Local Anesthetic Toxicity

Updated: Aug 17, 2017
  • Author: Raffi Kapitanyan, MD; Chief Editor: David Vearrier, MD, MPH  more...
  • Print
Overview

Practice Essentials

While generally safe, local anesthetic agents can be toxic if administered inappropriately, and in some cases may cause unintended reactions even when properly administered. The toxicity of local and infiltration anesthetics can be local or systemic. Systemic toxicity of anesthetics most often involves the central nervous system (CNS) or the cardiovascular system.

Signs and symptoms

Manifestations of local anesthetic toxicity typically appear 1 to 5 minutes after the injection, but onset may range from 30 seconds to as long as 60 minutes. [1] Toxicity manifestations can be categorized as follows:

  • CNS
  • Cardiovascular
  • Hematologic
  • Allergic
  • Local tissue

CNS manifestations

Classically, systemic toxicity begins with symptoms of CNS excitement such as the following:

  • Circumoral and/or tongue numbness
  • Metallic taste
  • Lightheadedness
  • Dizziness
  • Visual and auditory disturbances (difficulty focusing and tinnitus)
  • Disorientation
  • Drowsiness

With higher doses, initial CNS excitation is often followed by a rapid CNS depression, with the following features:

  • Muscle twitching
  • Convulsions
  • Unconsciousness
  • Coma
  • Respiratory depression and arrest
  • Cardiovascular depression and collapse

Cardiovascular manifestations

  • Chest pain
  • Shortness of breath
  • Palpitations
  • Lightheadedness
  • Diaphoresis
  • Hypotension
  • Syncope

Hematologic manifestations

Methemoglobinemia has been frequently reported in association with benzocaine use; however, lidocaine and prilocaine have also been implicated. At low levels (1-3%), methemoglobinemia can be asymptomatic, but higher levels (10-40%) may be accompanied by any of the following complaints:

  • Cyanosis
  • Cutaneous discoloration (gray)
  • Tachypnea
  • Dyspnea
  • Exercise intolerance
  • Fatigue
  • Dizziness and syncope
  • Weakness

Allergic manifestations

  • Rash
  • Urticaria
  • Anaphylaxis (very rare)

See Clinical Presentation for more detail.

Diagnosis

The evaluation of patients with possible toxicity from a local anesthetic should be guided by the clinical presentation. Blood levels of the anesthetic may be measured, although blood levels may not correlate with toxicity or may not be obtained at a clinically useful time.

Imaging studies are determined by the overall clinical picture. For example, if the patient has a seizure and the etiology of the seizure is not apparent, consider a head computed tomography scan.

See Workup for more detail.

Management

Attention to impending airway compromise, significant hypotension, dysrhythmias, and seizures takes precedence. Once other possible etiologies of the patient's new symptoms have been excluded, management of the specific symptoms can begin.

Treatment of local anesthetic toxicity may include the following [1] :

  • Airway management
  • Seizure suppression (benzodiazepines preferred)
  • Management of cardiac dysrhythmias
  • Lipid emulsion therapy

See Treatment and Medication for more detail.

Next:

Background

While generally safe, local anesthetic agents can be toxic if administered inappropriately, and in some cases may cause unintended reactions even when properly administered. Adverse effects are usually caused by high plasma concentrations of the agent, which may result from one of the following:

  • Inadvertent intravascular injection
  • Excessive dose or rate of injection
  • Delayed drug clearance
  • Administration into vascular tissue

Patient factors can also affect toxicity. For example, because lidocaine is hepatically metabolized, liver dysfunction increases the risk of toxicity. Because lidocaine is also protein bound, low protein states may also increase risk. Acidosis increases the risk because it favors dissociation of lidocaine from plasma proteins. Interactions with other drugs (eg, cimetidine, beta-blockers) can also affect lidocaine drug levels. See Etiology.

The toxicity of local and infiltration anesthetics can be localized or systemic. The localized adverse effects of anesthetic agents include neurovascular manifestations such as prolonged anesthesia and paresthesias, which may become irreversible.

Systemic toxicity of anesthetics most often involves the central nervous system (CNS) or the cardiovascular system. Concurrent administration of other drugs, such as benzodiazepines, may mask the development of CNS symptoms but not cardiovascular symptoms.

Relatively rarely (<1%), local anesthetic agents can affect the immune system, producing an immunoglobulin E (IgE)–mediated allergic reaction. Most cases are associated with the use of amino esters. Some anesthetics, particularly benzocaine, are associated with hematologic effects, namely methemoglobinemia.

CNS toxicity is biphasic. The earlier manifestations are due to CNS excitation, with problems such as seizures. Subsequent manifestations include CNS depression with a cessation of convulsions and the onset of unconsciousness and respiratory depression or arrest.

Cardiovascular effects occur at higher serum concentrations of local anesthetics. These effects may include reentrant arrhythmias. Acceleration of the ventricular rate has been reported in patients with atrial arrhythmias. See Presentation.

Treatment of local anesthetic toxicity may include the following [1] :

  • Airway management
  • Seizure suppression
  • Management of cardiac arrhythmias
  • Lipid emulsion therapy

See Treatment and Medication.

Previous
Next:

Pathophysiology

The onset of action, potency, and duration of action of a local anesthetic are determined by the agent's pKa, lipid solubility, protein binding, and vasodilatory effects, along with tissue pH. Increasing the dose by administering a high concentration shortens onset while increasing potency and duration of action, as well as increasing the possibility for the adverse/toxic reactions.

The pKa of an agent is the primary factor that determines its onset of action. A lower pKa increases tissue penetration and shortens onset of action, because of increased lipid solubility of nonionized (uncharged) particles. A pKa that is closer to pH optimizes penetration. In addition, inflammation in the extracellular space may decrease pH and may slow onset of action. Site of administration is also a factor; onset is prolonged in areas with increased tissue or nerve sheath size.

The following factors influence potency:

  • High partition coefficients that increase lipophilic properties promote passage of the anesthetic into the lipid nerve membrane, enhancing potency
  • Vasodilation promotes vascular absorption, thereby reducing locally available drug and decreasing potency
  • Addition of epinephrine or sodium bicarbonate increases pH, thereby increasing nonionized particles, which are more lipid soluble
  • Most local anesthetic solutions that contain premixed epinephrine contain preservatives; in these solutions, the pH is adjusted lower to maintain the stability of epinephrine and antioxidants

The following factors influence duration of action:

  • Addition of epinephrine to local anesthetic solutions prolongs duration of action by causing vasoconstriction and decreasing systemic absorption
  • Degree of protein binding primarily determines duration of action; high protein binding increases duration
  • Increasing pH (using sodium bicarbonate) also prolongs duration of action

Anesthetic concentration and dilution

Drug concentration is expressed as a percentage (eg, bupivacaine 0.25%, lidocaine 1%). Percentage is measured in grams per 100 mL (ie, 1% is 1 g/100 mL [1000 mg/100 mL], or 10 mg per mL).

Calculate the mg/mL concentration quickly from the percentage by moving the decimal point 1 place to the right, as in the following examples:

  • Bupivacaine 0.25% = 2.5 mg/mL
  • Lidocaine 1% = 10 mg/mL

When epinephrine is combined in an anesthetic solution, the result is expressed as a dilution (eg, 1:100,000), as follows:

  • 1:1000 means 1 mg per 1 mL (ie, 0.1%)
  • 1:10,000 means 1 mg per 10 mL (ie, 0.01%)
  • 1:2000 means 1 mg per 2 mL (ie, 0.05%)
  • 1:20,000 means 1 mg per 20 mL (ie, 0.005%)
  • 0.1 mL of 1:1000 epinephrine added to 9.9 mL of anesthetic solution = 1:100,000 dilution or 0.01 mg/mL

For higher dilutions, see Table 1, below.

Table 1. Epinephrine Content Examples (Open Table in a new window)

Solution Volume 1:100,000 (1 mg/100 mL) 1:200,000 (1 mg/200 mL)
1 mL 0.01 mg 0.005 mg
5 mL 0.05 mg 0.025 mg
10 mL 0.1 mg 0.05 mg
20 mL 0.2 mg 0.1 mg
Example: 50 mL of 1% lidocaine with epinephrine 1:100,000 contains lidocaine 500 mg and epinephrine 0.5 mg.

Toxicity mechanisms

CNS toxicity from local anesthetics manifests initially as CNS excitation, followed by CNS depression. This biphasic effect occurs because local anesthetics first block inhibitory CNS pathways (resulting in stimulation) and then eventually block both inhibitory and excitatory pathways (resulting in overall CNS inhibition).

Cardiovascular effects occur because these agents block sodium channels through a fast-in, slow-out mechanism that affects impulse conduction through the heart and nerve tissue. In the heart, this depresses Vmax (ie, the rate of depolarization during phase 0 of the cardiac action potential) and may lead to reentrant arrhythmias. Additionally, conduction through the sinus and atrioventricular nodes is suppressed.

Previous
Next:

Etiology

Local anesthetics can be divided into 2 groups: the esters and the amides. See Table 2, below.

Table 2. Local Anesthetic Agents Used Commonly for Infiltrative Injection (Open Table in a new window)

Agent Duration of Action Maximum Dosage Guidelines (Total Cumulative Infiltrative Injection Dose per Procedure*)
Esters
Procaine (Novocaine) Short (15-60 min) 7 mg/kg; not to exceed 350-600 mg
Chloroprocaine (Nesacaine) Short (15-30 min) Without epinephrine: 11 mg/kg; not to exceed 800 mg total dose



With epinephrine: 14 mg/kg; not to exceed 1000 mg



Amides
Lidocaine (Xylocaine) Medium (30-60 min) Without epinephrine: 4.5 mg/kg; not to exceed 300 mg
Lidocaine with epinephrine Long (120-360 min) With epinephrine: 7 mg/kg
Mepivacaine (Polocaine, Carbocaine) Medium (45-90 min) Long (120-360 min with epinephrine) 7 mg/kg; not to exceed 400 mg
Bupivacaine (Marcaine) Long (120-240 min) Without epinephrine: 2.5 mg/kg; not to exceed 175 mg total dose
Bupivacaine with epinephrine Long (180-420 min) With epinephrine: Not to exceed 225 mg total dose
Etidocaine (Duranest)



No longer available in United States



Long (120-180 min) Without epinephrine: 0.4 mg/kg; not to exceed 300 mg total dose



With epinephrine: 8 mg/kg



Prilocaine (Citanest) Medium (30-90 min) Body weight < 70 kg: 8 mg/kg; not to exceed 500 mg



Body weight >70 kg: 600 mg



Ropivacaine (Naropin) Long (120-360 min) 5 mg; not to exceed 200 mg for minor nerve block
*Nondental use, administer by small incremental doses; administer the smallest dose and concentration required to achieve desired effect; avoid rapid injection.

The occurrence of numerous fatalities associated with the cardiovascular toxicity of bupivacaine prompted a search for less toxic long-acting local anesthetic agents. This search resulted in the development of levobupivacaine and ropivacaine.

Bupivacaine is a 50:50 racemic mixture of a dextrorotatory R-(+)-enantiomer and a levorotatory S-(-)-enantiomer. Clinical studies demonstrated that the S-(-)-enantiomer, levobupivacaine, has less potential for CNS and cardiovascular toxicity. In particular, the intravascular dose required to cause lethality is almost 78% greater for levobupivacaine compared with the R-(+) enantiomer.

Further clinical trials in the 1990s led to the introduction in 1996 of ropivacaine, a pure S-(-) enantiomer. Ropivacaine, like bupivacaine, has the capacity to produce differential blockade but has a better sensorimotor dissociation at lower doses. This long-acting amide is the first local anesthetic drug developed with initial extensive toxicological studies before its clinical release. Although ropivacaine may be associated with acute CNS and cardiovascular toxicity, the incidence appears to be extremely low.

Local anesthetic toxicity can occur because of inadvertent intravascular injection or dosing error. Intravascular injection can cause toxicity even if the anesthetic was administered within the recommended dose range.

The minimum doses of anesthetics in which adverse reactions have occurred are listed in Table 3, below.

Table 3. Minimum Intravenous Toxic Dose of Local Anesthetic in Humans [2] (Open Table in a new window)

Agent Minimum Toxic Dose (mg/kg)
Procaine 19.2
Tetracaine 2.5
Chloroprocaine 22.8
Lidocaine 6.4
Mepivacaine 9.8
Bupivacaine 1.6
Etidocaine 3.4

In addition to high doses, high injection rates also increase the risk of adverse reactions to local anesthetics. Patient factors that increase risk include the following:

  • Renal or hepatic compromise
  • Metabolic or respiratory acidosis
  • Preexisting heart block or heart conditions
  • Pregnancy
  • Extremes of age
  • Hypoxia
Previous
Next:

Epidemiology

The frequency of local anesthetic toxicity is difficult to determine because these agents are used widely in a variety of settings, and most reactions are not reported. Systemic toxicity from local anesthetics may occur in as many as 1:1000 peripheral nerve blocks; however, most of these probably involve only minor subjective symptoms. [1]

In the United States in 2015, according to the American Association of Poison Control Centers (AAPCC), 1,334 single exposures to lidocaine were reported, along with 3,391 single exposures to other or unknown local and/or topical anesthetics. [3] Of the lidocaine exposures reported by the AAPCC, 534 occurred in children younger than 6 years.

Previous
Next:

Prognosis

If oxygenation, ventilation, and cardiac output are maintained, patients usually have a full recovery without sequelae. Without treatment, local anesthetic toxicity can result in seizures, respiratory depression or arrest, hypotension, cardiovascular collapse or cardiac arrest, and death. According to the AAPCC National Poison Data System 2015 Annual Report, 328 of the lidocaine exposures had no negative outcome; 178 exposures resulted in a minor outcome; 66, in a moderate outcome; and 22, in a major outcome; one death was reported. [3]

Previous
Next:

Patient Education

Advise patients with adverse reactions to a specific anesthetic agent to avoid that specific anesthetic agent in the future and to alert medical personnel of the reaction. If a patient has experienced an adverse reaction to one class of anesthetic (ester or amide), risk for adverse reactions is higher for all agents in that class. However, if the episode involved seizures, the patient should be reassured that this does not indicate an increased risk for the development of a seizure disorder in the future.

Previous