Hepatic platelet and leukocyte adherence during endotoxemia

INTRODUCTION: Liver microcirculation disturbances are a cause of hepatic failure in sepsis. Increased leukocyte-endothelial interaction, platelet adherence and impaired microperfusion cause hepatocellular damage. The time course and reciprocal influences of ongoing microcirculatory events during endotoxemia have not been clarified. METHODS: Male Wistar rats (232 ± 17 g) underwent cecal ligation and puncture (CLP). Intravital microscopy (IVM) was performed 0, 1, 3, 5, 10 and 20 hours after CLP. Mean erythrocyte velocity, leukocyte and platelet rolling in postsinusoidal venules and sticking of leukocytes and platelets in postsinusoidal venules and hepatic sinusoids were determined. Heart rate (HR), mean arterial pressure (MAP) and portal venous blood flow (PBF) were measured. Blood count and investigation of hepatic enzyme release was performed after each IVM time point. RESULTS: Hepatic platelet-endothelial adherence in liver sinusoids and postsinusoidal venules occurred one hour after the induction of endotoxemia. Leukocyte-endothelial interaction started three to five hours after CLP. A decrease of hepatic microperfusion could be observed at three hours in sinusoids and ten hours in postsinusoidal venules after CLP, although PBF was reduced one hour after CLP. HR remained stable and MAP decreased ten hours after CLP. Hepatic enzymes in blood were significantly elevated ten hours after CLP. CONCLUSION: Hepatic platelet-endothelial interaction is an early event during endotoxemia. Leukocyte adherence occurs later, which underlines the probable involvement of platelets in leukocyte recruitment. Although PBF is reduced immediately after CLP, the later onset of hepatic microperfusion decrease makes the existence of autoregulatory liver mechanisms likely

Pediatric Cardiac Surgical Patterns of Practice and Outcomes in Europe and China:An Analysis of the European Congenital Heart Surgeons Association Congenital Heart Surgery Database

Background: The European Congenital Heart Surgeons Association (ECHSA) Congenital Heart Surgery Database (CHSD) was founded in 1999 and is open for worldwide participation. The current dataset includes a large amount of surgical data from both Europe and China. Thepurposeofthisanalysisistocomparepatternsof practice and outcomes among pediatric congenital heart defect surgeries in Europe and China using the ECHSA-CHSD. Methods: We examined all European (125 centers, 58,261 operations) and Chinese (13 centers, 23,920 operations) data in the ECHSA-CHSD from 2006-2018. Operative mortality, postoperative length of stay, median patient age and weight were calculated for the ten benchmark operations for China and Europe, respectively. Results: Benchmark procedure distribution frequencies differed between Europe and China. In China, ventricular septal defect repair comprised approximately 70% of procedures, while Norwood operations comprised less than one percent of all procedures. Neonatal cardiac procedures were rare in China overall. For procedures in STAT mortality category 1, Chinese centers had lower operative mortality rates, while procedures in categories 3 and 5 mortality is lower in European centers. Operative mortality over the time period decreased from 3.89% to 1.64% for the whole cohort, with a sharper decline in China. This drop coincides with an increase of submitted procedures over this 13-year-period. Conclusion: Chinese centers had higher program-matic volume of congenital heart surgeries, while European centers have a more complex case mix. Palliation for patients with functionally univentricular heart was performed less commonly in China. These comparison of patterns of practice and outcomes demonstrate opportunities for continuing bidirectional transcontinental collaboration and quality improvement

Pediatric Cardiac Surgical Patterns of Practice and Outcomes in Japan and Europe

Objectives: The Japan Cardiovascular Surgery Database-Congenital section (JCVSD-Congenital) and the European Congenital Heart Surgeons Association (ECHSA) Congenital Heart Surgery Database (CHSD) share the same nomenclature. We aimed at comparing congenital cardiac surgical patterns of practice and outcomes in Japan and Europe using the JCVSD-Congenital and ECHSA-CHSD. Methods and Results: We examined Japanese (120 units, 63,365 operations) and European (96 units, 90,098 operations) data in JCVSD-Congenital and ECHSA-CHSD from 2011 to 2017. Patients' age and weight, periprocedural times, mortality at hospital discharge, and postoperative length of stay were calculated for ten benchmark operations. There was a significantly higher proportion of ventricular septal defect closures and Glenn operations and a significantly lower proportion of coarctation repairs, tetralogy of Fallot repairs, atrioventricular septal defect repairs, arterial switch operations, truncus repairs, Norwood operations, and Fontan operations in JCVSD-Congenital compared to ECHSA-CHSD. Postoperative length of stay was significantly longer following all benchmark operations in JCVSD-Congenital compared to ECHSA-CHSD. Mean STAT mortality score (Society of Thoracic Surgeons European Association for Cardio-Thoracic Surgery mortality score) was significantly higher in JCVSD-Congenital (0.78) compared to ECHSA-CHSD (0.71). Mortality at hospital discharge was significantly lower in JCVSD-Congenital (4.2%) compared to ECHSA-CHSD (6.0%, P < .001). Conclusions: The distribution of the benchmark procedures and age at the time of surgery differ between Japan and Europe. Postoperative length of stay is longer, and the mean complexity is higher in Japan compared to European data. These comparisons of patterns of practice and outcomes demonstrate opportunities for continuing bidirectional transcontinental collaboration and quality improvement

Ranking strategies to support toxicity prediction: a case study on potential LXR binders

The current paradigm of toxicity testing is set within a framework of Mode-of-Action (MoA)/Adverse Outcome Pathway (AOP) investigations, where novel methodologies alternative to animal testing play a crucial role, and allow to consider causal links between molecular initiating events (MIEs), further key events and an adverse outcome. In silico (computational) models are developed to support toxicity assessment within the MoA/AOP framework. This paper focuses on the evaluation of potential binding to the Liver X Receptor (LXR), as this has been identified among the MIEs leading to liver steatosis within an AOP framework addressing repeated dose and target-organ toxicity

Antithrombotic therapy in pediatric ventricular assist devices: Multicenter survey of the European EXCOR Pediatric Investigator Group

Objectives: Mechanical circulatory support for pediatric heart failure patients with the Berlin Heart EXCOR ventricular assist system is the only approved and established bridging strategy for recovery or heart transplantation. In recent years, the burden of thromboembolic events has led to modifications of the recommended antithrombotic therapy. Therefore, we aimed to assess modifications of antithrombotic practice among the European EXCOR Pediatric Investigator Group members. Methods: We sent a questionnaire assessing seven aspects of antithrombotic therapy to 18 European hospitals using the EXCOR device for children. Returned questionnaires were analyzed and identified antithrombotic strategies were descriptively compared to “Edmonton protocol” recommendations developed for the US EXCOR pediatric approval study. Results: Analysis of 18 received surveys revealed substantial deviations from the Edmonton protocol, including earlier start of heparin therapy at 6–12 h postoperatively and in 50% of surveyed centers, monitoring of heparin effectiveness with aPTT assay, administering vitamin K antagonists before 12 months of age. About 39% of centers use higher international normalized ratio targets, and platelet inhibition is changed in 56% including the use of clopidogrel instead of dipyridamole. Significant inter-center variability with multiple deviations from the Edmonton protocol was discovered with only one center following the Edmonton protocol completely. Conclusion: Current antithrombotic practice among European EXCOR users representing the treatment of more than 600 pediatric patients has changed over time with a trend toward a more aggressive therapy. There is a need for systematic evidence-based evaluation and harmonization of developmentally adjusted antithrombotic management practices in prospective studies toward revised recommendations