Local anesthetic systemic toxicity

Local Anesthetic Systemic Toxicity (LAST)

Local anesthetic systemic toxicity

Other names	LAST
Anesthetic relevance	High
Anesthetic management	Stop local anesthetic injection. Call for help. Administer intravenous lipid emulsion therapy.
Specialty	Regional anesthesia
Signs and symptoms	CNS: Tinnitus, perioral numbness, seizures, loss of consciousness CV: hypotension, bradycardia, arrhythmias, cardiovascular arrest
Diagnosis	Clinical
Treatment	IV lipid emulsion therapy
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Editor rating	In development
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Local anesthetic systemic toxicity (LAST) results from excessive plasma concentrations of local anesthetic drugs. It is a rare but potentially fatal event. It is most often from accidental intravascular injection of local anesthetic during performance of peripheral nerve blocks. It is less often from absorption of local anesthetics from tissue injection sites or topical application. The most common presentation of LAST includes signs of central nervous system toxicity, such as tinnitus, perioral numbness, seizures, and loss of consciousness, or cardiovascular toxicity, such as hypotension, bradycardia, arrhythmias, and cardiovascular arrest. Patients can also present with a combination of CNS and CV toxicity, and the presentation is typically progressive. The most effective management of LAST includes cessation of local anesthetic use and administration of intravenous lipid emulsion therapy.

Incidence

The incidence of major LAST events such as seizures or cardiac arrest is very low. This is likely due to increased awareness and preventative measures. In 2017, a retrospective study was performed to better understand the incidence of LAST in orthopedic patients receiving peripheral nerve blocks. This study included 238,472 patients who received a peripheral nerve block, and the incidence of major LAST events was 0.18%, which were defined in the study as cardiac arrest, seizures, and use of fat emulsion on the day of surgery.  This suggests that although LAST is a rare complication, it is of clinical significance. The incidence of minor LAST events such as tinnitus, perioral numbness, or metallic taste is probably higher, though much more likely to be unreported.

Pathophysiology

Local anesthetics exert their effect primarily by blocking voltage-gated sodium channels (VGSC), which prevents sodium influx, subsequent depolarization, and action potential generation.  “This conduction block impedes pain transmission from neuronal cells to the cerebral cortex, thereby producing analgesia and anesthesia. Toxicity occurs when LAs affect cardiac sodium channels or thalamocortical neurons in the brain.”  

Local anesthetics exhibit dose-related toxicity. Systemic absorption of local anesthetic depends on the dose injected, the specific site of injection, and the use of a vasoconstrictor in the local anesthetic solution.

1. Dose: Current published maximum doses are general guidelines rather than absolute dosage limits. Systemic toxicity has occurred at doses both within and above recommended ranges. The generally accepted practice is to use the lowest effective dose possible for each individual patient to achieve the desired effect, while minimizing the risk for LAST.
2. Location: For various regional blocks, the peak plasma concentrations of local anesthetics depend on the location of the block. One study reviewed a collection of data of local anesthetic blood levels from various sources, which indicated the pattern of order of peak concentrations associated with various regional blocks to be: intercostal > caudal > epidural > brachial plexus.
3. Vasoconstrictor: Epinephrine is often used in conjunction with local anesthetic. The effect of epinephrine is two-fold: it decreases the rate of absorption, which decreases the risk of toxicity. Epinephrine also prolongs the anesthetic effect. It is also used as an intravascular marker in which an increase in heart rate of ≥ 10 beats per minute after injection may suggest intravascular injection of local anesthetic.

In addition to the factors above, there are individual patient factors that may contribute to increased risk for toxicity. Extremes of age (< 4 months or older adults) may be at increased risk due to variations in hepatic clearance or function. Typically, repeat dosing or continuous infusions should be avoided in these age groups. Advanced end organ dysfunction, such as severe cardiac disease, hepatic disease, or renal insufficiency, may contribute to risk for toxicity. Pregnancy also increases the risk for LAST due to its hyperdynamic state of circulation, which can lead to rapid absorption. It is also theorized that hormonal changes may increase sensitivity of neural tissue to local block which may lead to cardiotoxicity.

In terms of prevention, utilizing the lowest effective dose, safe injection techniques, the use of ultrasound, routine monitoring, and avoidance of heavy sedation are all techniques used to reduce the risk of LAST.

Signs and symptoms

The clinical presentation of LAST is highly variable. It depends a variety of factors such as the dose, type, and properties of the local anesthetic, the technique, and individual patient characteristics. There should be high clinical suspicion for LAST whenever physiologic changes occur after administration of a local anesthetic. In a review article, the roughly 40% of cases presented immediately, and most cases presented within 12 hours. Only 11% of cases had onset of LAST ranging from 24 hours to 4 days, all of which involved continuous infusions of local anesthetic. The most common presentation of LAST includes signs of CNS toxicity, CV toxicity, or both. The presentation is typically progressive.

• CNS toxicity:
  • Local anesthetics readily cross the blood brain barrier
  • Clinical manifestations: lightheadedness, tinnitus, tongue numbness, metallic taste → CNS excitation (block inhibitory pathways) → CNS depression, seizure → coma
• Cardiovascular toxicity
  • Dose dependent blockade of Na channels → disruptions of cardiac conduction system → bradycardia, ventricular dysrhythmias, decreased contractility, hypotension, cardiovascular collapse/circulatory arrest
  • Bupivacaine has higher risk of CV toxicity
  • Approximately 3x the amount of local anesthetics are required to produce cardiovascular toxicity compared to CNS toxicity

Management

If LAST is suspected, the generally accepted management algorithm is as follows:

• Stop the injection. Call for help.  
• Manage the airway.
• Manage arrhythmias, provide cardiovascular support, arrange for cardiopulmonary bypass early on.
  • Note that resuscitation is different from ACLS algorithm.  
• Administer benzodiazepines for seizures.
• Reduce individual epinephrine doses to <1 mcg/kg
• AVOID: vasopressin, Ca channel blockers, Beta blockers, local anesthetics, and propofol (can further decrease cardiac contractility)
• Administer lipid rescue (early intralipid therapy)
  • ≤70 kg – 1.5 mL/kg IV bolus of 20% intralipid, followed by infusion at 0.25 mL/kg/minute IV
  • ≥70 kg – 100 mL IV bolus of 20% intralipid, followed by infusion of 200 to 250 mL IV over 15 to 20 minutes
  • If patient remains unstable, may repeat bolus and increase infusion rate
  • Note that the mechanism of action for lipid therapy is not fully understood and is theorized to be multimodal. One commonly accepted theory is the idea that lipid emulsion acts as a lipid sink, which could increase the rate of local anesthetic distribution into the tissues.

The American Society of Regional Anesthesia and Pain Medicine (ASRA) periodically updates its practice advisory on LAST. The most recent version of the ASRA LAST checklist was published in 2020 and can be found on its website. These guidelines will next be reviewed in 2025.