Correction to: Hyperinflammation Reduces Midazolam Metabolism in Critically Ill Adults with COVID‑19.
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ABSTRACT:
SUBMITTER: Smeets TJL
PROVIDER: S-EPMC11260267 | biostudies-literature | 2024 Jul
REPOSITORIES: biostudies-literature
Publications
Correction to: Hyperinflammation Reduces Midazolam Metabolism in Critically Ill Adults with COVID‑19.
Smeets Tim J L TJL Valkenburg Abraham J AJ van der Jagt Mathieu M Koch Birgit C P BCP Endeman Henrik H Gommers Diederik A M P J DAMPJ Sassen Sebastian D T SDT Hunfeld Nicole G M NGM
Clinical pharmacokinetics 20240701 7
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Project description:Background and objectiveMany patients treated for COVID-19 related acute respiratory distress syndrome in the intensive care unit are sedated with the benzodiazepine midazolam. Midazolam undergoes extensive metabolism by CYP3A enzymes, which may be inhibited by hyperinflammation. Therefore, an exaggerated proinflammatory response, as often observed in COVID-19, may decrease midazolam clearance. To develop a population pharmacokinetic model for midazolam in adult intensive care unit patients infected with COVID-19 and to assess the effect of inflammation, reflected by IL-6, on the pharmacokinetics of midazolam.MethodsMidazolam blood samples were collected once a week between March 31 and April 30 2020. Patients were excluded if they concomitantly received CYP3A4 inhibitors, CYP3A4 inducers and/or continuous renal replacement therapy. Midazolam and metabolites were analyzed with an ultra-performance liquid chromatography-tandem mass spectrometry method. A population pharmacokinetic model was developed, using nonlinear mixed effects modelling. IL-6 and CRP, markers of inflammation, were analyzed as covariates.ResultsThe data were described by a one-compartment model for midazolam and the metabolites 1-OH-midazolam and 1-OH-midazolam-glucuronide. The population mean estimate for midazolam clearance was 6.7 L/h (4.8-8.5 L/h). Midazolam clearance was reduced by increased IL-6 and IL-6 explained more of the variability within our patients than CRP. The midazolam clearance was reduced by 24% (6.7-5.1 L/h) when IL-6 increases from population median 116 to 300 pg/mL.ConclusionsInflammation, reflected by high IL-6, reduces midazolam clearance in critically ill patients with COVID-19. This knowledge may help avoid oversedation, but further research is warranted.
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2022-02-28 | GSE197259 | GEO
Project description:Purpose We aimed to evaluate the relation between admission COVID-19 associated
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Project description:Infections caused by SARS-CoV-2 may cause a severe disease, termed COVID-19, with significant mortality. Host responses to this infection, mainly in terms of systemic inflammation, have emerged as key pathogenetic mechanisms, and their modulation is the only therapeutic strategy that has shown a mortality benefit. Herein, we used peripheral blood transcriptomes of critically-ill COVID-19 patients obtained at admission in an Intensive Care Unit, to identify two clusters that, in spite of no major clinical differences, have different gene expression profiles that reveal different underlying pathogenetic mechanisms and ultimately have different ICU outcome. A transcriptomic signature was used to identify these clusters in an external validation cohort, yielding a similar result. These results illustrate the potential of transcriptomic profiles to identify patient endotypes and point to relevant pathogenetic mechanisms in COVID-19.
2023-04-29 | GSE206264 | GEO
Project description:Infections caused by SARS-CoV-2 may cause a severe disease, termed COVID-19, with significant mortality. Host responses to this infection, mainly in terms of systemic inflammation, have emerged as key pathogenetic mechanisms, and their modulation is the only therapeutic strategy that has shown a mortality benefit. Herein, we used peripheral blood transcriptomes of critically-ill COVID-19 patients obtained at admission in an Intensive Care Unit, to identify two clusters that, in spite of no major clinical differences, have different gene expression profiles that reveal different underlying pathogenetic mechanisms and ultimately have different ICU outcome. A transcriptomic signature was used to identify these clusters in an external validation cohort, yielding a similar result. These results illustrate the potential of transcriptomic profiles to identify patient endotypes and point to relevant pathogenetic mechanisms in COVID-19.
2022-02-28 | GSE197258 | GEO
Project description:Infections caused by SARS-CoV-2 may cause a severe disease, termed COVID-19, with significant mortality. Host responses to this infection, mainly in terms of systemic inflammation, have emerged as key pathogenetic mechanisms, and their modulation is the only therapeutic strategy that has shown a mortality benefit. Herein, we used peripheral blood transcriptomes of critically-ill COVID-19 patients obtained at admission in an Intensive Care Unit, to identify two clusters that, in spite of no major clinical differences, have different gene expression profiles that reveal different underlying pathogenetic mechanisms and ultimately have different ICU outcome. A transcriptomic signature was used to identify these clusters in an external validation cohort, yielding a similar result. These results illustrate the potential of transcriptomic profiles to identify patient endotypes and point to relevant pathogenetic mechanisms in COVID-19.
2022-02-28 | GSE197204 | GEO
Project description:Total plasma IgA glycosylation was compared between healthy volunteers and volunteers suffering fromo infections with either the influenza A virus or the severe acute respiratory syndrome corona virus 2. Data from functional assays of the same plasma samples, such as neutrophil extracellular trap formation is also available.
2024-10-22 | PXD057019 | Pride
Project description:AimsInflammation and organ failure have been reported to have an impact on cytochrome P450 (CYP) 3A-mediated clearance of midazolam in critically ill children. Our aim was to evaluate a previously developed population pharmacokinetic model both in critically ill children and other populations, in order to allow the model to be used to guide dosing in clinical practice.MethodsThe model was evaluated externally in 136 individuals, including (pre)term neonates, infants, children and adults (body weight 0.77-90 kg, C-reactive protein level 0.1-341 mg l-1 and 0-4 failing organs) using graphical and numerical diagnostics.ResultsThe pharmacokinetic model predicted midazolam clearance and plasma concentrations without bias in postoperative or critically ill paediatric patients and term neonates [median prediction error (MPE) <30%]. Using the model for extrapolation resulted in well-predicted clearance values in critically ill and healthy adults (MPE <30%), while clearance in preterm neonates was over predicted (MPE >180%).ConclusionThe recently published pharmacokinetic model for midazolam, quantifying the influence of maturation, inflammation and organ failure in children, yields unbiased clearance predictions and can therefore be used for dosing instructions in term neonates, children and adults with varying levels of critical illness, including healthy adults, but not for extrapolation to preterm neonates.
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Project description:Single-cell RNA-sequencing reveals a shift from focused IFN alpha-driven signals in COVID-19 ICU patients who survive to broad pro-inflammatory responses in fatal COVID-19 – a feature not observed in severe influenza. We conclude that fatal COVID-19 infection is driven by uncoordinated inflammatory responses that drive a hierarchy of T cell activation, elements of which can serve as prognostic indicators and potential targets for immune intervention.
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