An Evaluation of Remifentanil Propofol Response Surfaces for Loss of Responsiveness, Loss of Response to Surrogates of Painful Stimuli and Laryngoscopy in Patients Undergoing Elective Surgery

Johnson, Ken B.; Syroid, Noah; Gupta, Dhanesh K.; Manyam, Sandeep C.; Egan, Talmage D.; Huntington, Jeremy; White, Julia L.; Tyler, Diane O.; Westenskow, Dwayne R.

doi:10.1213/ane.0b013e3181606c62

Cited by 68 publications

(63 citation statements)

References 26 publications

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“…Other fields have more successfully shunned response additivity but still suffer from misunderstandings of Loewe addivity. For example, although nowhere is the concept of synergy more important and more discussed than in anesthesiology (45,72,77,108,142,143), one can find recent examples of uncritical application of linear Loewe additivity there as well (e.g., Refs. 38, 73, and 79).…”

Section: What Is the Problem?mentioning

confidence: 99%

Understanding synergy

Geary¹

2013

American Journal of Physiology-Endocrinology and Metabolism

138

181

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Analysis of the interactive effects of combinations of hormones or other manipulations with qualitatively similar individual effects is an important topic in basic and clinical endocrinology as well as other branches of basic and clinical research related to integrative physiology. Functional, as opposed to mechanistic, analyses of interactions rely on the concept of synergy, which can be defined qualitatively as a cooperative action or quantitatively as a supra-additive effect according to some metric for the addition of different dose-effect curves. Unfortunately, doseeffect curve addition is far from straightforward; rather, it requires the development of an axiomatic mathematical theory. I review the mathematical soundness, face validity, and utility of the most frequently used approaches to supra-additive synergy. These criteria highlight serious problems in the two most common synergy approaches, response additivity and Loewe additivity, which is the basis of the isobole and related response surface approaches. I conclude that there is no adequate, generally applicable, supra-additive synergy metric appropriate for endocrinology or any other field of basic and clinical integrative physiology. I recommend that these metrics be abandoned in favor of the simpler definition of synergy as a cooperative, i.e., nonantagonistic, effect. This simple definition avoids mathematical difficulties, is easily applicable, meets regulatory requirements for combination therapy development, and suffices to advance phenomenological basic research to mechanistic studies of interactions and clinical combination therapy research.

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Section: What Is the Problem?mentioning

confidence: 99%

Understanding synergy

Geary¹

2013

American Journal of Physiology-Endocrinology and Metabolism

138

181

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“…A single case report described awake laryngoscopy using a combination of midazolam and remifentanil. 31 However, drug concentrations fell in the extreme end (high opioid/low midazolam), and we could not use the findings as a reference to evaluate the validity of our findings. The AICc was chosen instead of AIC because the number of observations was not greater than the square of the number of the parameters.…”

Section: Discussionmentioning

confidence: 88%

Predicting the Best Fit: A Comparison of Response Surface Models for Midazolam and Alfentanil Sedation in Procedures With Varying Stimulation

Liou

Ting

Mandell

et al. 2016

Anesthesia &Amp; Analgesia

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“…The parameters 1 to 7 are used to calculate the volume and clearance of the compartments in a 2-compartment mammillary model using the covariates of patient age and weight and an infusion delay using pump rate, as shown in Appendix Table 1. The Masui et al model predicted the effect-site concentration for an infusion sequence of propofol, which was converted to a probability of loss of responsiveness (LOR) using parameters determined by Johnson et al 5 The model equation and parameters are given in the Appendix (Equation A1 and Appendix Table 2). An individual patient either responds or does not, so this probability has a different interpretation for an individual, and can be seen as a measure of patient sensitivity.…”

Section: Methodsmentioning

confidence: 99%