Lidocaine Toxicity

Etiology

Toxicity to local nerves and muscles is thought to be a consequence of the prolonged application of high drug concentrations, the effect of preservatives in the local anesthetic solution, or both.[5][6] Systemic local anesthetic toxicity is due to high systemic plasma levels of lidocaine due to the absorption of large doses of lidocaine, which depends mostly on the blood flow at the site of injection: tracheal > intercostal > caudal > paracervical > epidural > brachial plexus > subcutaneous. Also, blind injection of large volumes into a large muscular area, such as for lumbar plexus block or sciatic nerve blocks, can lead to systemic lidocaine toxicity. Spinal anesthetics are very low in total volume and do not cause systemic lidocaine toxicity. Inadvertent intra-arterial injections may cause local anesthetic toxicity in the tissue beds supplied by that artery, even in doses below the systemic toxic concentration. This complication is seen primarily with injections into the neck, causing central nervous system (CNS) symptoms often during the injection or shortly thereafter without progressing to cardiac toxicity.

Epidemiology

All sexes are affected equally by lidocaine toxicity. Patients who are likely to be more susceptible to local anesthetic toxicity are patients at the extremes of age and women who are pregnant. Rates of severe systemic toxicity (seizures with or without cardiac arrest) occur on the order of 1:10,000 for epidurals and up to 1:2000 for peripheral nerve blocks, depending on the type of block. Patients under sedation are at increased risk.

Pathophysiology

Most local anesthetics block voltage-gated sodium channels inside the cell, preventing subsequent channel activation and interfering with membrane depolarization's large transient sodium influx. Impulse conduction slows, the rate of rising and the magnitude of the action potential decrease, and the threshold for excitation is raised progressively until an action potential can no longer be generated and impulse propagation is abolished. Hence, the pronounced effect of lidocaine toxicity on cells relies on the propagation of action potentials such as the central nervous and the myocardial conduction systems. Local anesthetics also may block calcium and potassium channels and N-methyl-d-aspartate (NMDA) receptors to varying degrees.

Histopathology

All local anesthetics can cause direct neurotoxicity, depending on the dose and time of contact with the nerve. The occurrence of clinically relevant myopathy and myonecrosis has been described after continuous peripheral blocks, infiltration of wound margins, trigger point injections, and peri- and retrobulbar blocks. Histologically, myofibril hypercontraction progresses to lytic degeneration, edema, and necrosis. Regeneration usually occurs after 3 to 4 weeks. Concomitant steroid or epinephrine injections can worsen myonecrosis.

Toxicokinetics

Potency correlates with lipid solubility, which is the ability of the local anesthetic molecule to penetrate membranes in a hydrophobic environment.

The duration of action also correlates with lipid solubility and protein binding. Highly lipid-soluble and protein-bound local anesthetics have a longer duration of action, presumably because they are less likely to be cleared by blood flow. Local anesthetics that are highly lipid-soluble also exhibit a high degree of plasma protein binding, mostly to alpha-1-acid glycoprotein and, to a lesser extent, albumin; consequently, their elimination is prolonged. Blood flow to the tissue deposit of local anesthetic determines the absorption rate and is responsible for the plasma level. It will, however, also transport local anesthetics away from the tissue site, reducing the risk of direct nerve toxicity. Lidocaine has a 90% hepatic metabolism, and the elimination half-life is 1.5 to 2 hours, which can be prolonged up to 3.5 fold in patients with severe liver disease.

History and Physical

The CNS is the site of premonitory signs of overdose in awake patients. Early symptoms are circumoral numbness, tongue paresthesia, and dizziness. Sensory complaints may include tinnitus and blurred vision. Excitatory signs, such as restlessness, agitation, nervousness, or paranoia, may progress to muscle twitches and seizures. Ultimately, with large overdoses, CNS depression, including unconsciousness and coma, can occur. Hypotension and bradycardia can also be side effects of relative local anesthetic overdoses that sometimes occur during neuraxial blockade or nerve blocks performed near the CNS.

Major cardiovascular toxicity usually requires a higher lactic acid (LA) concentration in blood than that which produces seizures. Unintentional intravascular injection of local anesthetics during regional anesthesia produces severe cardiotoxic reactions, including hypotension, atrioventricular heart block, idioventricular rhythms, and life-threatening arrhythmias such as ventricular tachycardia and fibrillation and are usually the presenting signs of local anesthetic toxicity during general anesthesia.

Evaluation

The diagnosis is made clinically. The timing, dose, and site of the lidocaine injection are the main factors in considering systemic manifestations. It is important to keep in mind that even low doses injected inadvertently into an artery going to the brain can cause CNS symptoms.[6][7][8]

For direct local manifestations, such as pain seen in TNS, the concentration, and the injection site will help make the diagnosis. While imaging the spine with computed tomography (CT) or magnetic resonance imaging (MRI) will not help diagnose TNS. However, it will help to rule out other causes that may compress the structures within the spinal canal, which could also cause severe pain after neuraxial blockade and would require urgent surgical decompression. A lidocaine plasma level can be obtained, but it will take too long for the results to be meaningful for any treatment decisions.

Treatment / Management

Treatment of local anesthetic systemic toxicity (LAST) is symptomatic by raising the seizure threshold through pharmacologic interventions such as administering benzodiazepines, barbiturates, or propofol. Hyperventilation with high doses of oxygen reduces cerebral blood flow.[9][10](B3)

The other mainstay of treatment is reducing the free available local anesthetic concentration in the plasma by administering lipid emulsions. Due to the high lipid solubility, the infusion of lipid emulsions will bind free circulating local anesthetics and lower the plasma levels. The following is the treatment algorithm suggested by the American Society of Regional Anesthesia and Pain Medicine:

"Call for Help"

• Even premonitory CNS systems may progress to severe cardio-respiratory compromise, and many tasks may need to be done simultaneously, such as getting code carts and obtaining the lipid emulsion.

Initial Focus

• Airway management: ventilate with 100% oxygen
• Seizure suppression: benzodiazepines are preferred; AVOID propofol in patients having signs of cardiovascular instability

Alert the Nearest Facility Having Cardiopulmonary Bypass Capability

Management of Cardiac Arrhythmias

• Basic and Advanced Cardiac Life Support (ACLS) will require adjustment of medications and perhaps prolonged effort.
• AVOID vasopressin, calcium channel blockers, beta-blockers, and local anesthetics
• REDUCE individual epinephrine doses to <1 mcg/kg

Lipid Emulsion (20%) Therapy (values in parenthesis are for 70kg patient)

• Bolus 1.5 mL/kg (lean body mass) intravenously over 1 minute (~100mL)
• Continuous infusion 0.25 mL/kg/min (~18 mL/min; adjust by roller clamp)
• Repeat bolus once or twice for persistent cardiovascular collapse
• Double the infusion rate to 0.5 mL/kg/min if blood pressure remains low
• Continue infusion for at least 10 minutes after attaining circulatory stability
• Recommended upper limit: Approximately 10 mL/kg lipid emulsion over the first 30 minutes

Resuscitation may need to include cardiopulmonary bypass, as successful outcomes have been reported even after prolonged resuscitation, which may, in part, be explained by suggestions in animal models that bupivacaine, when added to cardioplegia solution, actually improves function and reduces the cellular damage of rat isolated hearts after prolonged, cold storage.

Differential Diagnosis

The timing of the onset of symptoms related to the injection or application of large doses of lidocaine will most likely make the diagnosis. However, coincidental seizures due to a seizure disorder or panic attacks with hyperventilation may confound the diagnosis.

For direct local toxicity symptoms after lidocaine injection, such as radicular pain, first exclude other causes, such as hematoma, that may compress structures in the spinal canal and require urgent surgical decompression. The timing of an epidural abscess to a central neuraxial block would make that diagnosis unlikely. Most epidural abscesses, however, are spontaneous and could potentially coincide with the injection.

Prognosis

The prognosis of lidocaine toxicity depends on the site of manifestation. CNS toxicity is either self-limited or quite amenable to treatment with benzodiazepines, has a good prognosis without sequelae, and does not need further neurologic testing. Cardiac toxicity may require prolonged resuscitation, but the prognosis after return to spontaneous circulation is often very good.

Complications

The complications that can manifest with lidocaine toxicity are as follows:

• Seizure
• Coma
• Hypotension
• Atrioventricular heart block
• Idioventricular rhythms
• Ventricular tachycardia and fibrillation
• Cardiovascular collapse and death