Midazolam is a short-acting water-soluble benzodiazepine (at pH less than 4), a member of a new class of imidazobenzodiazepine derivatives. At physiological pH the drug becomes much more lipid soluble. Water solubility minimises pain on injection and venous thrombosis compared with diazepam administered in organic solvent. Midazolam is a hypnotic-sedative drug with anxiolytic and marked amnestic properties. To date it has been used mostly by the intravenous route, for sedation in dentistry and endoscopic procedures and as an adjunct to local anaesthetic techniques. It has proved less reliable than thiopentone, but preferable to diazepam, as an intravenous induction agent and is unlikely to replace the other well established drugs. However, due to the cardiorespiratory stability following its administration, midazolam is useful for anaesthetic induction in poor-risk, elderly and cardiac patients. The short elimination half-life (1.5-3.5h) and the absence of clinically important long acting metabolites make midazolam suitable for long term infusion as a sedative and amnestic for intensive care, but clinical trials have yet to be completed. Thus, a combination of properties make midazolam a useful addition to the benzodiazepine group.

The pharmacokinetics of midazolam were studied in surgical patients given 0.3 mg kg-1 i.v. for either the induction of anaesthesia, or postoperative sedation following cardiopulmonary bypass. The short elimination half-life of midazolam (2.4 h in patients less than 50 yr undergoing minor surgery) was significantly, although not markedly, prolonged with age (4.1 h in patients greater than 50 yr undergoing minor procedures) and by the nature of the operation (3.8 h after major operative procedures). These changes were the result of alterations in clearance and volume of distribution with age, and in volume of distribution with nature of operation.

1 The pharmacokinetics of a fixed dose of midazolam (0.3 mg kg-1 i.v.) were studied in detail in 115 healthy patients or volunteers and nine were found with a prolonged elimination half-life. 2 A further 102 patients had an abbreviated pharmacokinetic study, of whom five showed a similar abnormality. 3 Defective hepatic metabolism of midazolam may be a factor in the aetiology of what appears to be a true phenomenon, occurring in 6% of over 200 fit subjects given a standard dose of the drug.

Eighty patients having anaesthesia for oral surgery requiring nasal intubation were randomly allocated to be intubated with either a plain Magill red rubber or cuffed polyethylene endotracheal tube and in a double blind manner, to receive xylometazoline 0.1% vasoconstrictor nasal spray. The extent of any epistaxis occurring was assessed by an independent observer. With the Magill tube there was bleeding in one out of twenty patients in both the vasoconstrictor group and non vasoconstrictor group at intubation and no bleeding in either of the two groups at extubation. With the polyethylene tube sixteen out of twenty patients had bleeding in the non vasoconstrictor group. This improved to seven out of twenty with the administration of vasoconstrictor drops at intubation (chi square 10.2; p < 0.01) in the polyethylene tube group. At extubation ten out of twenty patients had bleeding in the non vasoconstrictor group improving to two out of twenty with the administration of the vasoconstrictor (chi square 9.6; p,0.01). The use of the vasoconstrictor xylometazoline helped to reduce epistaxis that occurred during nasal intubation and further study into the type of endotracheal tube is recommended.

SummaryThe action of midazolam is influenced by serum protein binding as seen in the relationship hetween the time of onset of action of a fixed dose of the drug and ihe plasma albumin. Pretreatment with intravenous aspirin produces a decrease in the in vitro binding of midazolam. In vivo this is man$est as an increase in the rapidity of action of the benzodiazepines. Probenecid pretreatment will also cause a decrease in the onset time of midazolam. However this is not due to altered plasma protein binding of the sedative.