Failure of critically ill patients to metabolise midazolam

The pharmacokinetics of midazolam and its metabolite, 1-OH midazolam, were studied in six critically ill patients during and after a continuous intravenous infusion of midazolam. Four patients had an increased elimination half-life of midazolam; two were associated with a reduction in plasma clearance with low plasma concentrations of the metabolite, and two with normal metabolite levels and increased volume of distribution. The two patients with reduced clearance suffered from septic shock and were studied over a longer period. Their altered clearance was due to a reduced capability to form the 1-OH metabolite. As their condition improved, plasma concentrations of 1-OH midazolam increased and midazolam clearance returned towards normal. The impaired ability of critically ill patients with septic shock to metabolise midazolam, may be due to reduced organ perfusion and may lead to cumulation of midazolam in these patients.