Pharmacokinetic Drug Interaction Between Propofol and Remifentanil?

To the Editor: We read with interest the paper by Koitabashi et al. (1) on the addition of remifentanil to propofol infusions and the resultant decrease in Bispectral Index (BIS). The authors concluded that remifentanil has sedative/hypnotic properties, or that it potentiates the hypnotic effect of propofol. Puri has commented that other stimuli can add to the effect of remifentanil on BIS (2). Both explanations have focused on pharmacodynamic mechanisms—we would like to suggest an alternate pharmacokinetic hypothesis. The pharmacokinetics of propofol is dependent on cardiac output after both bolus administration (3) and during constant rate infusions (4). The mechanisms of this effect are a combination of recirculatory concepts and blood flow limited clearance (5). In the study of Koitabashi et al., remifentanil administration, especially in conjunction with a vasopressor, was likely to have produced a dose-dependent decrease in cardiac output. This would have resulted in an increase in arterial and brain propofol concentrations, and therefore anesthetic effect. This has been simulated in Figure 1, using a published physiological pharmacokinetic model (6).Figure 1: Simulation of physiological pharmacokinetic model.We also suggest that circulation-based pharmacokinetic drug interactions may potentially provide an explanation for other studies in which vasoactive drugs, such as clonidine and epinephrine (7), have been reported to affect BIS. G. L. Ludbrook, MBBS, PhD R. N. Upton, PhD