EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Key words : Halogenated anesthetic, Liver failure, Pediatric anesthesia, Transplantation

Sevoflurane, a halogenated anesthetic, is commonly used as anesthesia induction and maintenance in pediatric patients. Sevoflurane may lead to moderately elevated aminotransferase but does not tend to cause clinically significant hepatotoxicity. A few cases of hepatotoxicity were reported in clinical practice.^1,2 Influenza infection most commonly presents with upper respiratory tract symptoms and occasionally presents with lower respiratory tract symptoms. However, extrapulmonary presentations such as hepatitis are infrequently observed.³ Herein, we discuss a rare case in which sevoflurane was administered during tonsillectomy to a patient with influenza, and acute fulminant hepatitis developed. Informed consent was obtained from the parent or legal guardian before publication of this case report.

A 3.5-year-old male patient, without any known diseases, was hospitalized in the pediatric intensive care unit (PICU) with an early diagnosis of multiple organ failure based on symptoms of lethargy, hypoglycemia, uremia, and increased liver function tests after adenotonsillectomy. He had acidosis with hyperpnea. The patient had been premedicated with intravenous midazolam (1 mg), and anesthesia was induced and maintained with sevoflurane. The inspired concentration of sevoflurane ranged from 2% to 3% and was combined with an oxygen-air mixture (FiO₂ of 40%). Atracurium was administered for muscle relaxation. Tranexamic acid (100 mg) was administered locally, and compression was applied to the bleeding site during the operation. Blood pressure and other vital signs were monitored through the operation, and values were within reference ranges. The patient remained stable with good oxygenation and ventilation during surgery.

After the operation, the patient could not be extubated due to unconsciousness and inadequate ventilation. He was taken to the recovery room, and 3 hours later he was admitted to the PICU. At the time of admission to the PICU, the following details were noted: aspartate aminotransferase 13?250 U/L, alanine aminotransferase 9000 U/L, lactate dehydrogenase 25?000 U/L, total bilirubin 3.4 mg/dL, prothrombin time (PT) >120 seconds, activated partial throm-boplastin time (aPTT) 77 seconds, international normalized ratio (INR) >5.5, ammonia 33 μg/dL, lactate 17 mmol/L, blood urea nitrogen 24 mg/dL, and creatinine 1.89 mg/dL. The patient had no history of surgery, drug allergies, blood transfusions, or exposure to other hepatotoxic chemicals. Our routine procedure is to check basic biochemical parameters before surgery, and the laboratory work-up details for this patient were within reference ranges, including hemogram, aspartate aminotransferase, alanine aminotransferase, bilirubin, blood urea nitrogen, creatinine, PT, aPTT, and INR.

A review of the medical history showed that the patient had upper respiratory tract infection symptoms before the adenotonsillectomy operation; however, the parents had not informed the anesthesiologist and the surgical team about this issue. The patient had a fever, cough, and rhinorrhea for 2 days, and acetaminophen was given in 2 separate doses of 10 mg/kg to treat a fever of 38.5 °C. The patients’ parents were nonconsanguineous. Continuous venovenous hemodiafiltration was begun due to kidney failure and elevated ammonia level; total plasma exchange with fresh-frozen plasma was immediately performed on the patient with elevated PT, aPTT, and INR values; persistent and neurologic symptoms had become noticeable. Results from cranial computed tomography and cranial magnetic resonance imaging revealed no points of concern. Because the patient had earlier received acetaminophen, plasma levels of the drug were measured, which were within the reference range. After examinations for fulminant liver failure etiology, the following details were observed: results for autoimmune hepatitis markers were negative, hepatitis serology test was negative, HIV test was negative, TORCH serology panel (toxoplasmosis, rubella cytomegalovirus, herpes simplex, and HIV) was negative, and mycoplasma/chlamydia test was negative. A polymerase chain reaction test of a sample isolated from a respiratory swab was positive for influenza A. Abdominal ultrasonography showed heterogeneous echogenicity of the liver, with no evidence of masses. For tandem mass spectrometry, blood and urinary amino acids, plasma fatty acids, and urinary organic acids, all investigated for metabolic diseases, we found all measurements to be within reference range. A muscle biopsy was performed for the underlying mitochondrial disorder, and the results were deemed unremarkable.

The decision was made to perform liver transplant after fulminant liver failure symptoms became evident in the patient. At hour 24 of hospitalization, a liver transplant was performed with the patient’s mother as the donor. No pathologic finding was detected in the liver biopsy sent after transplant except massive hepatocellular necrosis and microvesicular steatosis, and these findings were considered to be concordant with liver failure. On postoperative day 16, the patient was uneventfully transferred to the ward.

Sevoflurane is a volatile anesthetic agent that does not produce trifluoroacetic acid and its related compounds, which are toxic substances produced by the degradation of other inhalation anesthetics that bind to liver microsomal proteins.⁴ Therefore, the risk of hepatotoxic immunologic response with sevoflurane is very low. Although animal studies suggest that all volatile anesthetics reduce blood flow to the liver in a dose-dependent manner, sevoflurane does not cause significant changes.⁵ Sevoflurane-associated liver failure is rare. Turillazzi and colleagues reported a case of a patient who had undergone sevoflurane general anesthesia twice in 2 days; liver enzymes strongly increased and remained elevated until death, which occurred on day 6 after the first sevoflurane exposure.⁶

Case reports relating to pediatric patients and sevoflurane complications are scarce, and there are only isolated case reports of sevoflurane-associated hepatic failure in elderly patients with comorbid illnesses. Singhal and colleagues reported a case of severe hepatic necrosis following sevoflurane anesthesia in a young adult whose liver biopsy results were consistent with drug-induced hepatotoxicity. The patient was possibly susceptible to toxicity due to an underlying Epstein-Barr virus infection; with conservative management, there was a gradual clinical improvement.⁷ There are some case reports that influenza A appears to cause severe hepatitis in some children.^8,9 However, Whitworth and collea-gues mentioned that 4 previously healthy children developed acute hepatitis or acute liver failure within 3 weeks of influenza A infection, and all influenza symptoms had begun about 5 days before the operation.⁹

In our case, symptoms for influenza began, at most, 2 days before, and all preoperative work-up was standard. Acute hepatitis causing fulminant hepatic failure developed soon after the adenoton-sillectomy operation. We investigated other possible causes of the fulminant hepatic failure, but viral serology results from the patient were negative, and all screening tests for metabolic diseases were normal. Also, the muscle biopsy and liver biopsy results did not provide information about the etiology. The patient’s symptoms related to the upper respiratory tract began to appear a few days before the operation, and a polymerase chain reaction test of a sample isolated from a respiratory swab was positive for influenza A. We speculate that, in this case, sevoflurane exposure in the setting of an influenza A infection incited acute liver failure; however, there remains a lack of conclusive evidence.

Although fulminant hepatic failure associated with sevoflurane is uncommon, it could emerge severely, especially in the presence of a predisposing factor. In such cases, etiology studies should be planned, and life support therapy should be administered. Finally, the patient should be informed to avoid reexposure to sevoflurane because of the risk of life-threatening complications.

Volume: 21 Issue: 6 June 2023

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