• Merel H Kuizenga, Pieter J Colin, Reyntjens Koen M E M KMEM, Daan J Touw, Hasan Nalbat, Froukje H Knotnerus, Vereecke Hugo E M HEM, and Struys Michel M R F MMRF.
• 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.) 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.) the Department of Basic and Applied Medical Sciences, Faculty of Medicine and Health Sciences (M.M.R.F.S.), Ghent University, Ghent, Belgium the Department of Anesthesiology and Reanimation, AZ St.-Jan Brugge-Oostende AV, Bruges, Belgium (H.E.M.V.).
• Anesthesiology. 2019 Dec 1; 131 (6): 1223-1238.

BackgroundThe 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).MethodsThis 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.ResultsThe 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) 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 (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).ConclusionsThe 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.

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