Clinical pharmacology of midazolam in infants and children

Midazolam is a parenteral benzodiazepine with sedative, amnesic, anxiolytic, muscle relaxant and anticonvulsant properties. The drug exerts its clinical effect by binding to a receptor complex which facilitates the action of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Midazolam has a faster onset and shorter duration of action than other benzodiazepines such as diazepam and lorazepam. The most serious adverse events associated with midazolam in children include hypoventiiation, decreased oxygen saturation, apnoea and hypotension. It is water soluble in the commercially prepared formulation but becomes lipid soluble at physiological pH and can then cross the blood brain barrier. It is metabolised in the liver by the cytochrome P450 system, and its chief metabolite is l-hydroxymethyl midazolam. The latter is conjugated to the glucuronide form, and it has only minimal biological activity. Midazolam is excreted primarily by the kidney. Its half-life in children over 12 months is reported to be 0.8 to 1.8 hours, with a clearance of 4.7 to 19.7 ml/min/kg. Doses given to children must be calculated on a mg/kg basis. For children 6 months to 5 years of age the initial dose is 0.05 to 0.1 mg/kg. A total dose up to 0.6 mg/kg titrated slowly may be necessary to achieve the desired endpoint. For children 6 to 12 years of age the initial dose is 0.025 to 0.05 mg/kg with a total dose up to 0.4 mg/kg to achieve the desired end-point.