Beyond Ether and Chloroform-A Major Breakthrough With Halothane.

BACKGROUND: The use of equipment powered by electricity in the operating room increased the risk of fires in the presence of flammable agents such as ether and cyclopropane. Chloroform was associated with cardiac arrhythmias and liver damage. The introduction of halothane in the late 1950s was heralded as a solution to many problems facing the specialty of anesthesia. We explore whether the manufacturer promptly reported halothane's adverse effects to regulatory agencies and practitioners. SOURCES: We consulted documents submitted by Ayerst Laboratories to federal authorities through the Freedom of Information Act, promotional advertisements, package inserts, published articles, and textbooks. RESULTS: Two major complications associated with the use of halothane, cardiac arrhythmias and the risk of hepatotoxicity, were disclosed by the manufacturer when the drug was first introduced to the US market. Reports appeared timely and complete; there was no apparent attempt to conceal or otherwise downplay these risks. CONCLUSION: The process of drug discovery and approval for clinical use has always been a lengthy, complex, and extremely expensive undertaking, with only a small minority of compounds receiving approval. The risk of adverse effects or drug interaction directly impacts commercial viability. In the case of halothane, the manufacturer disclosed major adverse effects, and the drug enjoyed decades of popularity until it was replaced by agents with a better drug profile.

First use of halothane in the United States, C. Ronald Stephen, M.D. (1916-2006).

Anesthesia is one of the most valued discoveries in all of history. Almost immediately after the first public demonstration of ether anesthesia, a search for a better drug began. Ether, despite its flammability, persisted as the primary inhalation agent for over a hundred years. The breakthrough came with the introduction of a non-flammable volatile anesthetic called halothane in 1955. The drug was approved by the FDA in 1958 and quickly became the most commonly used agent in the United States. It was a quantum leap forward in the safety of anesthetic drugs. It became obsolete in 1988 because of hepatotoxicity. Three eminent anesthesiologists: Drs. Abajian of Vermont, Siker of Pittsburgh and Stephen of Duke could have been the first to use halothane in the USA. My review of the documents and writings of the three confirm that Dr. C. Ronald Stephen of Duke University was indeed the first to use and publish on halothane anesthesia in the USA.

The introduction of halothane into clinical practice: the Oxford experience.

This paper reviews the clinical situation in anaesthesia before the introduction of halothane into clinical practice in 1956, emphasising the limitations of agents available at the time. The background to the development of halogenated hydrocarbon compounds as anaesthesia agents is presented, including the involvement of Imperial Chemical Industries in England. The Nuffield Department of Anaesthetics was involved in the clinical trials and the designing and execution of these. The results of their work and the problems encountered are presented.

Postoperative hepatic dysfunction in perspective. 1970.

Postoperative hepatic dysfunction will remain a difficult entity to place in perspective until increased data are obtained from prospective clinical trials. Ideally these data should compare hepatic dysfunction not only to other postoperative complications, both with regard to overall incidence and to mortality, but also to the overall risks of anesthesia and surgery. The contribution of drug-induced hepatic damage to postoperative hepatic dysfunction has remained unsettled since chloroform was first incriminated during the nineteenth century. The drug was condemned in 1912, without any attempt being made to determine the incidence of the so-called delayed chloroform poisoning, with the result that the drug is still in use and the chloroform controversy remains unsettled to this day. The halothane controversy is also unsettled and currently overshadows the former controversy, although academically of no greater importance. Although not an anesthetic, cincophen is another drug about which there is controversy concerning its hepatotoxic potential. Babior and Davidson noted that it was the first drug implicated in hepatic necrosis--presumably with the exception of chloroform--the first report appearing in 1922. In 1941 the Council on Pharmacy and Chemistry of the American Medical Association concluded that the case against cincophen was not proved and that an urgent need existed for controlled clinical studies. Twenty-five years later Babior and Davidson noted that such studies had still not been undertaken and that the situation was the same as it was a quarter of a century earlier. Perhaps the time has come for a prospective, randomized, controlled clinical trial to be undertaken so as to evaluate the hepatotoxicity of one of these drugs. Perhaps an anesthetic agent such as halothane, concerning multiple administrations of which there is currently serious question, would be a suitable choice for such a study. The drug is in wide use today, partly because of evidence of satisfactory death rates following its administration, but also because on the basis of much excellent physiological data--but an almost total lack of any confirmatory epidemiological evidence--it is thought to contribute positively toward a low overall incidence of postoperative morbidity. Perhaps in addition, as a corollary, the time has come when, as attempts to illuminate a well--enunciated problem of this nature--that is, to test a clearly formulated hypothesis--the isolated case report, the collection of isolated case reports, the series of patients reported in the absence of a proven comparable control group, and the uncontrolled survey, should be "laid to rest." At best they provide only additional hypothesis-formulating information. At worst, however, they give increased exposure to a suggestion concerning cause and effect upon which physicians may act to their patients' detriment if the hypothesis ultimately proves to be erroneous. MacMahon et al. have stated that although there is no clear-cut dividing line between descriptive and analytical epidemiology, most epidemiological studies can indeed be classified primarily as either hypothesis-formulating or hypothesis-testing. Just as we have conducted the definitive retrospective hypothesis-testing study--the National Halothane Study--demanded by the "halothane hepatitis" controversy, so must we now move to the final stage of epidemiological investigation (experimental epidemiology) by investigating the effects of multiple administrations of the drug. On this point the National Halothane Study acts more as a hypothesis-formulating study than as a hypothesis-testing study. Hill has noted that statistical problems must be dealt with by the statistical method. (ABSTRACT TRUNCATED)

[Approach to the scientific work of Jaume Raventós (1905-1982)]. / Aproximación a la obra científica de Jaume Raventós (1905-1982).

We analyze the scientific work done by Jaume Raventós (1905-1982) preceded by a brief biographic profile. The work of this Catalonian investigator has been separated into two stages: The first one, called the Barcelona period, is the training phase and comprises three moments: during the first one (1925-1927) the scientific participation of Raventós is still marginal; during the second period (1928-1933) he began to collaborate in large projects with A. Pi Sunyer and F. Doménech Alsina; and during the third period (1932-1934) he developed its own experimental line that culminated with his Doctoral Thesis. The second stage, called the British period, includes all work done during his exile at the United Kingdom. This phase can also be divided into three periods: the first one (1936-1939) took place in Edinburgh and was characterized by a continuation of the scientific line initiated in Barcelona; the second period developed in Manchester (1939-1954) and includes the studies with intravenous barbiturates; the third period (1956-1965) encompasses the last years of Raventós investigative activity which was devoted to the study of fluothane a new volatile anesthetic agent.