Local Anesthetic Systemic Toxicity: Management & More

open mouth and dentist syringe giving local anesthetic to patient

Key Points

  • Local anesthetic systemic toxicity is the rapid onset of severe central nervous system (CNS) depression, seizures and cardiac arrhythmias following local anesthetic administration.
  • Administer lipid emulsion therapy at the first sign of systemic toxicity.
  • Administer the following as additional supportive care:
    • Seizures: liberal benzodiazepines/barbiturates/propofol
    • Hypotension: IV fluids/vasopressors
    • QRS Widening: sodium bicarbonate
    • Arrhythmias: modified ACLS (i.e., low-dose epinephrine and amiodarone as needed, avoid lidocaine)
  • Administer methylene blue for methemeglobinemia
  • Consult with your local poison center at 1-800-222-1222

Local Anesthetic Systemic Toxicity

Local anesthetic systemic toxicity (LAST) is the rapid onset of severe CNS depression, seizures and cardiac arrhythmias following local anesthetic administration. In therapeutic use, local anesthetics decrease pain by blocking neuronal sodium voltage-gated channels proximal to the administration site. When systemically absorbed, this antagonism results in severe CNS depression, seizures, QRS widening, ventricular tachycardia, ventricular fibrillation, and/or asystole. CNS symptoms typically precede cardiac symptoms. In bupivacaine toxicity, however, CNS and cardiac symptoms occur simultaneously.1,2 Prodromal syndromes such as tinnitus, perioral numbness, confusion, and dizziness may precede more serious toxicity but are less common.3 Methemoglobinemia is most often reported following oral and dermal exposures to benzocaine, lidocaine, and prilocaine compared to other local anesthetics. Symptoms of methemoglobinemia include cyanosis, chocolate-brown blood and falsely low pulse oximetry readings (85%).

Risk Factors

LAST is more common in patients aged <6 years or >60 years, with low muscle mass, and comorbid conditions (e.g., cardiac disease, liver disease, and diabetes). Bupivacaine is the highest-risk local anesthetic given its low safety margin and difficulty in resuscitation; however, ropivacaine and lidocaine account for a large proportion of reported cases. Lastly, peripheral nerve blocks are 5 times more likely to cause LAST compared to epidural blocks.4

Incidence

LAST most commonly occurs in the operating room but is reported in other practice sites. Of 47 cases of LAST evaluated in a 2018 review, 67% of cases occurred in the operating room and 14% of cases occurred in the post anesthesia recovery unit. The remaining settings included office (11%), home (9%), ward (8%), and emergency department (8%).5

The incidence of LAST following peripheral nerve block has been reported from 0.04 to 1.8/1,000.6,7 The incidence of LAST following other routes of administration will most likely differ.

Dermal and oral exposures to local anesthetics can also result in LAST. A multi-poison center case series reported 37 pediatric local anesthetic dermal exposures over a 15-year period that experienced moderate-severe symptoms of LAST. Symptoms included cyanosis (29.7%), seizures (18.9%), and CNS depression (12.5%). The majority of cases occurred following home use prior to dermatologic procedures.8 Similarly, 5 of 99 pediatric patients exposed to oral benzocaine over a 10-year period experienced severe symptoms of LAST. Symptoms included methemoglobinemia, cyanosis, seizure, and metabolic acidosis. The majority of these cases occurred following inappropriate administration by a parent/guardian.9

Labs/Monitoring

Obtain an initial electrocardiogram and trend if worsening QRS.

For concerns of methemeglobinemia, obtain an arterial or venous blood gas with co-oximetry to measure methemoglobin.

Medical Management

Administer lipid emulsion therapy at the first sign of LAST using the following dosing strategy:

  • Bolus: 1.5 mL/kg 20% lipid emulsion IV infused over 1 minute (max 100 mL); may repeat twice
  • Maintenance: 0.25-0.50 mL/kg/min for 30-60 minutes
  • Total Max (bolus + maintenance): 12 mL/kg

Lipid emulsion therapy may interfere with serum chemistry. Though uncommon, adverse side effects of pancreatitis, bronchospasm, hyperamylasemia, and acute respiratory distress syndrome are reported.10,11

In addition to lipid emulsion therapy, provide the following supportive care:

  • If considering intubation for airway protection, use propofol and rocuronium.
  • Seizures: Lorazepam 2-4 mg (0.05-0.1 mg/kg) or other benzodiazepine every 5-10 minutes until seizure ablation. If refractory, consider barbiturates or propofol.
  • Hypotension: IV fluids; vasopressor(s) with more beta activity if refractory
  • QRS widening (>100 ms): Sodium Bicarbonate 8.4% 1-2mEq/kg IV bolus repeated until QRS narrows followed by infusion at 1.5-2x maintenance rate (150mEq in 1L D5W).
  • Arrhythmias: Modified advanced cardiovascular life support; preferred agents are low-dose epinephrine (e.g., 1 mcg/kg) and amiodarone. Avoid lidocaine.
  • Methemoglobinemia: Methylene Blue 1-2 mg/kg infused IV over 5 minutes

Extracorporeal membrane oxygenation may be appropriate in refractory cases. Consult with your poison center for patient-specific considerations and management.

Lipid Emulsion Therapy In-depth

Lipid emulsion therapy is the antidote commonly used for local anesthetic systemic toxicity. Lipid emulsion therapy is thought to work by forming a “lipid sink” in which lipophilic medications are sequestered. This decreases drug access to CNS and cardiac receptors and facilitates drug elimination. Other proposed mechanisms of action include direct cardiac and vasculature benefits such as vasoconstriction, increased inotropy, and metabolic support.12

Literature supporting use of lipid emulsion therapy is primarily based on animal studies and case series. A 2016 systematic literature review evaluated 83 cases of local anesthetic toxicity where lipid emulsion therapy was used as either monotherapy or in combination with other treatments. Possible benefit from lipid emulsion therapy was reported in 59 cases (71%), no reported benefit was reported in 4 cases (5%), and unclear benefit was reported in 10 cases (12%). Lipid therapy was used as monotherapy in 14 cases (17%) of which 10 cases (12%) had complete symptom resolution. Of all cases, two patients (2.4%) died.13

 

References

  1. Gitman M, Barrington MJ. Local Anesthetic Systemic Toxicity: A Review of Recent Case Reports and Registries. Reg Anesth Pain Med. 2018;43(2):124-130. doi:10.1097/AAP.0000000000000721
  2. Vasques F, Behr AU, Weinberg G, Ori C, Di Gregorio G. A Review of Local Anesthetic Systemic Toxicity Cases Since Publication of the American Society of Regional Anesthesia Recommendations: To Whom It May Concern. Reg Anesth Pain Med. 2015;40(6):698-705. doi:10.1097/AAP.0000000000000320
  3. Di Gregorio G, Neal JM, Rosenquist RW, Weinberg GL. Clinical presentation of local anesthetic systemic toxicity: a review of published cases, 1979 to 2009. Reg Anesth Pain Med. 2010;35(2):181-187. doi:10.1097/aap.0b013e3181d2310b
  4. 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
  5. Vasques F, Behr AU, Weinberg G, Ori C, Di Gregorio G. A Review of Local Anesthetic Systemic Toxicity Cases Since Publication of the American Society of Regional Anesthesia Recommendations: To Whom It May Concern. Reg Anesth Pain Med. 2015;40(6):698-705. doi:10.1097/AAP.0000000000000320
  6. Mörwald EE, Zubizarreta N, Cozowicz C, Poeran J, Memtsoudis SG. Incidence of Local Anesthetic Systemic Toxicity in Orthopedic Patients Receiving Peripheral Nerve Blocks. Reg Anesth Pain Med. 2017;42(4):442-445. doi:10.1097/AAP.0000000000000544
  7. Liu SS, Ortolan S, Sandoval MV, et al. Cardiac Arrest and Seizures Caused by Local Anesthetic Systemic Toxicity After Peripheral Nerve Blocks: Should We Still Fear the Reaper?. Reg Anesth Pain Med. 2016;41(1):5-21. doi:10.1097/AAP.0000000000000329
  8. Eisenberg JR, Tedford NJ, Becker SM, Weaver M, and Moss M. Adverse Outcomes in Topical Lidocaine Exposure: A Pediatric Case Series from the United States (US) National Poison Data System (NPDS). [abstract taken from 2022 ACMT Annual Scientific Meeting Abstracts - Virtual. 2022;18(2):92]
  9. Vohra R, Huntington S, Koike J, Le K, Geller RJ. Pediatric Exposures to Topical Benzocaine Preparations Reported to a Statewide Poison Control System. West J Emerg Med. 2017;18(5):923-927. doi:10.5811/westjem.2017.6.33665
  10. Levine M, Skolnik AB, Ruha AM, Bosak A, Menke N, Pizon AF. Complications following antidotal use of intravenous lipid emulsion therapy. J Med Toxicol. 2014;10(1):10-14. doi:10.1007/s13181-013-0356-1
  11. Cave G, Harvey M, Willres J, et al. LIPAEMIC report: results of clinical use of intravenous lipid emulsion in drug toxicity reported to an online lipid registry. J Med Toxicol. 2014;10:133–142.
  12. Fettiplace MR, Weinberg G. The Mechanisms Underlying Lipid Resuscitation Therapy. Reg Anesth Pain Med. 2018;43(2):138-149. doi:10.1097/AAP.0000000000000719
  13. Hoegberg LC, Bania TC, Lavergne V, et al. Systematic review of the effect of intravenous lipid emulsion therapy for local anesthetic toxicity. Clin Toxicol (Phila). 2016;54(3):167-193. doi:10.3109/15563650.2015.1121270

 

Author: Joseph E. Lambson, PharmD, Clinical Toxicology Fellow, Utah Poison Control Center 

Poison Control