title: The influence of remifentanil on the dynamic relationship between sevoflurane and surrogate anesthetic effect measures derived from the EEG.
abstract: 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.
authors.affiliation: Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands. e.olofsen@lumc.nl
authors.forename: Erik
authors.initials: E
authors.lastname: Olofsen
authors.forename: James W
authors.initials: JW
authors.lastname: Sleigh
authors.forename: Albert
authors.initials: A
authors.lastname: Dahan
mesh_terms: 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
chemical_list: D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D008738:Methyl Ethers; D010880:Piperidines; D000077149:Sevoflurane; D000077208:Remifentanil