Preservatives in Local Anesthetic Solutions

Published on 07/02/2015 by admin

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Last modified 22/04/2025

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Preservatives in local anesthetic solutions

Beth L. Ladlie, MD, MPH

Although allergies to local anesthetic agents are rare, they do exist, and allergic reactions to aminoester local anesthetic agents are more common than are reactions to aminoamide local anesthetic agents. Regardless of the subclass of the agent, local anesthetic preparations often contain additives that are intended to prolong their shelf life. Some adverse reactions after administration of local anesthetic agents may be caused by these additives (Table 118-1).

Table 118-1

Function and Possible Toxicity of Preservatives Used in Local Anesthetic Agents

Preservative Class	Function	Possible Toxicity
Sulfites	Antioxidant	Anaphylactoid reactionArachnoiditis
EDTA	Chelating agent	Low back pain at epidural injection site
Methylparaben	Antimicrobial	Anaphylactoid reaction

EDTA, Disodium ethylenediaminetetraacetate.

Sulfites

Sulfites are antioxidants used to stabilize vasoconstricting agents (e.g. epinephrine) that are often added to local anesthetic solutions. Common sulfites include bisulfite and metabisulfite. Sulfites are capable of inducing anaphylactoid reactions, which can include angioedema, urticaria, seizures, bronchospasm, and even death. Sulfites are present as preservatives in foods and beverages, so patients will likely have had multiple exposures to sulfites prior to receiving a local anesthetic solution that contains a sulfite.

Sodium bisulfite, which is the preservative in 2-chloroprocaine, has been implicated in the development of arachnoiditis. Multiple cases have been reported of healthy patients (i.e., American Society of Anesthesiologists category 1) who have experienced bilateral lower extremity paralysis and loss of sphincter control after receiving local anesthetic agents that contain sodium bisulfite; some of these patients have only partially recovered. Many of these patients had an unintentional dural puncture and injection of a large intrathecal volume of low-pH 2-chloroprocaine–containing sodium bisulfate. Because animal studies have shown that 2-chloroprocaine is neurotoxic, it may be that the bisulfite was not the culprit; however, this issue has not been well studied, leading some to speculate that there may have been synergistic effects.

Disodium ethylenediaminetetraacetate

Disodium ethylenediaminetetraacetate (EDTA) is a preservative added to local anesthetic agents to prolong shelf life and to enable the manufacturer to use an autoclave to sterilize the glass vials that contain the anesthetic agent. EDTA functions as a chelating agent and was originally introduced into local anesthetic agents to replace metabisulfite in 2-chloroprocaine. Large volumes (>40 mL) of epidurally injected 2-chloroprocaine formulated with EDTA have been implicated as the cause of severe pain at the injection site. The severity of EDTA-associated lumbar paraspinal muscle spasm and pain may be increased when patients are acidemic. There is no evidence of neurotoxicity resulting from EDTA.

Parabens

Parabens, most commonly methylparaben, is a bacteriostatic agent often present in multiuse vials of local anesthetic agents. It has antimicrobial activity against gram-positive bacteria and fungi. Its chemical structure is similar to that of para-aminobenzoic acid (PABA), which is a known potential allergen and structurally similar to the ester local anesthetic agents. Sensitive patients may experience anaphylactoid signs and symptoms. The use of methylparaben at clinically relevant doses has not been associated with neurotoxicity.

Substitution of preservative-containing solutions for preservative-free solutions

Sulfites and parabens have been associated with neurotoxicity, but because all preservatives are potentially neurotoxic, anesthesiologists commonly administer only preservative-free solutions into the epidural or intrathecal space. However, according to the Orange Book published by the U.S. Food and Drug Administration, preservative-free and preservative-containing medications are considered therapeutically equivalent, and manufacturers may substitute one type for the other without notifying physicians. At least one case of cauda equina syndrome has been reported after the patient received a formulation of chloroprocaine that had been changed to a generic agent containing sodium bisulfite.

Despite the toxicity of the substances discussed here, local anesthetic agents are widely used and well tolerated. Most of the preservatives seem to be safe for human use, but when a high volume of local anesthetic agent is to be used (as with peripheral nerve blockade), the anesthesia provider should take into account the potential toxicity of the preservative.

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