Fundam Clin Pharmacol. 2026 Jul;40(4):e70108. doi: 10.1111/fcp.70108.
ABSTRACT
BACKGROUND: Midazolam (MDZ) is used for sedation in critically ill patients. Although previous studies have examined MDZ pharmacokinetics in ICU patients, the differential effects of acute kidney injury (AKI) and chronic kidney disease (CKD), particularly in cohorts including COVID-19 and non-COVID-19 patients, remain insufficiently characterised.
OBJECTIVES: To investigate whether AKI and CKD are associated with dose-normalised exposure of MDZ, 1-hydroxy-midazolam (1-OH-MDZ) and 1-hydroxy-midazolam glucuronide (1-OH-MDZ-G) in critically ill adults.
METHODS: In this retrospective observational study, ICU patients receiving continuous intravenous MDZ were included. Plasma concentrations of MDZ, 1-OH-MDZ and 1-OH-MDZ-G were converted to concentration-to-dose (C/D) ratios. Cross-sectional analysis used the first sample per patient; longitudinal analysis included all samples in GEE models. Analyses were adjusted for age, sex, BMI, COVID-19 status, CYP3A4 inhibitor use, APACHE IV score, time since MDZ initiation and CRP.
RESULTS: Forty-seven patients contributed 137 samples. In the cross-sectional analysis, C/D ratios of MDZ and 1-OH-MDZ did not differ between patients with and without AKI, whereas 1-OH-MDZ-G C/D ratios were higher in AKI (median [IQR] 14.54 [6.14-26.20] vs. 4.53 [2.52-6.00]; p < 0.01). Longitudinal analysis showed that AKI (β = 0.87), AKI Stage 1 (β = 0.81), AKI Stages 2-3 (β = 0.97) and CKD (β = 0.72) were all significantly associated with higher 1-OH-MDZ-G C/D ratios (all p ≤ 0.03). No significant associations were observed for MDZ or 1-OH-MDZ.
CONCLUSION: AKI and CKD are associated with accumulation of 1-OH-MDZ-G in critically ill patients. Monitoring 1-OH-MDZ-G may help identify patients at risk of prolonged sedation and adverse outcomes.
PMID:42468972 | DOI:10.1111/fcp.70108