Pharmacokinetics of midazolam in patients recovering from cardiac surgery

The pharmacokinetics of midazolam has been studied in patients recovering from cardiac surgery, who required sedation for postoperative mechanical ventilation. Twelve males (mean age 64.5 years) with severe heart disease received an infusion of midazolam 15 mg.h-1 for 4 h, starting 1 to 3 h post surgery. Multiple blood samples were collected from each patient during the infusion and up to 48-93 h after it. The pharmacokinetic parameters of midazolam were determined using both moment analysis and the program NONMEM. The average terminal half-life was 10.6 h. The prolonged elimination was mainly due to a decrease in its metabolic clearance (0.25 l.min-1). The maintenance infusion dose of midazolam in such patients should be reduced. The time to recovery after stopping an infusion depends upon the amount of drug in the body at that time and a simulation of the plasma concentrations after various infusion regimens suggests that recovery will be delayed after prolonged (greater than 48 h) administration of midazolam to these patients. However, after shorter infusions (less than 12 h), redistribution of the drug away from the site of action was still occurring and recovery would be expected to be relatively rapid.