Variability of predicted propofol concentrations and measured sevoflurane concentrations during general anaesthesia:...

Variability is high in predicted propofol concentrations during clinical anaesthesia titrated by target-controlled infusion (TCI) to maintain a processed EEG parameter (bispectral index [BIS]) within a specified range. We have shown that the potential for improving the pharmacokinetic model is minimal. The drug titration paradox revealed that titration challenges the classical relationship between drug dose and effect in both individuals and the population. We hypothesised that dynamic factors during surgery beyond the static genetic, epigenetic, and other factors such as age, height, and weight affect the necessary dose. We compared the variability of measured end-tidal sevoflurane concentrations with predicted effect-site propofol concentrations when titrated to a BIS range of 40-60, with the hypothesis that the variability in measured sevoflurane concentrations would not be less than the variability in estimated propofol concentrations.

Clinical data from 2280 surgical procedures >1 h in duration were included in the analysis. Anaesthesia with sevoflurane or propofol was based on an institutional protocol. The titration performance for both drugs was assessed by comparing BIS values 30 min after skin incision. The variability of the required concentrations at the same time point was calculated and compared.

The achieved 30-min post-incision BIS ranges were not significantly different for sevoflurane or propofol TCI (30 [99% CI: 28-33] and 31 [99% CI: 27-36], respectively). The variability of sevoflurane concentrations was not significantly different from measured predicted propofol concentrations during BIS-guided anaesthesia (normalized concentration range of 0.89 [99% CI: 0.78-0.99] and 0.93 [99% CI 0.87-1.02).

Improvements in prediction accuracy of pharmacokinetic models beyond that of those already in clinical use are unlikely to reduce variability in target anaesthetic concentrations across patients in clinical practice.