MIDAZOLAM PHARMACOKINETICS IN PATIENTS UNDERGOING ABDOMINAL AORTIC-SURGERY

Fentanyl and its analogs are eliminated slowly by patients having abdominal aortic surgery. This is principally due to larger volumes of distribution, compared to the pharmacokinetics determined in other surgical patients. Midazolam, like these opioids, is a lipophilic organic base, suggesting that it may also have a larger volume of distribution in patients undergoing abdominal aortic reconstruction. The pharmacokinetics of intravenous midazolam, 0.25 mg/kg, were determined in patients undergoing elective infrarenal abdominal aortic surgery. The mean (+/-SD) age of the patients was 66.7 +/- 9.2 yr, and their mean weight was 74.3 +/- 12.7 kg. Blood samples were drawn at increasing intervals for 24 h after administration of midazolam, and serum midazolam concentrations were measured by gas-liquid chromatography. A 3 compartment model best described the concentration versus time data. Simulations of the times required for 20%, 50%, and 80% decreases in midazolam concentrations after stopping an infusion that maintains a constant plasma midazolam concentration were performed, comparing pharmacokinetic variables from this study with previously published values. Metabolic clearance was 361 +/- 97 mL/min. Rapid intercompartmental clearance was 2197 +/- 997 mL/min and slow intercompartmental clearance, 481 +/- 225 mL/min. The volume of the central compartment (V-c) and the volume of distribution at steady state (Vd(ss)) were 5.8 +/- 5.3 L and 118.2 +/- 70.4 L, respectively The elimination half-life was 6.3 +/- 3.6 h, 1.5- to 3-fold longer than has been previously reported in patients undergoing surgery. Compared to previously published studies of other groups of patients, metabolic clearance of midazolam was slower in patients undergoing abdominal aortic surgery. The Vd(ss) was in the upper part of the range of previously reported values. Simulations predicting the times required for 20%, 50%, and 80% decreases in midazolam concentrations after continuous infusions indicate that, under most conditions, the concentrations would not decrease more slowly in our patients, in spite of the longer elimination half-life. Although midazolam is eliminated more slowly in patients undergoing abdominal aortic surgery, these simulations suggest that this would not lengthen the time required for the midazolam concentrations to decrease below pharmacologically active levels after moderate doses. This is apparently due to relatively faster redistribution, due to a greater intercompartmental clearance: V-c ratio, and relatively greater capacity for redistribution of moderate doses, indicated by a greater Vd(ss):V-c ratio, as compared to patients undergoing nonaortic surgery.