History of Enflurane - New Jersey Anesthesia Professionals
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History of Enflurane

In the 1950s, the anesthetic halothane was coined the miracle anesthetic. The easy and rapid induction, quick recovery profile, and function as a moderate muscle relaxer made it the popular choice for anesthesiologists. Then, the hidden downsides were uncovered. It could lead to cardiovascular complications in the presence of adrenaline. Other patients experienced severe immune reactions, which caused liver damage when halothane was metabolized. Halothane’s metabolism would produce a reactive trifluoromethyl molecule (CF3-COO-) in the liver that could bond with hepatic protein structures and change their intrinsic immunogenicity. Then, the body’s immune system would launch an antibody-mediated response against hepatocytes, causing liver damage. This reaction increases in frequency and severity with recurrent exposure to halothane. To find safer anesthetic agents, Ross Terrell pioneered the development of 2-Chloro-1,1,2-trifluoroethyl-difluoromethyl ether, after a series of trials. His 347th compound delivered the desired properties, and enflurane entered both the anesthesia market and history.

Like its predecessor, enflurane provides rapid induction, adjustable anesthesia depth, and muscle relaxation. Clinical trials started in 1966 and finalized in 1968. Despite early warning signs such as electroencephalographic (EEG) changes, respiratory distress, and the production of inorganic fluoride ions during metabolism which carried the threat of nephrotoxicity and the possibility of hepatitis, enflurane became a pivotal anesthetic agent and received approval from the United States Food and Drug Administration in 1972. Its rise can be traced through the history of the anesthesia field through its status as the preferred inhalational anesthetic from the 1960s to the 1980s. [1]

However, problems arose with the use of enflurane as well. In 1986, a study published by Eger et al. reported ten cases of liver damage following its use in surgical procedures. At that time, there was no consensus on its supposed role in patient liver injury. Symptoms and clinical histories of patients adversely affected by enflurane often mirrored those associated with halothane-induced hepatitis, including chills, fever, nausea, anorexia, rash and eosinophilia. Liver damage attributed to enflurane typically involves centrilobular necrosis, a pathology resembling the hepatic lesions caused by halothane or methoxyflurane. [2]

Another problem was the prolonged recovery time from enflurane. A study published by Valanne & Korttila compared patient recovery for two groups: one anesthetized with isoflurane and the other with enflurane. They also compared the recovery time for both long and short anesthesia in the enflurane and isoflurane patient groups. Psychomotor tests were conducted to evaluate patients’ recovery. For long anesthesia, 100% of the patients who received enflurane suffered from an unsteady gait after 30 minutes, while only 78% of the patients who received isoflurane did. For long anesthesia, after 60 minutes, 38% of the enflurane patients struggled to walk while only 8% of the isoflurane patients struggled. After 60 minutes, 23% of the enflurane patients who underwent short anesthesia had an unsteady walk while only 6% of the isoflurane patients struggled. Additionally, the incidence of severe hypotension was higher in patients receiving enflurane for longer durations. These factors led to a gradual decline in the popularity of enflurane, which was eventually replaced by isoflurane, its structural isomer. Thus, enflurane’s place in the history of anesthesia was concluded. Newer halogenated anesthetics like isoflurane, sevoflurane, and desflurane, which display faster recovery profiles and lower hepatotoxicity, are now the preferred options for anesthesiologists. [3]


1. Jones, Ron. “A History of Inhaled Anesthetics.” Springer eBooks, 2014, pp. 609–27, doi:10.1007/978-1-4614-8441-7_46.

2. Eger, Edmond I., et al. “Is Enflurane Hepatotoxic?” Anesthesia & Analgesia, vol. 65, no. 1, Jan.1986, p. 21???30, doi:10.1213/00000539-198601000-00004.

3. Valanne, J., and K. Korttila. “Recovery Following General Anesthesia With Isoflurane or Enflurane for Outpatient Dentistry and Oral Surgery.” PubMed, vol. 35, no. 2, Mar. 1988, pp. 48–52, pubmed.ncbi.nlm.nih.gov/3166345.