Based on a case of apparent cardiotoxicity from a very low dose of bupivacaine in a patient with carnitine deficiency, G. L. Weinberg postulated that this metabolic derangement led to enhanced toxicity due to the accumulation of fatty acids within the cardiac myocyte. He hypothesized that administration of lipid would similarly potentiate bupivacaine cardiotoxicity, but experiments performed to test this hypothesis demonstrated exactly the opposite effect. Accordingly, he began systematic laboratory investigations, which clearly demonstrated the poten-tial efficacy of an intravenous lipid emulsion (ILE) for resuscita-tion from bupivacaine cardiotoxicity. Clinical confirmation came 8 years later with the report of the successful resuscitation of a patient who sustained an anesthetic-induced (bupivacaine plus mepivacaine) cardiac arrest refractory to standard advanced cardiac life support procedures (ACLS). Numerous similar reports of successful resuscitations soon followed, extending this clinical experience to other anesthetics including levobupivacaine and ropivacaine, anesthetic-induced CNS toxicity, as well as toxicity induced by other classes of compounds, eg, bupropion-induced cardiovascular collapse and multiform ventricular tachycardia provoked by haloperidol. Laboratory investigations have like-wise provided evidence of efficacy for treatment of diverse toxic challenges (eg, verapamil, clomipramine, and propranolol). The mechanism by which lipid is effective is incompletely understood, but almost certainly some of its effect is related to its ability to extract a lipophilic drug from aqueous plasma, thus reducing its effective concentration at tissue targets, a mecha-nism termed “lipid sink.” However, the extent of this extraction does not appear adequate to account for the magnitude of clini-cal effect, suggesting that other mechanisms at least contribute to the efficacy of lipid rescue. For example, bupivacaine has been shown to inhibit fatty acid transport at the inner mitochondrial membrane, and lipid might act by overcoming this inhibition serving to restore energy to the myocardium or derive benefit via elevation of intramyocyte calcium concentration. Although numerous questions remain, the evolving evidence is sufficient to warrant administration of lipid in cases of systemic anesthetic toxicity. Its use has been promulgated by a task force of the American Society of Regional Anesthesia (http://www.asra.com/ checklist-for-local-anesthetic-toxicity-treatment-1-18-12.pdf ), and administration of lipid has been incorporated into the most recent revision of ACLS guidelines for Cardiac Arrest in Special Situations. Importantly, propofol cannot be administered for this purpose, as the relatively enormous volume of this solu-tion required for lipid therapy would deliver lethal quantities of propofol.
The mechanism of local anesthetic neurotoxicity has been extensively investigated in cell culture, isolated axons, and in vivo models. These studies have demonstrated myriad deleterious effects including conduction failure, membrane damage, enzyme leakage, cytoskeletal disruption, accumulation of intracellular calcium, disruption of axonal transport, growth cone collapse, and apoptosis. It is not clear what role these factors or others play in clinical injury. It is clear, however, that injury does not result from blockade of the voltage-gated sodium channel per se, and thus clinical effect and toxicity are not tightly linked.