Toxicity, Local Anesthetics 

The need to perform painful procedures in the emergency department (ED) makes the use of local and infiltration anesthesia necessary components of patient care. While generally safe, anesthetic agents can be toxic if used in inappropriate doses or route. Even when properly administered, patients may experience unintended reactions to local anesthetics. The manifestations of toxicity associated with local anesthetic agents used in the ED and treatment strategies are discussed in this article.

Physiochemical variables

Local anesthetics can be divided into 2 groups: the esters and the amides. Onset of action, potency, and duration of action are determined by the specific local anesthetic's pKa, lipid solubility, protein binding, tissue pH, and vasodilatory effects. Increasing the dose by administering a high concentration shortens onset, while increasing potency and duration of action, as well as increasing possibility for the adverse/toxic reactions. Other factors that affect onset, potency, and duration are described below.

• Onset of action

  • pKa is the primary factor that determines onset of action.
  • Lower pKa increases tissue penetration and shortens onset of action; this is due to increased lipid solubility of nonionized (uncharged) particles.
  • pKa that is closer to pH optimizes penetration.
  • Inflammation in the extracellular space may decrease pH and may slow onset of action.
  • Site of administration influences onset (ie, prolonged in areas with increased tissue or nerve sheath size).
• Potency

  • Local anesthetics with high partition coefficients that increase lipophilic properties easily pass into the lipid nerve membrane.
  • Degree of vasodilation promotes vascular absorption, thereby reducing locally available drug and decreases potency.
  • Addition of epinephrine or sodium bicarbonate increases pH, thereby increasing nonionized particles, which are more lipid soluble.
  • Generally, 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.
• Duration of action

  • Addition of epinephrine to some 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 (addition of epinephrine or sodium bicarbonate) also prolongs duration of action.

Table 1. Local Anesthetic Agents Used Commonly for Infiltrative Injection (Open Table in a new window)

The search for less toxic long-acting local anesthetics was prompted after the occurrence of numerous fatalities associated with the cardiovascular toxicity of bupivacaine. The 50:50 racemic mixture of bupivacaine consists of the dextrorotatory R-(+)-enantiomer and the levorotatory S-(-)-enantiomer, in which the S-(-)-form is less toxic. The less toxic S-(-)enantiomer, known as levobupivacaine, has been involved in numerous clinical studies, which have demonstrated either, in vitro or in vivo, that this new long-acting amide 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 rare.

Dosage guidelines

Lower concentrations of local anesthetics are typically used for infiltration anesthesia.

Variation in local anesthetic dose is dependent on the procedure, the degree of anesthesia required, and individual patient circumstances.

Reduced dosage is indicated in debilitated or acutely ill patients; in very young children or geriatric patients; and in patients with liver disease, arteriosclerosis, or occlusive arterial disease.

Administrative techniques

Infiltration anesthesia is accomplished by administering the local anesthetic solution intradermally (ID), subcutaneously (SC), or submucosally across the nerve path supplying the area of the body requiring anesthesia. See Local Anesthetic Agents, Infiltrative Administration.

A common administrative technique is to subcutaneously inject the local anesthetic in a circular pattern around the operative site; this circular patterned administration is often referred to as field block technique.

Concentration

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 (see examples below).

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

Dilution

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

• 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 10 mL of anesthetic solution = 1:100,000 dilution or 0.01 mg/mL

Table 2. Epinephrine Content Examples (Open Table in a new window)

Adverse effects

Adverse effects are usually caused by high plasma concentrations of local anesthetic drug that result from inadvertent intravascular injection, excessive dose or rate of injection, delayed drug clearance, or administration into vascular tissue.

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

Systemic toxicity of anesthetics involves the central nervous system (CNS), the cardiovascular system, and the immune system. In relatively rare instances (< 1%), the effects on the immune system can produce 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. Cardiovascular effects are primarily those of direct myocardial depression and bradycardia, which may lead to cardiovascular collapse.

Note that toxicity of anesthetics may be potentiated in patients with renal or hepatic compromise, respiratory acidosis, preexisting heart block, or heart conditions. Toxicity may be potentiated during pregnancy, at the extremes of age, or in those with hypoxia. However, inadvertent intravascular injection is the most common cause of local anesthetic toxicity even if anesthetic was administered within the recommended dose range.

In the following table, the minimum doses of anesthetics in which adverse reactions have occurred are listed.

Table 3. Minimum Intravenous Toxic Dose of Local Anesthetic in Humans^[1] (Open Table in a new window)