OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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

ANNOTATED BIBLIOGRAPHY

References updated: 01 January 2018

• 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).
• 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).
• Patel PM, Patel HH, Roth DM. General anesthetics and therapeutic gases. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 527-564.

  (Textbook of pharmacology and therapeutics).
• Van der Reis L, Askin SJ, Frecker GN, Fitzgerald WJ. Letter: Hepatic necrosis after enflurane anesthesia. JAMA 1974; 227: 76. [PubMed: 4859632]

  (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).
• Denlinger JK, Lecky JH, Nahrwold ML. Hepatocellular dysfunction without jaundice after enflurane anesthesia. Anesthesiology 1974; 41: 86-7. [PubMed: 4834383]

  (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).
• 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: 189190]

  (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).
• Ona FV, Patanella H, Ayub A. Hepatitis associated with enflurane anesthesia. Anesth Analg 1980; 59: 146-9. [PubMed: 7189334]

  (66 year old woman developed high fevers after 2nd anesthesia exposure 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).
• Lewis JH, Zimmerman HJ, Ishak KG, Mullick FG. Enflurane hepatotoxicity. A clinicopathologic study of 24 cases. Ann Intern Med 1983; 98: 984-92. [PubMed: 6859708]

  (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).
• 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: 4036534]

  (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).
• Eger EI 2nd, Smuckler EA, Ferrell LD, Goldsmith CH, Johnson BH. Is enflurane hepatotoxic? Anesth Analg 1986; 65: 21-30. [PubMed: 3940466]

  (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).
• 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: 2894942]

  (Rats given anesthetics developed acylated hepatic microsomal protein adducts detectable by ELISA, halothane>> enflurane>> isoflurane).
• 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: 15390328]

  (

  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).
• 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: 16165719]

  (

  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).
• Björnsson E, Olsson R. Suspected drug-induced liver fatalities reported to the WHO database. Dig Liver Dis 2006; 38: 33-8. [PubMed: 16054882]

  (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. [PMC free article: PMC3654244] [PubMed: 18955056]

  (Among 300 cases of drug induced liver disease collected in the US between 2003 and 2008, 2 cases were attributed to desflurane, 1 to sevoflurane, but none to enflurane).
• 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: 20648003]

  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).
• 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. [PMC free article: PMC3992250] [PubMed: 20949552]

  (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).
• Safari S, Motavaf M, Seyed Siamdoust SA, Alavian SM. Hepatotoxicity of halogenated inhalational anesthetics. Iran Red Crescent Med J 2014; 16: e20153. [PMC free article: PMC4270648] [PubMed: 25593732]

  (Review of hepatotoxicity of the volatile halogenated anesthetics).
• Lin J, Moore D, Hockey B, Di Lernia R, Gorelik A, Liew D, Nicoll A. Drug-induced hepatotoxicity: incidence of abnormal liver function tests consistent with volatile anaesthetic hepatitis in trauma patients. Liver Int 2014; 34: 576-82. [PubMed: 23944929]

  (Retrospective analysis of records from 1556 patients admitted to a trauma unit during 2008 identified 47 cases of possible volatile anesthetic related liver injury, including 12 who developed ALT levels above 200 U/L of whom 11 had fever and 6 eosinophilia, but none were jaundiced or developed acute liver failure).
• Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases of which 5 [3%] were attributed to halothane and caused acute liver failure, while . [PubMed: 24552865]

  no other volatile anesthetic was listed).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 2 were attributed to isoflurane, 1 to sevoflurane, but none to halothane, enflurane or desflurane).