Midazolam Metabolism: Implications for Individualised Dosing?

Abstract

Aim To compare the clearance of midazolam and its metabolites in critically ill paediatric and adult patients. Method A prospective study conducted in paediatric and adult intensive care units. Patients over 2 years of age receiving midazolam for therapeutic sedation were eligible for enrolment. Midazolam and its metabolite concentrations were determined in plasma and urine. Results The median (interquartile range) steady‐state concentrations observed in the paediatric and adult groups were 90 mg/L (48–135) and 253 mg/L (148–404), respectively (p = 0.90). The median daily doses were 1.8 mg/kg (0.6–2.2) and 1.9 mg/kg (0.6–2.7), respectively (p = 0.84). Midazolam clearance in paediatric and adult patients was 1.1 mL/kg/min (0.9–3.8) and 2.9 mL/kg/min (0.9–3.8), respectively. Analysis of clearances by age identified two peaks in midazolam and its metabolites occurring around 12 years of age and at 45 years of age. Neither midazolam nor its metabolites appeared to accumulate in blood after long courses of treatment (> 3 days). Conclusion A conclusion that could be drawn from this study is that some of midazolam's pharmacokinetic variability may be explained by age‐related changes in metabolism. These findings require validation in a larger study.

Inter-individual variation in midazolam clearance in children

“…There was a twofold to fivefold variation in clearance values in three studies and a 133-fold variation in one study 1620 23 24…”

“…20 23–25 The CV ranged from 21% to 170%. Four studies gave the full range of clearance values for individual children.…”