Validity of the lipid sink - Accepted Pre-publication.pdf (818.95 kB)
Download file

Validity of the lipid sink as a mechanism for the reversal of local anesthetic systemic toxicity: A physiologically based pharmacokinetic model study

Download (818.95 kB)
journal contribution
posted on 15.04.2014, 00:00 authored by Ilin Kuo, Belinda S. Akpa
Background: In vitro observations support the lipid sink theory of therapeutic action by confirming the capacity of lipid emulsions to successfully uptake bupivacaine from aqueous media. However, competing hypotheses and some in/ex vivo small animal studies suggest a metabolic or positive inotropic effect underlies the dramatic effects of lipid therapy. Controlled clinical tests to establish causality and mechanism of action are an impossibility. In an effort to quantitatively probe the merits of a ‘sink’ mechanism, a physiologically-based pharmacokinetic (PBPK) model has been developed that considers the binding action of plasma lipid. Methods: The model includes no fitting parameters and accounts for concentration dependence of plasma protein and lipid:anesthetic binding as well as the metabolism of the lipid scavenger. Predicted pharmacokinetics were validated by comparison with data from healthy volunteers administered a non-toxic dose of bupivacaine. The model was augmented to simulate lipid therapy and extended to the case of accidental intravenous infusion of bupivacaine at levels known to cause systemic toxicity. Results: The model yielded quantitative agreement with available pharmacokinetic data. Simulated lipid infusion following an IV overdose was predicted to yield (i) an increase in total plasma concentration, (ii) a decrease in unbound concentration, and (iii) a decrease in tissue content of bupivacaine. Conclusions: 3 Results suggest that the timescale on which tissue content is reduced varies from organ to organ, with the concentration in the heart falling by 11% within 3 minutes. This initial study suggests that, in isolation, the lipid sink is insufficient to guarantee a reversal of systemic toxicity

History

Publisher Statement

Post print version of article may differ from published version. The final publication is available at www.lww.com/; DOI:10.1097/ALN.0b013e31828ce74d

Publisher

Lippincott, Williams & Wilkins

Language

en_US

issn

1528-1175

Issue date

01/03/2013

Usage metrics

Categories

Keywords

Exports