NLM NIDDK Livertox Database

Livertox

DRUG RECORD

 

ENFLURANE

 

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.

 

Background

Enflurane is a widely used major anesthetic agent, although its use has decreased recently with the availability of newer inhalational anesthetics.  Enflurane has a somewhat slow onset of action and is, therefore, used largely to maintain anesthesia after induction with other 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.

 

Hepatotoxicity

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 is very rare.  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.  The liver injury 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.

 

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.

 

Drug Class:  Halogenated Anesthetics

 

Other drugs in the Class:  Desflurane, Halothane, Isoflurane, Sevoflurane

 

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REPRESENTATIVE TRADE NAMES
Enflurane – Generic, Ethrane®

 

DRUG CLASS
Anesthetics, Inhalation

 

COMPLETE LABELING

FDA product labeling at DailyMed, National Library of Medicine, NIH

 

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DRUG	CAS REGISTRY NO	MOLECULAR FORMULA	STRUCTURE
Enflurane	13838-16-9	C3-H2-Cl-F5-O

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References Last Updated: 26 August 2011

1. Zimmerman HJ. Anesthetic agents. In, Zimmerman, HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999: pp. 457-82.  (Expert review of hepatotoxicity of anesthetic agents published in 1999; mentions that enflurane appears to be safer than halothane, but it has been implicated in at least 30 cases of hepatic injury with features similar to halothane hepatitis).

2. Kenna JG. Mechanism, pathology, and clinical presentation of hepatoxicity of anesthetic agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 2nd ed. New York: Informa Healthcare USA, 2007: pp 465-484.  (Review of liver injury from anesthetic agents published in 2007; mentions the incidence of enflurane hepatotoxicity appears to be 1:800,000 exposures and that clinical features are similar to those of halothane hepatitis).

3. Evers AS, Crowder CM, Balser JR. General anesthetics. In, Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 11th ed. New York: McGraw-Hill, 2006, pp. 341-68.  (Textbook of pharmacology and therapeutics).

4. Van der Reis L, Askin SJ, Frecker GN, Fitzgerald WJ. Letter: Hepatic necrosis after enflurane anesthesia. JAMA 1974; 227: 76. PubMed Citation  (62 year old woman with unsuspected cirrhosis developed fever 19 days after cholecystectomy using enflurane with subsequent rises in AST [176 to 3000 U/L], LDH [310 to 2000 U/L] and bilirubin [4.8 to 25.5 mg/dL], multiorgan failure and death at day 30).

5. Denlinger JK, Lecky JH, Nahrwold ML. Hepatocellular dysfunction without jaundice after enflurane anesthesia. Anesthesiology 1974; 41: 86-7. PubMed Citation  (40 year old man developed fever 1 day after receiving enflurane anesthesia [peak bilirubin 1.2 mg/dL, ALT ~900 U/L, AST 370 U/L, eosinophils 6%], resolving within 1 month).

6. Douglas HJ, Eger EI 2nd, Biava CG, Renzi C. Hepatic necrosis associated with viral infection after enflurane anesthesia. N Engl J Med 1977; 296: 553-5. PubMed Citation   (17 year old boy developed fever 3 days and diarrhea 4 days after enflurane anesthesia with subsequent hepatic failure [bilirubin not given, AST 13,000 U/L, LDH 8700 U/L] and death, autopsy showing massive necrosis and herpes virus inclusions).

7. Ona FV, Patanella H, Ayub A. Hepatitis associated with enflurane anesthesia. Anesth Analg 1980; 59: 146-9. PubMed Citation  (66 year old woman developed high fevers after 2nd anesthesia expsoure to enflurane within a few weeks [bilirubin 0.9 rising to 2.6 mg/dL, ALT 300 U/L, Alk P 368 U/L], also received antibiotics, including cephalexin).

8. Lewis JH, Zimmerman HJ, Ishak KG, Mullick FG. Enflurane hepatotoxicity. A clinicopathologic study of 24 cases. Ann Intern Med 1983; 98: 984-92. PubMed Citation  (Review of 10 published and 48 unpublished (FDA, AFIP) reports of enflurane hepatotoxicity; 24 considered likely, mean age 46 years, 16 had previous exposures, onset of fever in few hours to days after exposure, jaundice onset in 3 days to 3 weeks, eosinophilia in 29%, ALT 279-8000 U/L, LDH 260-10,000 U/L, Alk P 1-5 times ULN, bilirubin 1.2-32 mg/dL, 3 patients developed renal failure and 5 died).

9. Sigurdsson J, Hreidarsson AB, Thjodleifsson B. Enflurane hepatitis. A report of a case with a previous history of halothane hepatitis. Acta Anaesthesiol Scand 1985; 29: 495-6. PubMed Citation  (32 year old woman with history of halothane hepatitis was on phenobarbital and carbamazepine and underwent enflurane anesthesia, developing fever on day 1 and jaundice on day 2 [bilirubin 5.8 mg/dL, AST 517 U/L, Alk P 1.5 times ULN], resolving within 6 weeks).

10. Eger EI 2nd, Smuckler EA, Ferrell LD, Goldsmith CH, Johnson BH. Is enflurane hepatotoxic? Anesth Analg 1986; 65: 21-30. PubMed Citation  (Reanalysis of data from Lewis et al [1983] suggested that enflurane was not the cause of liver injury in most cases; other causes being viruses, sepsis, shock and other medications).

11. Christ DD, Satoh H, Kenna JG, Pohl LR. Potential metabolic basis for enflurane hepatitis and the apparent cross-sensitization between enflurane and halothane. Drug Metab Dispos 1988; 16: 135-40. PubMed Citation  (Rats given anesthetics developed acylated hepatic microsomal protein adducts detectable by ELISA, halothane>> enflurane>> isoflurane).

12. Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug-induced liver injury in the United States. Liver Transpl 2004; 10: 1018-23. PubMed Citation  (Among ~50,000 liver transplants done in the United States between 1990 and 2002, 137 [0.2%] were done for idiosyncratic drug induced acute liver failure, of which 3 were attributed to halothane and 1 to isoflurane, none to the other halogenated anesthetics).

13. Björnsson E, Jerlstad P, Bergqvist A, Olsson R. Fulminant drug-induced hepatic failure leading to death or liver transplantation in Sweden. Scand J Gastroenterol 2005; 40: 1095-101. PubMed Citation  (36 years of reporting to Swedish registry identified 103 cases of acute liver failure due to drugs, of which 16 were attributed to halothane [ranking #1] but none to the other halogenated anesthetics).

14. Björnsson E, Olsson R. Suspected drug-induced liver fatalities reported to the WHO database. Dig Liver Dis 2006; 38: 33-8. PubMed Citation  (In WHO database of fatal adverse drug reactions from 1968-2003, 4690 reports of drug induced liver fatality: halothane ranked fifth in frequency but most cases were reported before 1991).

15. 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, two cases were attributed to desflurane and one to sevoflurane, none to enflurane).

16. Devarbhavi H, Dierkhising R, Kremers WK, Sandeep MS, Karanth D, Adarsh CK. Single-center experience with drug-induced liver injury from India: causes, outcome, prognosis, and predictors of mortality. Am J Gastroenterol 2010; 105: 2396-404. PubMed Citation  (313 cases of drug induced liver injury were seen over a 12 year period at a large hospital in Bangalore, India; none were attributed to anesthetic agents].

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