Halothane Hepatitis: Fact Or Fallacy* B

7 o 8

HALOTHANE HEPATITIS: FACT OR FALLACY* B. R. SIMPSON, D. PHIL., F.F.A.R.C.S., L. STRUNIN, F.F.A.R.C.S.. AND B. WALTON, F.F.A.R.C.S. Anesthetics Unit The London Hospital London, England

EVEN moderate opinion" 2 has accepted the two reports3 4 of anesthetists ostensibly sensitive to halothane as prima facie evidence for the existence of "halothane hepatitis." Belfrage and his colleagues. reported an anesthetist who became jaundiced and, when anesthetised with halothane two months later, became ill with malaise, fever, myalgia, and abnormal liver function. This patient did not become jaundiced on this occasion; three weeks later his liver-function tests returned to normal. Klatskin and Kimberg4 reported another anesthetist who initially developed jaundice, which was diagnosed as infectious hepatitis. During the following year he had three relapses which appeared to relate to his practice as an anesthetist. When challenged with a suban- esthetic dose of halothane, he developed fever, arthralgia but, again, no jaundice. His liver function returned to normal two weeks later. Although these two reports appear convincing on first inspection we believe that careful scrutiny reveals several points which may cast doubt on the diagnosis of halothane hypersensitivity made in each case. It is known that the air in operating rooms5 and the rubber tubing from anesthetic machines used to administer halothane" contain measurable concentrations of halothane. Therefore, once halothane has been used in an operating area, the anesthetist will be exposed to it even if he does not actually use halothane himself. It is of interest that some anesthetists who have allegedly demonstrated sensitivity to halothane have in fact returned to work and have not demonstrated thereafter evidence of liver dysfunction. The claim is made that they do not administer halothane themselves and are therefore not exposed. The above data, however, would seem to show that they must, in fact, be inhaling small quantities

*Presented at a meeting of the Section on Anesthesia and Resuscitation of the New York Academy of Medicine on November 11, 1972. Bull. N. Y. Acad. Med. HALOTHANE HEPATITIS 7 0 9

TABLE I

Recurrent drug-induced hepatitis Relapse viral hepatitis

Jaundice usual Jaundice rare Hepatitis subsides rapidly Hepatitis 2-3 weeks' duration

of halothane. The history of the anesthetist described by Klatskin and Kimberg reveals several anomalies. In November i962, while at home, he suffered a relapse of liver dysfunction which was apparently pro- voked by physical activity. In January i963 he worked for a full two weeks before the return of his symptoms; further, during the period from January i964 until November I965, he had occasional contact with halothane without evidence of relapse. It is of interest that, although halothane has been detected in the expired air5' 7and blood7 of operating room personnel and that metabolites of halothane have been found in their urine, so few alleged reactions have been reported. Indeed, a survey of causes of death among anesthetists8 showed no evidence of a higher incidence of liver disease, as compared with that of the general population. Babior and Trey9 have suggested that recurrent, drug-induced hepatitis differs from relapsing viral hepatitis as outlined in Table I. It appears clear into which of the categories the two anesthetists described above can be more readily placed! Many factors other than the anesthetic agent may be involved when a patient develops hepatic dysfunction after anesthesia and surgical operation. These include preexisting liver disease or heart failure, con- comitant drug therapy (e.g., antibiotics, diuretics, narcotics, steroids), hypoxia or hypotension, blood transfusion, and severe infection. In such circumstances it is hardly surprising that all anesthetic agents and techniques in common use have been incriminated. Henderson and Gordon'0 have shown that the incidence of postoperative liver damage has risen in the last two decades (Table II). This increase, which has occurred regardless of the anesthetic agents used, is attributed to the increasing complexity of surgical operations and the wider use of blood transfusion and potentially hepatotoxic drugs-other than anesthetic agents. Nevertheless, since halothane was first introduced in 1956,1" a steady trickle of clinical reports has appeared alleging a cause-and-effect

Vol. 49, No. 8, August 1973 7 I 0 B. R. SIMPSON AND OTHERS

TABLE II.-JAUNDICE PER 1,000*

1953-1956 1.1 1960-1963 4.2 Halothane 4.1 N,0 + relaxant 4.1 Cyclopropane 7.4

*Reproduced by permission from Henderson, J. C. and Gordon, R. A.: Canad. Anesth. Soc. J. 11:453-59, 1964. relation between halothane and postoperative liver damage. These reports led to a number of retrospective surveys, the largest of which was the United States National Halothane Study.12 This study reviewed retrospectively the incidence of fatal massive hepatic necrosis occurring within six weeks of anesthesia in some 85o,ooo patients undergoing operation in 34 institutions. Of these, about 25o,ooo had received halothane. Eighty-two cases of massive hepatic necrosis were recorded. All but nine of these, however, were considered by the panel of experts to be explicable by factors other than the anesthetic agent. Seven of the nine "unexplained" cases had received halothane, and four of these had previously received the agent within six weeks of the final surgical procedure. However, four of the seven cases had previously been pub- lished, and two others were known to the participating institutions before the study began. Thus this extensive review elicited only one new case of massive hepatic necrosis associated with halothane. The over-all incidence of massive hepatic necrosis in this study was approximately one in io,ooo. This statistic is often misquoted as the incidence of halothane hepatitis;13 however, at worst, the true incidence of massive hepatic necrosis associated with halothane was seven of 250,000 or about one in 35,ooo. Further, the preexisting knowledge of six of the seven cases may have prejudiced the validity of this statistic. Halothane is now administered in 70 to 90% of all anesthetics in those countries where it is freely available.14 Since hepatic damage after surgical operation and anesthesia is increasing, it is not surprising that, in spite of the reassurance of the early reviews and clinical reports, further studies, reviews, and leading articles have attempted to link the administration of halothane-particularly multiple administration-with

Bull. N. Y. Acad. Med. HALOTHANE HEPATITIS I I HALOTHANE HEPATITIS 7

liver dysfunction. It is difficult to place the data from some of these studies in perspective. For example, Trey and his colleagues", 16 did not relate the number of patients who died with massive hepatic necrosis to the total number of patients who received halothane. Several of the surveys depend on second-hand information, and the risk inherent in relying on such reports is exemplified by a recent paper entitled "He- patic Necrosis Associated with Halothane Anesthesia";17 perusal of the case histories in this paper reveals that two of eight patients quoted did not in fact receive halothane. A small series of patients subjected to multiple halothane anesthetics for radium treatment of carcinoma of the cervix uteri was reviewed by Hughes and Powell,18 who described an incidence of severe liver damage greater than 2%. However, if this high incidence in fact had been related to the administration of halothane, one would have expected similar findings from other centers, since thus far halothane has been part of more than 50 million anesthetics. Sharpstone and his colleagues's reported a series of i i cases of postoperative jaundice in which nine patients had unexplained fever and three had jaundice after previous halothane administration. All the patients became jaundiced after further administration of halothane, and six died of massive hepatic necrosis. Halothane was thought to be re- sponsible, although five of the patients had malignant disease, one had cholelithiasis with a subphrenic abscess, and one had cirrhosis of the liver. It is of particular interest that no less than five of the I I cases described were suffering from malignant disease-as were at least five of the I cases of liver dysfunction following halothane anaesthesia investigated by Paronetto and PoppeP20-as hepatitis is aggravated by a reduction in the immune responses such as occurs with malignancy.21' 22 Further, Park et al.,23 using the lymphocyte transformation test as an index of the immune response following anesthesia and surgery, have demonstrated that the "normal" inhibition of immune responses following anesthesia and operation is particularly protracted in patients with malignant disease. Subsequent information has cast doubt on the validity of one of the cases in this report.'9 Two weeks before his first anesthetic, the patient had the clinical laboratory investigations outlined in Table III. Although caution is necessary, of course, in interpreting these results in a patient with pyrexia of unknown origin, when that patient subse-

Vol. 49, No. 8, August 1973 SIMPSON AND R. OTHERS 7712I 2 B. R. SIMPSON

TABLE III. PREOPERATIVE LABORATORY RESULTS

W.B.C. 19,000 E.S.R. 59 mm./hr. ZnSO, turbidity 5 units Alk. phosphatase 84 int. KA units/liter [20-90] Asp. aminotransferase 23 I.U./liter [2-20] Al. aminotransferase 28 I.U./liter [4.5-17] Total protein 8.6 Albumin 4.4 Globulin 4.2

Figures in brackets refer to the normal ranges for the laboratory concerned. quently died with hepatic failure, it is difficult to justify the statement that "liver function had been normal before the first anesthetic." The view that unexplained postoperative fever after halothane should preclude its subsequent use (a point initially made as part of the caveat issued by the panel of the National Halothane Study)12 is supported by Sharpstone and his colleagues.' Trey and his colleagues' 16 showed, however, that postoperative fever is as common after the use of other anesthetic agents as it is after halothane, and this was confirmed by Dykes,24 who described a variety of postoperative temperature patterns regardless of the anesthetic agent used. Further, as part of a nationwide survey of postoperative jaundice at present being undertaken by the Anesthetics Unit at the London Hospital, a variety of postoperative temperature patterns after previous halothane exposures has been found (Table IV). It may be seen that pyrexias of unknown origin following the previous halothane exposure are as common among cases where the cause of the jaundice is clear (e.g., gallstones, massive hemol- ysis), as among cases where the cause of the jaundice is unexplained,

TABLE IV. PATTERNS OF PYREXIA AFTER PENULTIMATE ANESTHESIA

Cause of Apyrexial "Normal" Pyrexia Pyrexia jaundice postop. cause unknown pyrexia apparent origin

Patients with multiple Clear [12] 4 2 3 3 halothane exposures Unexplained [39] 16 5 8 10

Figures in brackets refer to total numbers in each group. Bull. N. Y. Acad. Med. HALOTHANE HEPATITIS HALOTHANE HEPATITIS 7137 I 3 and halothane may thus be involved. In addition, it is of interest that some 40% of the "unexplained cases" were apyrexial after their previous exposure. Although the National Halothane Study showed that the great ma- ority of cases of massive hepatic necrosis were attributable to causes other than the anesthetic agent, there remains a small number of cases for whom no adequate explanation exists. Two groups of patients give cause for concern: overweight, middle-aged patients and patients subjected to multiple exposures to anesthesia, often for minor surgical procedures. The latter concern was recently strengthened by Mushin and his colleagues,14 who reported evidence which ostensibly showed that patients receiving two halothane anesthetics within a month are more likely to develop postoperative hepatic dysfunction. These investigators reported a statistical comparison of three groups of patients-a control group of surgical patients, 54 patients reported to the Committee on Safety of Drugs (which collects reports of adverse reactions to drugs within the United Kingdom) during the period I964-1969, and 74 patients from the literature. The latter two groups were made up of patients who had become jaundiced after multiple halothane anesthetics and, within these groups, there was an apparent excess of patients who had had two anesthetics within one month. Mushin and his colleagues concluded that "halothane should, if possible be avoided in patients who have had it before, particularly if this was within the previous four weeks." This study was based on the hypothesis that halothane hepatitis is a sensitization phenomenon; therefore no clinical details of the patients were provided. It is important to note that all cases of jaundice associated with halothane reported to the Committee on Safety of Drugs were included. The crux of the matter is, however, whether the jaundice in these cases was unexplained. The National Halothane Study12 reported 82 cases of fatal postoperative massive hepatic necrosis, but in only nine of these did the panel of experts decide that no alternative adequate explanation existed other than the anesthesia. These data sug- gest that only some io% of postoperative liver damage is likely to be attributable to the anesthetic agent. Similarly, in our own study, the jaundice in many cases investigated may well have been due to factors other than the anesthetic agent. It is unlikely, therefore, that all the cases reported to the Committee on Safety of Drugs were in fact un-

Vol. 49, No. 8, August 1973 7147 I 4 B. R. SIMPSON AND OTHERS

TABLE V. CRUDE OVER-ALL POSTOPERATIVE DEATH RATES PER 10,000

Operation No previous Previous Previous general anesthesia nonhalothane halothane

Low death rate 18 82 84 Mid death rate 193 461 431 High death rate 868 1,354 1,183 explained, and the apparent excess figure of 68%14 of the total cases of jaundice reported to the committee or who became jaundiced after two operations within a month-with an alleged cause-and-effect relation with halothane-should be considerably reduced. In addition, the two groups of patients reported to the committee and collected from the literature were limited to anesthetics repeated within IO years; it is therefore misleading to include in the calculations the 230% of the control group who received their penultimate anesthetic more than io years previously. Recalculation shows that 13 % of the control group, and not the 7% stated,14 received two anesthetics within one month. Thus the apparent excess of patients who became jaundiced after two operations within a month, with an alleged cause-and-effect relation with halothane, may not exist. However, the high incidence of jaundice after operations repeated within a month remains a matter of concern. It is of interest therefore that a finding from the National Halothane Study12 demonstrates that repeated low-risk operations have an unex- pectedly high mortality, regardless of the anesthetic agents used (Table V). Klatskin25 has listed the criteria which should be fulfilled by a drug if it is to be considered a direct hepatotoxin. These are summarized in Table VI. Halothane clearly fulfills none of these criteria. In recent times, therefore, controversy about halothane hepatitis has centered on four main themes: first, hypersensitivity to halothane; second, hypersensitivity to a macromolecule consisting of some hypothetical metabolite of halothane combined with a protein complex; third, hepatotoxicity of a halothane metabolite and, fourth, claims that halothane hepatitis can be differentiated from viral hepatitis. The postulate of hypersensitivity to halothane has been advanced on the triad of clinical stigmata, the presence of antimitochondrial anti-

Bull. N. Y. Acad. Med. HALOTHANE HEPATITIS 7 I 5 HALOTHANEHEPATITIS 715~~~~~~~~~~~~~~~

TABLE VI. CRITERIA FOR HEPATOTOXICITY OF A DRUG

The lesions: 1) Exhibit a distinctive histological pattern 2) Vary in severity in direct relation to the dose 3) Can be elicited in all individuals 4) Are reproducible in animals 5) Appear after a predictable and usually brief latent period following exposure bodies,26 and the demonstration of lymphocyte transformation by halothane in patients with postoperative liver dysfunction.20 As evidence of clinical stigmata, Doniach27 quotes reports of "leukocytosis with eosinophilia, joint pains, rashes and bronchospasm . . . and in two cases abnormal lymphocytes similar to those seen in infectious mononucleosis have been noted in the peripheral blood." Halothane has been administered more than 50 million times. Might it not be reasonable to expect more than two cases with abnormal lymphocytes if the relation had been anything more than coincidental? References to joint pains, rashes, and bronchospasm are rare indeed, and may have many causes. Further, eosinophilia was not found in any of the i i cases reported by Sharp- stone and his colleagues.'9 Sherlock28 includes malaise, fever, transient arthralgias, and rashes amongst the prodromal features of viral hepatitis, and it has been estimated that some 200 to 3oo patients each year are likely to be subjected to anesthesia while incubating viral hepatitis.29 Certainly the features mentioned by Doniach27 have been reported occa- sionally in association with liver damage after halothane anesthesia, but is their relation correlated or merely casual? Antimitochondrial antibodies are found in a wide variety of liver diseases: e.g., primary biliary cirrhosis, active chronic hepatitis, crypto- genic cirrhosis, and chlordiazepoxide jaundice. It is possible that antimitochondrial antibodies may reflect an autoimmune response to liver damage, the implication being that liver damage releases tissue-specific antigen to which the subject may not have acquired full immunological tolerance. The initial report by Paronetto and Popper20 of positive in vitro lymphocyte transformation in the presence of halothane in some patients with alleged halothane hepatitis has already been criticized.30 As part of our study of postoperative jaundice we have repeated these tests on

Vol. 49, No. 8, August 1973 7 I 6 B. R. SIMPSON AND OTHERS patients and physicians from our survey, whose histories have left us with the opinion that there was a high index of suspicion that halothane might be invclved in the etiology of their hepatic dysfunction.3 The responses obtained from our patients and physicians were not signifi- cantly different from the results obtained from a control group. Thus there is no evidence from this data to support the existence of cell- mediated hypersensitivity to halothane in our subjects, and the previous work20 has not been confirmed. Before discussing the second and third postulates, a brief review will be presented of the new information which has become available on the metabolism of halothane. Seventy-five to eighty per cent of halothane is expired unchanged from the lungs. Trifluoroacetic acid (TFA) is the major metabolite in the liver, and recently a second minor metabolite, trifluoroacetyl ethanolamide (TFAET), has been identified.32 33 The strong carbon-fluorine bond has been confirmed. Winrow and his colleagues33 have recovered TFAET from mice dosed with TFA. Top- ham and Longshaw,34 in rats and dogs, and Strunin and his colleagues,35 in the isolated canine-liver-perfusion preparation, have demonstrated a progressive rise in unchanged halothane in bile during administration of halothane. TFA is present unconjugated in bile-despite its small molecular weight-but neither TFAET nor other polar metabolites have been demonstrated in bile. TFA undergoes enterohepatic recirculation, which explains its long half-life in liver. The major urinary metabolite is TFA, with TFAET also present in small amounts. On the basis of chemical theory it has been suggested that trifluoroethanol (TFE) and trifluoro- acetaldehyde (TF aldehyde) are possible intermediate metabolites. These substances, however, have not been identified in the rat, mouse, guinea pig, cat, dog, marmoset, or man. Turning, then, to the second postulate: that is, hypersensitivity to a halothane metabolite, Cohen32 recently found two unidentified metabolites of high molecular weight in liver and argued that these could not be TFA or TFE because they were still present after heating the liver to dryness, and the boiling point of both these materials are volatile. Since then, however, Winrow and his colleagues33 deduced that at a pH of about seven, TFA would be present in liver as a nonvolatile acid salt. Appropriate extraction and recovery procedures by these workers has demonstrated these metabolites to be salts of TFA and TFAET. It is generally accepted that polar, low-molecular-weight compounds

Bull. N. Y. Acad. Med. HALOTHANE HEPATITIS 7 I 7 -~~~~~AOHN HEAII 1 may give misleading results on Sephadex columns. Rodriguez and his colleagues2" demonstrated antimitochondrial antibodies in cases of alleged halothane hepatitis and postulated that a metabolite of halothane might form a stable complex with mitochondria. Schumer and his colleagues,36 however, showed that halothane was not preferentially taken up by mitochondrial fractions of liver cells. There is, therefore, little supporting evidence for hypersensitivity to a halothane metabolite. Let us turn now to the third postulate: that is, hepatotoxicity of a metabolite of halothane. If the causal agent were a normal metabolite it would be produced consistently and should fulfill the criteria laid down for a hepatotoxin. It may well be that the concept of a hepatotoxin as defined by Klatskin (Table VI) is outmoded. For example, chloroform and carbon tetrachloride do not produce consistent dose- dependent damage. With both drugs, however, liver damage can be enhanced by pretreatment with enzyme-inducing agents and inhibited by enzyme inhibitors. 37, 38 No such pattern has been established for halothane. On the other hand, if an abnormal metabolite were involved one might expect a genetic or familial link to have been established- as with malignant hyperpyrexia-but none has been shown. The two major products of metabolism of halothane, TFA and TFAET, are non- toxic. The lethal dose of each is in excess of 2 gr./kg. orally in rats and, when death occurs, the liver is not primarily involved. Further, the pattern of metabolism does not vary from species to species. There is therefore little supporting evidence at present for hepatoxicity of halothane metabolites. Sherlock39 has claimed that halothane hepatitis can be differentiated from viral hepatitis on clinical, immunological, and morbid anatomical grounds. We have already dealt with the clinical and immunological aspects. The morbid anatomical differentiation appears to depend for recognition on "the experience of the pathologist," and it must be stressed that no pathologist or group of pathologists has attempted to differentiate halothane hepatitis from viral hepatitis without prior knowledge of the histories of the patients concerned. It is of further interest that authorities in the field of electron microscopy fail to agree on the expected findings in halothane hepatitis.4042 It would appear, therefore, that there is little justification at the present time for the statement that halothane hepatitis can be differentiated from viral hepatitis.

Vol. 49, No. 8, August 1973 B. R. AND OTHERS 7187 I 8 SIMPSON OTHERS

Let us now consider the evidence for an alternative hypothesis for postoperative jaundice. The incidence of viral hepatitis is unknown but increasing.43 It is thought to be affecting an older-age group; 800 of the patients reported by Harville and Summerskill'1 were over 40 years of age. As mentioned above, this age group seems particularly susceptible to jaundice after anesthesia and surgery. The ratio of overt to subclin- ical cases of viral hepatitis may be as high as 1 2: I,44 and it has been estimated that in the United States alone some 200 to 300 patients each year are likely to be submitted to anesthesia while incubating viral hepatitis.2 It is now known that for both infectious and serum hepatitis oral or parenteral transmission is possible, and virus can be spread by naso- pharyngeal secretions4' and excreta.46 Hepatitis-associated antigen (HAA) relates only to serum (long-incubation) hepatitis.47 Further, hepatitis may occur without antigen,48 antigen may only be found trans- iently,49 the antigen may be bound by antibody,49 and subspecies of HAA may not react with the antiserum.49 A negative test for HAA does not therefore exclude serum hepatitis. Recently developed radioimmunoassay tests for HAA are considerably more sensitive, and Lander and his colleagues50 have shown that some i0 to 150% of the normal population in the United States have HAA antibodies in their serum. On the basis of a series, as: yet small, of investigations in Eng- land, Zuckerman5" expects that comparable figures will pertain. No established test for infectious hepatitis exists and other viruses may also cause hepatitis. It could be argued therefore that viral hepatitis cannot at present be excluded in any patient who develops jaundice after anesthesia and operation.

SUMMARY At present, therefore, there is no evidence to support the concept of a cause-and-effect relation between halothane and postoperative jaundice after either single or multiple exposures. On the other hand, it is not possible to make a firm and categorical statement to the effect that halothane, as with any other anesthetic agent, is never primarily involved when postoperative jaundice occurs. Viral hepatitis cannot at present be ruled out in any individual case. Evidence suggests that the risks of postoperative liver damage, in common with the risk of death, rises precipitously if two exposures to anes-

Bull. N. Y. Acad. Med. HALOTHANE HEPATITIS 7 I 9

thesia and operation occur within a short period, regardless of the anesthetic agent used. This may relate to the known depression of immune responses engendered by exposure to halothane anesthesia and surgery. In light of this, how does one answer the question: "What anesthetic should be used in a patient who had a pyrexia of unknown origin or liver damage following a previous operation?" Operations of election should be postponed in order to lengthen the interval between the two periods of nonspecific stress. If an operation cannot be postponed there is no logical reason for not using halothane. However, it is not possible to state categorically that if further halothane or any other agent is used in these circumstances postoperative liver damage will not occur. Fur- ther, if liver damage does occur it will not be possible to state categorically that the anesthetic agent was culpable. The choice of anesthesia must be in the best over-all interests of the patient, and further detailed accurate information is required about cases of liver dysfunction following surgery and anaesthesia before the mechanisms involved can be elucidated further.

REFER E N C E S 1. Dykes, M. H. M., Gilbert, J. P., and 8. Bruce, D. L., Eide, K. A., Linde, H. McPeek, B.: Halothane in the United W., and Eckenhoff, J. E.: Causes of States. Brit. J. Anaesth. 44:925, 1972. death among anesthesiologists: 20 year 2. Little, D. M.: Editorial comment. Sur- survey. Anesthesiology 29:565, 1968. vey Anesth. 16:449, 1972. 9. Babior, B. M. and Trey, C.: In: Anaes- 3. Belfrage, S., Ahlgren, I., and Axelson, thesia and the Liver, Dykes, M. H. M., S.: Halothane hepatitis in an anaesthe- editor. Little, Brown, Boston, 1970, p. tist. Lancet 2:1466, 1966. 337. 4. Klatskin, G. and Kimberg, D. V.: Re- 10. Henderson, J. C. and Gordon, R. A. The current hepatitis attributable to halo- incidence of postoperative jaundice with thane sensitisation in an anaesthetist. special reference to halothane. Canad. New Eng. J. Med. 280:515, 1969. Anaesth. Soc. J. 11:453, 1964. 5. Linde, H. W. and Bruce, D. L.: Occu- 11. Raventos, J.: The action of Fluothane, pational exposure of anaesthetists to a new volatile anaesthetic. Brit. J. halothane, nitrous oxide and radiation. Pharmacol. 11:394, 1956. Anesthesiology 30:363, 1969. 12. Bunker, J. P., Forrest, W. H., Mostel- 6. Dykes, M. H. M. and Laasberg, L. H.: ler, F., and Vandam, L. D.: The Na- Clinical implications of halothane con- tional Halothane Study. A Study of the tamination of the anesthetic circle. Possible Association Between Anes- Anesthesiology 35:648, 1971. thesia and Postoperative Hepatic Ne- 7. Hallen, et al.: Measurement of halo- crosis. Washington, D.C., Govt. Print. thane in the atmosphere of operating Off., 1944. theatres and in the expired air and 13. Byrd, B. F., Rollin, A. D., and Va- blood of the personnel during routine sudeo, P.: Serious sequelae of general anaesthetic work. Acta Anesth. Scand. anaesthesia. Ann. Surg. 175:673, 1972. 14:17, 1970. 14. Mushin, W. W., Rosen, M., and Jones,

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E. V.: Post-halothane jaundice in rela- 27. Doniach, D.: Cell-mediated immunity in tion to previous administration of halo- halothane hypersensitivity. New Eng. J. thane. Brit. Med. J. 1:18, 1971. Med. 283:277, 1970. 15. Trey, C., Lipworth, L., Chalmers, T. C., 28. Sherlock, S.: Diseases of the Liver and Davidson, C. S., Gotlieb, L. S., Popper, Biliary Systems. Oxford & Edinburgh, H., and Saunders, S. J.: Fulminant Blackwell, 1968. hepatic failure presumable contribution 29. Dykes, M. H. M. and Bunker, J. P.: of halothane. New Eng. J. Med. 279: Hepatotoxicity and anaesthestics. Phar- 798, 1968. macol. Phys. 4:1, 1970. 16. Trey, C., Lipworth, L., and Davidson, 30. Bruce, D. L. and Raymon, F.: Test for C. S.: Clinical syndrome of halothane halothane sensitivity. New Eng. J. Med. hepatitis. Anesth. Analg. (Cleveland) 286:1218, 1972. 48:1033, 1969. 31. Walton, B., Dumonde, D. C., Williams, 17. Peters, R. L., Edmondson, H. A., Reyn- C., Jones, D., Strunin, J. M., Layton, J., olds, T. B., Meister, J. C., and Cur- Strunin, L., and Simpson, B. R.: Fail- phey, T. J.: Hepatic necrosis associated ure to demonstrate increased lympho- with halothane anaesthesia. Amer. J. cyte transformation in patients with Med. 47:748, 1969. postoperative jaundice and physicians 18. Hughes, M. and Powell, L. W.: Recur- with alleged halothane hypersensitivity. rent hepatitis in patients receiving J.A.M.A. In press. multiple halothane anaestheties for ra- 32. Cohen, E. N. and Hood, N.: Applica- dium treatment of carcinoma of the tion of low temperature autoradiogra- cervix uteri. Gastroenterology 58:790, phy to studies of the uptake and me- 1970. tabolism of volatile anaesthetics in the 19. Sharpstone, P., Medley, D. R. R., and mouse. III. Halothane. Anesthesiology Williams, R.: Halothane hepatitis-a 31:553, 1969. preventable disease? Brit. Med. J. 1: 33. Winrow, M. and Topham, J.: Unpub- 448, 1971. lished data. 20. Paronetto, F. and Popper, H.: Halo- 34. Topham, J. and Longshaw, S.: Studies thane hepatitis. New Eng. J. Med. 283: with halothane. I: Distribution and ex- 277, 1970. cretion of halothane metabolites in ani- 21. Harville, D. D. and Summerskill, W. mals. Anesthesiology 35:388, 1968. H. J.: Surgery in acute hepatitis. 35. Strunin, L., Strunin, J. M., and Simp- J.A.M.A. 184:257, 1963. son, B. R.: Unpublished data. 22. Fenster, L. F.: Viral hepatitis in the 36. Schumer, W., Erve, P. R., Obernolte, elderly. An analysis of 23 patients over R. P., Bombeck, D. T., and Sadove, 65 years of age. Gastroenterology 49: M. S.: The effect of inhalation of halo- 262, 1965. genated anaesthetics on rat liver mito- 23. Park, S. K., Wallace, H. A., Brody, J., chondrial function. Anesthesiology 35: and Blakemore, W. S.: Immunosup- 253, 1971. pressive effect of surgery. Lancet 1:53, 37. Brodie, B. V., Cho, A. K., Krishna, G., 1971. and Reid, W. D.: Drug metabolism in 24. Dykes, M. H. M.: Unexplained post- man: Past, present and future. Ann. operative fever. Its value as a sign of N.Y. Acad. Sci. 179:11, 1971. halothane sensitisation. J.A.M.A. 216: 38. Scholler, K. L.: Modification of the ef- 641, 1971. fects of chloroform on the rat liver. 25. Klatskin, G.: In: Diseases of the Liver, Brit. J. Anaesth. 42:603, 1970. Schiff, L., editor. Philadelphia, Lippin- 39. Sherlock, S.: Halothane hepatitis. Gut. cott, 1969, p. 498. 12:324, 1971. 26. Rodriguez, M., Paronetto, F., Schaffner, 40. Klion, F. M., Schaffner, F., and Pop- F., and Popper, H.: Antimitochondrial per, H.: Hepatitis after exposure to antibodies in jaundice following drug halothane. Ann. Intern. Med. 71:467, administration. J.A.M.A. 208:148, 1969. 1969.

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41. Keeley, A. F., Trey, C., Marcon, N., antigen. Tentative considerations of the Iseri, 0. A., and Gottlieb, L.S.: Anic- clinical and public-health aspects. New teric halothane hepatitis: Histologic Eng. J. Med. 285:987, 1971. and ultrastructural lesion associated 47. Prince, A. M., Hargrove, R. L., Szmu- with postoperative fever in two pa- ness, W., Cherubim, C. E., Fontana, tients. Gastroenterology 58:967, 1970. V. J., and Jeffries, G. H.: Immunologi- 42. Uzunalimoglu, B., Yardley, J. H., and cal distinction between infectious and Boitnott, J. K.: The liver and mild serum hepatitis. New Eng. J. Med. 282: halothane hepatitis. Amer. J. Path. 61: 987, 1970. 457, 1970. 48. Blumberg, B. S., Sutnick, A. I., and 43. McCollum, R. W.: Epidemiologic pat- London, W.: Australia antigen as a terns of viral hepatitis. Amer. J. Med. hepatitis virus. Amer. J. Med. 48:1, 32:657, 1962. 1970. 44. Eisenstein, A. B., Aach, R. A., Jacob- 49. Editorial: More about Australia anti- sohn, W., and Goldman, A.: An epidem- gen and hepatitis. Lancet 2:347, 1970. ic of infectious hepatitis in a general 50. Lander, J. J., Alter, H. J., and Purcell, hospital. J.A .M.A. 185:171, 1963. R. H.: Frequency of antibody to hepa- 45. Krugman, S. and Giles, J. P.: Viral titis-associated antigen as measured by hepatitis. J.A.M.A. 212:1019, 1970. a new radioimmunoassay technique. J. 46. Chalmers, T. C. and Alter, H. J.: Man- Immunol. 106:1166, 1971. agement of the asymptomatic carrier 51. Zuckerman, A. J.: Personal communica- of the hepatitis-associated (Australia) tion, 1972.

Vol. 49, No. 8, August 1973