Benzodiazepines

Diazepam

Oral absorption of diazepam is more rapid in children than adults, and 0.1 to 0.3 mg/kg orally usually provides excellent peak sedation within 1 hour. Intravenous administration is painful and not well tolerated; diazepam may also be administered rectally. Because the liver is the main site of degradation, this medication should be given with caution to any patient with hepatic disease.^[153] Diazepam has an extremely long half-life in neonates (80 hours) and may be contraindicated until

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Midazolam

Midazolam is water soluble and therefore not usually painful on intravenous administration. It should be noted that because of its water solubility, it takes three times as long to reach a peak electroencephalographic effect as the more fat-soluble diazepam. The clinical importance of this observation is that one should wait at least 3 minutes between intravenous doses to avoid "stacking" of effect.^[155] The short elimination half-life (≅2 hours) in comparison to diazepam (18 hours) offers an advantage for use as a premedicant in children. Midazolam is the only benzodiazepine approved by the Food and Drug Administration for use in neonates; in this population, the half-life is much longer (6 to 12 hours).^{[156] [157]} In addition, severe hypotension has been reported in neonates after bolus administration, and the potential for this problem is apparently increased in neonates also receiving fentanyl.^[158] Midazolam is rapidly absorbed after intramuscular (0.1 to 0.15 mg/kg, maximum of 7.5 mg), oral (0.25 to 1.0 mg/kg, maximum of 20 mg), rectal (0.75 to 1.0 mg/kg, maximum of 20 mg), nasal (0.2 mg/kg), or sublingual (0.2 mg/kg) administration.^{[159] [160] [161] [162] [163] [164]} Nasal administration is uncomfortable for most children.^[165] The major problem with oral or sublingual administration is the strong aftertaste, but a variety of syrups may be used to disguise its aftertaste. The sedation achieved is not usually sleep (with doses up to 3.0 mg/kg rectally), but rather a compliant, happy state.^[163] If sleep occurs, a relative overdose has probably been given. Midazolam must always be used with caution when administered with narcotics because of the potential for respiratory depression. One important interaction is that erythromycin, calcium channel blockers, protease inhibitors, and even grapefruit juice produce a clinically important delay in midazolam metabolism because of cytochrome P450 inhibition.^{[166] [167] [168]} In this circumstance, either midazolam should be avoided or the dose reduced by 50%.^[166] One further concern is that with nasal administration there is the theoretical possibility of CNS toxicity as a result of drug entering the CNS along neural connections (olfactory nerves).^[169] Because neurotoxicity has never been examined and most children cry with nasal administration, I believe that this route should generally be avoided.^[170]