Isoflurane is a commonly used inhalational anesthetic and has an excellent safety record. Isoflurane has been linked to rare instances of severe acute liver injury resembling halothane induced liver injury in small case series and individual case reports.
Isoflurane (eye" soe flur' ane) is a widely used major anesthetic agent with rapid onset of action and rapid dispersal. Isoflurane is a halogenated anesthetic, similar in structure and activity to halothane, desflurane, enflurane and sevofurane. Isoflurane is typically given in inhaled concentrations of 0.5% to 3% in oxygen. Because of its pungent odor and somewhat slow onset of action, isoflurane is typically used to maintain anesthesia after induction with other agents such as nitrous oxide, fentanyl and propofol. Isoflurane became available for use in the United States in 1979. Isoflurane must be administered in a controlled situation by a properly trained anesthesiologist or nurse anesthetist.
Prospective, serial blood testing often demonstrates minor transient elevations in serum aminotransferase levels in the 1 to 2 weeks after major surgery and halogenated anesthetic agents. Appearance of ALT levels above 10 times the upper limit of normal, however, is distinctly unusual and points to significant hepatotoxicity. Clinically apparent, severe hepatic injury from isoflurane is very rare, only isolated case reports and small case series having been published. The injury is marked by acute elevations in serum aminotransferase levels (5- to 50-fold) and appearance of jaundice within 2 to 21 days of surgery. There are usually minimal increases in alkaline phosphatase and gammaglutamyl transpeptidase levels. Jaundice is usually preceded by a day or two of fever and may be accompanied by rash and eosinophilia. The acute liver injury may be self-limited and resolve within 4 to 8 weeks, but can be severe and associated with acute liver failure. A strong risk factor is previous exposure to any of the halogenated anesthetics and particularly a history of halothane hepatitis or unexplained fever and rash after anesthesia with one of these agents. The differential diagnosis of acute liver injury after surgery and anesthesia is sometimes difficult, and a clinical picture similar to isoflurane hepatitis can be caused by shock or ischemia, other idiosyncratic forms of drug induced liver injury and acute viral or herpes hepatitis.
Likelihood score: B (highly likely cause of clinically apparent liver injury).
Mechanism of Injury
The mechanism of isoflurane hepatotoxicity is suspected to be similar to that of halothane and associated with creation of reactive intermediates. Isoflurane is metabolized to some extent by the microsomal drug metabolizing enzyme CYP 2E1 to a trifluoroacetylated reactive intermediate (TFA) that is capable of binding to multiple intracytoplasmic proteins forming potentially immunogenic adducts. The TFA adducts induce antibodies that can be detected in patients with isoflurane, desflurane as well as halothane hepatotoxicity and are also found in a proportion of health care workers exposed to the volatile anesthetics.
Outcome and Management
Severity ranges from mild and transient aminotransferase elevations without symptoms or other evidence of liver injury, to a self limited symptomatic acute hepatitis-like reaction to severe, acute hepatic failure. The severity and prognosis may relate in part of patient age, being more severe in the elderly and both milder and less common in children. Obesity may also be both a predisposing factor and predictor of outcome. Chronic liver injury from isoflurane exposure has not been described. Patients with isoflurane induced hepatitis should be cautioned against future exposure to fluorinated hydrocarbon anesthetics such as halothane, enflurane, desflurane or sevoflurane.
Case 1. Isoflurane hepatotoxicity in a patient with previous history of halothane-induced hepatitis.
[Modified from: Hasan F. Isoflurane hepatotoxicity in a patient with a previous history of halothane-induced hepatitis. Hepatogastroenterology 1998; 45: 518-22. PubMed Citation]
A 35 year old woman with diabetes and a previous history of elevated ALT levels after halothane exposure underwent arthroscopy under general anesthesia with isoflurane. Her perioperative and postoperative liver profile was normal. Two weeks later, she presented with jaundice. Of interest, she had a history of halothane induced liver injury 1 and 7 years previously, both episodes associated with jaundice and marked serum aminotransferase elevations. On physical examination she was jaundiced and had mild hepatomegaly. Laboratory examination revealed total bilirubin 27.2 mg/dL, ALT 1950 U/L, alkaline phosphatase 226 U/L, albumin 3.5 g/dL, total protein 7.5 g/dL, and prothrombin time 16 sec (normal 11 sec). Complete blood counts were normal. Abdominal ultrasound showed hepatomegaly with increased echogenicity throughout the liver. The gallbladder, common bile duct, spleen and portal veins were normal. Tests for acute hepatitis A, B and C were negative as were autoantibodies. Liver biopsy showed severe, predominantly centrozonal necrosis and cell loss with diffuse inflammatory infiltrates. The patient was treated with supportive measures and the liver function tests improved spontaneously. She was discharged after 16 days of hospitalization and recovered after 12 weeks. Subsequently, she underwent abscess drainage under propofol anesthesia without incident.
|| Hepatocellular (R=25.5)
|| 3+ (jaundice, hospitalization)
|| 1 to 2 weeks
|| 3 months
|Other medications:|| Indomethacin, insulin|
|Feb 18, 1987
|Mar 03, 1987
|Aug 12, 1993
|Aug 24, 1993
|Sep 17, 1994
|Sep 23, 1994
||Jaundice, liver biopsy
* Converted from micromoles to mg/dL.
Severe isoflurane hepatotoxicity is rare. Most commonly the injury presents with fever and jaundice 3 to 14 days after surgery. Many affected patients have a history of previous halothane or isoflurane exposure. Female gender, as in this patient, is a risk factor. The latency period of halothane anesthetic induced liver dysfunction decreases with the frequency of exposure. Rash occurs in 10% of patients. This is a diagnosis of exclusion, and the most common causes of jaundice postoperatively that require exclusion are sepsis, biliary disease, parenteral nutrition related jaundice and shock or ischemia. Recovery is expected after 3 to 4 months. Rechallenge should be avoided, using total intravenous anesthetic technique whenever possible, which this patient later underwent without difficulty.
REPRESENTATIVE TRADE NAMES
Isoflurane – Generic, Forane®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NO
References updated: 01 January 2018
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