Abstract: Contribution of midazolam and its 1-hydroxy metabolite to preoperative sedation in children: a pharmacokinetic-pharmacodynamic analysis.

Authors:

Johnson TN, Rostami-Hodjegan A, Goddard JM, Tanner MS, Tucker GT.

Institution:

University of Sheffield, Academic Unit of Molecular Pharmacology and Pharmacogenetics, Division of Clinical Sciences (South), Royal Hallamshire Hospital, Sheffield S10 2JF, UK.

Source:

Br J Anaesth. 2002 Sep;89(3):428-37.

Abstract:

BACKGROUND: Oral midazolam is widely used for preoperative sedation in children. We have studied the pharmacokinetics (PK) of both midazolam and its active 1-hydroxy metabolite and their contributions to sedative effect in 45 children attending for day surgery. METHODS: Blood samples (two per individual) were collected at the beginning and end of the surgical procedure. Plasma midazolam and 1-hydroxymidazolam (1-OHMDZ) were measured by HPLC. Sedation score (score: 1 = awake, 2 = drowsy/asleep) was recorded at the same time as the first blood sample. The population-PK software P-Pharm was used to analyse the data. Age, weight, sex, concomitant drugs, and the metabolic ratio, 1-OHMDZ/midazolam were investigated as co-variates of the PK of midazolam and 1-OHMDZ. The pharmacokinetic-pharmacodynamic (PK-PD) modelling of the score in relation to plasma midazolam and 1-OHMDZ was performed using logistic regression analysis. RESULTS: A median dose of 0.5 mg kg-1 was given to the children, median age 5 yr (range from 9 months to 12 yr) and weight 21 kg (range 8-75 kg). Average concentrations of midazolam 150 ng ml-1 and 1-OHMDZ 90 ng ml-1 were observed in the first plasma samples. These concentrations resulted in an odds ratio of 4 in favour of score 2 vs 1. The best PK-PD model included both midazolam and 1-OHMDZ as active moieties and predicted correct scores in 86% of cases. CONCLUSION: Studies of midazolam should evaluate the contribution of 1-OHMDZ to the overall PD effect. The metabolite 1-OHMDZ has approximately half the activity of the parent drug and can compensate for at least part of the decreased effect due to increased midazolam metabolism.

Keywords:

Paediatric Surgery Premedication Benzodiazepine Midazolam Anxiety