Local Anesthetic Toxicity

Etiology

Accidental intravascular injection during the administration of local anesthetics has long been recognized as the most common cause of LAST. However, certain co-morbidities can also increase the risk of local anesthetic overdose and, in turn, systemic toxicity. These include hepatic dysfunction, cardiac disease, pregnancy, and metabolic syndromes. Additionally, patients at the extremes of age are at greater risk of toxicity due to reduced clearance of the anesthetics. Specifically, infants (younger than 4 months old) have low a-acid glycoprotein plasma concentrations, which can result in lower intrinsic clearance of bupivacaine.[4][5]

Epidemiology

The reported incidence of LAST is highly variable. Some studies report 0 events after over 12,000 nerve blocks, whereas others report an incidence of up to 25 per 10,000 nerve blockades. One study reported seizures in 79 of 10,000 brachial plexus blockade procedures. This complication was due to LAST CNS toxicity as a result of the intravascular local anesthetic injection. Although the published data has been inconsistent, 1 common theme prevails: optimizing the management of LAST is of the utmost importance moving forward.[6][7]

Pathophysiology

A mechanism for LAST has been difficult to establish, as its clinical presentation is highly variable. Additionally, the number of randomized clinical trials exploring specific mechanisms is limited. Most theories are based upon which binding site, ion channel, signaling pathway, or enzyme is involved in CNS and cardiac toxicity or their treatment.[8][9] Local anesthetics inhibit many components of the oxidative phosphorylation pathway. Thus, LAST affects the 2 organs that are inherently less tolerant of anaerobic metabolism, the heart and brain.

Cardiac toxicity is an important component of LAST, and most instances are related to accidental intravascular injection. Local anesthetics bind to and inhibit voltage-gated sodium channels. Leading to conduction disturbances, contractile dysfunction, and ventricular arrhythmias that are seen in local anesthetic-induced cardiac toxicity. The incidence of cardiac toxicity increases with bupivacaine, a longer-acting anesthetic. Bupivacaine avidly blocks inactive sodium channels during the cardiac action potential at 0.2 micrograms/ml concentration. This is done in a “fast-in/slow-out fashion,” meaning bupivacaine binds very quickly to a large proportion of sodium channels during the cardiac action potential but releases from the channels slowly during diastole, resulting in a large proportion of the medication accumulating at 60 to 150 beats per minute. Lidocaine at 5 to 10 micrograms/ml also results in substantial sodium channel blockade during a cardiac action potential. However, in contrast to bupivacaine, lidocaine follows the “fast-in/fast-out” principle, meaning it releases from sodium channels rapidly during diastole. This allows for a quicker recovery and a reduced incidence of cardiac toxicity when compared to bupivacaine.

CNS toxicity is another important consequence of LAST. While it is comprised of many initial prodromal features, it most often manifests as seizures. One mechanistic theory is centered around Twik-related acid-sensitive K+ channels (TASK). These pH-sensitive channels generate neuronal potassium "leak" currents. Local anesthetic inhibition causes membrane depolarization and increased neuronal excitability. As these channels are expressed throughout the brain, this is the suggested mechanism for seizures in this setting.

History and Physical

Early recognition of CNS and cardiac toxicity in LAST can drastically change the clinical course. Following a single local anesthetic injection, LAST presented within 50 seconds in 50% of cases studied and within 5 minutes in 75% of cases. If potentially toxic doses are administered, then it is recommended that patients be observed for at least 30 minutes.

LAST most commonly presents with CNS changes. Initial signs and symptoms include agitation, confusion, dizziness, drowsiness, dysphoria, auditory changes, tinnitus, perioral numbness, metallic taste, and dysarthria. Without adequate recognition and treatment, these signs as symptoms can progress to seizures, respiratory arrest, and/or coma. While CNS toxicity often presents with the above initial features, the most common consequence is seizures. Additionally, in the setting of intravascular injection, seizures can be the initial presentation.

Historically, local anesthetic literature suggested that cardiac toxicity is often presented after antecedent CNS toxicity. However, with more potent local anesthetics, cardiac toxicity has been found to arise concurrently with seizures or even precede them. Hypotension and bradycardia are often the first signs of cardiac toxicity. However, arrhythmias are responsible for most reported cases, with bradyarrhythmias being the most common. Additional signs of cardiac toxicity include hypertension, dyspnea, pain, wide complex, ST-segment changes, asystole, tachycardia, and ventricular ectopy/tachycardia/fibrillation.

Evaluation

Often, no tests are needed as local anesthetic toxicity is a clinical diagnosis. Depending on the circumstances, a complete blood count, chemistry, and electrocardiogram may be considered.[10]

Treatment / Management

Initial management of LAST should be focused on airway management, circulatory support, and reduction of systemic side effects. Immediate ventilation and oxygenation to prevent hypoxia and acidosis can facilitate resuscitation and reduce the likelihood of progression to seizures or cardiovascular collapse. If seizures do occur, immediate administration of benzodiazepines is recommended to prevent injury and acidosis. Propofol or thiopental can be used if benzodiazepines are unavailable. However, these agents may worsen any associated hypotension or cardiac depression. If these medications are unable to control tonic-clonic seizure movements, small doses of succinylcholine should be intermittently administered to stop muscular activity and further acidosis.[6][7][11]

Management of local anesthetic-induced cardiac arrest is focused on restoring cardiac output. This is done to re-establish tissue perfusion and, in turn, prevent and treat any underlying acidosis. Standard ACLS guidelines are recommended in this situation, with a few adjustments. Small doses of epinephrine (less than 1 microgram/kg) are preferred. Vasopressin should be avoided, as it can result in pulmonary hemorrhage. Additionally, calcium-channel blockers and B-adrenergic-receptor blockers are not recommended. If ventricular arrhythmias do occur, amiodarone is the preferred pharmacotherapy, as local anesthetics and procainamide can exacerbate the existing toxicity.

Recent case studies support the use of lipid emulsion therapy as soon as prolonged seizure activity or local anesthetic-induced arrhythmias are suspected. Theories suggest it improves cardiac conduction, contractility, and coronary perfusion by drawing the lipid-soluble local anesthetic out of the cardiac tissue. A bolus of 1.5 mL/kg of 20% lipid emulsion and a subsequent infusion of 0.25 ml/kg per minute should be given. The infusion should be continued for 10 minutes after hemodynamic stability is attained. An additional bolus and an infusion rate increase to 0.5 mL/kg per minute can be administered if stability is not achieved. The maximum recommended dose for initial administration is approximately 10 mL/kg for 30 minutes. If cardiac stability has not been achieved following the modified ACLS guidelines and subsequent lipid emulsion therapy, then cardiopulmonary bypass is recommended until the local anesthetic has cleared.

Differential Diagnosis

The differential diagnoses for local anesthetic toxicity include the following:

• Anxiety disorder
• Anaphylaxis
• Illicit drug toxicity

Complications

The complications that can manifest with local anesthetic toxicity are as follows:

• Seizures
• Cardiac arrest
• Hypotension
• Arrhythmias
• Death