Defining plasma concentration ranges for central nervous system and cardiovascular toxicity of local anesthetics: A systematic review

Local anesthetic systemic toxicity (LAST), although rare, can lead to severe central nervous system (CNS) and cardiovascular system (CVS) complications, including seizures and cardiac arrest. Reliable human plasma concentration thresholds associated with CNS and CVS toxicity remain poorly defined, limiting clinicians' ability to contextualize measured concentrations. This systematic review aimed to evaluate human data to define plasma concentration ranges associated with moderate and severe CNS and CVS toxicity following the administration of commonly used local anesthetics in adult and pediatric patients. This systematic review was preregistered on PROSPERO (CRD420251274220). MEDLINE, Embase, and Cochrane CENTRAL were searched from inception through December 27, 2025, with no language restrictions. Eligible studies included human participants who developed CNS or CVS toxicity after exposure to bupivacaine, levobupivacaine, lidocaine, mepivacaine, or ropivacaine, with reported arterial or venous plasma concentrations measured within 5 min of symptom onset. Due to substantial heterogeneity, evidence was synthesized narratively without a formal meta-analysis. Forty-eight studies were included, predominantly case reports and case series, with a smaller number of pharmacokinetic studies. CNS toxicity generally occurred at lower plasma concentrations than severe CVS toxicity across all agents. Moderate CNS symptoms occurred at lower concentrations than seizures or coma, whereas severe CNS toxicity often overlapped with concentrations associated with moderate CVS toxicity. This review provides clinically relevant plasma concentration ranges associated with CNS and CVS toxicity for commonly used local anesthetics in humans. These values should not be interpreted as absolute toxicity thresholds but may aid clinicians in interpreting plasma concentrations during suspected LAST events. Clinical Trial Number: CRD420251274220.