ArticleClinical pharmacokinetics2022
Hyperinflammation Reduces Midazolam Metabolism in Critically Ill Adults with COVID-19.
Article in Clinical pharmacokinetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 10 citations in OpenAlex.
- Association of Acute Kidney Injury and Chronic Kidney Disease With Concentration-To-Dose Ratios of Midazolam and Its Main Metabolites in Critically Ill Adults.Fundamental & clinical pharmacology · 2026Observational
- Sedation as an Immunomodulator of Inflammatory Responses in the Lung-Brain Axis of ARDS.International journal of molecular sciences · 2026Review
- Pharmacogenetics in ICU patients: a short introduction.Intensive care medicine · 2025Article
- Association of NR1I2 Polymorphism with Midazolam Clearance in Mechanically Ventilated ICU Patients: A Population Pharmacokinetic and Pharmacogenetic Study.Drug design, development and therapy · 2025Article
- Pharmacokinetics of Enteral Lormetazepam in Mechanically Ventilated ICU Patients with COVID-19: An Adjunct Sedative Study.Clinical pharmacokinetics · 2024Article
- The relation between inflammatory biomarkers and drug pharmacokinetics in the critically ill patients: a scoping review.Critical care (London, England) · 2024Article
- The Clearance of Midazolam and Metabolites during Continuous Renal Replacement Therapy in Critically Ill Patients with COVID-19.Blood purification · 2024Article
- Usefulness of Inhaled Sedation in Patients With Severe ARDS Due to COVID-19.Respiratory care · 2023Article
Corrections and comments
- Erratum issued
Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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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