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)