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Population Pharmacodynamics of Propofol and Sevoflurane in Healthy Volunteers Using a Clinical Score and the Patient State Index: A Crossover Study

Kuizenga, M. H., Colin, P. J., Reyntjens, K. M. E. M., Touw, D. J., Nalbat, H., Knotnerus, F. H., Vereecke, H. E. M. & Struys, M. M. R. F., 17-Sep-2019, In : Anesthesiology. 16 p.

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  • Population Pharmacodynamics of Propofol and Sevoflurane in Healthy Volunteers Using a Clinical Score and the Patient State Index A Crossover Study

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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 shoutAntinociceptive drug effects can be assessed as the presence or absence of tolerance to tetanic stimulusThe 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 IndexThe sevoflurane Patient State Index values associated with a 50% probability of tolerance to the standard stimuli were higher for than those for propofolAdding a 2 ng · ml 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 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) 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).

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.

Original languageEnglish
Number of pages16
JournalAnesthesiology
Publication statusE-pub ahead of print - 17-Sep-2019

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