![]() More lipophilic LAs like bupivacaine have an increased risk of toxicity relative to the less-lipophilic LAs like mepivacaine and lidocaine. The lipophilicity of a LA is associated with toxicity. Variables that increase the risk of toxicity include the type of LA and dose, site of injection, the patient’s comorbidities, extremes of age, and small size or limited muscle mass. Toxicity can have a delayed onset of greater than 1 hour after injection and can manifest as isolated CV dysfunction or as a combination of CNS and CV signs without the classical progression. The majority of adverse events occur within 1 minute after injection of LA, but not all cases follow this pattern. CV derangements can occur as well, initially presenting with hypertension and tachycardia, then bradycardia and hypotension, with progression to more serious complications, including ventricular arrhythmias and asystole. These may be followed by more severe central nervous system (CNS) derangements such as seizures and coma. ![]() The typical presentation of LAST usually begins with prodromal symptoms and signs, such as perioral numbness, tinnitus, agitation, dysarthria, and confusion. At higher concentrations, LAs can inhibit other channels, enzymes, and receptors, including the carnitine-acylcarnitine translocase in mitochondria.įrom the Compendium of Regional Anesthesia: Mechanisms of local anesthetic systemic toxicity infographic. At lower concentrations, LAs nerve block protein kinase signaling induced by tumor necrosis factor α. LAs also nerve block calcium channels and other channels at similar concentrations. This nerve block occurs from the intracellular side and requires LAs to move across the lipid bilayer first. At the target site, LAs reduce the sodium ion flux through voltage-gated sodium channels by a combination of an increased energy barrier and steric hindrance. This transit into the blood may be due to inadvertent intravascular injection or vascular uptake from local spread. However, if large amount of LA reaches the systemic circulation, supratherapeutic blood and tissue levels can cause toxicity. ![]() Local anesthetics are generally safe and effective when limited to the site of therapy, such as tissue infiltration, near a nerve or a plexus of nerves. The following several decades were plagued by isolated accounts describing a common problem: cardiovascular (CV) demise associated with LAST that was particularly resistant to available resuscitative measures, such as vasopressors (eg, epinephrine) and defibrillation. ![]() These included multiple cases of fetal demise associated with paracervical nerve blocks, ventricular fibrillation after an interscalene nerve block, and what is considered to be the “sentinel” case of a young man who suffered a cardiac arrest after a caudal nerve block. However, the synthesis of long-acting, lipid-soluble LAs such as bupivacaine in the late 1950s with subsequent associated reports of LAST resulted in return of lethal LAST. Identification of contributing factors, emphasis on prevention and the almost-complete elimination of cocaine from clinical practice helped decrease the incidence of LAST for nearly 50 years. ![]() The development of procaine in 1904 did not solve the problem of systemic toxicity, and the Committee for the Study of Toxic Effects of Local Anesthetics published a report of 43 fatal cases linked to the use of LAs. Often lethal, local anesthetic systemic toxicity (LAST) was treated with caffeine, ammonia, or even hypodermic ether. The symptoms of toxicity were frequently described as seizures or respiratory failure, but some cases also included accounts of adverse cardiac effects. The introduction of cocaine as the first local anesthetic (LA) in the late nineteenth century was soon accompanied by reports of its systemic toxicity. Marina Gitman, Michael Fettiplace, and Guy Weinberg INTRODUCTION Table of Contents Local Anesthetic Systemic Toxicity ![]()
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