The influence of remifentanil on the dynamic relationship between sevoflurane and surrogate anesthetic effect measures derived from the EEG.
BACKGROUND
The authors modeled the influence of remifentanil on the dynamics of sevoflurane using three parameters derived from the electroencephalogram: 95% spectral edge frequency (SEF), canonical univariate parameter (CUP), and Bispectral Index (BIS).


METHODS
Thirty-six patients with American Society of Anesthesiologists physical status class I or II were recruited, of which 12 received a target remifentanil concentration of 0 ng/ml, eight 2 ng/ml, eight 4 ng/ml, and another eight 8 ng/ml. Next (before surgery), several step-wise changes in the end-tidal sevoflurane concentration (F(ET,sevo)) were performed. A data acquisition system simultaneously recorded F(ET,sevo), the raw electroencephalogram, BIS, and SEF. The authors used a combination of an effect compartment and an inhibitory sigmoid E(MAX) model to describe the relation between F(ET,sevo) and BIS, SEF, and CUP. Model parameters (t(1/2)k(e0), E(MAX), E(MIN), C(50), gamma, CUP weight factors) were estimated using the population data analysis program NONMEM. Significant remifentanil model parameter dependencies (P < 0.01) were determined.


RESULTS
Determined from SEF, remifentanil had no effect on t(1/2)k(e0) (1.91 +/- 0.26 min [mean +/- standard error]) but caused an increase in C(50) (baseline = 1.48 +/- 0.12%; 80% increase at 8 ng/ml) and decrease in E(MIN) (baseline = 10.8 +/- 0.6 Hz; 80% reduction at 8 ng/ml). Determined from CUP, remifentanil caused a dose-dependent decrease in t(1/2)k(e0) (baseline = 4.31 +/- 1.00 min; 60% decrease at 8 ng/ml), with no effect on C(50) (baseline = 0.88 +/- 0.13%). Determined from BIS, remifentanil caused a dose-dependent decrease in t(1/2)k(e0) (baseline value = 3.11 +/- 0.32 min; 40% decrease at 8 ng/ml), without affecting C(50) (baseline = 1.12 +/- 0.05%). Median R(2) values of the pooled data set were 0.815 for SEF, 0.933 for CUP (P < 0.01 vs. SEF), and 0.952 for BIS (P < 0.01 vs. SEF and CUP). Addition of remifentanil increased the R(2) values for CUP only.


CONCLUSIONS
Remifentanil accelerates sevoflurane blood-brain equilibration without affecting its hypnotic potency as determined from BIS and CUP. In terms of R(2), the authors' pharmacodynamic model describes the anesthetic-BIS relation best.
Olofsen
Erik
E
Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands. e.olofsen@lumc.nl
Sleigh
James W
JW
Dahan
Albert
A
D000328:Adult; D000465:Algorithms; D000704:Analysis of Variance; D000769:Anesthesia, Inhalation; D018685:Anesthetics, Inhalation / Q000493:pharmacokinetics; D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000493:pharmacokinetics; D001499:Bayes Theorem; D004347:Drug Interactions; D004569:Electroencephalography / Q000187:drug effects*; D005260:Female; D006207:Half-Life; D006801:Humans; D007267:Injections; D008297:Male; D008738:Methyl Ethers / Q000493:pharmacokinetics; D008875:Middle Aged; D015233:Models, Statistical; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics; D000077208:Remifentanil; D000077149:Sevoflurane
D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D008738:Methyl Ethers; D010880:Piperidines; D000077149:Sevoflurane; D000077208:Remifentanil