Local anesthetics are commonly used in most medical and dental practice. While adverse effects are rare, the rising prevalence of local anesthetics in practice has resulted in a greater incidence of local anesthetic toxicity. From minor symptoms to major cardiac or central nervous system (CNS) effects, local anesthetic systemic toxicity (LAST) is an important consequence of which to be aware. Systemic toxicity was originally associated with seizures and respiratory failure. However, in the 1970s, cardiac effects were also recognized, as bupivacaine-associated fatal cardiac toxicity was discovered in healthy adults. This article reviews the mechanisms, frequency, clinical characteristics, treatment, and prevention of LAST.
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.
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, one common theme prevails in that optimizing the management of LAST is of the utmost importance moving forward.
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 are 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.
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 the 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 a concentration of 0.2 micrograms/ml. 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 will also result 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.
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 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.
Often no tests are needed as local anesthetic toxicity is a clinical diagnosis. Depending on the circumstances, a complete blood count (CBC), chemistry, and ECG may be considered.
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.
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 in fact 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 that 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 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 increase of the infusion rate 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.
Prevention of any adverse event is often referred to as the most effective "treatment." However, it is important to recognize that no specific intervention can eliminate risk. Prevention in the setting of LAST revolves around preventing intravascular injection.
Intravascular test dosing, specifically with epinephrine, is a reliable method of prevention. In cases where the heart rate increases by 10 beats per minute or more, or the systolic blood pressure rises by 15 mm Hg or more, 10 to 15 micrograms/ml of intravascular test dosing with epinephrine has a sensitivity of 80%. While this test is important, it is important to recognize certain patient characteristics which can render this test unreliable. These factors include patients who are anesthetized with general or neuraxial anesthesia, sedated patients, the elderly, or patients taking beta-blockers.
Ultrasound guidance is another method of preventing intravascular injection. However, there are no formal randomized controlled trials that either confirm or deny a reduction of the toxicity.
Limiting anesthetic dose can also prevent LAST, as studies show that in most peripheral nerve blocks, patients are often given too must anesthetic resulting in an overdose. Total dose (the product of volume x concentration) should be the minimum amount of anesthetic needed to produce the required effect. This strategy is especially useful in patients who are at a greater risk for LAST, such as those described above.
Local anesthetic systemic toxicity is a serious consequence of which to be aware. Early recognition can drastically change its clinical course. Research today is focused on lipid emulsion therapy for severe local anesthetic systemic toxicity and its prodromes. While developing new treatment plans can help limit associated morbidity and mortality, prevention continues to be one of the most effective therapies for LAST.
Local anesthetics are widely used in most healthcare facilities. These agents can be injected at the bedside for a minor procedure, in the operating room or in the emergency department. In almost all cases where local anesthetics are used, nurses are often present for monitoring of the patient. The nurse should not only monitor the vital signs but also maintain verbal contact with the patient when the local anesthetic is injected. Once an adverse reaction occurs, the key is supportive care with close monitoring. In addition, the patient should be advised to wear a medical alert bracelet if the reaction was due to an allergy. However, if the patient developed a seizure, then the risk of a repeat event is unlikely.  (Level V)
Patients who develop an adverse reaction or a seizure can be managed with supportive care that includes oxygenation and hydration. Most patients recover without any sequelae. Without treatment, the patient is at risk for hypotension, cardiac arrest, and seizures. Data from the poison control centers reveals that in 2016, there were only four deaths from local anesthetics. (Level V)
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