Pharmacokinetics and Pharmacodynamics of Propofol in ASA III Patients Undergoing Abdominal Aortic Surgery
Paweł Wiczling (1), Agnieszka Bienert (2), Paweł Sobczyński (3), Roma Hartmann-Sobczyńska (4), Krzysztof Bieda (3), Aleksandra Marcinkowska (2), Maria Malatyńska (2), Edmund Grześkowiak (2)
(1) Department of Biopharmaceutics and Pharmacokinetics, Medical University of Gdansk, Poland; (2) Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences; (3) Department of Anaesthesiology and Intensive Therapy, Poznan University of Medical Sciences, (4) Department of Experimental Anaesthesiology, Poznan University of Medical Sciences, Poland
Objectives: Available propofol pharmacokinetic protocols for target-controlled infusion (TCI) have been driven in healthy individuals. However, the disposition as well as the response to any given drug may be altered in clinical conditions. The aim of the study was to examine population pharmacokinetics (PK) and pharmacodynamics (PD) of propofol during total intravenous anesthesia (propofol/fentanyl) monitored by bispectral index (BIS) in ASA physical status III patients scheduled for abdominal aortic surgery.
Methods: Population nonlinear mixed-effect modeling was done using NONMEM IV. Data was obtained from ten male patients of 50 to 75 years age and weighing between 50 and 92 kg. The target-controlled infusion system (Diprifusor) was used to administrate propofol. Fentanyl at a dose of 2–3 µg/kg was administered whenever inadequate analgesia was assessed throughout the surgery. The bispectral index (BIS) served to monitor the depth of anesthesia. The propofol dosing was adjusted to keep BIS level between 40 and 60. Blood samples for propofol assay were collected from forearm veins at 0, 1, 3, 5, 10, 15, 30 minutes after the beginning of the infusion, then every 30 minutes until the end of anesthesia and after 1, 3, 5, 10, 15, 30, 60, 90, 120, 240 minutes after the termination of the propofol infusion.
Results: A two compartment model was used to describe propofol PK. Typical values of the central and peripheral volume of distribution, and the metabolic and inter-compartmental clearance were VC = 24.7 l, VT = 112 l, Cl = 2.64 l/min and Q = 0.989 l/min. Delay of the anesthetic effect, with respect to plasma concentrations, was described by the effect compartment with the rate constant for the distribution to the effector compartment equal to 0.240 min-1. The BIS index was linked to the effect site concentrations through a sigmoidal Emax model with EC50 = 2.19 mg/l. The body weight, age, blood pressure were not identified as statistically (p<0.001) significant covariates for all PK/PD parameters.
Conclusions: The population PK/PD model was successfully developed to describe the time course and variability of propofol concentration and BIS index in ASA III patients undergoing aortic surgery.