Novel in vitro and mathematical models for the prediction of chemical toxicity

The focus of much scientific and medical research is directed towards understanding the disease process and defining therapeutic intervention strategies. The scientific basis of drug safety is very complex and currently remains poorly understood, despite the fact that adverse drug reactions (ADRs) are a major health concern and a serious impediment to development of new medicines. Toxicity issues account for ∼21% drug attrition during drug development and safety testing strategies require considerable animal use. Mechanistic relationships between drug plasma levels and molecular/cellular events that culminate in whole organ toxicity underpins development of novel safety assessment strategies. Current in vitro test systems are poorly predictive of toxicity of chemicals entering the systemic circulation, particularly to the liver. Such systems fall short because of (1) the physiological gap between cells currently used and human hepatocytes existing in their native state, (2) the lack of physiological integration with other cells/systems within organs, required to amplify the initial toxicological lesion into overt toxicity, (3) the inability to assess how low level cell damage induced by chemicals may develop into overt organ toxicity in a minority of patients, (4) lack of consideration of systemic effects. Reproduction of centrilobular and periportal hepatocyte phenotypes in in vitro culture is crucial for sensitive detection of cellular stress. Hepatocyte metabolism/phenotype is dependent on cell position along the liver lobule, with corresponding differences in exposure to substrate, oxygen and hormone gradients. Application of bioartificial liver (BAL) technology can encompass in vitro predictive toxicity testing with enhanced sensitivity and improved mechanistic understanding. Combining this technology with mechanistic mathematical models describing intracellular metabolism, fluid-flow, substrate, hormone and nutrient distribution provides the opportunity to design the BAL specifically to mimic the in vivo scenario. Such mathematical models enable theoretical hypothesis testing, will inform the design of in vitro experiments, and will enable both refinement and reduction of in vivo animal trials. In this way, development of novel mathematical modelling tools will help to focus and direct in vitro and in vivo research, and can be used as a framework for other areas of drug safety science

Evolving outcomes of extracorporeal membrane oxygenation support for severe COVID-19 ARDS in Sorbonne hospitals, Paris

International audienceBackground: Extracorporeal membrane oxygenation (ECMO) was frequently used to treat patients with severe coronavirus disease-2019 (COVID-19)-associated acute respiratory distress (ARDS) during the initial outbreak. Care of COVID-19 patients evolved markedly during the second part of 2020. Our objective was to compare the characteristics and outcomes of patients who received ECMO for severe COVID-19 ARDS before or after July 1, 2020. Methods: We included consecutive adults diagnosed with COVID-19 in Paris-Sorbonne University Hospital Network ICUs, who received ECMO for severe ARDS until January 28, 2021. Characteristics and survival probabilities over time were estimated during the first and second waves. Pre-ECMO risk factors predicting 90-day mortality were assessed using multivariate Cox regression. Results: Characteristics of the 88 and 71 patients admitted, respectively, before and after July 1, 2020, were comparable except for older age, more frequent use of dexamethasone (18% vs. 82%), high-flow nasal oxygenation (19% vs. 82%) and/or non-invasive ventilation (7% vs. 37%) after July 1. Respective estimated probabilities (95% confidence intervals) of 90-day mortality were 36% (27-47%) and 48% (37-60%) during the first and the second periods. After adjusting for confounders, probability of 90-day mortality was significantly higher for patients treated after July 1 (HR 2.27, 95% CI 1.02-5.07). ECMO-related complications did not differ between study periods. Conclusions: 90-day mortality of ECMO-supported COVID-19-ARDS patients increased significantly after July 1, 2020, and was no longer comparable to that of non-COVID ECMO-treated patients. Failure of prolonged non-invasive oxygenation strategies before intubation and increased lung damage may partly explain this outcome

Prevalence, characteristics and outcome of cardiac manifestations in critically-ill antiphospholipid syndrome patients

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Management of renal replacement therapy among adults in French intensive care units: A bedside practice evaluation

International audienceBackgroundThis study aimed to investigate renal replacement therapy (RRT) practices in a representative nationwide sample of French intensive care units (ICUs).MethodsFrom July 1 to October 5 2021, 67 French ICUs provided data regarding their ICU and RRT implementation. We used an online questionnaire to record general data about each participating ICU, including the type of hospital, number of beds, staff ratios, and RRT implementation. Each center then prospectively recorded RRT parameters from 5 consecutive acute kidney injury (AKI) patients, namely the indication, type of dialysis catheter used, type of catheter lock used, type of RRT (continuous or intermittent), the RRT parameters initially prescribed (dose, blood flow, and duration), and the anticoagulant agent used for the circuit.ResultsA total of 303 patients from 67 ICUs were analyzed. Main indications for RRT were oligo-anuria (57.4%), metabolic acidosis (52.1%), and increased plasma urea levels (47.9%). The commonest insertion site was the right internal jugular (45.2%). In 71.0% of cases, the dialysis catheter was inserted by a resident. Ultrasound guidance was used in 97.0% and isovolumic connection in 90.1%. Citrate, unfractionated heparin, and saline were used as catheter locks in 46.9%, 24.1%, and 21.1% of cases, respectively.ConclusionsPractices in French ICUs are largely compliant with current national guidelines and international literature. The findings should be interpreted in light of the limitations inherent to this type of study