Local anesthetics are used widely to provide anesthesia via subcutaneous (SC) injection; topical application to skin and mucous membranes; and epidural, spinal, and regional nerve blocks. In addition, lidocaine is used IV as an antiarrhythmic agent, and cocaine is a popular recreational drug. Commonly used agents are divided into two chemical groups: ester-linked and amide-linked (Table II-2).

Toxicity from local anesthetics (other than cocaine) is usually caused by therapeutic overdose (ie, excessive doses for local nerve blocks), inadvertent intravascular injection, or accidental injection of products meant for dilution (eg, 20% lidocaine) instead of those formulated for direct administration (2% solution). Acute injection of lidocaine has also been used as a method of homicide. To prolong the duration of effect, local anesthetics are often administered together with epinephrine, which can contribute to toxicity. Subcutaneous infiltration of large volumes of dilute lidocaine with epinephrine (tumescent anesthesia) used in cosmetic and dermatologic procedures has resulted in a number of cases of toxicity.

1. Local anesthetics bind to sodium channels in nerve fibers, blocking the sodium current responsible for nerve conduction and thereby increasing the threshold for conduction and reversibly slowing or blocking impulse generation. In therapeutic concentrations, this results in local anesthesia. High concentrations result in CNS and cardiovascular toxicity.
2. Bupivacaine is more cardiotoxic than other local anesthetics, with a narrow toxic-to-therapeutic ratio and with numerous reports of rapid cardiovascular collapse and sometimes death. In addition to causing sodium channel blockade, bupivacaine inhibits carnitine acyltransferase, which is essential for fatty acid transport, resulting in mitochondrial dysfunction that is thought to contribute to cardiotoxicity.
3. Some local anesthetics (eg, benzocaine, prilocaine, lidocaine) can cause methemoglobinemia.
4. Pharmacokinetics. With subcutaneous injection, peak blood levels are reached in 10-60 minutes, depending on the vascularity of the tissue and whether a vasoconstrictor such as epinephrine has been added. Ester-type drugs are hydrolyzed rapidly by plasma cholinesterase and have short half-lives. Amide-type drugs are metabolized by the liver, have a longer duration of effect, and may accumulate after repeated doses in patients with hepatic insufficiency. For other kinetic values, see Table II-63.

Systemic toxicity occurs when brain levels exceed a certain threshold. Toxic levels can be achieved with a single large subcutaneous injection, with rapid IV injection of a smaller dose, inadvertent intravascular injection, or by accumulation of drug with repeated doses. The recommended maximum single subcutaneous doses of the common agents are listed in Table II-2. With IV regional anesthesia, doses as low as 1.4 mg/kg for lidocaine and 1.3 mg/kg for bupivacaine have caused seizures, and doses as low as 2.5 mg/kg for lidocaine and 1.6 mg/kg for bupivacaine have caused cardiac arrest.

1. Toxicity due to local anesthetic effects includes prolonged anesthesia and, rarely, permanent sensory or motor deficits. Spinal anesthesia may block nerves to the muscles of respiration, causing respiratory arrest, or may cause sympathetic blockade, resulting in hypotension.
2. Toxicity resulting from systemic absorption of local anesthetics most commonly affects the CNS and the cardiovascular system. For most anesthetics such as lidocaine and mepivacaine, CNS toxicity precedes cardiovascular toxicity, while the reverse is seen with bupivacaine.
   1. Neurological toxicity includes headache, confusion, tinnitus, perioral numbness, slurred speech, muscle twitching, anxiety, agitation, convulsions, coma, and respiratory arrest.
   2. Cardiotoxic effects include hypotension, sinus arrest, widening of the QRS complex, bradycardia, atrioventricular block, ventricular tachycardia/fibrillation, and asystole. Cardiac arrest due to bupivacaine is often refractory to usual treatment.
   3. Epinephrine toxicity may include palpitations, headache, tachycardia, hypertension, and ventricular arrhythmias.
3. Methemoglobinemia (see also) may occur after exposure to benzocaine, prilocaine, or lidocaine.
4. Allergic reactions (bronchospasm, hives, and shock) are uncommon and occur almost exclusively with ester-linked local anesthetics. Methylparaben, which is used as a preservative in some multidose vials, may be the cause of some reported hypersensitivity reactions.
5. Features of toxicity caused by cocaine are discussed.

Is based on history of use and typical clinical features. Abrupt onset of confusion, slurred speech, anxiety or convulsions in a patient receiving lidocaine infusion for arrhythmias should suggest lidocaine toxicity.

1. Specific levels. Serum levels of some local anesthetics may confirm their role in producing suspected toxic effects, but these levels must be obtained promptly because they fall rapidly.
   1. Serum concentrations of lidocaine greater than 6-10 mg/L are considered toxic.
   2. Lidocaine is often detected in comprehensive urine toxicology screening as a result of use either as a local anesthetic (eg, for minor procedures in the emergency department) or as a cutting agent for illicit drugs.
2. Other useful laboratory studies include electrolytes, glucose, BUN and creatinine, cardiac troponin, ECG monitoring, arterial blood gases or pulse oximetry, and methemoglobin level (benzocaine).

1. Emergency and supportive measures
   1. Maintain an open airway and assist ventilation if necessary.
   2. Treat coma, seizures, hypotension, arrhythmias, and anaphylaxis if they occur. Low-dose epinephrine is preferred for pressor support. For ventricular arrythmias use amiodarone rather than sodium channel blocking antiarrhythmic drugs. Extracorporeal circulatory assistance (eg, balloon pump or partial cardiopulmonary bypass) has been used for the short-term support of patients after acute massive overdose with 20% lidocaine solution or inadvertent intravascular administration of bupivacaine.
   3. Monitor vital signs and ECG for at least 6 hours.
2. Specific drugs and antidotes. Intravenous lipid emulsion (Intralipid) therapy may augment the return of spontaneous circulation after cardiac arrest caused by local anesthetics, including bupivacaine, levobupivacaine, ropivacaine, mepivacaine and lidocaine. Administer a 1.5-mL/kg bolus of Intralipid 20%, repeated up to two times if necessary, followed by an infusion of 0.25-0.50 mL/kg/min for 30-60 minutes.
3. Decontamination
   1. Parenteral exposure. Decontamination is not feasible.
   2. Ingestion. Administer activated charcoal orally if conditions are appropriate (see Table I-37). Gastric lavage is not necessary after small-to-moderate ingestions if activated charcoal can be given promptly.
4. Enhanced elimination. The role of extracorporeal elimination is limited. Lidocaine has a moderate volume of distribution, but at therapeutic levels a large percentage (40-80%) is protein bound making hemodialysis relatively ineffective. Dialysis might be considered after a massive overdose or when metabolic elimination is impaired because of circulatory collapse or severe liver disease.