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Anesthesiology. 2013 Jun;118(6):1350-61. doi: 10.1097/ALN.0b013e31828ce74d.

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

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Department of Chemical Engineering, University of Illinois at Chicago, Chicago, Ilinois 60607, USA.



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 that 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 model has been developed that considers the binding action of plasma lipid.


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 nontoxic dose of bupivacaine. The model was augmented to simulate lipid therapy and extended to the case of accidental IV infusion of bupivacaine at levels known to cause systemic toxicity.


The model yielded quantitative agreement with available pharmacokinetic data. Simulated lipid infusion following an IV overdose was predicted to yield (1) an increase in total plasma concentration, (2) a decrease in unbound concentration, and (3) a decrease in tissue content of bupivacaine.


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 min. This initial study suggests that, in isolation, the lipid sink is insufficient to guarantee a reversal of systemic toxicity.

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