Local anesthetic systemic toxicity: current perspectives

Abstract

Local anesthetic systemic toxicity (LAST) is a life-threatening adverse event that may occur after the administration of local anesthetic drugs through a variety of routes. Increasing use of local anesthetic techniques in various healthcare settings makes contemporary understanding of LAST highly relevant. Recent data have demonstrated that the underlying mechanisms of LAST are multifactorial, with diverse cellular effects in the central nervous system and cardiovascular system. Although neurological presentation is most common, LAST often presents atypically, and one-fifth of the reported cases present with isolated cardiovascular disturbance. There are several risk factors that are associated with the drug used and the administration technique. LAST can be mitigated by targeting the modifiable risk factors, including the use of ultrasound for regional anesthetic techniques and restricting drug dosage. There have been significant developments in our understanding of LAST treatment. Key advances include early administration of lipid emulsion therapy, prompt seizure management, and careful selection of cardiovascular supportive pharmacotherapy. Cognizance of the mechanisms, risk factors, prevention, and therapy of LAST is vital to any practitioner using local anesthetic drugs in their clinical practice.

Keywords: local anesthetic; regional anesthesia; therapy; toxicity.

Figure 1

Chemical structures of ester and amide local anesthetic agents with examples of each.

Figure 2

Representation of key LA cellular targets contributing to local anesthetic systemic toxicity. Notes: In the plasma membrane, LAs block the Na_v channel (Na⁺), potassium (K⁺) and calcium channels (Ca²⁺). Inhibition of second messenger systems on metabotropic transmembrane G-protein-coupled receptors leads to inhibition of ERK and pi3K. This leads to dysregulation of downstream kinase pathways, including a reduction in Akt and, thus, mTOR. Mitochondrial phosphorylation of AMP to ATP is inhibited, leading to an increase in the inhibitory, energy-sensing kinase AMPK, which in turn further mitigates mTOR. Other inhibitory targets include PKA, calcium-dependent contractility inhibition at the sarcomere, and modulation of the RyR. Red rings represent sites of action of LAs. Dotted lines represent inhibitory actions. Abbreviations: AMP, adenosine monophosphate; ATP, adenosine triphosphate; LA, local anesthetic; RyR, ryanodine receptor.