CASE

 A 34-year-old male presents to the emergency department from his urologist’s office after exhibiting word-finding difficulty and confusion during an elective surgery. He had previously been feeling well and is otherwise healthy. Per discussion with his urologist, the patient reported continued discomfort during the procedure, so he was given additional lidocaine until his pain was sufficiently managed. He developed symptoms that progressed from dizziness to word-finding difficulty and confusion. It was subsequently noticed that he had accidentally been treated with 2% lidocaine without epinephrine instead of 1% lidocaine without epinephrine, thus doubling the intended dose.

The patient arrived in the emergency department hypertensive to 160/95 but his vitals were otherwise within normal limits. His exam was notable only for intermittent stuttering speech as well as repetitive questioning and confusion. Labs, including a complete blood count, complete metabolic panel, and venous blood gas, were all normal. Serial EKGs showed normal sinus rhythm with narrow QRS complexes, normal intervals, and no evidence of ischemia.

DIAGNOSIS

Local Anesthetic Systemic Toxicity (LAST)

DISCUSSION

Local anesthetics are widely used in both inpatient and outpatient settings. They work by reversibly binding to sodium channels on conducting tissues, halting the propagation of action potentials [1]. Esters, such as benzocaine, are metabolized by plasma cholinesterase to Para-aminobenzoic acid(PABA), a known allergen, while amides like lidocaine are metabolized by the liver to metabolites less often associated with allergic reactions [1].

Other adverse effects from local anesthetics include local tissue damage and methemoglobinemia, but their most feared complication is Local Anesthetic Systemic Toxicity (LAST) [1]. Accidental vascular injection is the most common way such toxicity occurs, though this can also happen with the administration of a single overdose or multiple therapeutic doses by any route [2].

It is traditionally taught that central nervous system (CNS) symptoms manifest first, with early symptoms like lightheadedness and disorientation preceding an excitatory phase characterized by tremors and seizures, followed by depressive symptoms eventually leading to coma. Cardiovascular effects can then develop and include hypotension, decreased inotropy, conduction delays, and dysrhythmias [1]. However, one should not rely solely on this paradigm when monitoring for toxicity, as it has been found that LAST encompasses a wide variety of presentations in regards to symptom onset, which can range from under one minute up to an hour after administration, as well as progression and severity [3].

The simplest way to avoid LAST is to use the minimum local anesthetic necessary to achieve the desired effect. While there are many tables listing maximum “safe” doses of various local anesthetics (see an example below), it is crucial to remember these values are only estimates that don’t account for route of administration or patient factors such as age and comorbidities, all of which can impact toxicity [4]. Knowing other drug properties such as onset of action and half-life as well as the concept of additive toxicity will allow for safer combination of these medications for simultaneous use or for serial injections [1]. Finally, certain techniques can reduce the chances of accidental intravascular injection, including ultrasound guidance, aspirating before injecting, and giving test doses of epinephrine-containing anesthetic to assess for adrenergic effects [5].

If LAST is suspected, one must discontinue the offending drug. Correcting hypoxemia, acidemia, and hyperkalemia, all of which potentiate toxicity, is also important [1]. Seizures should be treated with benzodiazepines while being sure to avoid sodium channel blocking medications such as phenytoin, which can exacerbate this condition [5]. For cardiovascular effects, ACLS protocol should be followed with a few notable exceptions. To minimize its arrhythmogenic potential, epinephrine should be administered at 1 mcg/kg, and amiodarone should preferentially be used for ventricular dysrhythmias as both procainamide and lidocaine are members of the amide local anesthetic class [5].

Lipid emulsion is the antidote for LAST, though evidence-based, validated guidelines for when and how to administer this drug are lacking [7]. It is generally accepted that for severe or rapidly deteriorating CNS and/or cardiovascular toxicity, lipids should be given in combination with the typical treatments listed above [8]. However, in early or less severe cases, treatment is largely left up to physician discretion. It is recommended that some combination of a bolus and infusion be administered with a total dose of up to 10-12mL/kg, [5] but there are few definite rules beyond this.

For instance, the American Society of Regional Anesthesia (ASRA) recommends 20% lipid emulsion therapy for “any LAST event judged to be potentially serious,” and stresses that the order of administration is less important than expeditiously starting treatment [5]. For patients over 70 kg, ASRA recommends a 100mL bolus and a 200-250mL infusion over 15-20 minutes, and for patients under 70kg it endorses a bolus of 1.5mL/kg as well as an infusion of 0.25mL/kg/min [5]. The American College of Medical Toxicology (ACMT) recommends a similar combination of bolus and infusion, noting that repeat boluses are reasonable if the patient fails to respond initially, and that the infusion rate can be titrated to effect as well [7]. The ACMT acknowledges that “it is completely appropriate” for a physician to use their judgment to guide their management regimen [7]. Adverse effects of lipid emulsion, such as blood clots, fat embolism, pancreatitis, allergic reaction, acute kidney injury, and interference with extracorporeal life support (ECLS), which can be used in cases of refractory LAST, are uncommon and generally outweighed by potential benefits [8].

CASE RESOLUTION

Poison control had been contacted prior to the patient’s arrival and based on their initial recommendations, the patient was treated with a 1.5 ml/kg bolus of 20% lipid emulsion. Upon further review of the patient’s presentation and emergency department course, it was decided not to administer further lipid emulsion. Over a recommended four-hour observation period, the patient’s symptoms completely resolved and he was ultimately discharged home for outpatient urology follow up.

TAKE-AWAYS

·      Though commonly used in many medical settings, local anesthetics are not benign agents

·      The development of CNS and/or cardiac signs and symptoms during the administration of local anesthetics should prompt immediate evaluation and management

·      Lipid emulsion therapy is the antidote to LAST and should be used in cases of severe toxicity or at the provider’s discretion, ideally in consultation with a toxicologist

KEY WORDS

·      Toxicology

·      Anesthetics

·      Lipid Emulsion

AUTHOR: Sean Reid, MD is a third year resident at Brown University/Rhode Island Hospital

FACULTY REVIEWER: Kristina McAteer, MD

REFERENCES

1.     Sztajnkrycer M. Local Anesthetics. In: Goldfrank's Toxicologic Emergencies. 11th ed. New York, NY: Mc Graw Hill Education; 2019:994-1003.

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 Nov-Dec;40(6):698-705.

3.     Di Gregorio G, Neal J, Rosenquist R, Weinberg G. Clinical Presentation of Local Anesthetic Systemic Toxicity: A Review of Published Cases, 1979-2009. Reg Anesth Pain Med. 2010;35:181-187.

4.     Rosenberg P, Veering B, Urmey W. Maximum Recommended Doses of Local Anesthetics: A Multifactorial Concept. Reg Anesth Pain Med. 2004;29(6):564-575.

5.     Neal J, Barrington M, Fettiplace M, Gitman M, Memtsoudis S, Morwald E, Rubin D, Weinberg G. 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;43:113-123.

6.     Warren L, Pak A. Local Anesthetic Systemic Toxicity. In: Post T, ed. UpToDate. Waltham, Mass.:Uptodate;2022. www.uptodate.com. Accessed March 15, 2022.

7.     ACMT. ACMT Position Statement: Guidance for the Use of Intravenous Lipid Emulsion. J Med Toxicol. 2017;13(1):124–125.

8.     Gosselin S, Bania T. Lipid Emulsion. In: Goldfrank's Toxicologic Emergencies. 11th ed. New York, NY: Mc Graw Hill Education; 2019:1004-1010.