Portable hypothermic oxygenated machine perfusion for organ preservation in liver transplantation: A randomized, open-label, clinical trial.

BACKGROUND AND AIMS: In liver transplantation, cold preservation induces ischemia, resulting in significant reperfusion injury. Hypothermic oxygenated machine perfusion (HMP-O 2 ) has shown benefits compared to static cold storage (SCS) by limiting ischemia-reperfusion injury. This study reports outcomes using a novel portable HMP-O 2 device in the first US randomized control trial. APPROACH AND RESULTS: The PILOT trial (NCT03484455) was a multicenter, randomized, open-label, noninferiority trial, with participants randomized to HMP-O 2 or SCS. HMP-O 2 livers were preserved using the Lifeport Liver Transporter and Vasosol perfusion solution. The primary outcome was early allograft dysfunction. Noninferiority margin was 7.5%. From April 3, 2019, to July 12, 2022, 179 patients were randomized to HMP-O 2 (n=90) or SCS (n=89). The per-protocol cohort included 63 HMP-O 2 and 73 SCS. Early allograft dysfunction occurred in 11.1% HMP-O 2 (N=7) and 16.4% SCS (N=12). The risk difference between HMP-O 2 and SCS was -5.33% (one-sided 95% upper confidence limit of 5.81%), establishing noninferiority. The risk of graft failure as predicted by Liver Graft Assessment Following Transplant score at seven days (L-GrAFT 7 ) was lower with HMP-O 2 [median (IQR) 3.4% (2.4-6.5) vs. 4.5% (2.9-9.4), p =0.024]. Primary nonfunction occurred in 2.2% of all SCS (n=3, p =0.10). Biliary strictures occurred in 16.4% SCS (n=12) and 6.3% (n=4) HMP-O 2 ( p =0.18). Nonanastomotic biliary strictures occurred only in SCS (n=4). CONCLUSIONS: HMP-O 2 demonstrates safety and noninferior efficacy for liver graft preservation in comparison to SCS. Early allograft failure by L-GrAFT 7 was lower in HMP-O 2 , suggesting improved early clinical function. Recipients of HMP-O 2 livers also demonstrated a lower incidence of primary nonfunction and biliary strictures, although this difference did not reach significance.

Biliary atresia and liver transplantation in the United States: A contemporary analysis.

BACKGROUND: Biliary atresia (BA) remains the number one indication for paediatric liver transplantation (LT) worldwide but is an uncommon indication for older LT recipients. The impact of recent donor allocation changes, pervasive organ shortage and evolving LT practices on the BA LT population is unknown. METHODS: We identified patients who underwent LT between January 2010 and December 2021 using the UNOS database. We compared clinical outcomes between patients with BA and those with non-BA cholestatic liver disease. Groups were stratified by age, <12 years (allocated via PELD system) and ≥12 years (allocated via MELD system). Waitlist outcomes were compared using competing-risk regression analysis, graft survival rates were compared using Kaplan-Meier time-to-event analysis and Cox proportional hazards modelling provided adjusted estimates. RESULTS: There were 2754 BA LT waitlist additions and 2206 BA LTs (1937 <12 years [younger], 269 ≥12 years [older]). There were no differences in waitlist mortality between BA and non-BA cholestatic patients. Among BA LT recipients, there were 441 (20.0%) living-donor liver transplantations (LDLT) and 611 (27.7%) split deceased-donor LTs. Five-year graft survival was significantly higher among BA versus non-BA cholestatic patients in the older group (88.3% vs. 79.5%, p < .01) but not younger group (89.3% vs. 89.5%). Among BA LT recipients, improved graft outcomes were associated with LDLT (vs. split LT: HR: 2, 95% CI: 1.03-3.91) and higher transplant volume (volume >100 vs. <40 BA LTs: HR: 3.41, 95% CI: 1.87-6.2). CONCLUSION: Liver transplant outcomes among BA patients are excellent, with LDLT and higher transplant centre volume associated with optimal graft outcomes.

Hepatic Stellate Cells Directly Inhibit B Cells via Programmed Death-Ligand 1.

We demonstrated previously that mouse hepatic stellate cells (HSCs) suppress T cells via programmed death-ligand 1 (PD-L1), but it remains unknown whether they exert any effects on B cells, the other component of the adaptive immune system. In this study, we found that mouse HSCs directly inhibited B cells and that PD-L1 was also integrally involved. We found that HSCs inhibited the upregulation of activation markers on activated B cells, as well as the proliferation of activated B cells and their cytokine/Ig production in vitro, and that pharmaceutically or genetically blocking the interaction of PD-L1 with programmed cell death protein 1 impaired the ability of HSCs to inhibit B cells. To test the newly discovered B cell-inhibitory activity of HSCs in vivo, we developed a protocol of intrasplenic artery injection to directly deliver HSCs into the spleen. We found that local delivery of wild-type HSCs into the spleens of mice that had been immunized with 4-hydroxy-3-nitrophenylacetyl-Ficoll, a T cell-independent Ag, significantly suppressed Ag-specific IgM and IgG production in vivo, whereas splenic artery delivery of PD-L1-deficient HSCs failed to do so. In conclusion, in addition to inhibiting T cells, mouse HSCs concurrently inhibit B cells via PD-L1. This direct B cell-inhibitory activity of HSCs should contribute to the mechanism by which HSCs maintain the liver's immune homeostasis.

Hemophilia Liver Transplantation Observational Study.

Hepatitis C virus (HCV) infection is the leading cause of liver disease in hemophilia patients. In those with human immunodeficiency virus (HIV)/HCV coinfection, the rate of liver disease progression is greater than in HCV monoinfected individuals. Despite antiretroviral therapy, which slows HCV liver disease progression, some require transplantation. Whether transplant outcomes are worse in hemophilic (H) rather than nonhemophilic (NH) candidates is unknown. In order to determine rates and predictors of pretransplant and posttransplant survival, we conducted a retrospective observational study using United Network for Organ Sharing national transplant registry data, comparing HCV+ H and NH candidates. We identified 2502 HCV+ liver transplant candidates from 8 US university-based transplant centers, between January 1, 2004 to December 31, 2010, including 144 HIV+ (6%) and 2358 HIV-; 36 H (1%) and 2466 NH; 1213 (48%) transplanted and 1289 not transplanted. Other than male predominance and younger age, each were P < 0.001. Baseline data were comparable between H and NH. In univariate analysis, 90-day pretransplant mortality was associated with higher baseline Model for End-Stage Liver Disease (MELD; hazard ratio [HR] = 1.15; P < 0.001), lower baseline platelet count (HR = 0.9 per 25,000/µL; P = 0.04), and having HIV/HCV+ hemophilia (P = 0.003). In multivariate analysis, pretransplant mortality was associated with higher MELD (P < 0.001) and was significantly greater in HIV+ than HIV- groups (P = 0.001). However, it did not differ between HIV+ H and NH (HR = 1.7; P = 0.36). Among HIV/HCV+, posttransplant mortality was similar between H and NH, despite lower CD4 in H (P = 0.04). In conclusion, this observational study confirms that hemophilia per se does not have a specific influence on transplant outcomes and that HIV infection increases the risk of mortality in both H and NH patients. Liver Transplantation 23 762-768 2017 AASLD.

Liver transplantation for unresectable colorectal liver metastases: A systematic review.

The use of liver transplantation (LT) for liver metastases attempted in the early 1990's was associated with poor perioperative outcomes and unacceptably low overall survival. Recently, there has been renewed interest in LT as a treatment option for colorectal liver metastases (CLM) in countries where organ supply is high. To date, no meticulous analysis about the efficacy, safety and outcomes of LT in CLM patients has been published. We present the first systematic review on the subject.

Hepatic Stellate Cells Inhibit T Cells through Active TGF-ß1 from a Cell Surface-Bound Latent TGF-ß1/GARP Complex.

Hepatic stellate cells (HSCs) inhibit T cells, a process that could help the liver to maintain its immunoprivileged status. HSCs secrete latent TGF-ß1, but the detailed mechanisms by which latent TGF-ß1 is activated and whether it plays any role in HSC-mediated T cell suppression remain unclear. Glycoprotein A repetitions predominant (GARP) is a surface marker of activated regulatory T cells. GARP binds latent TGF-ß1 for its activation, which is critical for regulatory T cells to suppress effector T cells; however, it is still unclear whether GARP is present on HSCs and whether it has any impact on HSC function. In this study, we found that TGF-ß1(+/-) HSCs, which produce reduced levels of TGF-ß1, showed decreased potency in inhibiting T cells. We also found that pharmaceutical or genetic inhibition of the TGF-ß1 signaling pathway reduced the T cell-inhibiting activity of HSCs. Additionally, using isolated primary HSCs, we demonstrated that GARP was constitutively expressed on HSCs. Blocking GARP function or knocking down GARP expression significantly impaired the potency of HSCs to suppress the proliferation of and IFN-γ production from activated T cells, suggesting that GARP is important for HSCs to inhibit T cells. These results demonstrate the unexpected presence of GARP on HSCs and its significance in regard to the ability of HSCs to activate latent TGF-ß1 and thereby inhibit T cells. Our study reveals a new mechanism for HSC-mediated immune regulation and potentially for other conditions, such as liver fibrosis, that involve HSC-secreted TGF-ß1.

Role of donor hemodynamic trajectory in determining graft survival in liver transplantation from donation after circulatory death donors.

Donation after circulatory death (DCD) donors show heterogeneous hemodynamic trajectories following withdrawal of life support. Impact of hemodynamics in DCD liver transplant is unclear, and objective measures of graft viability would ease transplant surgeon decision making and inform safe expansion of the donor organ pool. This retrospective study tested whether hemodynamic trajectories were associated with transplant outcomes in DCD liver transplantation (n = 87). Using longitudinal clustering statistical techniques, we phenotyped DCD donors based on hemodynamic trajectory for both mean arterial pressure (MAP) and peripheral oxygen saturation (SpO2 ) following withdrawal of life support. Donors were categorized into 3 clusters: those who gradually decline after withdrawal of life support (cluster 1), those who maintain stable hemodynamics followed by rapid decline (cluster 2), and those who decline rapidly (cluster 3). Clustering outputs were used to compare characteristics and transplant outcomes. Cox proportional hazards modeling revealed hepatocellular carcinoma (hazard ratio [HR] = 2.53; P = 0.047), cold ischemia time (HR = 1.50 per hour; P = 0.027), and MAP cluster 1 were associated with increased risk of graft loss (HR = 3.13; P = 0.021), but not SpO2 cluster (P = 0.172) or donor warm ischemia time (DWIT; P = 0.154). Despite longer DWIT, MAP and SpO2 clusters 2 showed similar graft survival to MAP and SpO2 clusters 3, respectively. In conclusion, despite heterogeneity in hemodynamic trajectories, DCD donors can be categorized into 3 clinically meaningful subgroups that help predict graft prognosis. Further studies should confirm the utility of liver grafts from cluster 2. Liver Transplantation 22 1469-1481 2016 AASLD.

Rejection triggers liver transplant tolerance: Involvement of mesenchyme-mediated immune control mechanisms in mice.

UNLABELLED: Liver tolerance was initially recognized by the spontaneous acceptance of liver allografts in many species. The underlying mechanisms are not completely understood. However, liver transplant (LT) tolerance absolutely requires interferon (IFN)-γ, a rejection-associated inflammatory cytokine. In this study, we investigated the rejection of liver allografts deficient in the IFN-γ receptor and reveal that the liver graft is equipped with machineries capable of counterattacking the host immune response through a mesenchyme-mediated immune control (MMIC) mechanism. MMIC is triggered by T effector (Tef) cell-derived IFN-γ that drives expression of B7-H1 on graft mesenchymal cells leading to Tef cell apoptosis. We describe the negative feedback loop between graft mesenchymal and Tef cells that ultimately results in LT tolerance. Comparable elevations of T-regulatory cells and myeloid-derived suppressor cells were observed in both rejection and tolerance groups and were not dependent on IFN-γ stimulation, suggesting a critical role of Tef cell elimination in tolerance induction. We identify potent MMIC activity in hepatic stellate cells and liver sinusoidal endothelial cells. MMIC is unlikely exclusive to the liver, given that spontaneous acceptance of kidney allografts has been reported, although less commonly, probably reflecting variance in MMIC activity. CONCLUSION: MMIC may represent an important homeostatic mechanism that supports peripheral tolerance and could be a target for the prevention and treatment of transplant rejection. This study highlights that the graft is an active participant in the equipoise between tolerance and rejection and warrants more attention in the search for tolerance biomarkers.

Liver transplantation for nonalcoholic steatohepatitis in young patients.

Nonalcoholic steatohepatitis (NASH) is the hepatic manifestation of obesity and insulin resistance. The aim of this study was to determine the frequency of NASH as an indication for liver transplantation (LT) in children and young adults and to characterize patient and graft survival. The study included all children and young adult patients (up to the age of 40 years) who underwent LT in the United States for NASH cirrhosis from the 1987 to 2012 United Network for Organ Sharing (UNOS) database. Kaplan-Meier analysis was used to assess patient and graft survival. A total of 330 patients were included, 68% were Caucasian, and the mean BMI was 33.6 ± 6.3. Age at time of LT ranged between 4 and 40 years (mean 33.9 ± 6.6 years). Fourteen subjects were <18 years of age at time of LT and 20 were between the ages of 18 and 25 years. Median follow-up after 1st LT was 45.8 months [10.7, 97.3]. During this time, 30% of subjects (n = 100) died and 11.5% (n = 38) were retransplanted including 13 for NASH recurrence. In conclusion, NASH can progress to end-stage liver disease requiring LT in childhood and early adulthood. A significant number of young patients transplanted for NASH cirrhosis required retransplantation.

All-trans retinoic acid induces arginase-1 and inducible nitric oxide synthase-producing dendritic cells with T cell inhibitory function.

Hepatic stellate cells (HSC) are a major source of the immunoregulatory metabolite all-trans retinoic acid (ATRA), which may contribute to the generation of tolerogenic dendritic cells (DCs) in the liver. The present study seeks to clarify the mechanism(s) through which ATRA promotes the development of tolerogenic DCs. Although bone marrow-derived ATRA-treated DCs (RA-DCs) and conventional DCs had comparable surface phenotype, RA-DCs had diminished stimulatory capacity and could directly inhibit the expansion of DC/OVA-stimulated OT-II T cells. Arginase-1 (Arg-1) was found promote suppression because 1) ATRA was a potent inducer of Arg-1 protein and activity, 2) the Arg-1 inhibitor N(w)-hydroxy nor-l-arginine partially reversed suppression, and 3) the suppressive function of RA-DCs was partially compromised using OT-II T cells from GCN2(-/-) mice, which are insensitive to Arg-1. Inducible NO synthase (iNOS), however, was found to be a more significant contributor to RA-DC function because 1) ATRA potentiated the expression of IFN-γ-induced iNOS, 2) suppressive function in RA-DCs was blocked by the iNOS inhibitor N(G)-monomethyl-l-arginine, monoacetate salt, and 3) RA-DCs derived from iNOS(-/-) mice exhibited near complete loss of tolerogenic function, despite sustained Arg-1 activity. The expression of iNOS and the suppressive function of RA-DCs were dependent on both IFN-γ and ATRA. Furthermore, the in vivo behavior of RA-DCs proved to be consistent with their in vitro behavior. Thus, we conclude that ATRA enhances both Arg-1 and iNOS expression in IFN-γ-treated DCs, resulting in a tolerogenic phenotype. These findings elucidate mechanisms through which ATRA may contribute to liver immune tolerance.

Myeloid-derived suppressor cells as a potential therapy for experimental autoimmune myasthenia gravis.

We recently demonstrated that hepatic stellate cells induce the differentiation of myeloid-derived suppressor cells (MDSCs) from myeloid progenitors. In this study, we found that adoptive transfer of these MDSCs effectively reversed disease progression in experimental autoimmune myasthenia gravis (EAMG), a T cell-dependent and B cell-mediated model for myasthenia gravis. In addition to ameliorated disease severity, MDSC-treated EAMG mice showed suppressed acetylcholine receptor (AChR)-specific T cell responses, decreased levels of serum anti-AChR IgGs, and reduced complement activation at the neuromuscular junctions. Incubating MDSCs with B cells activated by anti-IgM or anti-CD40 Abs inhibited the proliferation of these in vitro-activated B cells. Administering MDSCs into mice immunized with a T cell-independent Ag inhibited the Ag-specific Ab production in vivo. MDSCs directly inhibit B cells through multiple mechanisms, including PGE2, inducible NO synthase, and arginase. Interestingly, MDSC treatment in EAMG mice does not appear to significantly inhibit their immune response to a nonrelevant Ag, OVA. These results demonstrated that hepatic stellate cell-induced MDSCs concurrently suppress both T and B cell autoimmunity, leading to effective treatment of established EAMG, and that the MDSCs inhibit AChR-specific immune responses at least partially in an Ag-specific manner. These data suggest that MDSCs could be further developed as a novel approach to treating myasthenia gravis and, even more broadly, other diseases in which T and B cells are involved in pathogenesis.

The effect of Guidelines in surgical decision making: The paradigm of hepatocellular carcinoma.

It is not inconceivable to envision surgeons, offering extended liver resection in patients beyond the Barcelona Clinic Liver Cancer (BCLC) staging system criteria with intermediate/advanced hepatocellular carcinoma (HCC), to be found negligent since extensive liver resection is correlated with increased morbidity compared to conservative or palliative treatment. Given that no other classification system than BCLC has been adopted widely for HCC staging and treatment, a revision of the BCLC algorithm and clinical guidelines should be tailored using new molecular and clinical treatment algorithms, as well as including patient's preferences.

Impact of donor age in liver transplantation from donation after circulatory death donors: A decade of experience at Cleveland Clinic.

The use of liver grafts from donation after circulatory death (DCD) donors remains controversial, particularly with donors of advanced age. This retrospective study investigated the impact of donor age in DCD liver transplantation. We examined 92 recipients who received DCD grafts and 92 matched recipients who received donation after brain death (DBD) grafts at Cleveland Clinic from January 2005 to June 2014. DCD grafts met stringent criteria to minimize risk factors in both donors and recipients. The 1-, 3-, and 5-year graft survival in DCD recipients was significantly inferior to that in DBD recipients (82%, 71%, 66% versus 92%, 87%, 85%, respectively; P = 0.03). Six DCD recipients (7%), but no DBD recipients, experienced ischemic-type biliary stricture (P = 0.01). However, the incidence of biliary stricture was not associated with donor age (P = 0.57). Interestingly, recipients receiving DCD grafts from donors who were <45 years of age (n = 55) showed similar graft survival rates compared to those receiving DCD grafts from donors who were ≥45 years of age (n = 37; 80%, 69%, 66% versus 83%, 72%, 66%, respectively; P = 0.67). Cox proportional hazards modeling in all study populations (n = 184) revealed advanced donor age (P = 0.05) and the use of a DCD graft (P = 0.03) as unfavorable factors for graft survival. Logistic regression analysis showed that the risk of DBD graft failure increased with increasing age, but the risk of DCD graft failure did not increase with increasing age (P = 0.13). In conclusion, these data suggest that stringent donor and recipient selection may ameliorate the negative impact of donor age in DCD liver transplantation. DCD grafts should not be discarded because of donor age, per se, and could help expand the donor pool for liver transplantation.

The role of complement component 3 (C3) in differentiation of myeloid-derived suppressor cells.

Myeloid-derived suppressor cells (MDSCs) play an important role in the regulation of the immune response. MDSC expansion occurs in many circumstances, including cancer, inflammation, stresses, and transplant tolerance. Liver transplants in mice are spontaneously accepted, but hepatocyte transplants are acutely rejected, suggesting the immunoregulatory activities of liver nonparenchymal cells. We have reported that hepatic stellate cells (HpSCs), the stromal cells in the liver, are immensely immunosuppressive and can effectively protect islet transplants via induction of MDSCs. The present study shows that the addition of HpSCs into dendritic cell (DC) culture promoted development of MDSCs, instead of DCs, which was highly dependent on complement component 3 (C3) from HpSCs. The C3(-/-) HpSCs lost their ability to induce MDSCs and, consequently, failed to protect the cotransplanted islet allografts. HpSCs produced complement activation factor B and factor D which then enhanced C3 cleavage to activation products iC3b and C3d. Addition of exogenous iC3b, but not C3d, into the DC culture led to the differentiation of MDSCs with potent immune-inhibitory function. These findings provide novel mechanistic insights into the differentiation of myeloid cells mediated by local tissue cells, and may assist in the development of MDSC-based therapy in clinical settings.

Enhancing kidney function with thrombolytic therapy following donation after cardiac death: a multicenter quasi-blinded prospective randomized trial.

Kidneys from donors after cardiac death (DCD) are at risk for inferior outcomes, possibly due to microthrombi and additional warm ischemia. We describe an organ procurement organization-wide trial utilizing thrombolytic tissue plasminogen activator (tPA) during machine pulsatile perfusion (MPP). A kidney from each recovered kidney pair was prospectively randomized to receive tPA (50 mg Alteplase) or no tPA (control) in the MPP perfusate. From 2011 to 2013, 24 kidneys were placed with enrolled recipients from 19 DCD kidney donors. There were no significant differences for absolute values of flow or resistance while undergoing MPP between the groups, nor rates of achieving discrete flow and resistance targets. While there was a trend toward lower creatinine and higher glomerular filtration rates in the tPA group at 3, 6, 9, and 12 months, these differences were not significant. Delayed graft function (DGF) rates were 41.7% in the tPA group vs. 58.4% in the control group (OR 0.51, 95%CI 0.10-2.59, p = 0.68). Death-censored graft survival was similar between the groups. In this pilot study, encouraging trends are seen in kidney allograft function independent of MPP parameters following DCD kidney transplantation for those kidneys receiving thrombolytic tPA and MPP, compared with standard MPP.

Stearoyl-CoA desaturase plays an important role in proliferation and chemoresistance in human hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is often diagnosed at an advanced stage, when it is not amenable for aggressive therapies such as surgical resection or liver transplantation. Current therapeutic options achieve clinical responses in only a small percentage of cases. As a consequence, effective approaches for prevention and treatment are greatly needed. Altered lipid metabolism has been recently linked to HCC pathogenesis. The aims of this study were to define the cellular and molecular mechanisms linking stearoyl-CoA desaturase (SCD), the rate-limiting enzyme and an essential regulator of lipid homeostasis in liver cells, to carcinogenesis in HCC. MATERIAL AND METHODS: HCC and normal liver specimens were collected. Human HCC cell lines: HepG2, Hep3B, and PLC/PLF/5 were used for immunoblot, cell viability, proliferation, and apoptosis assays. Small interfering RNAs were used for genetic inhibition, and 10, 12 conjugated linoleic acid was used for pharmacologic SCD inhibition. RESULTS: SCD was strongly expressed in surgically resected HCC (n = 64) and various human HCC cell lines (HepG2, Hep3B, and PLC/PLF/5). The levels of SCD negatively correlated with degree of tumor differentiation (P < 0.01). Treatment of these HCC cell lines with a panel of chemotherapeutic drugs resulted in a time-dependent, phosphatidylinositol 3 kinase- and c-Jun N-terminal kinases1/2-mediated upregulation of SCD expression, which paralleled the degree of resistance to drug-induced apoptosis. Specific genetic or pharmacologic SCD suppression resulted in inhibition of cell proliferation (P < 0.001) and significantly increased sensitivity to chemotherapy-induced apoptosis. CONCLUSIONS: Our data suggest that increased SCD expression plays an important role in HCC development and resistance to chemotherapy-induced apoptosis, and this is in part mediated by phosphatidylinositol 3 kinase/c-Jun N-terminal kinases activation. Specific targeted interruption of this pathway in HCC could be a desirable approach in designing novel therapeutic strategies.

Oxygen consumption predicts outcome in porcine partial liver grafts.

BACKGROUND: High oxygen consumption (OC) in recipients of cadaveric whole liver grafts is associated with a poor prognosis. The aim of this study is to investigate the relationship between intraoperative hepatic OC and graft function and survival in a porcine partial liver graft model. MATERIAL AND METHODS: Experiments followed the Guiding Principles in the Care and Use of Laboratory Animals. Fourteen female pigs, 46-69 kg, received liver allografts of 17%-39% liver volume and were followed for 14 d. We measured donor and recipient body weights, percentage graft weight and expressed it as a percentage of standard liver volume, cold ischemia time, hepatic artery flow (HAF), portal vein flow (PVF), graft volume at sacrifice, serum lactate, prothrombin time, aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine, albumin, total protein, alkaline phosphatase, total bilirubin, and recipient survival. OC was calculated as follows: OC (mL/100 g/min) = ([Hemoglobin {Hb} × 1.34 × SaO2 + 0.003 × PaO2] × HAF + [Hb × 1.34 × SpO2 + 0.003 × PpO2] × PVF - [Hb × 1.34 × SvO2 + 0.003 × PvO2] × [HAF + PVF])/graft weight (100 g), and animals were divided into two groups: low OC group (OC < 2.0 mL/100 g/min) and high OC group (OC ≥ 2.0 mL/100 g/min). RESULTS: In survival analysis, four of seven low OC recipients (57% [n = 7]) survived until the end of the study period compared with one of seven high OC recipients (14% [n = 7]). The low OC group had a significantly higher survival rate than that of the high OC group (P = 0.041). Low OC was associated with higher HAF (mL/100 g/min) after reperfusion compared with that of the high OC group, 29.0 ± 13.8 versus 16.0 ± 11.1 mean ± standard deviation; P = 0.073. Serum alkaline phosphatase and total bilirubin in the low OC group were significantly better than those of the high OC group. Serum lactate was comparable in both groups. Graft weight at the time of sacrifice in the low OC group tended to be higher than that in the high OC group, but not significantly (P = 0.097). CONCLUSIONS: High intraoperative OC is associated with lower HAF, decreased graft function, and decreased survival in the porcine partial liver graft model.

Piperacillin/tazobactam for surgical prophylaxis during pancreatoduodenectomy: meta-analysis.

BACKGROUND: Pancreatoduodenectomy is associated with an increased incidence of surgical-site infections, often leading to a significant rise in morbidity and mortality. This trend underlines the inadequacy of traditional antibiotic prophylaxis strategies. Hence, the aim of this meta-analysis was to assess the outcomes of antimicrobial prophylaxis, comparing piperacillin/tazobactam with traditional antibiotics. METHODS: Upon registering in PROSPERO, the international prospective register of systematic reviews (CRD42023479100), a systematic search of various databases was conducted over the interval 2000-2023. This inclusive search encompassed a wide range of study types, including prospective and retrospective cohorts and RCTs. The subsequent data analysis was carried out utilizing RevMan 5.4. RESULTS: A total of eight studies involving 2382 patients who underwent pancreatoduodenectomy and received either piperacillin/tazobactam (1196 patients) or traditional antibiotics (1186 patients) as antibiotic prophylaxis during surgery were included in the meta-analysis. Patients in the piperacillin/tazobactam group had significantly reduced incidences of surgical-site infections (OR 0.43 (95% c.i. 0.30 to 0.62); P < 0.00001) and major surgical complications (Clavien-Dindo grade greater than or equal to III) (OR 0.61 (95% c.i. 0.45 to 0.81); P = 0.0008). Subgroup analysis of surgical-site infections highlighted significantly reduced incidences of superficial surgical-site infections (OR 0.34 (95% c.i. 0.14 to 0.84); P = 0.02) and organ/space surgical-site infections (OR 0.47 (95% c.i. 0.28 to 0.78); P = 0.004) in the piperacillin/tazobactam group. Further, the analysis demonstrated significantly lower incidences of clinically relevant postoperative pancreatic fistulas (grades B and C) (OR 0.67 (95% c.i. 0.53 to 0.83); P = 0.0003) and mortality (OR 0.51 (95% c.i. 0.28 to 0.91); P = 0.02) in the piperacillin/tazobactam group. CONCLUSION: Piperacillin/tazobactam as antimicrobial prophylaxis significantly lowers the risk of postoperative surgical-site infections, major surgical complications (complications classified as Clavien-Dindo grade greater than or equal to III), clinically relevant postoperative pancreatic fistulas (grades B and C), and mortality, hence supporting the implementation of piperacillin/tazobactam for surgical prophylaxis in current practice.