Abstract
BackgroundKinetics of inhaled agents are often described by physiological models. However, many pharmacokinetic concepts, such as context-sensitive half-times, have been developed for drugs described by classical compartmental models. We derived classical compartmental models that describe the course of the alveolar concentrations (FA) generated by the physiological uptake and distribution models used by the Gas Man® program, and describe how distribution volumes and clearances relate to tissue volumes and blood flows.MethodsGas Man® was used to generate FA vs. time curves during the wash-in and wash-out period of 115 min each with a high fresh gas flow (8 L.min-1), a constant alveolar minute ventilation (4 L.min-1), and a constant inspired concentration (FI) of halothane (0.75%), isoflurane (1.15%), sevoflurane (2%), or desflurane (6%). With each of these FI, simulations were ran for a 70 kg patient with 5 different cardiac outputs (CO) (2, 3, 5, 8 and 10 L.min-1) and for 5 patients with different weights (40, 55, 70, 85, and 100 kg) but the same CO (5 L.min-1). Two and three compartmental models were fitted to FA of the individual 9 runs using NONMEM. After testing for parsimony, goodness of fit was evaluated using median prediction error (MDPE) and median absolute prediction error (MDAPE). The model was tested prospectively for a virtual 62 kg patient with a cardiac output of 4.5 L.min-1 for three different durations (wash-in and wash-out period of 10, 60, and 180 min each) with an FI of 1.5% halothane, 1.5% isoflurane, sevoflurane 4%, or desflurane 12%.ResultsA three-compartment model fitted the data best (MDPE = 0% and MDAPE ≤ 0.074%) and performed equally well when tested prospectively (MDPE ≤ 0.51% and MDAPE ≤ 1.51%). The relationship between CO and body weight and the distribution volumes and clearances is complex.ConclusionThe kinetics of anesthetic gases can be adequately described e by a mammilary compartmental model. Therefore, concepts that are traditionally thought of as being applicable to the kinetics of intravenous agents can be equally well applied to anesthetic gases. Distribution volumes and clearances cannot be equated to tissue volumes and blood flows respectively.
Highlights
Kinetics of inhaled agents are often described by physiological models
The models described the data almost perfectly (MDPE = 0% and median absolute prediction error (MDAPE) ≤ 0.074%), indicating that a 3 compartment mammilary model is sufficient to capture the pharmacokinetic behavior of the anesthetic gases in a high flow open circuit
The time course of FA of a potent inhaled anesthetic generated by a physiological uptake model (Gas Man®) can be well described using a classical three compartmental model derived from data generated by the very same physiological model (Gas Man®)
Summary
Kinetics of inhaled agents are often described by physiological models. Many pharmacokinetic concepts, such as context-sensitive half-times, have been developed for drugs described by classical compartmental models. We derived classical compartmental models that describe the course of the alveolar concentrations (FA) generated by the physiological uptake and distribution models used by the Gas Man® program, and describe how distribution volumes and clearances relate to tissue volumes and blood flows
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