MIDAZOLAM PHARMACOKINETICS IN PATIENTS UNDERGOING ABDOMINAL AORTIC-SURGERY

Fentanyl and its analogs are eliminated slowly by patients having abdo minal aortic surgery. This is principally due to larger volumes of dis tribution, compared to the pharmacokinetics determined in other surgic al patients. Midazolam, like these opioids, is a lipophilic organic ba se, suggesting that it may also have a larger volume of distribution i n patients undergoing abdominal aortic reconstruction. The pharmacokin etics of intravenous midazolam, 0.25 mg/kg, were determined in patient s undergoing elective infrarenal abdominal aortic surgery. The mean (/-SD) age of the patients was 66.7 +/- 9.2 yr, and their mean weight w as 74.3 +/- 12.7 kg. Blood samples were drawn at increasing intervals for 24 h after administration of midazolam, and serum midazolam concen trations were measured by gas-liquid chromatography. A 3 compartment m odel best described the concentration versus time data. Simulations of the times required for 20%, 50%, and 80% decreases in midazolam conce ntrations after stopping an infusion that maintains a constant plasma midazolam concentration were performed, comparing pharmacokinetic vari ables from this study with previously published values. Metabolic clea rance was 361 +/- 97 mL/min. Rapid intercompartmental clearance was 21 97 +/- 997 mL/min and slow intercompartmental clearance, 481 +/- 225 m L/min. The volume of the central compartment (V-c) and the volume of d istribution 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 underg oing 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 concentra tions 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 elim inated more slowly in patients undergoing abdominal aortic surgery, th ese 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 relative ly faster redistribution, due to a greater intercompartmental clearanc e: V-c ratio, and relatively greater capacity for redistribution of mo derate doses, indicated by a greater Vd(ss):V-c ratio, as compared to patients undergoing nonaortic surgery.