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The reported successful use of IV lipid emulsions in local anesthetic intoxications is thought to be due to lipid sequestration of local anesthetics. However, controlled efficacy studies were lacking, and other mechanisms of action have also been suggested. We investigated the effect of lipid infusion on plasma concentrations and cardiovascular effects of 2 local anesthetics differing in lipophilicity, bupivacaine, and mepivacaine.Bupivacaine (n = 20) or mepivacaine (n = 20) was infused into a central vein of anesthetized (isoflurane 1%, FIO2 0.21) pigs until mean arterial blood pressure decreased to 50% from baseline. Isoflurane was discontinued and FIO2 was increased to 1.0. Ten pigs in each local anesthetic group were treated with 20% lipid emulsion (ClinOleic®), and 10 pigs with Ringer's solution: 1.5 mL/kg in 1 minute followed by an infusion of 0.25 mL · kg−1 · min−1 for 29 minutes. Five additional pigs were infused bupivacaine and Intralipid®. Total and nonlipid-bound local anesthetic concentrations were determined from repeated blood samples.There were no overall differences in total or nonlipid-bound plasma local anesthetic concentrations between the lipid and Ringer's groups. However, plasma median total bupivacaine concentration was 21% and 23% higher at 20 and 30 minutes, respectively, in the lipid group (P = 0.016 without Holm–Bonferroni correction). There was also no overall difference between lipid and Ringer's groups in the rate of recovery of hemodynamic and electrocardiographic variables. Median mean arterial blood pressure in the lipid group with bupivacaine intoxication was 16 mm Hg and 15 mm Hg higher than in the corresponding Ringer's group at 10 and 15 minutes, respectively (P = 0.016 and P = 0.021, respectively, without Holm–Bonferroni correction). Intralipid® also caused no difference between total plasma and nonlipid-bound concentrations of bupivacaine with no apparent enhancement of recovery.Lipid emulsion neither had any measurable effect on the disposition of the studied local anesthetics in plasma, nor did it improve the rate of recovery from intoxication by either local anesthetic as measured by hemodynamic variables.