP/angiography/CECT. Although MDCT findings were generally similar to surgical findings of vascular involvement, MDCT overestimated the incidence of pathological vascular involvement., Conclusions: Multidetector row CT imaging can potentially offer more accurate staging of pancreatic cancer and may be useful to surgeons both in preoperative planning and for intraoperative guidance.