Interactions of propofol and remifentanil on bispectral index under 66% N(2)O: analysis by dose-effect curve, isobologram, and combination index

Abstract

Background: Propofol and remifentanil are usually co-administered and have shown synergistic effect for anesthesia. However, the synergistic effect of the two drugs on hypnosis measured by bispectral index (BIS) was controversial in previous studies. The aim of this study was to identify the interaction of propofol and remifentanil on BIS and the optimal dose combinations for hypnosis under 66% N(2)O during surgery.

Methods: Patients (age 55-75 and American Society of Anesthesiologists [ASA] 1-2) undergoing gastrectomy were enrolled in this study. Propofol and remifentanil were co-administered incrementally at 1 : 1 potent ratio (the P1R1 group), at 1 : 2 potent ratio (the P1R2 group), or at 2 : 1 potent ratio (the P2R1 group) using effect site target-controlled infusion and BIS was measured. 66% N(2)O was concomitantly administered to all groups. The dose-effect curves, the 90% effective dose (EC(90)) for adequate hypnosis (BIS 40), isobolograms and combination index were obtained by Calcusyn program (Biosoft) to reveal the interaction of propofol and remifentanil.

Results: The P2R1 group showed synergistic action on BIS. However, the other groups needed larger amount of each drug than the doses of additive action. The EC(90) of the P2R1 group was propofol, 3.34 µg/ml and remifentanil, 2.41 ng/ml under 66% of N(2)O.

Conclusions: Propofol dominant co-administration is needed for dose reduction in BIS guided hypnosis.

Keywords: Bispectral index; Isobologram; Propofol; Remifentanil; Synergies.

Fig. 1

Hemodynamic changes. ^*p < 0.05 compared to 15, 30, 45, 60 minutes in the P1R2 group. ^†p < 0.05 between the P1R2 and P2R1 group. P1R2: propofol : remifentanil 1 : 2 potency, P2R1: propofol : remifentanil 2 : 1 potency.

Fig. 2

The dose-effect curve of propofol of the P1R1, P1R2, and P2R1 groups. The effect site concentration of propofol in the P1R1, P1R2, and P2R1 groups and the hypnotic effect are shown as the X and Y axes, respectively. The P2R1 group required the lowest effect site concentration of propofol for EC₉₀. P1R1: propofol : remifentanil 1 : 1 potency, P1R2: propofol : remifentanil 1 : 2 potency, P2R1: propofol : remifentanil 2 : 1 potency, EC₉₀: 90% effective dose.

Fig. 3

The dose-effect curve of remifentanil of the P1R1, P1R2, and P2R1 groups. The effect site concentration of remifentanil in the P1R1, P1R2, and P2R1 groups and the hypnotic effect are shown as the X and Y axes, respectively. The P2R1 group required the lowest effect site concentration of remifentanil for EC₉₀. P1R1: propofol : remifentanil 1 : 1 potency, P1R2: propofol : remifentanil 1 : 2 potency, P2R1: propofol : remifentanil 2 : 1 potency, EC₉₀: 90% effective dose.

Fig. 4

Isobologram. The EC₉₀ for single administration were placed on the X- and Y-axes with the 95% confidence limits. The dashed lines connecting both EC₉₀ represents the theoretical line of additivity. The ⊙ in the middle of the graph depict the experimentally derived EC₉₀ in each group with the 95% confidence limits as error bars. The isobologram shows the synergistic interaction in the P2R1 group, and the antagonistic interaction in the P1R1 and P1R2 groups at EC₉₀. EC₉₀: 90% effective dose, P2R1: propofol : remifentanil 2 : 1 potency, P1R1: propofol : remifentanil 1 : 1 potency, P1R2: propofol : remifentanil 1 : 2 potency.