Comparison of 3 guideline lipid emulsion regimens for local anesthetic systemic toxicity: an in silico study of bolus duration, total dose, and treatment delay in intravenous bupivacaine overdose

Purpose: Lipid emulsion is the only specific antidote for local anesthetic systemic toxicity, but no dose-finding study has been conducted. We compared 3 published regimens and alternative schedules that deliver the same dose in different ways using a human model of intravenous bupivacaine overdose. Methods: A 14-compartment human bupivacaine model was independently reimplemented without fitted parameters, replacing first-order lipid elimination with a saturable term. Toxicity was modeled as 112.5 mg administered intravenously over 3 minutes. Benefit was defined as the predicted maximum decrease in myocardial bupivacaine within 30 minutes, and harm as the predicted relative lipid load, indexed by peak plasma triglyceride concentration. Neither measure is a validated surrogate. Results: The 3 guidelines specify the same doses but different bolus durations: 1 minute versus 2-3 minutes. At a matched dose of 12 mL/kg, myocardial bupivacaine decreased by 30.5% with the 1-minute bolus and 24.9% with the 2.5-minute bolus, with the same lipid load. The completed American Society of Regional Anesthesia and Pain Medicine regimen (7.64 mL/kg) achieved a 24.6% decrease versus 24.9% with 12 mL/kg; thus, complete regimens differ in schedule as well as dose. Repeating the 1-minute bolus twice, for a total of 4.5 mL/kg, achieved a 31.9% decrease with 62% less emulsion. Start time had the greatest effect: the best regimen achieved a 41.8% decrease when started at the end of the injection, but only 9.6% when started at 10 minutes. Conclusion: In this bupivacaine model, bolus duration distinguished the regimens more than dose did, and delay had a greater effect than either, eliminating most of the benefit without changing the lipid load. Treatment should begin at the first signs of toxicity, and 20% lipid emulsion should be immediately available wherever local anesthetics are used.