Enfurane is a commonly used volatile anesthetic agent with an excellent safety record. Case series and isolated case reports of severe acute liver injury similar to halothane hepatitis attributed to enflurane have been published, but are rare.
Enflurane (en flur' ane) is a widely used halogenated inhalation anesthetic agent similar to halothane, desflurane, sevoflurane and isoflurane. Enflurane has a somewhat slow onset of action and is, therefore, used largely to maintain anesthesia after induction with other agents. Enflurane became available in 1972 and is still in use, although less widely than other the more modern halogenated inhalation agents. Enflurane must be administered in a controlled situation by a properly trained and credentialed anesthesiologist or nurse anesthetist and is typically given in concentrations up to 1.5% to 4% with oxygen.
Prospective, serial blood testing often demonstrates minor transient elevations in serum aminotransferase levels in the 1 to 2 weeks after major surgery and anesthesia. 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 enflurane has been reported but is very rare. The injury resembles halothane hepatotoxicity and is marked by acute elevations in serum aminotransferase levels (5- to 50-fold) and appearance of jaundice 2 to 21 days after surgery and anesthesia. There are usually minimal increases in alkaline phosphatase and gammaglutamyl transpeptidase levels. The liver injury is often 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.
Mechanism of Injury
The mechanism of enflurane hepatotoxicity is suspected to be similar to that of halothane and associated with creation of reactive intermediates of enflurane. Enflurane 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 enflurane- 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 a 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 enflurane exposure has not been described. Patients with enflurane induced hepatitis should be cautioned against future exposure to a fluorinated hydrocarbon anesthetic such as halothane, desflurane, isoflurane or sevoflurane.
REPRESENTATIVE TRADE NAMES
Enflurane – Generic, Ethrane®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 02 April 2014
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Kenna JG. Mechanism, pathology, and clinical presentation of hepatoxicity of anesthetic agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013: pp 403-422. (Review of liver injury from anesthetic agents; mentions the incidence of enflurane hepatotoxicity is much less than with halothane, in the order of 1:800,000 exposures but that clinical features of the injury are similar to those of halothane hepatitis).
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Björnsson E, Olsson R. Suspected drug-induced liver fatalities reported to the WHO database. Dig Liver Dis 2006; 38: 33-8. PubMed Citation (The WHO database of fatal adverse drug reactions from 1968-2003 includes 4690 reports of drug induced liver fatality: halothane ranked fifth in frequency but most cases were reported before 1991).
Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN).Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation (Among 300 cases of drug induced liver disease collected in the United States between 2003 and 2008, 2 cases were attributed to desflurane, 1 to sevoflurane, but none to enflurane).
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Reuben A, Koch DG, Lee WM; Acute Liver Failure Study
Group. Drug-induced acute liver failure: results of a U.S. multicenter,
prospective study. Hepatology 2010; 52: 2065-76. PubMed
Citation (Among 1198 patients with acute
liver failure enrolled in a US prospective study between 1998 and 2007, 133 were
attributed to drug induced liver injury, of which 1 was attributed to
halothane, 1 to isoflurane, but none to enflurane).
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