The questioner requests dosage recommendations for intravenous injections of Dormicum (midazolam) i

Fråga: The questioner requests dosage recommendations for intravenous injections of Dormicum (midazolam) in children of different ages for sedation prior to intestinal biopsy. No other premedication will be used in addition to midazolam. The procedure takes approximately 30 minutes, and requires a moderately deep sedation.

Sammanfattning: The recommended dose for intravenous injection of midazolam in children for preoperative sedation is around 0.1 mg/kg. Proportionally higher doses are required in children than in adults with respect to bodyweight and there is also a large variation between individuals that should be considered.

Svar: Midazolam is a benzodiazepine derivative which has similar general properties to diazepam: rapid sedative and sleeping actions and a short duration. It also exerts an anticonvulsant and muscle- relaxant effect. It is used as a sedative and premedicant in minor surgical and anaesthetic procedures (1-2). Midazolam can be administered by the intravenous, intramuscular, rectal, intranasal or oral routes. Only the parenteral form is registered in Sweden. Midazolam is biotransformed by microsomal oxidation. It undergoes hydroxylation and subsequent glucuronidation (11). No information regarding specific dosage for INTRAVENOUS injection of midazolam is available in FASS (3) for children. For sedation in diagnostic or surgical procedures carried out under local anaesthesia, the manufacturer (2) recommends 2.5-5 mg intravenous either alone or in combination with anticholinergics, 5-10 minutes before the start of the procedure.

In a prospective study (10) given midazolam before esophagoduodenoscopy of 20 children between 6 and 18 years old it was concluded that children metabolize and excrete midazolam more rapidly than adults. Sedation adequate for endoscopy was safely achieved in the majority of children with a miadzolam dose of 0.05 to 0.1 mg/kg and a mean peak midazolam concentration greater than 200 ug/L (10). Midazolam clearance tends to be greater and terminal half-life shorter in children than in adults. Because of the close association of sedation with midazolam concentration and the greater clearance of the drug in children, larger weight-adjusted doses may be required in children than in adults to achieve the same duration of sedation (10). The rapid onset of effect and the close chronologic correlation of drug effect with plasma concentration, along with the short distribution half-life of midazolam, are consistent with rapid equilibration of the drug between the plasma compartment and central nervous system. This reflects the high lipid solubility of midazolam at physiologic pH, which facilitates rapid passive diffusion of the drug across the blood-brain barrier (10).

A treatment guide of about 0.1 mg/kg intravenous injection of midazolam for children is given at the hospital of S:t Göran in Stockholm (5). It is very difficult to give general recommendations however, as proportionately higher doses are required in small children than in bigger children and adults in relation to bodyweight. There is also a large variation of doses required between individuals. Genetic factors such as extensive or slow metabolisers may be involved (11). Likewise, changes in Vd or other physiological factors such as surgical stress may influence the t- 1/2-beta of midazolam. The changes in Vd in young patients undergoing major procedures are believed to be related to changes in midazolam binding to plasma proteins, biological fluid compartments, or alterations in regional blood flow (11).

For RECTAL administration for preoperative sedation in children a dose of 0.35-0.45 mg/kg bodyweight 20-30 minutes before induction of general anaesthesia is recommended by the manufacturer (2). At the hospital of S:t Göran (5) 0.3 mg/kg is usually given, but doses up to 0.5 mg/kg have sometimes been given. According to the source above, 0.3 mg/kg given to a patient of about 30 kg, will cause the patient to be quite heavily sedated, but the effect in a child of about 5 kg will be much less (5). According to another source (9), the effect of a dose of around 0.2 mg midazolam/kg bodyweight is not very different from that of placebo and is not sufficient for effective premedication. Midazolam is effectively and rapidly absorbed by the rectal route, and can therefore be used as an alternative to intramuscular injection. This will eliminate the stress associated with injection (8).

INTRAMUSCULAR administration in children also requires proportionally higher doses than in adults with respect to bodyweight (2). 0.15-0.20 mg/kg bodyweight is a recommended dose (2). This should be administered 20-30 minutes before induction of anaesthesia (2).

For INTRANASAL administration, the Östra Hospital in Gothenburg (4) recommends 0.3 mg/kg bodyweight. This method of administration has a rapid absorption, and avoids "first pass metabolism" and painful injections (6).