Journal of Anesthesia

, Volume 24, Issue 3, pp 386–393 | Cite as

Electroencephalographic response following midazolam-induced general anesthesia: relationship to plasma and effect-site midazolam concentrations

  • Wakako Miyake
  • Yutaka Oda
  • Yuko Ikeda
  • Satoshi Hagihira
  • Hiroyoshi Iwaki
  • Akira Asada
Original Article



To examine the relationships between effect-site concentrations and electroencephalographic parameters after the induction of general anesthesia with midazolam.


Twenty-four patients with American Society of Anesthesiologists status I or II were randomly allocated to receive either an intravenous (i.v.) bolus of midazolam 0.2 mg kg−1 (small-dose group, n = 12) or 0.3 mg kg−1 (large-dose group, n = 12) for induction of general anesthesia in a double-blind experimental design. The bispectral index (BIS), 95% spectral edge frequency (SEF95), spectral power density, and plasma concentrations of midazolam were measured for 60 min following the induction of general anesthesia.


Plasma and simulated effect-site concentrations of midazolam were significantly higher in the large-dose group than in the small-dose group (P = 0.005 and <0.001, respectively). There was a correlation between the relative beta ratio and BIS (r 2 = 0.30, P < 0.001; n = 168); however, effect-site concentrations of midazolam showed no association with BIS, relative beta ratio, or SEF95 (r 2 = 0.07, 0.11 and 0.01, respectively; n = 168). The electroencephalographic spectral power density in the beta-band (≥13 and <30 Hz) was significantly increased after induction and was significantly larger in the large-dose group than in the small-dose group (P = 0.009).


Following the induction of general anesthesia with i.v. midazolam 0.2 or 0.3 mg kg−1, the BIS was positively correlated with the relative beta ratio. Despite a rapid decrease in the plasma and effect-site concentrations of midazolam, the average BIS remained >60 for 60 min after induction, reflecting an increased power of the electroencephalographic high-frequency band.


Bispectral index Electroencephalogram Midazolam Relative beta ratio Spectral edge frequency 



This study was supported in part by the Fund for Specific Research from Osaka City University.


  1. 1.
    Reves JG, Glass PSA, Lubarsky DA, McEvoy MD. Intravenous nonopioid anesthetics. In: Miller RD, editor. Miller’s anesthesia. 6th ed. Philadelphia: Elsevier Churchill Livingstone; 2005. p. 317–78.Google Scholar
  2. 2.
    Johansen JW, Sebel PS. Development and clinical application of electroencephalographic bispectrum monitoring. Anesthesiology. 2000;93:1336–44.CrossRefPubMedGoogle Scholar
  3. 3.
    Glass PS, Bloom M, Kearse L, Rosow C, Sebel P, Manberg P. Bispectral analysis measures sedation and memory effects of propofol, midazolam, isoflurane, and alfentanil in healthy volunteers. Anesthesiology. 1997;86:836–47.CrossRefPubMedGoogle Scholar
  4. 4.
    Kaneshiro Y, Oda Y, Iwakiri K, Masada T, Iwaki H, Hirota Y, Kondo K, Takaoka K. Low hepatic cytochrome P450 3A activity is a risk for corticosteroid-induced osteonecrosis. Clin Pharmacol Ther. 2006;80:396–402.CrossRefPubMedGoogle Scholar
  5. 5.
    Hamaoka N, Oda Y, Hase I, Mizutani K, Nakamoto T, Ishizaki T, Asada A. Propofol decreases the clearance of midazolam by inhibiting CYP3A4: an in vivo and in vitro study. Clin Pharmacol Ther. 1999;66:110–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Ibrahim A, Karim A, Feldman J, Kharasch E. The influence of parecoxib, a parenteral cyclooxygenase-2 specific inhibitor, on the pharmacokinetics and clinical effects of midazolam. Anesth Analg. 2002;95:667–73.CrossRefPubMedGoogle Scholar
  7. 7.
    Greenblatt DJ, Ehrenberg BL, Gunderman J, Locniskar A, Scavone JM, Harmatz JS, Shader RI. Pharmacokinetic and electroencephalographic study of intravenous diazepam, midazolam, and placebo. Clin Pharmacol Ther. 1989;45:356–65.PubMedGoogle Scholar
  8. 8.
    Buhrer M, Maitre PO, Hung O, Stanski DR. Electroencephalographic effects of benzodiazepines. I. Choosing an electroencephalographic parameter to measure the effect of midazolam on the central nervous system. Clin Pharmacol Ther. 1990;48:544–54.PubMedGoogle Scholar
  9. 9.
    Kuizenga K, Wierda JM, Kalkman CJ. Biphasic EEG changes in relation to loss of consciousness during induction with thiopental, propofol, etomidate, midazolam or sevoflurane. Br J Anaesth. 2001;86:354–60.CrossRefPubMedGoogle Scholar
  10. 10.
    Vuyk J, Hennis PJ, Burm AG, de Voogt JW, Spierdijk J. Comparison of midazolam and propofol in combination with alfentanil for total intravenous anesthesia. Anesth Analg. 1990;71:645–50.CrossRefPubMedGoogle Scholar
  11. 11.
    Rendic S, Di Carlo FJ. Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metab Rev. 1997;29:413–580.CrossRefPubMedGoogle Scholar
  12. 12.
    Schneider G, Gelb AW, Schmeller B, Tschakert R, Kochs E. Detection of awareness in surgical patients with EEG-based indices—bispectral index and patient state index. Br J Anaesth. 2003;91:329–35.CrossRefPubMedGoogle Scholar
  13. 13.
    Hagihira S, Takashina M, Mori T, Ueyama H, Mashimo T. Electroencephalographic bicoherence is sensitive to noxious stimuli during isoflurane or sevoflurane anesthesia. Anesthesiology. 2004;100:818–25.CrossRefPubMedGoogle Scholar
  14. 14.
    Morimoto Y, Hagihira S, Koizumi Y, Ishida K, Matsumoto M, Sakabe T. The relationship between bispectral index and electroencephalographic parameters during isoflurane anesthesia. Anesth Analg. 2004;98:1336–40.CrossRefPubMedGoogle Scholar
  15. 15.
    Buhrer M, Maitre PO, Crevoisier C, Stanski DR. Electroencephalographic effects of benzodiazepines. II. Pharmacodynamic modeling of the electroencephalographic effects of midazolam and diazepam. Clin Pharmacol Ther. 1990;48:555–67.PubMedGoogle Scholar
  16. 16.
    Gugino LD, Chabot RJ, Prichep LS, John ER, Formanek V, Aglio LS. Quantitative EEG changes associated with loss and return of consciousness in healthy adult volunteers anaesthetized with propofol or sevoflurane. Br J Anaesth. 2001;87:421–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Seubert CN, Mahla ME. Neurologic monitoring. In: Miller RD, editor. Miller’s anesthesia. 7th ed. Philadelphia: Churchill Livingstone; 2009. p. 1477–514.Google Scholar
  18. 18.
    Murayama T, Shingu K, Ogawa T, Tomoda K, Shindo K, Tamai S, Mori K. Flumazenil does not antagonize halothane, thiamylal or propofol anaesthesia in rats. Br J Anaesth. 1992;69:61–4.CrossRefPubMedGoogle Scholar
  19. 19.
    Ekman A, Lindholm ML, Lennmarken C, Sandin R. Reduction in the incidence of awareness using BIS monitoring. Acta Anaesthesiol Scand. 2004;48:20–6.CrossRefPubMedGoogle Scholar
  20. 20.
    Avidan MS, Zhang L, Burnside BA, Finkel KJ, Searleman AC, Selvidge JA, Saager L, Turner MS, Rao S, Bottros M, Hantler C, Jacobsohn E, Evers AS. Anesthesia awareness and the bispectral index. N Engl J Med. 2008;358:1097–108.CrossRefPubMedGoogle Scholar
  21. 21.
    de Wildt SN, de Hoog M, Vinks AA, van der Giesen E, van den Anker JN. Population pharmacokinetics and metabolism of midazolam in pediatric intensive care patients. Crit Care Med. 2003;31:1952–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Bauer TM, Ritz R, Haberthur C, Ha HR, Hunkeler W, Sleight AJ, Scollo-Lavizzari G, Haefeli WE. Prolonged sedation due to accumulation of conjugated metabolites of midazolam. Lancet. 1995;346:145–7.CrossRefPubMedGoogle Scholar

Copyright information

© Japanese Society of Anesthesiologists 2010

Authors and Affiliations

  • Wakako Miyake
    • 1
  • Yutaka Oda
    • 1
  • Yuko Ikeda
    • 1
  • Satoshi Hagihira
    • 2
  • Hiroyoshi Iwaki
    • 3
  • Akira Asada
    • 1
  1. 1.Department of AnesthesiologyOsaka City University Graduate School of MedicineAbeno-ku, OsakaJapan
  2. 2.Department of Anesthesiology and Intensive Care Medicine, Graduate School of MedicineOsaka UniversityOsakaJapan
  3. 3.Department of Orthopaedic SurgeryOsaka City University Graduate School of MedicineOsakaJapan

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