Physiologically Based Pharmacokinetic Modeling of Sevoflurane Uptake with Multicompartment Lung and Dead Space Dynamics

We developed a physiologically based pharmacokinetic (PBPK) model of sevoflurane uptake that integrates a multicompartment lung configuration with cyclic ventilation and a rebreathing dead space. Lung compartments were modeled as dynamically expanding and contracting with respiration, and the governing ordinary differential equations for gas transport and uptake were implemented in Simulink. Model performance was evaluated against the clinical study by Lu et al., which reported arterial, venous, and end-tidal sevoflurane concentrations during 60 min of controlled ventilation. In the two-compartment alveolar configuration, arterial concentrations matched clinical values for the first 20–25 min but fell below thereafter, whereas the single-compartment alveolar configuration overestimated early-phase values yet closely reproduced steady-state results. Introducing a gradual fixed-volume transfer between compartments, while retaining the dead space design, produced close agreement across the entire simulation. Although not capturing all potential inter-compartment interactions, this hybrid approach offers a more physiologically plausible representation than conventional single- or two-compartment alveolar models. The dead space, configured to limit alveolar filling during inspiration and return residual gas during expiration, diluted alveolar sevoflurane whenever the inspiratory tidal volume carried a higher concentration than the alveoli. This physiologically grounded framework aligns closely with clinical data and provides a practical tool for predicting anesthetic gas kinetics in situations where direct measurement is not feasible, such as in the fetus. It is also applicable to obese patients with altered perfusion distribution due to altered body composition, and with right-to-left pulmonary shunt resulting from the supine position.