Drug-induced Liver Disease during Continuous Epidural Block with Bupivacaine

A 62-yr-old man with a 4-month history of T4–T5 PHN was admitted to the hospital for pain relief. He had taken 5 mg amlodipine daily for 5 yr. At the time of admission, laboratory tests, including complete blood count, liver function and enzymes, C-reactive protein (CRP), blood urea nitrogen, creatinine, electrolytes, and bleeding and coagulation times were unremarkable. After admission, an epidural injection of 0.25% bupivacaine, 4 ml, was administered four times daily, and a continuous epidural infusion of 0.25% bupivacaine was administered at a rate of 2 ml/h using a disposable continuous infusion device. The patient rested in a bed for 1 h after every bolus injection. Blood pressure and heart rate recorded every 10 min and oxygen saturation monitored continuously by pulse oximetry (Spo²) did not change at any time during treatment. Continuous infusion was performed for 12 days, and the frequency of bolus injection was decreased gradually. Also, 25 mg amitriptyline was administered daily. On the 18th day after admission to the hospital, the patient developed erythema on the trunk, a fever of 38–39°C, and general malaise. The total dose of infused bupivacaine was 1,980 mg. There was no sign of epidural catheter infection. However, blood tests showed increases in aspartate aminotransferase (AST) to 221 (normal range, 11–32) IU/l, alanine aminotransferase (ALT) to 220 (11–32) IU/l, alkaline phosphatase (ALP) to 214 (6–39) IU/l, γ-glutamyl transpeptidase (γ-GTP) to 268 (3–40) IU/l, and CRP to 1.9 (< 0.3) mg/dl. These values increased over the next week, reaching peaks of 512 IU/l AST, 976 IU/l ALT, 630 IU/l ALP, 673 IU/l γ-GTP, and 8.0 mg/dl CRP. Total bilirubin concentration increased to 2.1 (0.3–1.2) mg/dl, and the percentage of eosinophilic cells was 9 (0–7)%. Abdominal computed tomography and echography showed nothing abnormal. Tests for serologic markers of acute hepatitis A (immunoglobulin M anti–hepatitis A virus), B (immunoglobulin M anti–hepatitis B core antigen and –hepatitis B surface antigen), and C (immunoglobulin M anti–hepatitis C virus) were negative. Tests for immunoglobulin M anti–cytomegalo virus (CMV), anti–Epstein Barr virus (EBV), and anti–herpes zoster virus (HZV) were negative, as well. Although lymphocyte cell stimulation tests (LSTs) with amlodipine, amitriptyline, and bupivacaine were negative, the increase in liver enzymes was most suggestive of drug-induced liver disease. The epidural block and other medications were discontinued. Skin eruption and fever resolved within a week. The patient received laser therapy for control of pain. The increased liver enzymes returned gradually to normal within the next 21 days. Administration of amitriptyline and amlodipine was restarted, and the patient was discharged from the hospital without incident. However, 2 months later, he was readmitted for severe pain. An epidural injection of 4 ml lidocaine, 1%, was administered 4 times daily for 2 weeks and twice daily for 1 week. There was no increased transaminase or eosinophilia during the treatment. Since this time, the patient has been taking amitriptyline for 2 yr, and his liver function has been normal.

A 72-yr-old woman had left lower extremity pain caused by an L4–L5 herniated disc. The patient had not been taking any medication. At the time of her admission to the hospital, her blood test results were normal. After admission, an epidural injection of 6 ml bupivacaine, 0.125%, was administered to the patient 4 times daily for 2 weeks and twice daily for 5 days. Blood pressure and Spo²were stable during epidural infusion. On the 20th day after admission, she reported headache and nausea and had erythema on the trunk and a fever of 38–39°C. The total dose of epidural infused bupivacaine was 495 mg. There was no sign of epidural catheter infection. However, blood tests showed increases in AST to 305 IU/l, ALT to 221 IU/l, ALP to 140 IU/l, γ-GTP to 100 IU/l, and CRP to 1.4 mg/dl. These values increased over the next week, reaching peaks of 891 IU/l AST, 779 IU/l ALT, 496 IU/l ALP, 450 IU/l γ-GTP, and 4.2 mg/dl CRP. Total bilirubin concentration increased to 9.6 mg/dl, and the percentage of eosinophilic cells increased to 12%. Abdominal computed tomography and echography showed nothing abnormal. Acute hepatitis A, B, and C and hepatitis CMV, EBV, and HZV were ruled out after serologic testing. Although an LST with bupivacaine was negative, epidural block was discontinued. Skin eruption and fever resolved within a week. An L5 root block with lidocaine and steroids for control of pain was administered to the patient. The increased liver enzymes returned gradually to normal within the next 32 days.

A 67-yr-old woman had experienced T5–T6 PHN for 3 months and had been taking 50 mg diclofenac daily. In addition, she had trigeminal neuralgia and had taken 300 mg carbamazepine daily for more than 5 yr. At the time of her admission to the hospital, administration of a 5-ml epidural injection of 0.25% bupivacaine 4 times daily, continuous infusion of 0.25% bupivacaine at 2 ml/h, and 20 mg amitriptyline daily were begun. Dicrofenac, 25 mg, was administered occasionally. There was no decrease in blood pressure during epidural infusion. Blood tests on the 14th day after admission showed increases in AST to 44 IU/l, ALT to 99 IU/l, ALP to 233 IU/l, and γ-GTP to 94 IU/l. The total dose of epidural infused bupivacaine was 2,210 mg. She was asymptomatic, but her liver function deteriorated over the next 20 days, showing peak values of 93 IU/l AST, 282 IU/l ALT, 391 IU/l ALP, and 322 IU/l γ-GTP. The percentage of eosinophilic cells was 9%. Abdominal computed tomography and echography showed nothing abnormal. Acute hepatitis A, B, and C and hepatitis CMV, EBV, and HZV were ruled out by serologic testing. LSTs with amitriptyline, bupivacaine, dicrofenac, and carbamazepine were negative; however, we discontinued continuous epidural block and medications. The patient received laser therapy, and the increased concentrations of liver enzymes gradually returned to normal within 48 days. Amitriptyline administration was restarted without incident, and the patient was discharged from the hospital. Six months later, she had T10–T11 herpes zoster and was readmitted for pain control. This time, an epidural injection of 4 ml lidocaine, 1%, was administered 4 times daily for 10 days and twice daily for 5 days, in addition to 20 mg amitriptyline daily. There was no increased transaminase or eosinophilia during or after her second hospital stay.

An 84-yr-old woman had a 3-month history of T2–T3 PHN. She had taken 25 mg dicrofenac occasionally before admission to the hospital. At the time of admission, her blood test results were normal. For continuous epidural block, 0.25% bupivacaine, 4 ml, was injected 4 times daily, in addition to continuous 0.125% bupivacaine at a rate of 2 ml/h. She did not take other medications after admission. Her blood pressure and Spo²were stable during epidural infusion. On the 13th day after admission, she reported general malaise and loss of appetite and had a fever of 38–39°C. The total dose of epidural infused bupivacaine was 1,200 mg. Blood tests showed increases in AST to 381 IU/l, ALT to 709 IU/l, ALP to 926 IU/l, γ-GTP to 147 IU/l, and CRP to 2.3 mg/dl and an increased amount of eosinophilic cells (12%). No sign of epidural catheter infection was observed. Abdominal computed tomography and echography did not determine the cause of the symptoms. Tests for serologic markers of acute hepatitis A, B, and C were negative; hepatitis CMV, EBV, and HZV also were ruled out. The fever resolved within 5 days. Although the results of LSTs with bupivacaine and dicrofenac were negative, we decided that bupivacaine-induced liver disease was the most likely cause of the symptoms. We changed from bupivacaine to lidocaine. After this change, the increased amount of liver enzymes normalized gradually over the next 25 days.

The patients’ histories, clinical courses, symptoms, and signs were all consistent with drug-induced liver disease. No evidence indicated that the patients had visceral herpes zoster. Other possible causes of liver disease, such as a biliary disorder or ongoing viral hepatitis, were ruled out. Although extended epidural block may cause a decrease in hepatic blood flow, limited epidural block does not change blood flow. 3Limited epidural blocks with a small dose of bupivacaine were administered to the patients, and their blood pressure and Spo²did not decrease during block.

Drug-induced liver injury can be a direct toxic injury, an allergic reaction, or a metabolic aberration. Direct toxic injury is predictable, dose-related, reproducible in animal models, and associated with a relatively short latency period. With the allergic reaction, the exposure period is usually 1–5 weeks, and skin rash, fever, and eosinophilia are common. The response to challenge test is usually prompt. With the metabolic aberration, metabolic idiosyncratic abnormalities are implicated, the exposure period varies from weeks to months, and features of hypersensitivity, such as eosinophilia, are absent. 4Because direct toxic drugs were not administered, these patients’ responses should be classified as allergic reaction or metabolic aberration. Patient 1 had fever and skin rash, and patient 2 had fever, skin rash, and eosinophilia. Fever and eosinophilia were observed in patient 4. These patients’ responses seem to fall into the category of allergic reaction, whereas the response of patient 3 seems to be a metabolic aberration because she was asymptomatic.

Although the sensitivity of the LST is low, several reports show successful use of the test to detect hypersensitivity reactions in the liver. 5,6The belief is that the test often gives false-negative results but only rarely gives false-positive results in cases of drug hypersensitivity, so a positive result should establish the presence of drug hypersensitivity. 5We believed that drug-induced liver disorder was very likely in these patients despite the negative tests with all drugs used.

Other drugs may cause liver dysfunction. However, amlopidine (case 1), carbamazine (case 3), and diclofenace (cases 3 and 4) had been taken for several months or years before admission and in some cases were uneventfully reintroduced after resolution of the lever disorder. Amitryptyline was administerd to two patients after admission (cases 1 and 3), but in both, the drug was readministered without difficulty after discontinuation of bupivacaine and normalization of liver enzyme concentrations. These factors make it unlikely that these other drugs were the cause of the changes seen in these patients.

We consider bupivacaine to be the most possible cause of liver injury in these patients. First, changing from bupivacaine to lidocaine with readministration of other medications normalized liver function. Furthermore, bupivacaine was the only drug being used when liver injury was observed in patients 2 and 4. Second, we had long-term experience in the use of lidocaine for control of pain in PHN patients before we began using bupivacaine. Despite having used lidocaine for the past 10 yr in PHN patients, we did not observe drug-induced liver disease as in these patients. We did not administer a challenge test to readminister bupivacaine because drug readministration is inappropriate and unethical. Because local anesthetics often contain preservative agents, clinical manifestations might be elicited by sensitization to such substances. That circumstance is unlikely in these patients because bupivacaine and lidocaine have the same preservative agent, and lidocaine did not elicit clinical manifestations.

Three of our four patients had PHN. Varicella-zoster viral infection is known to involve the CD4⁺population of lymphocytes and to result in suppression of immunity. 7However, none of these patients were in the acute stage of herpes zoster, and one patient had lumbar disc hernia. There are several reports that the necessary duration of continuous epidural block for the treatment of PHN is approximately 4 weeks. 8,9In Japan, it is common to perform continuous epidural infusion for pain relief in PHN patients for long periods, and bupivacaine use is increasing. It is possible that this practice may result in an increase in drug-induced liver disease. Because such liver injury occurs with low frequency, liver function test screening of all patients to whom this drug is administered may not be practical. However, symptoms of liver disease or abnormalities in liver function warrant immediate discontinuation of the drug.

The authors thank Wasa Ueda, M.D., Department of Anesthesiology and Resuscitology, Kochi Medical School, Nankoku City, Kochi, Japan, for reviewing the manuscript.