Defining plasma concentration ranges for central nervous system and cardiovascular toxicity of local anesthetics: A systematic review.
5 affiliations
- 1Department of Medicine (DIMED), University of Padua, Padua, Italy.
- 2Institute of Anesthesia and Intensive Care, University Hospital of Padua, Padua, Italy.
- 3Department of Anesthesiology and Reanimation, Ondokuz Mayis University Faculty of Medicine, Samsun, Türkiye.
- 4Department of Anesthesiology and Reanimation, Istanbul University-Cerrahpasa Faculty of Medicine, Istanbul, Türkiye.
- 5Department of Anesthesiology and Reanimation, Health Science University, Istanbul Kanuni Sultan Süleyman Education and Training Hospital, Istanbul, Türkiye.
Abstract
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.
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BibTeX
@article{cassai2026defining,
title = {{Defining plasma concentration ranges for central nervous system and cardiovascular toxicity of local anesthetics: A systematic review.}},
author = {Alessandro De Cassai and Burhan Dost and Yunus Emre Karapinar and Esra Turunc and Engin İhsan Turan and Tommaso Pettenuzzo and Paolo Navalesi},
journal = {Saudi journal of anaesthesia},
year = {2026},
month = oct,
doi = {10.4103/sja.sja_428_26},
url = {https://europepmc.org/article/MED/42960009},
note = {CC BY-NC-SA},
}
RIS
TY - JOUR
TI - Defining plasma concentration ranges for central nervous system and cardiovascular toxicity of local anesthetics: A systematic review.
AU - Alessandro De Cassai
AU - Burhan Dost
AU - Yunus Emre Karapinar
AU - Esra Turunc
AU - Engin İhsan Turan
AU - Tommaso Pettenuzzo
AU - Paolo Navalesi
PY - 2026
DA - 2026/10/01
JO - Saudi journal of anaesthesia
DO - 10.4103/sja.sja_428_26
UR - https://europepmc.org/article/MED/42960009
AB - 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.
SN - 1658-354X
SN - 0975-3125
ER -