Local Anesthetic Toxicity

Etiology

Supratherapeutic levels of local anesthetics can lead to LAST[1], with accidental intravascular injection being the most recognized cause. However, even in the absence of direct intravascular injection, the risk of LAST can increase, depending on the injection site and its vascularity[2]. Highly vascular areas promote greater systemic absorption of the anesthetic, increasing the risk of LAST. Additionally, many local anesthetics, including lidocaine and bupivacaine, possess vasodilatory properties, which can accelerate systemic absorption [1][4]. Since local anesthetic toxicity is additive, continuous catheter-based techniques are associated with a higher risk of LAST[1].

The timing of symptom onset provides valuable insight into the mechanism of toxicity. Symptoms appearing within 5 minutes are typically indicative of direct intravascular injection or partial intravascular injection[1], while those emerging within 20-30 minutes suggest systemic absorption. Approximately 25% of cases present symptoms within the first minute of injection, 22% within 1–5 minutes, 10% within 6–10 minutes, and 20% within 11–30 minutes. However, variations in onset time have been observed, with studies reporting that 22% of cases develop symptoms within 30 minutes and 23% within 60 minutes [5]. The most recent American Society of Regional Anesthesia and Pain Medicine (ASRA) practice advisory on LAST has observed a continued shift of LAST toward delayed presentation, with a significant number of cases presenting between 11 and 60 minutes after injection and, in some cases, over an hour[6]. 

Epidemiology

The incidence of LAST is variable but generally low, with recent literature reporting occurrences between 2 and 2.8 per 10,000 cases[6]. Patients at the extremes of age or those with organ dysfunction are at a higher risk. Pregnancy increases the risk of developing LAST due to increased cardiac output and reduced alpha-1 acid glycoprotein concentration, which increases systemic abruption and leads to a higher peak serum concentration [7]. 

Neonates and infants have lower levels of plasma-binding proteins and immature hepatic clearance, leading to increased free local anesthetic levels in the plasma, which enhances its clinical effects. Although the overall incidence of LAST is lower in children than in adults, it occurs in approximately 8 per 100,000 injections in pediatric patients[8], with those under three years of age being most affected. In elderly patients, reduced organ perfusion and impaired hepatic function slow the clearance of local anesthetics, further increasing the risk. Additionally, end-organ dysfunction in any age group increases the risk of LAST.

Pathophysiology

Local anesthetics are structurally classified as either aminoamides or aminoesters[1]. Aminoesters are metabolized in the plasma through hydrolysis by pseudocholinesterase, while aminoamides undergo hepatic biotransformation via aromatic hydroxylation, N-dealkylation, and amide hydrolysis. The classification of local anesthetics as either esters or amides is determined by the nature of their intermediate chain.

These agents differ in several key properties, including acid dissociation constant (pKa), lipophilicity, and protein binding[9][10]. Lipophilicity correlates with potency, while protein-binding capacity influences the agent's adequate circulating levels and therefore the duration of action. Increased hydrophilicity results in faster dissociation from the lipid bilayer in an aqueous environment, leading to a shorter duration of action.

These factors, along with the vascularity of the injection site, impact the peak plasma concentration and the time required to reach peak levels, ultimately affecting the risk of developing LAST.

Local anesthetics exert their primary effect by blocking voltage-gated sodium channels in cell membranes, preventing sodium influx, depolarization, and the generation of action potentials, particularly in the cardiac and central nervous systems (CNS). Additionally, they can block calcium and potassium channels, modulate cholinergic and N-methyl-D-aspartate (NMDA) receptors, and interfere with intracellular metabolic processes[11][2]. As a result, local anesthetics can produce a wide range of toxicological effects.

History and Physical

The classic presentation of LAST begins within minutes of local anesthetic injection, often accompanied by prodromal symptoms such as a metallic taste, perioral paresthesia, visual and auditory disturbances, dysarthria, dysgeusia, muscle twitching, agitation, hallucinations, and altered mental status.[12][13][2] Up to one-third of cases progress to significant cardiovascular involvement, including dysrhythmias and/or hypotension, while 20% of patients present with isolated, less severe cardiovascular symptoms. The cardiovascular manifestations of LAST vary widely, including conduction abnormalities, hypotension, and dysrhythmias such as bradycardia (with or without AV block), supraventricular tachycardias, ventricular tachycardia, ventricular fibrillation, and other malignant arrhythmias. Severe cases can rapidly deteriorate into bradycardia, hypotension, and ultimately, cardiac arrest.[2]

CNS toxicity is the most common initial manifestation, occurring in approximately 80% of cases, with seizures reported in up to 68% of patients.

Evaluation

No specific test is needed as LAST is a clinical diagnosis. When symptoms arise following local anesthetic administration, the clinician should have a high index of suspicion for LAST. Depending on the circumstances, a CBC, chemistry panel, and electrocardiogram may be considered.

Treatment / Management

Management of LAST requires early recognition, immediate discontinuation of the anesthetic, and standard resuscitation based on symptoms, except lipid emulsion therapy. The use of 20% lipid emulsion (Intralipid 20%) for LAST is an off-label indication; it is generally well tolerated. Intravenous lipid emulsion aids in resuscitation by sequestering and redistributing local anesthetics while also enhancing cardiac output through vasoconstriction and direct cardiotonic effects.

Supportive care should focus on maintaining oxygenation and ventilation, with early endotracheal intubation if necessary. Seizures should be managed with benzodiazepines. In cases of hypotension, IV fluids and vasopressors may be required. If ventricular tachycardia or fibrillation occurs, amiodarone is the preferred first-line treatment[1], while lidocaine should be avoided. Cardioversion or defibrillation should be performed as needed, and epinephrine dosing should be reduced to 1 µg/kg. For refractory cardiac arrest, extracorporeal membrane oxygenation (ECMO) may be a viable option.(B2)

Lipid emulsion 20% should be administered in cases of refractory seizures or cardiotoxicity associated with LAST.

According to ASRA guidelines, lipid emulsion dosing should be based on ideal body weight[6]. 

Dosing (per ASRA guidelines, based on ideal body weight:

• >70 kg: Bolus 100 mL IV over 2–3 minutes, followed by a 250 mL IV infusion over 15 to 20 minutes
• <70 kg: Bolus 5 mL/kg IV over 2–3 minutes, followed by an infusion of 0.25 mL/kg/min.[6]

The American College of Medical Toxicology (ACMT) and Association of Anesthetists of Great Britain and Ireland (AAGBI) recommend a bolus of 1.5 mL/kg of lipid emulsion for all patients.[14][2](B3)

Once hemodynamic stability is achieved, the lipid infusion should be continued for at least 15 minutes.

Monitoring and observation depend on the severity of symptoms. Patients with isolated neurological symptoms should be observed for a minimum of 2 hours, whereas those with cardiovascular involvement should be monitored for 4 to 6 hours.

Lipid emulsion contains egg yolk phospholipids and soybean oil, and is contraindicated in patients with allergies to these substances.

Methemoglobinemia can be associated with LAST, and in cases of refractory hypoxia, methylene blue has been successfully used as a treatment.[15]

Differential Diagnosis

The symptoms of LAST may closely resemble other perioperative complications or be obscured by sedation, so care must be taken to ensure timely diagnosis. Seizures may be caused by epilepsy or other causes of seizures, such as hypoglycemia, other electrolyte abnormalities, or infections. Arrhythmias may be caused by the patient’s underlying cardiac pathology, channelopathies, medication-induced QTc prolongation, or other causes.

Prognosis

LAST is a clinical diagnosis, with seizures being the most common symptom, occurring in 60%–70% of cases[17]. An important pharmacological consideration is the cardiovascular collapse to CNS ratio (CC: CNS), which represents the ratio of the drug dose required to induce cardiovascular collapse to the dose that causes seizures. A higher CC: CNS ratio indicates a greater safety margin, [2] as CNS symptoms typically appear before cardiac toxicity. Cardiac toxicity is the most critical factor influencing LAST severity and outcomes. Bupivacaine, a highly potent local anesthetic, is more likely to cause cardiovascular toxicity, whereas the less potent lidocaine primarily leads to neurologic toxicity. Bupivacaine is also among the most challenging local anesthetics to treat in LAST cases[17].

Most patients recover without any sequelae. Poison control center data (2016) reported 4 deaths from local anesthetics.

Complications

Hypoxia, hypercapnia, and acidosis can exacerbate LAST and interfere with resuscitation efforts. Seizures further exacerbate metabolic derangements, and prompt management is essential. Benzodiazepines are considered first-line therapy for seizures due to their relatively stable hemodynamic profile.

Data on LAST-related morbidity and mortality remain limited. According to the 2019 American Association of Poison Control Centers National Poison Data System Annual Report, 686 local anesthetic exposures were identified as potential LAST cases, with nearly half presenting no symptoms. Among those who developed symptoms, 36% had minor symptoms, 14% had moderate symptoms, and 3.5% had severe symptoms. The mortality rate was 0.4%. Similar findings were reported in 2020, highlighting the importance of emergency clinicians remaining vigilant about this significant complication.