Clinical pharmacokinetics of midazolam in intensive care patients, a wide interpatient variability?

Abstract

The pharmacokinetics of midazolam and its metabolites were studied in 17 patients on mechanical ventilation in a general intensive care unit who were receiving a continuous intravenous infusion of midazolam, adjusted according to the level of induced sedation. Three patients were studied twice. Serum midazolam and alpha-hydroxymidazolamglucuronide levels were determined during and after infusion. The sedation level was scored on a four-point scale. Half of the observed patients were still drowsy or asleep 10 hours after termination of midazolam infusion. In only one patient was midazolam serum elimination half-life less than 2 hours and in six patients the half-life was greater than 10 hours. A wide range of midazolam serum levels was associated with adequate sedation, and similarly the midazolam levels at the moment of awakening were highly variable. The serum concentration ratio of midazolam/alpha-hydroxymidazolamglucuronide at the end of the infusion varied from 0.03 to 15.6. Renal function could account for only a part of this variation.

Pharmacokinetics of midazolam and its main metabolite 1-hydroxymidazolam in intensive care patients

“…A variability in serum concentrations and t 1/2 13 has been previously reported in intensive care patients [4]. However, the mean values of elimination half life and volume of distribution were higher than those reported in healthy subjects [2,8,9].…”

“…The major metabolite, I-hydroxymidazolam, is pharmacologically active [3] and consequently may contribute to the central nervous system effects of the parent drug. Limited data on circulating concentrations of I-hydroxymidazolam are available [4] essentially due to the lack of sensitivity of the analytical methods published previously. In a preliminary study [5], we have found significant concentrations of unconjugated J-hydroxymidazolam in patients receiving intravenous administration of the drug.…”

“…In a preliminary study [5], we have found significant concentrations of unconjugated J-hydroxymidazolam in patients receiving intravenous administration of the drug. Besides, a wide interpatient variability in serum concentration and elimination half life of midazolam has been described [4] in intensive care patients. Therefore, the aim of the present work was to evaluate the pharmacokinetic parameters of midazolam but also those of its main metabolite, I-hydroxymidazolam, after intravenous administration of the parent drug to intensive care patients.…”

Diazepam or midazolam for orotracheal intubation in the ICU?

“…25,26 Obese patients have an increased volume of distribution due to enhanced distribution in peripheral adipose tissues and interactions with other drugs that are metabolized through the cytochrome p450 system can influence the clinical response. 27 Benzodiazepines have synergistic interactions with other drugs like opioids that were simultaneously used in most patients. Pharmacokinetics of almost all drugs, including sedatives, are not well known in critically ill patients.…”

Pharmacokinetic‐EEG effect relationship of midazolam in aging BN/BiRij rats

“…Also in the treatment of sleep disorders in the elderly, midazolam was reported to be effective and well-tolerated, provided that it is given in a carefully titrated, appropriate dose (Lachnit et al, 1983). Several authors emphasized the importance of titrating the dose, since dose requirement for midazolam is reduced in elderly patients (Kanto et al, 1986;Bell et al, 1987;Oldenhof et al, 1988). In a study in 800 patients in which the dose of intravenous midazolam required to produce adequate sedation prior to upper gastro-intestinal endoscopy was measured, an important decrease of approximately 75% in dose requirement from the age of 15 years to the age of 85 years was observed (Bell et al, 1987).…”