Hepatic Failure in a Child After Acetaminophen and Sevoflurane Exposure

Acetaminophen is often used for analgesia and sevoflurane for anesthesia in children. There are no reports indicating potential hepatotoxicity of these drugs in combination. We report a case of a 3-yr-old girl who developed severe hepatic failure after acetaminophen and sevoflurane exposure during and after anesthesia and surgery. Case Report A previously healthy 3-yr-old girl, body weight 20 kg, underwent appendectomy after 3 days of vomiting, anorexia, and fever. She had no history of anesthesia, allergy, or hepatitis. At admission, she was alert and conscious. Acetaminophen was given rectally for pain relief before surgery. Aspartate aminotransferase and lactic dehydrogenase were slightly increased, and alanine aminotransferase, bilirubin, alkaline phosphatase, and eosinophils were normal (Table 1). Preoperative sedation with diazepam 10 mg and morphine 3 mg rectally was followed by a transient rash.Table 1: Medication CharacteristicsAnesthesia was induced by IV thiopental 200 mg, suxamethonium 40 mg, and fentanyl citrate 40 μg and maintained by sevoflurane, N2O, and oxygen delivered by a semiclosed circle system connected to the endotracheal tube. Fresh gas flow was 2 L/min. Anesthesia lasted 45 min (minimum alveolar anesthetic concentration-hour 0.38) and was completed by extubation. The lowest arterial oxygen saturation observed was 98%, and the lowest blood pressure was 95/50. Before surgery, metronidazole 500 mg, gentamicin 80 mg, and penicillin 2 × 106 IU were given IV. After surgery, the patient was treated with acetaminophen and diclofenac rectally and with ketobemidone IM (Table 1). She suffered from pain and never regained complete alertness. Two days after the surgery, she answered relevantly and could drink. On Day 4, she became comatose, rectal bleeding occurred, and bleeding time was prolonged. Hepatic enzymes and bilirubin were increased, whereas platelets and coagulation factors II, VII, and X were decreased (Table 1). Eosinophils and creatinine were normal. P-acetaminophen was 99 mg/L 1 h after administration. The average dose of acetaminophen had been 100 mg · kg−1 · d−1 rectally for 4 days. Hepatic failure was diagnosed, and N-acetylcysteine was given IV because acetaminophen might be involved. On Day 5, the patient was in coma state III to IV. On Day 7, she improved, and N-acetylcysteine was discontinued. On Day 11, she could eat and drink by herself, and hepatic biochemistry approached normal levels. The results of serologic tests for hepatitis A virus, hepatitis B virus, hepatitis C virus, Epstein-Barr virus, and cytomegalovirus were negative. A liver biopsy performed after 1 mo showed slight reactive changes and no necrosis. Discussion At admission, the patient was fasting, and liver enzymes were almost normal. A rash was noted, suggesting an allergic reaction; however, there was no eosinophilia. During surgery, our patient was exposed to sevoflurane, a halothanelike anesthetic released for clinical use in Japan in 1990. Only a few cases of hepatotoxicity related to sevoflurane have been reported (1–3). Sevoflurane is expected to be less hepatotoxic than halothane because it is metabolized less, and the main metabolite is different and rapidly glucuronated (4). Nevertheless, glutathione serum-transferase increases after sevoflurane anesthesia in children (5) and adults (6). A degradation product, compound A, is detectable when sevoflurane is administered through a circle system containing a soda lime absorber (7). If glutathione stores are depleted by fasting and large doses of acetaminophen are administered, compound A can be nephrotoxic and hepatotoxic in rats (8). In our case, a semiclosed anesthetic circle system was used, minimizing accumulation of compound A, and the renal function remained normal. Acetaminophen undergoes hepatic degradation, including conjugation to glutathione. Large doses may deplete glutathione stores, and a metabolite causes centrilobular necrosis (9). Fasting depletes glutathione stores and increases toxicity in rats (10). In children, reversible hepatotoxicity has been reported after >150 mg/kg for two to four days (11). Fatalities have occurred after 160–400 mg · kg−1 · d−1 for one to six days (12). In our case, the patient received 175 mg/kg within the first 24 hours after admission and an average of 100 mg · kg−1 · d−1 for four days. The initial dose was large but very close to the dose needed to achieve analgesia (13). P-acetaminophen was 99 mg/L when hepatic failure occurred. Concentrations >120 mg/L four hours after single doses of acetaminophen are considered toxic (14). Viral illness and fasting (15), as well as anesthesia with enflurane (16), may increase acetaminophen toxicity. The levels of hepatotoxic metabolites in our case are unknown. No signs of hepatic necrosis were found after one month. In this case, the cause of hepatic failure was uncertain. We suggest that a synergistic effect of fasting, a very large dose of acetaminophen, and sevoflurane exposure was the cause of hepatic failure in our patient. The dosage of 175 mg/kg acetaminophen within the first 24 hours after admission might have been the primary contributing factor. We recommend that fasting children undergoing treatment with acetaminophen and anesthesia with sevoflurane be very closely monitored.