The Drug Titration Paradox: Correlation of More Drug With Less Effect in Clinical Data
abstract
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While analyzing clinical data where an anesthetic was titrated based
on an objective measure of drug effect, we observed paradoxically
that greater effect was associated with lesser dose. With this study
we sought to find a mathematical explanation for this negative
correlation between dose and effect, to confirm its existence with
additional clinical data, and to explore it further with Monte Carlo
simulations. Automatically recorded dosing and effect data from more
than 9,000 patients was available for the analysis. The anesthetics
propofol and sevoflurane and the catecholamine norepinephrine were
titrated to defined effect targets, i.e., the processed
electroencephalogram (Bispectral Index, BIS) and the blood pressure.
A proportional control titration algorithm was developed for the
simulations. We prove by deduction that the average dose-effect
relationship during titration to the targeted effect will associate
lower doses with greater effects. The finding of negative
correlations between propofol and BIS, sevoflurane and BIS, and
norepinephrine and mean arterial pressure confirmed the titration
paradox. Monte Carlo simulations revealed two additional factors
that contribute to the paradox. During stepwise titration toward a
target effect, the slope of the dose-effect data for the population
will be "reversed," i.e., the correlation between dose and
effect will not be positive, but will be negative, and will be
"horizontal" when the titration is "perfect."
The titration paradox must be considered whenever data from clinical
titration (flexible dose) studies are interpreted. Such data should
not be used naively for the development of dosing guidelines.
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citation
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Schnider T, Minto C F, Filipovic M. The Drug Titration Paradox:
Correlation of More Drug With Less Effect in Clinical Data. Clin
Pharmacol Ther 2021; 110:401-408.
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type
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journal paper/review (English)
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date of publishing
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17-02-2021
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journal title
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Clin Pharmacol Ther (110/2)
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ISSN electronic
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1532-6535
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pages
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401-408
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PubMed
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33426670
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DOI
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10.1002/cpt.2162
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