A Comprehensive Mechanism for Reversal of Cardiac Pharmacotoxicity by Intravenous Lipid Emulsion

Intravenous lipid emulsion was identified in 1998 as a treatment for local anesthetic toxicity and successfully translated into clinical practice in 2006. As with many drugs, practitioners first used intravenous lipid emulsion without full mechanistic insight. In order to more fully understand the mechanisms underlying the reversal of cardiac pharmacotoxicity, we used in vivo, ex vivo and in silico models to tease apart the mechanisms. We identified a multi-modal mechanism that included a scavenging effect, whereby the new intravenous lipid compartment facilitated an accelerated redistribution of drug from heart (and other toxin sensitive organs) to muscle and liver for storage and detoxification. Second, we identified a benefit to the cardiovascular system that improved blood pressure and cardiac output further improving redistribution. Finally, we found that changes in kinase signaling facilitated these improvements. Lipid emulsion drove pro-survival kinase pathways and improved energy processing to improve outcomes. In summary, the three components provide a comprehensive mechanism to explain the rapid recovery from cardiac pharmacotoxicity by intravenous lipid emulsion.