Introduction

The amide local anesthetics including lidocaine, bupivacaine and ropivacaine are commonly used for pain control during minor surgery or invasive procedures such as biopsies, small excisions or dental work. These local anesthetics have not been linked to serum enzyme elevations, but when given as constant infusions or repeated injections have been occasionally mentioned as possible causes of clinically apparent liver injury.

Background

Lidocaine (lye' do kane), bupivacaine (bue piv' a kane) and ropivacaine (roe piv' a kane) are commonly used local anesthetics that are chemically referred to as aminoethylamides or amide local anesthetics. Their mechanism of anesthetic action is believed to be based upon inhibition of voltage-gated sodium channels, which results in membrane stabilization and slowing of membrane depolarization and repolarization. Local anesthetics have been shown to be effective and are used widely in preventing or reducing pain from minor surgery, incisions, biopsies, dental and obstetrical procedures and pain from wounds. They are usually given as a single injection locally into a lesion or the area of incision, but can be given as infusions for hours or for several days by epidural or wound-based catheters. Local anesthetic infusions can also be used for postoperative pain management. They have excellent tolerance and safety. Local anesthetics have variable durations of action, and short acting versions are often given with epinephrine, which decreases the rate of absorption limiting systemic exposure and prolonging the duration of action. Lidocaine was approved for use as a local anesthetic in the 1948 originally under the commercial name Xylocaine, ropivacaine in 1990 (Naropin), and bupivacaine in 1990 (Marcaine). Other less commonly used amide anesthetics include articaine (Septocaine: 2000), mepivacaine (Carbocaine: 1960), and prilocaine (Citanest: 1965). A liposomal and longer acting preparation of bupivacaine was approved for use in controlling postsurgical pain in 2011 (Exparel). Side effects of the local anesthetics are usually dose related and occur mostly as a result of systemic administration or exposure. They include neurological symptoms such as drowsiness, tinnitus, dizziness and twitching as well as gastrointestinal effects such as nausea, vomiting and constipation. Cardiovascular depression can also occur and ventricular arrhythmias, especially with higher doses.

Hepatotoxicity

In clinical trials with the amide local anesthetics, serum aminotransferase and alkaline phosphatase elevations were rarely reported and were generally no more common than with placebo or comparator injections. Despite widespread use for many decades, the local amide anesthetics, when given as single or limited injections or infusions, have not been convincingly linked to instances of clinically apparent liver injury, and liver toxicity is not mentioned in product labels. Nevertheless, there have been several case series of jaundice arising a few days to as long as a month after use of bupivacaine given over several days as a constant infusion or as repeated injections into a localized area of pain. Some reports mentioned concurrent administration of an antibiotic such as cefazolin during the perioperative period, which might have accounted for the liver injury. However, in other reports, only bupivacaine was given. The liver injury was mixed or cholestatic and mild-to-moderate in severity, resolving within 1 to 2 months of onset without residual evidence of liver injury. In many instances, there was an accompanying low grade fever, rash or eosinophilia, suggesting a hypersensitivity reaction.

Likelihood score (lidocaine, articaine, mepivacaine, prilocaine, ropivacaine): E (unlikely causes of clinically apparent liver injury).

Likelihood score (bupivacaine): C (probable cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which bupivacaine might cause liver injury is unknown, but is most likely due to an idiosyncratic hypersensitivity reaction. The amide local anesthetics are metabolized locally and do not affect the activity of cytochrome P450 enzymes.

Management

The liver injury linked to exposures to amide anesthetics has largely been limited to use of bupivacaine given by infusion or multiple injections over a period of 1 to 3 days. The injury was invariably self-limited, and no instance of chronic liver injury, vanishing bile duct syndrome or acute liver failure has been linked to bupivacaine or other local anesthetics. There have been no reports of recurrence after reexposure to bupivacaine, but in several instances patients with jaundice from bupivacaine infusions have later tolerated injections or infusions with lidocaine.

Drug Class: Anesthetics, Local

Case 1. Immunoallergic hepatitis arising 3 weeks after a 2 day course of bupivacaine infusions for postoperative pain control.

[Modified from Case 2 of: Chintamaneni P, Stevenson HL, Malik SM. Bupivacaine drug-induced liver injury: a case series and brief review of the literature. J Clin Anesth 2016; 32: 137-41. PubMed Citation]

A 51 year old man developed fever, dark urine, pruritus and jaundice 3 weeks after an inguinal herniorrhaphy, during which he received bupivacaine injections followed by constant infusions into the area of the incision for two days postoperatively. He also received a single dose of cefazolin at the time of surgery and had taken simvastatin for hyperlipidemia for several years. He recovered from the surgery without complications until several weeks later when symptoms of fever and jaundice arose. He had no previous history of liver disease or risk factors for viral hepatitis. He drank an average of 10 beers weekly. On presentation, he was jaundiced but had no stigmata of chronic liver disease. Laboratory results showed elevations in liver tests, and serum bilirubin subsequently peaked at 9.5 mg/dL, ALT 491 U/L, AST 262 U/L and alkaline phosphatase 378 U/L, yielding an R ratio of ~4.3. The eosinophil count was 9%. He tested negative for markers of acute hepatitis A, B and C and for herpes simplex and Epstein-Barr virus infection. Autoantibodies were not detected. Imaging of the liver by ultrasound and CT showed no evidence of biliary obstruction or hepatic abnormalities. A liver biopsy showed a “mixed” cholestatic and hepatocellular pattern and occasional eosinophils. He recovered rapidly and all liver tests were normal 4 weeks later.