ToxCard: Local Anesthetic Systemic Toxicity

Authors: Alex Rogers, MD (EM Resident Physician, Christus Spohn/Texas A&M University School of Medicine, Corpus Christi, TX); J.D. Cambron, DO (EM Attending Physician, Christus Spohn/Texas A&M University School of Medicine, Corpus Christi, TX)// Reviewed by: Anthony Spadaro, MD (@TSpadaro91, Medical Toxicology Fellow, Rutgers New Jersey Medical School, Newark, NJ); James Dazhe Cao, MD (@JamesCaoMD, Associate Professor of EM, Medical Toxicology, UT Southwestern Medical Center, Dallas, TX); Alex Koyfman, MD (@EMHighAK); Brit Long, MD (@long_brit)

Case:

You are in the middle of a shift when you receive a call that EMS is 15 minutes out with an active cardiac arrest. The patient is a 56-year-old woman who was being prepped for an arthroscopic knee procedure at an outpatient surgery center. She reportedly received a landmark guided peripheral nerve block with bupivacaine and shortly thereafter developed generalized seizures. She then became hypotensive and progressed to asystole arrest.

Questions:

1. What are the clinical manifestations of Local Anesthetic Systemic Toxicity (LAST)?
2.  How do we manage patients in LAST?
3.  Which patients will require intravenous lipid emulsion (ILE) therapy?

Background:

Local anesthetics (LAs) have been a part of clinical care since the late 1800s with the introduction of cocaine as a topical and infiltrative anesthetic. [1-5] Since then, many more medications have been developed and deployed. These medications are a vital tool in the care of ED patients, from simple local analgesia for a laceration repair to regional analgesia for painful procedures. The majority of local anesthetics have a common structure of a lipophilic aromatic ring, a hydrophilic amine group, and a linking group. [2] This linking group can be either an amide (e.g., lidocaine) or an ester (e.g., cocaine). Metabolism of ester anesthetics is by plasma cholinesterase, whereas amides are metabolized by the cytochrome P450 system in the liver. [6]

Action of local anesthetics is dependent upon the molecule crossing the plasma membrane in a unionized form. [2] The local anesthetic then gains a proton to become a charged particle (ionized), which then binds the inner portion of the sodium channel, blocking propagation of action potentials. Toxicity from these drugs can take multiple forms. [1-5] This post focuses on the identification and management of Local Anesthetic Systemic Toxicity (LAST). While not specifically reviewed in this post, check out the methemoglobinemia tox card for more information about one of the other known events that can occur with local anesthetic administration.

Epidemiology

• Most common cause: inadvertent intravascular injection. [2,5,7]
• Rarer causes: continuous infusion, such as using lidocaine as an antiarrhythmic, and topical application. [5,8]
• In one review the incidence of LAST was estimated to be 2.7 per 10,000 cases of peripheral nerve blocks. [3]
• Higher risk patients include: Those at the extreme of ages, pre-existing hepatic dysfunction, and those with certain mitochondrial disease. [3]

Clinical Presentation:

• Manifestations are central nervous system (CNS) aberrations and cardiovascular (CV) dysfunction. [3-5,7]
• Symptom onset is usually within 1 minute of intravascular injection but can be delayed if multiple injections or continuous infusion. [5]
• Prodromal symptoms include: Confusion, dizziness, tinnitus, metallic taste, perioral numbness. [1,5]
• CNS symptoms include: Seizure, coma, altered mental status. [1]
• CV manifestations include: Bradycardia, tachycardia, ventricular dysrhythmias, cardiac arrest. [1-5]

Diagnosis:

Diagnosis is predicated on recognition of the clinical syndrome, as laboratory analysis will not return in a time frame to treat the patient. [5,9] Symptoms generally begin with the prodromal symptoms, followed very rapidly by CNS and CV symptoms. [1-3,5,7,9] All patients developing symptoms of LAST should be placed on a continuous cardiac monitor and have an ECG performed. [2] Labs that may be useful after the initial resuscitation and for the admitting physician may include a basic metabolic panel and an arterial or venous blood gas analysis. [2]

Prevention:

• Know the absolute maximums dosage of the local anesthetic being used. [9]
• Continually aspirate when inserting a needle for infiltration around a wound. [1,2]
• Consider using a physiological marker to help identify inadvertent vascular injection, such as epinephrine. [3]
• If performing a nerve block with ultrasound guidance, always know where the tip of your needle is. [5]
• If local anesthetics are being used in nerve blocks any fashion, your facility should have lipid emulsion therapy available.

Management:

Figure 1. Long B, Chavez S, Gottlieb M, Montrief T, Brady WJ. Local Anesthetic Systemic Toxicity: A Narrative Review for Emergency Clinicians. The American Journal of Emergency Medicine. 2022;59:42-48. doi:10.1016/j.ajem.2022.06.017

LAST management [1]

• The most important step is to discontinue the culprit medication [1-6].
• Supportive care includes: protecting the airway if necessary, supplemental oxygen if needed, and vasopressor support if the patient is hypotensive. Acidemia from hypoventilation or tissue hypoxia will worsen LAST.
• For patients who in cardiac arrest standard Advanced Cardiac Life Support (ACLS) should be initiated. [2,9]
• Benzodiazepines are the first line treatment for seizures. [2,9]
• If there are ventricular dysrhythmias: amiodarone is a reasonable option and lidocaine should be avoided. [1]
  • This should be a given, but lidocaine is still in some clinician’s ACLS algorithm but is not routinely recommended and should be avoided in the setting of LAST.
  • If epinephrine is used, small initial doses ( <1 ug/kg) are preferred.
  • Vasopressin is not recommended.
  • Avoid calcium channel blockers and beta-blockers.
  • Dysrhythmias associated with LAST tend to be refractory to pharmacologic treatment, so discussion with cardiology or toxicology is generally helpful.
• For patients with hemodynamic instability, cardiac arrest, or seizures, give ILE (Intralipid®). For further discussion on ILE see: lipid emulsion therapy. [1,9]
  • Initial dose: For patients > 70 kg bolus 100 mL of 20% lipid emulsion over 2-3 minutes followed by an infusion of 200-250 mL over 15-60 minutes and fo patients < 70 kg bolus 1.5 mL/kg of 20% lipid emulsion over 2-3 minutes followed by an infusion of 0.25 mL/kg/min for 30-60 minutes. [2]
  • If patient remains unstable, re-bolus lipid emulsion and increase infusion to 0.5 mL/kg/min. [2]
  • Do not exceed dose of 12 mL/kg without consultation with toxicology services
  • Contraindications: allergies to eggs or soybeans, disorders of fat metabolism, and severe liver dysfunction. [2]

Case Follow-Up:

After performing 2 rounds of ACLS, the department pharmacist is able to arrange for ILE to be brought down to the patient’s bedside. The patient remains hemodynamically unstable, and bolus of 1.5 mL/kg is given followed by a continuous infusion. Hemodynamics slowly begin to stabilize, and the patient is transferred to the ICU for further post-cardiac arrest care.

Clinical Pearls:

• LAST is a clinical diagnosis and should be suspected in patients exposed to a local anesthetic who is having signs and symptoms of neurologic or cardiac toxicity.
• Management of LAST starts with discontinuation of the offending agent, supportive care, and ACLS.
• The current standard of care in severe local anesthetic toxicity is ILE given as a bolus, with an infusion if necessary.
• Prevention is directly related to technique and limiting the dose to the minimum effective dose possible.
• If ILE is not available in your department, we advise you to obtain it and develop a protocol for its use.

References:

1. Long B, Chavez S, Gottlieb M, Montrief T, Brady WJ. Local Anesthetic Systemic Toxicity: A Narrative Review for Emergency Clinicians. The American Journal of Emergency Medicine. 2022;59:42-48. doi:10.1016/j.ajem.2022.06.017
2. Nelson LS, Lewin NA, Howland MA, Hoffman RS, Goldfrank LR, Flomenbaum NE. Goldfrank’s Toxicologic Emergencies. 11th ed. McGraw Hill Companies, Inc; 2019.
3. Gitman M, Fettiplace MR, Weinberg G, Neal JM, Barrington MJ. Local Anesthetic Systemic Toxicity: A Narrative Literature Review and Clinical Update on Prevention, Diagnosis, and Management. Plastic & Reconstructive Surgery. 2019;144(3):783-795. doi:10.1097/PRS.0000000000005989
4. Mercado P, Weinberg GL. Local Anesthetic Systemic Toxicity: Prevention and Treatment. Anesthesiology Clinics. 2011;29(2):233-242. doi:10.1016/j.anclin.2011.04.007
5. Vasques F, Behr AU, Weinberg G, Ori C, Gregorio GD. A Review of Local Anesthetic Systemic Toxicity Cases Since Publication of the American Society of Regional Anesthesia Recommendations: To Whom It May Concern. Regional Anesthesia and Pain Medicine. 2015;40(6):698-705. doi:10.1097/AAP.0000000000000320
6. Felice KL, Schumann HM. Intravenous Lipid Emulsion for Local Anesthetic Toxicity: A Review of the Literature. J Med Toxicol. 2008;4(3):184-191. doi:10.1007/BF03161199
7. Olson K, Smollin C, eds. Poisoning & Drug Overdose. 8th ed. McGraw Hill; 2022.
8. Walters E, Wurster Ovalle V, Yin S, Dribin T. Infant with Status Epilepticus Secondary to Systemic Lidocaine Toxicity from Topical Application. BMJ Case Rep. 2020;13(1):e233119. doi:10.1136/bcr-2019-233119
9. Neal JM, Barrington MJ, Fettiplace MR, et al. The Third American Society of Regional Anesthesia and Pain Medicine Practice Advisory on Local Anesthetic Systemic Toxicity: Executive Summary 2017. Reg Anesth Pain Med. 2018;43(2):113-123. doi:10.1097/AAP.0000000000000720