Because the hypodermic needle was not invented until 1855, the first general anesthetics were des-tined to be inhalation agents. Diethyl ether (known at the time as “sulfuric ether” because it was pro-duced by a simple chemical reaction between ethyl alcohol and sulfuric acid) was originally prepared in1540 by Valerius Cordus. Ether was used for frivolous purposes (“ether frolics”), but not asan anesthetic agent in humans until 1842, when Crawford W. Long and William E. Clark indepen-dently used it on patients for surgery and dental extraction, respectively. However, they did not pub-licize their discovery. Four years later, in Boston, on October 16, 1846, William T.G. Morton conducted the first publicized demonstration of general anes-thesia for surgical operation using ether. The dra-matic success of that exhibition led the operating surgeon to exclaim to a skeptical audience: “Gentle-men, this is no humbug!”
Chloroform was independently prepared by von Leibig, Guthrie, and Soubeiran in 1831. Although first used by Holmes Coote in 1847, chloroform was introduced into clinical practice by the Scot Sir James Simpson, who administered it to his patients to relieve the pain of labor. Ironically, Simpson had almost abandoned his medical prac-tice after witnessing the terrible despair and agony of patients undergoing operations without anesthesia.
Joseph Priestley produced nitrous oxide in 1772, and Humphry Davy first noted its analgesic properties in 1800. Gardner Colton and Horace Wells are credited with having first used nitrous oxide as an anesthetic for dental extractions in humans in 1844. Nitrous oxide’s lack of potency (an 80% nitrous oxide concentration results in analge-sia but not surgical anesthesia) led to clinical dem-onstrations that were less convincing than those with ether.
Nitrous oxide was the least popular of the three early inhalation anesthetics because of its low potency and its tendency to cause asphyxia when used alone . Interest in nitrous oxide was revived in 1868 when Edmund Andrews administered it in 20% oxygen; its use was, how-ever, overshadowed by the popularity of ether and chloroform. Ironically, nitrous oxide is the only one of these three agents still in widespread use today. Chloroform superseded ether in popularity in many areas (particularly in the United Kingdom), but reports of chloroform-related cardiac arrhythmias, respiratory depression, and hepatotoxicity eventu-ally caused practitioners to abandon it in favor of ether, particularly in North America.
Even after the introduction of other inhala-tion anesthetics (ethyl chloride, ethylene, divinyl ether, cyclopropane, trichloroethylene, and flurox-ene), ether remained the standard inhaled anes-thetic until the early 1960s. The only inhalation agent that rivaled ether’s safety and popularity was cyclopropane (introduced in 1934). However, both are highly combustible and both have since been replaced by a succession of nonflammable potent fluorinated hydrocarbons: halothane (developed in 1951; released in 1956), methoxyflurane (developed in 1958; released in 1960), enflurane (developed in 1963; released in 1973), and isoflurane (developed in 1965; released in 1981).
Two newer agents are now the most popu-lar in developed countries. Desflurane (releasedin 1992), has many of the desirable properties of isoflurane as well as more rapid uptake and elimi-nation (nearly as fast as nitrous oxide). Sevoflu-rane, has low blood solubility, but concerns about the potential toxicity of its degradation products delayed its release in the United States until 1994 . These concerns have proved to be largely theoretical, and sevoflurane, not desflurane, has become the most widely used inhaled anes-thetic in the United States, largely replacing halo-thane in pediatric practice.