Newly Published
Perioperative Medicine  |   September 2019
Population Pharmacodynamics of Propofol and Sevoflurane in Healthy Volunteers Using a Clinical Score and the Patient State Index: A Crossover Study
Author Notes
  • From the Departments of Anesthesiology (M.H.K., P.J.C., K.M.E.M.R., H.N., F.H.K., H.E.M.V., M.M.R.F.S.) and Clinical Pharmacy and Pharmacology (D.J.T.), University Medical Center Groningen and the Department of Pharmacy, Section of Pharmacokinetics, Toxicology and Targeting, (D.J.T.), University of Groningen, Groningen, The Netherlands; the Department of Bioanalysis, Faculty of Pharmaceutical Sciences (P.J.C.) and the Department of Basic and Applied Medical Sciences, Faculty of Medicine and Health Sciences (M.M.R.F.S.), Ghent University, Ghent, Belgium; and the Department of Anesthesiology and Reanimation, AZ St.-Jan Brugge-Oostende AV, Bruges, Belgium (H.E.M.V.).
  • 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).×
  • Part of this study was presented as a poster titled “Comparison between Two Versions of the Patient State Index® during Propofol and Sevoflurane Anesthesia, with or without Remifentanil” at Euroanaesthesia, the European Anaesthesiology Congress, June 4, 2017, in Geneva, Switzerland.
    Part of this study was presented as a poster titled “Comparison between Two Versions of the Patient State Index® during Propofol and Sevoflurane Anesthesia, with or without Remifentanil” at Euroanaesthesia, the European Anaesthesiology Congress, June 4, 2017, in Geneva, Switzerland.×
  • Submitted for publication September 13, 2018. Accepted for publication August 2, 2019.
    Submitted for publication September 13, 2018. Accepted for publication August 2, 2019.×
  • Correspondence: Address correspondence to Dr. Kuizenga: University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. m.h.kuizenga@umcg.nl. 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 / Pharmacology
Perioperative Medicine   |   September 2019
Population Pharmacodynamics of Propofol and Sevoflurane in Healthy Volunteers Using a Clinical Score and the Patient State Index: A Crossover Study
Anesthesiology Newly Published on September 18, 2019. doi:10.1097/ALN.0000000000002966
Anesthesiology Newly Published on September 18, 2019. doi:10.1097/ALN.0000000000002966
Abstract

Editor’s Perspective:

What We Already Know about This Topic:

  • Hypnotic drug effects can be assessed as the presence or absence of standard clinical endpoints, such as tolerance to calling the person by name and tolerance to shake and shout

  • Antinociceptive drug effects can be assessed as the presence or absence of tolerance to tetanic stimulus

  • The Patient State Index is a processed, electroencephalographic-derived index that is considered by some to be a drug-independent representation of the depth of sedation and anesthesia

What This Article Tells Us That Is New:

  • A four-period randomized sequence crossover study determined the concentration–effect relationships for both propofol and sevoflurane, both with and without remifentanil coadministration, with effects measured as tolerance to standard stimuli and by the Patient State Index

  • The sevoflurane Patient State Index values associated with a 50% probability of tolerance to the standard stimuli were higher for than those for propofol

  • Adding a 2 ng · ml−1 predicted effect-site remifentanil concentration increased all Patient State Index values associated with a 50% probability of tolerance to the standard stimuli, but 4 ng · ml−1 produced additional effects only during propofol administration

Background: The population pharmacodynamics of propofol and sevoflurane with or without opioids were compared using the endpoints no response to calling the person by name, tolerance to shake and shout, tolerance to tetanic stimulus, and two versions of a processed electroencephalographic measure, the Patient State Index (Patient State Index-1 and Patient State Index-2).

Methods: This is a reanalysis of previously published data. Volunteers received four anesthesia sessions, each with different drug combinations of propofol or sevoflurane, with or without remifentanil. Nonlinear mixed effects modeling was used to study the relationship between drug concentrations, clinical endpoints, and Patient State Index-1 and Patient State Index-2.

Results: The C50 values for no response to calling the person by name, tolerance to shake and shout, and tolerance to tetanic stimulation for propofol (µg · ml−1) and sevoflurane (vol %; relative standard error [%]) were 1.62 (7.00)/0.64 (4.20), 1.85 (6.20)/0.90 (5.00), and 2.82 (15.5)/0.91 (10.0), respectively. The C50 values for Patient State Index-1 and Patient State Index-2 were 1.63 µg · ml−1 (3.7) and 1.22 vol % (3.1) for propofol and sevoflurane. Only for sevoflurane was a significant difference found in the pharmacodynamic model for Patient State Index-2 compared with Patient State Index-1. The pharmacodynamic models for Patient State Index-1 and Patient State Index-2 as a predictor for no response to calling the person by name, tolerance to shake and shout, and tetanic stimulation were indistinguishable, with Patient State Index50 values for propofol and sevoflurane of 46.7 (5.1)/68 (3.0), 41.5 (4.1)/59.2 (3.6), and 29.5 (12.9)/61.1 (8.1), respectively. Post hoc C50 values for propofol and sevoflurane were perfectly correlated (correlation coefficient = 1) for no response to calling the person by name and tolerance to shake and shout. Post hoc C50 and Patient State Index50 values for propofol and sevoflurane for tolerance to tetanic stimulation were independent within an individual (correlation coefficient = 0).

Conclusions: The pharmacodynamics of propofol and sevoflurane were described on both population and individual levels using a clinical score and the Patient State Index. Patient State Index-2 has an improved performance at higher sevoflurane concentrations, and the relationship to probability of responsiveness depends on the drug used but is unaffected for Patient State Index-1 and Patient State Index-2.