Rethinking the Boundaries of Local Anesthetic Systemic Toxicity in the Era of Sustained-Release Formulations

Sustained-release local anesthetic formulations introduce prolonged and dynamic exposure patterns that challenge current frameworks for assessing local anesthetic systemic toxicity (LAST). Recent pharmacovigilance findings, pharmacokinetic evidence, and reports of delayed and recurrent LAST further support the need to re-evaluate LAST across three conceptual boundaries. First, the exposure boundary challenges the use of recommended maximum doses as stand-alone safety thresholds. Co-administration, formulation stability, and the local tissue microenvironment may influence drug release and systemic exposure. Second, the temporal boundary emphasizes that a lower initial peak plasma concentration does not necessarily imply a shorter window of vulnerability, particularly when systemic exposure is prolonged or follows a bimodal pattern. Third, the resuscitation endpoint boundary highlights that return of spontaneous circulation (ROSC) does not necessarily indicate resolution of the underlying toxicological process, as hemodynamic instability may recur after initial ROSC. Assessment of LAST associated with sustained-release formulations should not be limited to administered dose or peak plasma concentration but should consider the entire exposure trajectory. Future guidelines should also define long-term monitoring windows, specific triggers for continuous infusion of lipid emulsion, and safe upper limits for lipid emulsion dosing.