Newly Published
Perioperative Medicine  |   January 2020
Pharmacokinetics and Pharmacodynamics of Remimazolam (CNS 7056) after Continuous Infusion in Healthy Male Volunteers: Part II. Pharmacodynamics of Electroencephalogram Effects
Author Notes
  • Submitted for publication May 28, 2019. Accepted for publication December 1, 2019.
    Submitted for publication May 28, 2019. Accepted for publication December 1, 2019.×
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • A.E. and J.S. contributed equally to this article.
    A.E. and J.S. contributed equally to this article.×
  • Correspondence: Address correspondence to Dr. Jeleazcov: Anästhesiologische Klinik, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Krankenhausstrasse 12, D-91054 Erlangen, Germany. christian.jeleazcov@kfa.imed.uni-erlangen.de. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine / Central and Peripheral Nervous Systems / Pharmacology
Perioperative Medicine   |   January 2020
Pharmacokinetics and Pharmacodynamics of Remimazolam (CNS 7056) after Continuous Infusion in Healthy Male Volunteers: Part II. Pharmacodynamics of Electroencephalogram Effects
Anesthesiology Newly Published on January 14, 2020. doi:https://doi.org/10.1097/ALN.0000000000003102
Anesthesiology Newly Published on January 14, 2020. doi:https://doi.org/10.1097/ALN.0000000000003102
Abstract

Editor’s Perspective:

What We Already Know about This Topic:

  • Intravenously administered remimazolam can produce deep sedation quickly from which the patient recovers rapidly due, in part, to its relatively high clearance by tissue esterases

  • Electroencephalogram measures with a significant correlation to sedation scales provide a continuous noninvasive method for quantifying central nervous system drug effects without the need to stimulate the patient

What This Article Tells Us That Is New:

  • Electroencephalogram changes during remimazolam infusion in 20 adult male volunteers were characterized by an initial increase in the beta frequency band and a late increase in the delta frequency band

  • Beta ratio had a monotonic relationship to Modified Observer’s Assessment of Alertness and Sedation scores and could be modeled using a standard sigmoid Emax pharmacodynamic model

  • The standard sigmoid Emax model failed to describe the time course of the Narcotrend Index appropriately; it was necessary to extend the model by adding a second sigmoid term with a second effect site concentration

Background: Remimazolam (CNS 7056) is a new ultra-short acting benzodiazepine for IV sedation. This study aimed to investigate the electroencephalogram (EEG) pharmacodynamics of remimazolam infusion.

Methods: Twenty healthy male volunteers received remimazolam as continuous IV infusion of 5 mg/min for 5 min, 3 mg/min for the next 15 min, and 1 mg/min for further 15 min. Continuous EEG monitoring was performed by a neurophysiologic system with electrodes placed at F3, F4, C3, C4, O1, O2, Cz, and Fp1 (10/20 system) and using the Narcotrend Index. Sedation was assessed clinically by using the Modified Observer’s Assessment of Alertness and Sedation scale. Pharmacodynamic models were developed for selected EEG variables and Narcotrend Index.

Results: EEG changes during remimazolam infusion were characterized by an initial increase in beta frequency band and a late increase in delta frequency band. The EEG beta ratio showed a prediction probability of Modified Observer’s Assessment of Alertness and Sedation score of 0.79, and could be modeled successfully using a standard sigmoid Emax model. Narcotrend Index showed a prediction probability of Modified Observer’s Assessment of Alertness and Sedation score of 0.74. The time course of Narcotrend Index was described by an extended sigmoid Emax model with two sigmoid terms and different plasma–effect equilibration times.

Conclusions: Beta ratio was identified as a suitable EEG variable for monitoring remimazolam sedation. Narcotrend Index appeared less suitable than the beta ratio for monitoring the sedative effect if remimazolam is administered alone.