End-ischemic hypothermic oxygenated perfusion for extended criteria donors in liver transplantation: a multicenter, randomized controlled trial-HOPExt.

BACKGROUND: Given the scarce donor supply, an increasing number of so-called marginal or extended criteria donor (ECD) organs are used for liver transplantation. These ECD liver grafts are however known to be associated with a higher rate of early allograft dysfunction and primary non-function because of a greater vulnerability to ischemia-reperfusion injury. The end-ischemic hypothermic oxygenated machine perfusion (HOPE) technique may improve outcomes of liver transplantation with ECD grafts by decreasing reperfusion injury. METHODS: HOPExt trial is a comparative open-label, multicenter, national, prospective, randomized, controlled study, in two parallel groups, using static cold storage, the gold standard procedure, as control. The trial will enroll adult patients on the transplant waiting list for liver failure or liver cirrhosis and/or liver malignancy requiring liver transplantation and receiving an ECD liver graft from a brain-dead donor. In the experimental group, ECD liver grafts will first undergo a classical static cold (4 °C) storage followed by a hypothermic oxygenated perfusion (HOPE) for a period of 1 to 4 h. The control group will consist of the classic static cold storage which is the gold standard procedure in liver transplantation. The primary objective of this trial is to study the efficacy of HOPE used before transplantation of ECD liver grafts from brain-dead donors in reducing postoperative early allograft dysfunction within the first 7 postoperative days compared to simple cold static storage. DISCUSSION: We present in this protocol all study procedures in regard to the achievement of the HOPExt trial, to prevent biased analysis of trial outcomes and improve the transparency of the trial results. Enrollment of patients in the HOPExt trial has started on September 10, 2019, and is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov NCT03929523. Registered on April 29, 2019, before the start of inclusion.

Early intrahepatic recurrence of HBV infection in liver transplant recipients despite antiviral prophylaxis.

Background & Aims: Prophylaxis with nucleos(t)ide analogues (NUCs) and hepatitis B immunoglobulin (HBIG) has decreased the rate of HBV recurrence after orthotopic liver transplantation (OLT), but the duration of this prophylaxis remains debated. Our aim was to investigate the recurrence of both intrahepatic and serum HBV markers after OLT in patients receiving long-term NUC and HBIG prophylaxis. Methods: A total of 31 HBV-positive patients benefiting from OLT were prospectively enrolled in five French centres between 2012 and 2015. Tissue samples from the native liver, liver reperfusion biopsy, and 12-month post-OLT (M12) biopsy were collected. Intrahepatic HBV markers were quantified using Droplet Digital PCR. Serum hepatitis B core-related antigen (HBcrAg) and HBsAg were quantified using the Lumipulse platform. Results: Among the 31 patients, 26 were HBeAg negative and 28 had undetectable serum HBV DNA at OLT. All patients received HBIG and NUC after OLT, and serum HBV DNA was undetectable at M12. Of the 27 available native livers, 26 had detectable total HBV DNA (median, 0.045 copies/cell), 21 were positive for cccDNA (0.001 copies/cell), and 19 were positive for 3.5-kb HBV RNA (0.0004 copies/cell). Among the 14 sequential reperfusion and M12 biopsies, seven were positive for HBV markers on the reperfusion sampling, and six of them were also positive at M12. Of the 27 patients with available serum samples at M12, eight were positive for HBcrAg and five were positive for HBsAg by ultrasensitive quantification, although they were negative by conventional techniques. Overall, among the 17 patients having a matched biopsy and serum sample at M12, only one had undetectable HBV markers in both the liver and serum. Conclusions: Our results demonstrate a very early detection of viral genome in the graft and intrahepatic viral recurrence despite NUC and HBIG prophylaxis. Clinical Trials Registration: This study is registered at ClinicalTrials.gov (NCT02602847). Impact and Implications: In this work, we show that, despite the recommended prophylaxis based on NUC and HBIG, HBV can infect the new liver very rapidly after transplantation. Twelve months after transplantation, the majority of patients had at least one HBV marker detected in either serum or the liver. Therefore, our results demonstrate early intrahepatic viral recurrence despite NUC and HBIG therapy and underline the importance of an optimal patient compliance to the antiviral prophylaxis to prevent viral rebound.

Effect of intravenous lidocaine on pain after head and neck cancer surgery (ELICO trial): A randomised controlled trial.

BACKGROUND: Treatment of postoperative pain after ear, nose and throat (ENT) cancer surgery is mainly morphine administration. Additional systemic lidocaine has shown promising results in some surgical procedures. OBJECTIVE: The main objective was to evaluate morphine consumption in the first 48 postoperative hours after intra-operative lidocaine infusion during major ENT cancer surgery. DESIGN: A randomised, double-blind, placebo-controlled trial. SETTING: Bicentric study including a university hospital and a major cancer centre, conducted from December 2016 to December 2019. PATIENTS: A total of 144 patients undergoing major ENT cancer surgery were included. INTERVENTION: The patients were randomly assigned to receive intravenous lidocaine or placebo during surgery and in the recovery room. MAIN OUTCOME MEASURES: Endpoints were postoperative morphine consumption in the first 24 and 48 h postoperatively, intra-operative remifentanil consumption, adverse events occurrence and assessment 3 to 6 months after surgery with the McGill pain questionnaire. RESULTS: A total of 118 patients were included (lidocaine n  = 57; placebo n  = 61, 26 patients were excluded). There was no significant difference in morphine consumption during the first 48 postoperative hours in the lidocaine group compared with the placebo group with a median [IQR] of 0.60 [0.30 to 1.03] mg kg -1 vs. 0.57 [0.37 to 0.96] mg kg -1 , total dose 44 [21 to 73.3] mg vs. 38 [23.3 to 56.5] mg, P  = 0.92.There was no significant difference between the two groups in any of the other endpoints, including at follow up 3 to 6 months after surgery. CONCLUSION: Intravenous lidocaine in ENT cancer surgery did not show any additional analgesic or morphine-sparing effect 48 h after surgery. Three to six months after surgery, there was no significant difference in pain scores or consumption of analgesics. Patients treated pre-operatively with opioids were not evaluated in the study. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02894710 and EUDRACT number 2015-005799-90.

Extracorporeal Albumin Dialysis in Liver Failure with MARS and SPAD: A Randomized Crossover Trial.

INTRODUCTION: Liver failure is associated with hepatic and extrahepatic organ failure leading to a high short-term mortality rate. Extracorporeal albumin dialysis (ECAD) aims to reduce albumin-bound toxins accumulated during liver failure. ECAD detoxifies blood using albumin dialysis through an artificial semipermeable membrane with recirculation (molecular adsorbent recirculating system, MARS) or without (single-pass albumin dialysis, SPAD). METHODS: We performed a randomized crossover open trial in a surgical intensive care unit. The primary outcome of the study was total bilirubin reduction during MARS and during SPAD therapies. The secondary outcomes were conjugated bilirubin and bile acid level reduction during MARS and SPAD sessions and tolerance of dialysis system devices. Inclusion criteria were adult patients presenting liver failure with factor V activity <50% associated with bilirubin ≥250 µmol/L and a complication (either hepatic encephalopathy, severe pruritus, or hepatorenal syndrome). For MARS and SPAD, the dialysis flow rate was equal to 1,000 mL/h. RESULTS: Twenty crossovers have been performed. Baseline biochemical characteristics (bilirubin, ammonia, bile acids, creatinine, and urea) were not statistically different between MARS and SPAD. Both ECAD have led to a significant reduction in total bilirubin (-83 ± 67 µmol/L after MARS; -122 ± 118 µmol/L after SPAD session), conjugated bilirubin (-82 ± 61 µmol/L after MARS; -105 ± 96 µmol/L after SPAD session), and bile acid levels (-64 ± 75 µmol/L after MARS; -56 ± 56 µmol/L after SPAD session), all nondifferent comparing MARS to SPAD. CONCLUSION: A simple-to-perform SPAD therapy with equal to MARS dialysate flow parameters provides the same efficacy in bilirubin and bile acid removal. However, clinically relevant endpoints have to be evaluated in randomized trials to compare MARS and SPAD therapies and to define the place of SPAD in the liver failure care program.

Economic Study of 2-Stage Exchange in Patients With Knee or Hip Prosthetic Joint Infection Managed in a Referral Center in France: Time to Use Innovative(s) Intervention(s) at the Time of Reimplantation to Reduce the Risk of Superinfection.

Objective: Chronic prosthetic joint infections (PJI) are serious complications in arthroplasty leading to prosthesis exchange and potential significant costs for health systems, especially if a subsequent new infection occurs. This study assessed the cost of chronic PJI managed with 2-stage exchange at the Lyon University Hospital, CRIOAc Lyon reference center, France. A threshold analysis was then undertaken to determine the reimbursement tariff of a hypothetical preventive device usable at the time of reimplantation, which possibly enables health insurance to save money according to the risk reduction of subsequent new infection. This analysis was also performed for a potential innovative device already available on the market, a dual antibiotic loaded bone cement used to fix cemented prosthesis that releases high concentrations of gentamicin and vancomycin locally (G+V cement). Method: Patients >18 years, admitted for a hip or knee chronic PJI managed with 2-stage exchange, between January 1, 2013, and December 31, 2015, were retrospectively identified. Following, resource consumption in relation to inpatient hospital stay, hospitalization at home, rehabilitation care, outpatient antibiotic treatments, imaging, laboratory analysis, and consultations were identified and collected from patient records and taken into account in the evaluation. Costs were assessed from the French health insurance perspective over the 2 years following prosthesis reimplantation. Results: The study included 116 patients (median age 67 y; 47% hip prosthesis). Mean cost of chronic PJI was estimated over the 2 years following prosthesis reimplantation at €21,324 for all patients, and at €51,697 and €15,745 for patients with (n = 18) and without (n = 98) a subsequent new infection after reimplantation, respectively. According to the threshold analysis the reimbursement tariff (i) should not exceed €2,820 for a device which can reduce the risk of a new infection by 50% and (ii) was between €2,988 and €3,984 if the G + V cement can reduce the risk of a new infection by 80% (this reduction risk is speculative and has to be confirmed by clinical trials). Conclusion: This study revealed that chronic PJI requiring a 2-stage revision is costly, with significant costs in relation to the reimplantation procedure (about 15 k€). However, following reimplantation the rate of subsequent new infection remained high, and the cost of reimplantation following a new infection is considerable, reaching 50k€ per patient. These first cost estimates of managing chronic PJI with 2-stage exchange in France underline the economic interest of preventing new infections.

Efficiency and Safety of an Early Dose Adjustment of Ribavirin in Patients Infected With Hepatitis C Underexposed to the Drug and Treated With Peginterferon Ribavirin.

BACKGROUND: Ribavirin exposure after the first dose (D0AUC0-4h) >1755 mcg·h·L is predictive of sustained virological response (SVR) in patients with hepatitis C treated with peginterferon and ribavirin. The aim of this study was to test the benefit of ribavirin early dose adjustment based on this target in naïve patients infected with genotype 1. METHODS: A multicenter randomized controlled trial with two parallel groups; fixed-dose (FD) group: standard of care in 2010-2011, ie, peginterferon-α2a 180 mcg·wk and weight-based ribavirin 1000-1200 mg/d during 48 weeks; adapted-dose (AD) group: increase of ribavirin dose if D0AUC0-4h <1755 mcg·h·L. RESULTS: A total of 221 patients were included, 110 in the AD group and 111 in the FD group with similar baseline characteristics. In the perprotocol analysis, SVR was higher in the AD group (55.1% versus 40.4%; P = 0.042), especially in patients with D0AUC0-4h <1755 mcg·h·L (54.3% versus 31.9%; P = 0.029). In the intention-to-treat analysis, the difference was not significant (50% versus 41%; P = 0.197). Ribavirin trough concentrations (C0s) at week 4 of treatment (intention-to-treat analysis) were higher in patients achieving SVR (2.06 versus 1.72 mg/L, P = 0.003). In the subgroup of patients with AUC0-4h <1755 mcg·h·L, 46% of patients with AD achieved a C0 >2.0 mg/L versus 22% of patients with FD (P = 0.013). Grade 1 anemia (but not other grades) was more frequent in the AD group (70% versus 48%, P = 0.001). The number of dose reductions or discontinuation of ribavirin was similar in both groups. CONCLUSIONS: Early ribavirin dose adjustment increases SVR in patients underexposed to ribavirin without increasing grade II-IV anemia. Such a strategy could be useful in patients with no access to new antiviral drugs.

Mechanisms of the triglyceride- and cholesterol-lowering effect of fenofibrate in hyperlipidemic type 2 diabetic patients.

In humans, the precise mechanisms of the hypolipidemic action of fenofibrate, a peroxisome proliferator-activated receptor-alpha agonist, remain unclear. To gain insight on these mechanisms, we measured plasma lipids levels, lipids synthesis (hepatic de novo lipogenesis and cholesterol synthesis), and mRNA concentrations in circulating mononuclear cells (RT-PCR) of hydroxymethylglutaryl (HMG)-CoA reductase, LDL receptor, LDL receptor- related protein (LRP), scavenger receptor class B type I (SR-BI), ABCAI, and liver X receptor (LXR)-alpha in 10 control subjects and 9 hyperlipidemic type 2 diabetic patients. Type 2 diabetic subjects were studied before and after 4 months of fenofibrate administration. Fenofibrate decreased plasma triglycerides (P < 0.01) and total cholesterol (P < 0.05) concentrations and slightly increased HDL cholesterol (P < 0.05). Hepatic lipogenesis, largely enhanced in diabetic subjects (16.1 +/- 2.1 vs. 7.5 +/- 1.6% in control subjects, P < 0.01), was decreased by fenofibrate (9.8 +/- 1.5%, P < 0.01). Fractional cholesterol synthesis was normal in diabetic subjects (3.5 +/- 0.4 vs. 3.3 +/- 0.5% in control subjects) and was unchanged by fenofibrate (3.5 +/- 0.5%). Absolute cholesterol synthesis was, however, increased in diabetic subjects before and after fenofibrate (P < 0.05 vs. control subjects). HMG-CoA reductase, LDL receptor, LRP, and SR-BI mRNA concentrations were not different in type 2 diabetic and control subjects and were unchanged by fenofibrate. LXR-alpha mRNA levels were increased (P < 0.05) by fenofibrate. ABCAI mRNA concentrations, which were decreased in diabetic subjects (P < 0.05) before fenofibrate, were increased (P < 0.05) by fenofibrate to values comparable to those of control subjects. The plasma triglyceride-lowering effect of fenofibrate is explained in part by a decrease in hepatic lipogenesis, the moderate fall in total plasma cholesterol is not explained by a reduction of whole-body cholesterol synthesis, and the increase in LXR-alpha and ABCAI mRNA levels suggests that fenofibrate stimulated reverse cholesterol transport.