The effects of acute changes in renal function on the pharmacokinetics of midazolam during long-term infusion in ICU patients

Abstract

This study investigated the pharmacokinetics of midazolam and its main metabolite, 1-hydroxymethylmidazolam glucoronide, during long-term i.v. infusion in 39 mechanically ventilated ICU patients of whom 6 were in acute renal failure (ARF). The mean infusion rate of midazolam was similar (9.4 vs 8.7 mg/h) in the control patients and those with ARF. The renal clearance of 1-hydroxymethylmidazolam glucuronide was much lower in the ARF group than in the control group (3.9 vs 136 ml/min). Consequently, its plasma elimination half-life after discontinuation was also greatly prolonged, but this shouldn't cause very prolonged sedative effects since this metabolite is much less active than the parent drug. However, the half-life of midazolam itself was also significantly longer in patients with ARF than in the control group (13.2 vs 7.6 h). Apparently, this was caused by a combination of a slightly lower total clearance and a higher volume of distribution. Therefore, regular reassessment of the degree of sedation and appropriate adaptation of the infusion rate of midazolam are recommended in ICU patients with ARF.