In children, rectal midazolam is being used increasingly for premedication, as this substance is reported to have a short half-life and rapid action. Above all it is the only known diazepam derivative with a good correlation of plasma concentration and clinical action despite its receptor binding capacity. As pharmacokinetic data in children are lacking and different dose regimens for rectal premedication exist, we studied plasma concentrations in 3 groups of children. METHODS. After obtaining informed parental consent we studied children aged 3-7 years (15-30 kg body weight) ASA I status scheduled for minor elective surgery. Group 1 (n = 6) received 0.1 mg/kg midazolam i.v. for induction of anesthesia. Group 2 (n = 10) was premedicated with 0.35 mg/kg midazolam, instilled just behind the anal sphincter; group 3 (n = 5) received 0.5 mg/kg midazolam rectally. Blood samples were drawn up to 120 min after application. The anesthesia technique consisted of N2O/O2, enflurane, intubation and the use of muscle relaxants, if necessary. Midazolam plasma levels were measured by HPLC. RESULTS. There were no differences with respect to age or body weight. Group 1: half-life in children was shorter than in adults, Vdss was smaller and clearance identical. Group 2: Rectal midazolam 0.35 mg/kg has a remarkably short onset of action with peak plasma concentrations (71 ng/ml) in the range of sedative levels in adults occurring in 7.5 min. After 2 h they reached levels of 30 ng/ml. Group 3 patients had peak levels of midazolam of 246 ng/ml after 12.5 min, falling to an average concentration of 120 ng/ml after 2 h. The bioavailability of rectal midazolam, comparing the area under the median curves, is 4.7% in group 2 and 16.1% in group 3.
Conclusions: The pharmacokinetics of midazolam in our patients showed a shorter half-life, probably due to the higher hepatic clearance based on the high CI in children, as midazolam is known to have a first-pass effect of 30-70%. The increased metabolic transformation and the smaller amount of fatty tissue accounts for the smaller Vdss in children compared to adults. Rectal midazolam has a remarkably short onset and especially in a dose of 0.5 mg/kg prolonged action due to ongoing resorption from the rectum as demonstrated by the clinically relevant plasma concentrations. This fact must be taken into consideration in the overall anesthesia management.(ABSTRACT TRUNCATED AT 400 WORDS)