At what concentration of midazolam should a patient wake up after sedation with midazolam 40 mg/h a

Fråga: At what concentration of midazolam should a patient wake up after sedation with midazolam 40 mg/h and diprivane 1200 mg/h due to status epilepticus? Concentration of midazolam was 25 nM, alpha-hydroxymidazolam 100 nM and hydroxymidazolam-glucuronide 600 nM found approximately 24 hours after infusion therapy was ended.

Sammanfattning: The patient should wake at midazolam plasma concentrations less than 280 nM and alpha-hydroxymidazolam less than 80 nM. Not very high concentrations were observed in the present case. The concentration of alpha-hydroxymidazolam found may well contributed and other medications may also have added to the prolonged sedation.

Svar: Midazolam is a water-soluble benzodiazepine derivative and the molecular weight of its hydrochloride is 362.2 g/mol (1).

Midazolam is extensively metabolized by the cytochrome P450-dependent system in the liver. The principal metabolite is alpha-hydroxymidazolam, which is rapidly conjugated with glucuronic acid, although a small proportion is further hydroxylated to alpha-4-dihydroxymidazolam. The other metabolite is 4-hydroxymidazolam. The alpha-hydroxymidazolam is biologically active but has a shorter half-life than midazolam. Midazolam is extensively bound to plasma proteins (94-98%) and small changes in protein binding will produce large changes in the amount of available free drug (1).

Plasma concentrations greater than 100 ug/L induce sleep. The minimum effective concentration is from 30 to 100 ug/L. The correlation between effect and drug concentration is closer when the midazolam and alpha-hydroxymidazolam concentration are considered together. There is a wide variation in response. Following infusions of midazolam to maintain sedation in the intensive care unit, patients with normal metabolism wake up at plasma midazolam concentrations of 100 ug/L=280 nM and alpha-hydroxymidazolam levels of about 30 ug/L=80 nM (1).