Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
CHAPTER I-I. INTRODUCTION John P. Bunker Stanford University School of Medicine Palo Alto, California BACKGROUND OF THE STUDY After extensive laboratory investigation, halothane (Fluothane), 2-bromo-2-chloro-1,1,l- trifluoroethane, was introduced to clinical anesthesia in England in 1956 and in the United States in 1958. Careful consideration had been given to the possibility that halothane, in common with many other halogenated compounds, might damage the liver, but in its early years of use it appeared to have an impressive record of safety. Studies of hepatic function in the experimental animal and in man gave no indication of halothane- induced hepatic damage. However, isolated re- ports of massive hepatic necrosis after halothane anesthesia soon appeared and suggested the need for further investigation. In December 1961, the Committee on Anesthesia of the National Academy of Sciences-National Research Council desig- nated a study group to report periodically on all clinical aspects of halothane anesthesia, and to give special attention to any evidence of associa- tion with fatal postoperative hepatic necrosis. In October 1962, a subcommittee of three was appointed to make recommendations on the need for and the feasibility of a clinical study of the relationship of halothane anesthesia to hepatic necrosis. The subcommittee found the evidence in- sufficient to establish or refute a causal relation- ship between halothane and postoperative hepatic damage. Postoperative mortality from all causes was estimated at approximately 2 percent, but the number of deaths attributable to massive hepatic necrosis was thought to be very small, perhaps one in 10,000 operations. No data were available on the incidence of hepatic necrosis in patients receiving other anesthetic agents or on the role of pre-existing hepatic disease, viral hepatitis, or prolonged operative shock as etio- logic factors in postoperative hepatic failure. For these reasons, preliminary plans for a randomized clinical trial were drawn up and a pilot study was begun in one medical center. In May 1963, a drug warning was issued by the manufacturer on the basis of 12 new cases of fatal hepatic necrosis that followed surgical pro- cedures in which halothane was used; several of the deaths followed cholecystectomy. The warning stated that "the administration of halothane to patients with known liver or biliary tract disease is not recommended." In the same month the NAS-NRC Subcommittee on the National Halo- thane Study was appointed, its members repre- senting anesthesiology, statistics, internal medicine, pathology, and surgery. The National Halothane Study was initiated in June 1963 with funds provided by the National Institute of Gen- eral Medical Sciences. It was recognized at the outset that the Study would be large and difficult, but it was agreed that halothane was a drug of enough potential value to justify the most careful examination of its imputed risk, as well as its over-all safety. Before the Subcommittee completed its plans for a cooperative study, several additional cases of hepatic necrosis were reported. Some in- stitutions had begun to restrict the use of halo- thane to a few specific indications, but most potential collaborators probably would have cooperated in a randomized trial, and they did continue to use halothane during the course of the National Halothane Study. Thus, the ethical issue might not have been an overriding factor if the clinical trial had seemed the only way of obtaining data on which to base an inference. Considerations of feasibility and effort, however, strongly favored the retrospective survey as a first step and one that might make a large clinical trial unnecessary. The plans for a clinical trial were discontinued in favor of a survey of experience in the years before the issue of hepatotoxicity had been seriously raised. Fifty-four medical centers volunteered to participate in the collaborative retrospective study. When provided with the exacting require- ments of the proposed protocol, 16 of them, in view of limitations of personnel and problems in record retrieval, decided against participation. The protocol was tested and refined in a pilot study of the December 1962 records of the re- maining 38 institutions. Three withdrew, and 35 contributed data on the 4-year period 1959 through 1962; 34 met the requirements of the protocol and their data constitute the basis of this report. OBJECTIVES OF THE STUDY The primary objective of the Study was to compare halothane with other general anesthetics regarding incidence of fatal massive hepatic necrosis within 6 weeks of anesthesia. An equally important objective was a comparison regarding total hospital mortality within 6 weeks of anes- thesia, because it was recognized that, even if halothane were responsible for death from
hepatic necrosis more often than other anes- thetics, the incidence would probably be small compared with an estimated over-all operative mortality of approximately 2 percent. Indeed, a slight superiority in over-all mortality for halothane could well outweigh any excess of deaths resulting from massive hepatic necrosis. GENERAL SCOPE OF THE STUDY It was anticipated that the incidence of fatal massive hepatic necrosis could be very small, and that differences among anesthetics in their effect on total mortality might also be small. If death rates are about 2 percent and it is desired to detect differences measured in tenths of 1 percent, then it is necessary to take a sample large enough to include many thousands of deaths. The experience of one million operations ap- peared to constitute a study of appropriate size. To bring so large a body of experience under scrutiny, it was necessary to obtain data from a large number of hospitals for a period of several years. A 4-year period was chosen, and the participation of many hospitals served to broaden the medical experience on which any conclusions ultimately would be based. Because it was in 1963 that several new reports of massive hepatic necrosis after halothane anesthesia precipitated widespread concern, and because that concern may well have influenced the selection of anes- thetics from then on, the survey was limited to the 4-year period 1959 through 1962. The protocol was designed to generate the data summarized briefly below and presented in detail in Part II. Deaths To determine the number of deaths, the protocol required each hospital to report post- operative deaths that occurred in the hospital within 6 weeks of general anesthesia, and to abstract the case records, categorizing them by the anesthetic agents used at the patients' last operations. Population Sample To provide information on the population of patients from which the deaths were gathered, each hospital was required to report the number of administrations of general anesthesia in the survey period, categorized by anesthetic agents, and to abstract the records for a randomly selected sample of these cases. Death Rates The information on deaths and population sample was used to calculate crude death rates for the different anesthetic agents and to adjust them for differences in type of operation and such other variables as age, sex, and preopera- tive physical status. Massive Hepatic Necrosis Each death that was thought to represent massive hepatic necrosis was reported and a photocopy of the patient's chart and sections of hepatic tissue were submitted for review by an invited panel of six pathologists with a special interest in hepatic disorders. The protocol pro- vided that members of the panel of pathologists should independently: (1) describe the morpholo- gic features in each tissue section submitted and estimate the degree of necrosis without knowl- edge of the anesthetic agent or the clinical his- tory; and then (2) review an abstract of the clinical history, again with the anesthetic agent unknown, and express an opinion as to the pos- sible etiology of the microscopic lesion. Monthly Reports The protocol required that the participating institutions provide for each month: (1) a count of the total number of cases of general anesthesia of all types; (2) for the random sample of general anes- thetics, a list of individual cases giving the chart number and date of operation for each; (3) a list of all hospital deaths occurring within 6 weeks of the administration of a general anesthetic, including the patients' chart numbers and dates of deaths; (4) coded abstracts of the clinical records of all patients who died within 6 weeks of general anesthesia and of those identified in the random sample, including chart number, age, sex, date of discharge or death, whether necropsy was performed, whether massive hepatic necrosis was described at necropsy or given as a clinical diagnosis, cause of death, other clinical diag- noses, anesthetic agents used, physical status (evaluated preoperatively), duration of anesthesia, operations in the previous 4 years (100 two-digit operation codes were provided for coding operative procedures), and previous exposure to halothane; (5) a list of final diagnoses for each ab- stracted death that was necropsied; and (6) photostatic copies of the relevant por- tions of the clinical record and blocks or slides of hepatic tissue from each case with indications of massive hepatic necrosis, possible massive hepatic necrosis, or hepatitis.
CHAPTER I-2. PHARMACOLOGY OF HALOTHANE S. H. Ngai Columbia University, College of Physicians and Surgeons, and Presbyterian Hospital, New York, New York This chapter offers a brief summary of the pertinent pharmacologic features of halothane. In certain areas our knowledge is not definitive or complete in spite of a large volume of reports. Moreover, clinical attributes of halothane are not always clearly defined, in that they can be influenced by the manner in which it is admin- istered and by the physical status of the patient. More detailed information is available in several reviews and monographs, for example, those by Johnstone (29), Stephen and Little (65), Sadove and Wallace (55), Papper and Kitz (47), Ngai (42), Price and Cohen (48), and Severing- haus and Larson (63). PHYSICAL AND CHEMICAL PROPERTIES Halothane (2-bromo-2-chloro-1,1,l-trifluo- roethane; Fluothane) is a heavy, colorless, and volatile liquid with a molecular weight of 197, a boiling point of 50.2 C, and a vapor pressure at 20 C of 243 mm Hg. Thymol (0.01 wt percent) is added to the liquid as a stabilizer. When stored in tinted glass containers or in clinical vapor- izers and protected from light, halothane is stable and degradation products are not found even after long periods. Before 1965, commer- cial halothane contained certain impurities in trace amounts, largely in the form of trans- and cis-dichlorohexafluorobutene, 0.01 to 0.02 vol percent (10). This contaminant is one of the by- products of the manufacturing process. Since early 1965, it and other impurities have been largely eliminated from commercial halothane (54). The possible hepatotoxicity of contaminants is discussed in Part V of this report. Halothane has a not unpleasant, oleaginous, sweetish odor. Mixtures of its vapor and oxygen are nonflammable in all proportions. However, in direct contact with open flame or spark, the compound is broken down to noxious products, such as phosgene. Halothane is compatible with all other anesthetics and with the commonly used carbon dioxide absorbents, such as Baralyme and soda lime. It causes deterioration of rubber and plastic materials; the vaporizers used for clini- cal administration, however, are made of re- sistant materials. SOLUBILITY COEFFICIENTS, UPTAKE, DISTRIBUTION, AND ELIMINATION Halothane has the following solubility co- efficients at 36 C (Oswald): blood/gas, 2.3; brain/blood, 2.6; liver /blood, 2.6; kidney/blood, 1.6; muscle/blood, 3.5; and fat/blood, 60 (32). The blood/gas solubility coefficient is higher than those of anesthetic gases (ethylene, cyclo- propane, and nitrous oxide) and lower than those of other anesthetic vapors (trichloroethylene, chloroform, methoxyflurane, and diethyl ether). Halothane is highly soluble in fat. Its oil/gas solubility coefficient (224) is exceeded only by those of chloroform (265), methoxyflurane (825), and trichloroethylene (960). Therefore, according to the principles that determine the uptake of inert gases by the body, during inhalation of halothane vapor equilibration between the in- spired concentration and that in the body should be slower than with anesthetic gases and faster than with other anesthetic vapors. Studies on uptake of halothane in man have confirmed this prediction. An estimated 10 to 12 hr are required to reach 95 percent equilibrium (58). In contrast, 95 percent equi- librium is reached in 10 min with cyclo- propane (52,57). In clinical practice, induction of anesthesia with halothane can be achieved in a few minutes by using the principle of "overpres- sure," i.e., by administering the vapor in a con- centration greater than that required for the maintenance of anesthesia. The vapor concentra- tion is gradually lowered when surgical anes- thesia is produced. During the initial period of inhalation, halo- thane is carried principally to richly vascularized organs and tissues, the brain, heart, liver, kid- neys, and muscles. Because the tissue/blood partition coefficients of these organs are rela- tively low, equilibration with blood occurs rela- tively quickly. As inhalation continues, more and more of the absorbed halothane is taken up by fat, which has a high tissue/blood solubility coefficient and a relatively poor blood supply. The slow and sustained uptake of halothane by fat accounts for the long period required to achieve equilibrium between the inspired mixture and the body as a whole. Complete equilibrium is seldom attained under clinical circumstances.
Elimination of halothane occurs almost completely via the lungs, following the reverse of the uptake pattern. Clearance of halothane from blood and lean tissues occurs promptly; approxi- mately half the halothane in the body is cleared in 20 min. Patients usually recover from halo- thane anesthesia, to the point of responding to auditory stimuli, in 10 to 15 min. Complete clearance, however, requires many hours be- cause of the high solubility in fat. In the experimental animal, halothane labeled with isotopes (i*C or 36 Cl) undergoes metabolic degradation in the body to the extent of 3 to 10 percent, the major products being chloride, bromide, and trifluoracetic acid (68). These findings remain to be confirmed and the metabolic pathways defined. ANESTHETIC CONCENTRATIONS AND TECH- NIQUES OF ADMINISTRATION Halothane is a potent anesthetic capable of producing anesthesia to any depth. Concentra- tions of halothane vapor required to induce and maintain anesthesia depend on several factors, including the physical status of the patient, the degree of sedation from preanesthetic medica- tion, and the conjoint use of other anesthetics and adjunct drugs. In unpremedicated dogs, the minimal anes- thetic concentration in the alveolar air (defined as that necessary to prevent movement in re- sponse to a painful stimulus) is 0.87 percent (18). In healthy patients with adequate preanesthetic sedation, an inspired concentration of 2 to 3 percent of halothane in oxygen produces surgical anesthesia in 10 to 15 min. More rapid induction can be achieved with higher concentrations. This is possible because, unlike diethyl ether, halo- thane does not irritate the respiratory tract to cause cough or laryngospasm. For the same reason and because of its potency and relatively low solubility in blood, constant attention is required during induction with halothane to avoid inadvertent overdosage when using "overpres- sure." One to two percent of halothane vapor in oxygen is required to maintain surgical anes- thesia. The concomitant use of nitrous oxide re- duces the required concentration of halothane in the inspired air. According to Saidman and Eger (56), the alveolar concentration of halothane required to prevent response to a standard stimulus is 0.76 percent when administered with oxygen and 0.2 percent when administered with nitrous oxide (70 to 75 percent) and oxygen. A precision vaporizer is necessary for the safe administration of halothane because of its potency and its high vapor pressure at room temperature. Several such vaporizers have been designed. One type (33) embraces the "drawover" principle. A portion of the carrier gas (oxygen or a mixture of oxygen and another gaseous an- esthetic, such as nitrous oxide) is diverted through a vaporizing chamber. The mixture laden with halothane vapor after dilution is then delivered to the anesthetic circuit. The pro- portion of gas diverted through the vaporizing chamber can be controlled. In addition, a ther- mocompensatory mechanism is provided so that changes in ambient temperature over a wide range will not alter the concentration of halothane vapor delivered. In another type of vaporizer (39), the carrier gas (oxygen) is bubbled through liquid halothane. The effluent mixture is fully saturated with halothane vapor. The concentration of halo- thane vapor delivered from the vaporizer can be calculated from the temperature of the liquid halothane and the vapor pressure of halothane at that temperature. Dilution with oxygen or a mix- ture of oxygen and other anesthetics in the breathing circuit gives the desired anesthetic concentration. In both systems, the halothane is vaporized outside the anesthetic circuit. The concentration of the vapor delivered to the cir- cuit is independent of the patient's ventilatory activity. Halothane may be administered by any of the commonly used anesthetic systems, varying from nonrebreathing to closed rebreathing tech- niques. In the nonrebreathing method, the in- spired concentration of halothane equals the con- centration delivered from the anesthetic apparatus. With an increasing proportion of rebreathing, the inspired concentration is pro- portionally lower and less predictable than that delivered from the anesthetic machine. The common practice is to use a semiclosed system with a total gas flow varying from 3 to 6 liters/ min and an efficient carbon dioxide absorber in the rebreathing circuit. In the completely closed rebreathing technique, which is rarely used, the amount of halothane vapor added to the anesthetic circuit may exceed the uptake, re- sulting in an increasing halothane concentration. In those circumstances, constant monitoring of the inspired halothane concentration with such devices as an infrared or ultraviolet analyzer is desirable. EFFECTS ON PHYSIOLOGIC SYSTEMS Nervous System The effect of halothane on the central nerv- ous system in producing anesthesia is probably the same as that of other general anesthetics (14). Anesthetics depress the secondary afferent sys- tems, i.e., the reticular activating system of the brainstem, to reduce the afferent input to the cerebral cortex. Halothane also depresses sub- cortical structures that regulate somatic and visceral functions. The electroencephalogram during halothane anesthesia shows characteristic changes that correlate with increasing depth of anesthesia (22). Loss of consciousness is associated with the disappearance of alpha rhythm. The primary pattern during light anesthesia is a fast rhythm
(15 to 26 cycles/sec) with a low voltage (10 to 25|/v). With increasing depth of anesthesia the fast rhythm and low voltage gradually change to slow rhythm (2 to 3 cycles/sec) and high voltage (100 to 300 #v). Periods of electrical silence (burst suppression) then occur, interspersed with slow activity of reduced voltage. Complete ab- sence of cortical activity has been observed during profound anesthesia. In general, these electroencephalographic changes are similar to those associated with other potent anesthetics. Halothane appears to sensitize the peripheral mechanoreceptors thus far examined, including the pulmonary stretch receptors and the carotid baroreceptors (6,9,71). The stimulus threshold for these receptors is decreased and the fre- quency of discharge in response to a given physi- ologic stimulus is increased. The possible sig- nificance of this action of halothane in terms of neural regulation of respiration and circulation will be discussed later. Halothane, like other potent anesthetics, depresses somatic reflexes (44). It does not ap- pear to interfere with neuromuscular trans- mission in vivo (44,70). Therefore, skeletal muscle relaxation is produced through an action on the central nervous system, but only during deep anesthesia. However, the neuromuscular blockade of d-tubocurarine is potentiated by halothane (70). Cerebral oxygen consumption is reduced by 15 percent during moderate depths of anesthesia with halothane, but that is partly explained on the basis of lowered body temperature (11). Cerebral blood flow increases (51 ml/100 g-min) in the face of a reduced arterial pressure, indicating cerebral vasodilation (cerebrovascular resist- ance, 1.1 mm Hg/ml/100 g-min) (74). The re- sponse of cerebral vessels to changes in carbon dioxide tension remains intact: vasoconstriction occurs during hypocapnia and vasodilation with hypercapnia. However, cerebral hypoxia has not been demonstrated during hypocapnia produced by hyperventilation, a common clinical practice (11). Cerebrospinal fluid pressure in- creases during halothane anesthesia, probably as a result of cerebral vasodilation (23,36). Respiratory System Halothane does not irritate the respiratory tract; during halothane anesthesia, mucous secretion is minimal and the bronchial muscles are relaxed. Halothane is a respiratory depressant; it reduces the respiratory amplitude and slightly increases the rate. The increase in respiratory rate is probably in part the result of sensitiza- tion of the pulmonary stretch receptors (45,71). In dogs, arterial carbon dioxide tension re- mains within normal limits when alveolar halo- thane concent-dtion is 0.7 percent or lower. Above this concentration the arterial carbon dioxide tension rises linearly with increasing depth of anesthesia (38). Similarly, in man, during halothane anesthesia (1 to 3 percent inspired concentration) with spontaneous respiration, the alveolar carbon dioxide tension is in- creased (15,16). Both in animals and in man, the ventilatory response to a carbon dioxide chal- lenge decreases in proportion to increasing depth of anesthesia (16,21,45,63). Circulatory System Halothane depresses cardiovascular func- tions. With a moderate depth of anesthesia, bradycardia, hypotension, and reduced cardiac output are regularly observed. These effects may be explained in part by a direct depressant action of halothane on the heart and blood ves- sels. The central action of halothane appears to play an important role in that similar circula- tory depression can be produced when the dis- tribution of halothane is limited to the head with perfusion techniques (51). In experimental animals and in man, halothane depresses myocardial contractil- ity (34,41,64). Peripheral vasodilation (an in- crease in blood flow in the skin and muscles) has been observed in man with the venous oc- clusion plethysmographic technique. The re- sponse of peripheral vessels to intra-arterially infused norepinephrine is reduced (7). In the mesoappendiceal microvessels of the rat, vaso- motion is maintained during light to moderate halothane anesthesia (1 to 2 percent inspired concentration). Blood flow in the capillary bed, as estimated by direct observation, remains adequate. The reactivity of precapillaries to topically applied epinephrine appears enhanced. However, during deeper anesthesia (3 percent inspired concentration), vasomotion, blood flow, and epinephrine reactivity are depressed (2). Circulatory homeostatic compensation is notably absent during halothane anesthesia. Barostatic reflexes are markedly de- pressed (43,51), although it has been suggested that sensitization of baroreceptors may con- tribute to the hypotensive action of halothane (6). Plasma concentrations of epinephrine and nor- epinephrine remain unchanged (50). Ventricular arrhythmias may occur, re- sulting mostly from surgical manipulation during light anesthesia or from hypercapnia. Halothane sensitizes the heart to the arrhythmic action of catecholamines. In animals, intravenous admin- istration of epinephrine during halothane anes- thesia may result in ventricular tachycardia or fibrillation (53). However, in man, the use of epinephrine during halothane anesthesia is ap- parently safe if the dose of epinephrine is limited (not exceeding 10 ml of 1:100,000 solution in any given 10 min nor 30 ml/hr) and if precautions are taken to ensure adequate pulmonary ventila- tion (31). The use of vasopressors other than catecholamines, such as phenylephrine, ephedrine, etc., also in limited dose, is not accompanied by serious arrhythmias. 334-553 O-69â2
Liver and Kidneys In man, halothane significantly reduces the splanchnic blood flow (mean reduction, 25percent) without changing splanchnic vascular resistance. The decrease in splanchnic blood flow is pre- sumably the result of reduced arterial pressure. Hepatic oxygen consumption remains unchanged with a slight decrease in hepatic venous oxygen tension (from a mean of 53 to 47 mm Hg). How- ever, evidence of tissue hypoxia, as estimated by production of "excess" lactate, has not been observed. Addition of carbon dioxide to the in- spired mixture restores the splanchnic blood flow to control levels by producing vasodilation (20,49). In dogs and in man, halothane decreases renal function. Glomerular filtration, renal plasma flow, urine flow, and sodium and chloride clearance all decrease significantly but are readily reversible on recovery from anes- thesia (8,37). It is assumed that these changes are correlated with those of systemic hemodynamics, i.e., decreases in cardiac output and arterial pressure. Furthermore, the decrease in urine volume and sodium excretion may be reversed by the prophylactic administration of saline or mannitol (37). Possible hepatotoxic effects of halothane have been extensively studied in a variety of animal species, including mice, rats, rabbits, guinea pigs, dogs, and monkeys. In contrast to chloroform, which produces liver necrosis with regularity, halothane does not cause liver necrosis after single or repeated administrations to these animals (29). Experiments have also been performed on protein-deficient mice. Halothane did not cause demonstrable pathologic changes in the liver (73). In rats and dogs, administration of halothane with a hypoxic or hypercapnic mix- ture also failed to cause liver necrosis (26,27,40). However, granular and fatty degeneration of the liver has been observed in mice, rats, guinea pigs, rabbits, and dogs (3,17,25,30,46,60,67). The effect of halothane on liver function has been examined in man and compared with other commonly used anesthetics in limited series. The results are discussed in Chapter 1-3. Digestive System Halothane decreases salivary and mucous glandular secretion. It relaxes the smooth muscle of the gastrointestinal tract and inhibits motility. Recovery occurs when halothane is with- drawn (35). The incidence of nausea and vomiting after halothane anesthesia is significantly lower than after anesthesia with other agents. In large series of cases, the reported incidence varied from 2 to 10 percent. According to Bellville et.al. (5), the incidence of postoperative nausea and vomiting was 27 percent with cyclopropane, 16 percent with diethyl ether, and 13 percent with thiopental-nitrous oxide. Metabolism In man given morphine or barbiturate and scopolamine for premedication, oxygen uptake falls to 72 to 87 percent of predicted basal values during halothane anesthesia (1.3 to 1.9 percent inspired concentration in mixture of 75 percent nitrous oxide and 25 percent oxygen) (62). The reduction in oxygen uptake is accompanied by considerable decreases in cardiac output and arterial pressure. When administered alone and without premedication, halothane (0.7 to 1 percent expired concentration) does not significantly alter oxygen uptake compared with predicted basal values (66). However, a decrease in oxygen uptake occurs if the body temperature is lowered significantly. The reduction in oxygen uptake observed in the first report is assumed to be attributable to premedicants and circulatory depression. A decrease in tissue perfusion may result in an oxygen debt to be repaid during recovery from anesthesia (61). The influence of halothane on oxygen con- sumption in tissue slices in vitro has been studied (28). Halothane in concentrations of 1 and 2 percent appears to decrease oxygen consump- tion in rat brain, heart, and liver. For reasons unknown, the depressant effect on brain slices is not reversible. Anaerobic glycolysis in brain homogenates was not affected by halothane in concentrations (5 percent) that had a marked effect on oxygen consumption. In the dog, halothane reduced blood glucose levels significantly (19 mg percent below the control). The transfer of glucose but not fructose from plasma to tissues is impeded; the half- time of the glucose tolerance test is prolonged (39 min), compared with that of animals in a control group (24 min) (24). CLINICAL USE OF HALOTHANE Since its introduction to clinical practice, halothane has received increasing acceptance. In the vast majority of cases, halothane is being administered in conjunction with a thiobarbitu- rate, nitrous oxide, and a neuromuscular block- ing agent when muscle relaxation is required. With this balanced technique it is possible to provide a smooth course of light surgical anesthesia with a relatively low concentration of halothane. The important advantages of halothane are: Nonflammability, which abolishes the risk of anesthetic explosion from static discharge and the risk in surgical procedures requiring the use of electrical equipment. Anesthetic fires and explosions, although not officially reportable, occur once in about 100,000 administrations with an estimated death rate of one in 2 to 3 million administrations. This would mean ap- proximately five to 10 deaths per year in the United States.
Absence of respiratory tract irritation, which permits a nonstressful, rapid induction of anesthesia. Major respiratory complications, such as laryngospasm, "expiratory spasm," and bronchospasm, occur rarely during this critical period. In addition, halothane is effective in the amelioration of bronchospasm because it relaxes bronchial muscle. Halothane is therefore used therapeutically in asthmatic crises, particu- larly bronchospasm occurring during anes- thesia. Relatively uneventful and rapid recovery from anesthesia, with a low incidence of post- anesthetic nausea and vomiting. This attribute may be important after certain surgical pro- cedures in terms of preventing wound dehiscence and disturbance of fluid and electrolyte balance. Absence of significant metabolic effect. Al- though the clinical significance of metabolic de- rangements observed during anesthesia with some other agents is ill-defined, it would appear that the benign effects of halothane may contribute to the general well-being of the surgical patient. However, halothane is not an ideal anes- thetic;* it does have undesirable pharmacologic properties. But in clinical use these disad- vantages can be minimized by practice and by techniques developed through proper training and experience. Circulatory depression. Shortly after the introduction of halothane into clinical use, a number of reports called attention to the hazards of overdosage and circulatory collapse. Such reports have largely ceased to appear, because of increasing experience and development of knowledge concerning the physical properties of halothane, uptake by the human body, anesthetic concentrations required, and the use of precision vaporizers. Depression of cardiovascular function is still evident when halothane is ad- ministered as the sole anesthetic, especially when used to provide muscular relaxation. In clinical practice, combined use with other agents, such as nitrous oxide and thiobarbiturate, and *An ideal anesthetic, according to the views of Seevers and Waters (59), Beecher and Ford (4), and Artusio and van Poznak (1), should be inexpensive to produce, pure, stable, and nonflammable; it should have low solubility coefficients in blood and tissues and an intermediate potency; it should not depress respiration or circulation, or cause major dis- turbance of other physiologic functions; it should provide adequate muscular relaxation; and the induction of anesthesia should be swift and pleasant, and recovery should be free from ill effects of the anesthetic. neuromuscular blocking agents, to a large extent minimizes the cardiovascular depression. Questions have also been raised as to the physiologic significance of minimal or even moderate decreases in cardiac output and arterial pressure. Where measurements have been made in man, e.g., cerebral and splanchnic circulation and metabolism, moderate hypoten- sion and decrease in blood flow to these areas in the absence of vasoconstriction are not associated with a significant reduction in tissue oxygen con- sumption or with any evidence of tissue hypoxia. Halothane has been used to produce de- liberate hypotension. The absence of sympatho- adrenal activation during halothane anesthesia and the possible deleterious effects of prolonged peripheral vasoconstriction, as shown by studies on shock, place halothane in an advantageous position in the management of patients in im- pending shock or shock, provided, of course, that appropriate steps are taken to correct blood- volume deficiency. Respiratory depression. This effect is not unique in anesthesia. With current concepts and practices of anesthesia, and with the increased training and ability of the anesthetist to provide adequate ventilation during anesthesia, respira - tory depression due to halothane should not be considered a practical disadvantage. The smooth-muscle relaxing action of halo- thane on the gravid uterus (19, 69) has been con- sidered by some as disadvantageous in the man- agement of obstetric patients. Impeding of the birth process and increased postpartum hemor- rhage could result from such uterine relaxation. Thus, it has been recommended that halothane not be used in obstetrics except when uterine relaxation is required (12). This point is debat- able. Reports of experience in large series of cases have failed to show that the incidence of postpartum hemorrhage is higher with halothane anesthesia, except when operative obstetric pro- cedures were involved (13,72). Another action of halothane. namely, in- crease in intracranial pressure, has been in- terpreted as disadvantageous in the management of anesthesia for neurosurgical procedures. It has not been proved that this increase in intra- cranial pressure is indeed deleterious. The ad- vantages of halothane mentioned above have made it an agent of choice in the minds of those re- sponsible for the anesthetic care of these pa- tients. The possible hepatotoxic effect of halothane in man is one of the primary subjects studied by the Subcommittee on the National Halothane Study.
REFERENCES 1. Artusio, J. F., Jr., and A. van Poznak. The concept of intermediate potency. Far East J. Anesth. 2:27, 1958. 2. Baez, S., and L. R. Orkrn. Effects of anes- thetics on the response of the microcircu- lation to circulating humors. Anesthesiology 24:568-579, 1963. 3. Balestra, L., and B. Giardina. Studio speri- mentale comparative sulle modificazioni istologiche del fegato e del rene nella intossicazione acuta da chloroformio, Fluothane e metossifluorano. Minerva Anesta. 30:311-318, 1964. 4. Beecher, H. K., and C. Ford. Anesthesia: Fifty years of progress. Surg. Gynec. Obstet. 101:105-139, 1955. (Internat. Abstr. Surg.) 5. Bellville, J. W., I. D. Bross, and W. S. Howland. Postoperative nausea and vomiting. IV. Factors related to postoperative nausea and vomiting. Anesthesiology 21:186-193, 1960. 6. Biscoe, T. J., and R. A. Millar. The effect of halothane on carotid sinus baroreceptor ac- tivity. J. Physiol. 173:24-37, 1964. 7. Black, G. W., and L. McArdle. The effects of halothane on the peripheral circulation in man. Brit. J. Anaesth. 34:2-10, 1962. 8. Blackmore, W. P., K. W. Erwin, O. F. Wie- gand, and R. Lipsey. Renal and cardio- vascular effects of halothane. Anesthesi- ology 21:489-495, 1960. 9. Cessi, C., G. A. Molinary, and G. Bortot. Effects of ether, trichlorethylene and Fluothane on the pulmonary stretch recep- tors of the rat. First European Congress of Anesthesia. 1962. 10. Cohen, E. N., H. W. Brewer, J. W. Bellville, and R. Shor. The chemistry and toxicology of dichlorohexafluorobutene. Anesthesi- ology 26:140-153, 1965. 11. Cohen, P. J., H. Wollman, S. C. Alexander, P. E. Chase, and M. G. Behar. Cerebral carbohydrate metabolism in man during halothane anesthesia: Effects of PaCCi2 on some aspects of carbohydrate utilization. Anesthesiology 25:185-191, 1964. 12. Crawford, J. S. The place of halothane in ob- stetrics. Brit. J. Anaesth. 34:386-390, 1962. 13. Cutter, J. A., and B. D. King. Use of halo- thane (Fluothane) in obstetric anesthesia: Preliminary report. New York J. Med. 60:503-511, 1960. 14. Davis, H. S.. V. E. Quitmeyer, and W. F. Collins. The effect of halothane (Fluothane) on the thalamus and midbrain reticular formation. Anaesthesia 16:32-49, 1961. 15. Deutsch, S., H. W. Linde, R. D. Dripps, and H. L. Price. Circulatory and respiratory actions of halothane in normal man. Anes- thesiology 23:631-638, 1962. 16. Devine, J. C., W. K. Hamilton, and C. B. Pittinger. Respiratory studies in man dur- ing Fluothane anesthesia. Anesthesiology 19:11-18, 1958. 17. du Cailar, J., J. Rioux, M. Marty, and E. Rieule. L'halothane est-il susceptible d'entrainer une intoxication hepatique chronique chez 1 "anesthesiste? Apropos de faits cliniques et d'une etude experi- mentale. Ann. D'anesthesiol. Franc. 4:433-437, 1963. 18. Eger, E. I., II, B. Brandstater, L. J. Saidman, M. J. Regan, J. W. Severinghaus, and E. S. Munson. Equipotent alveolar concentrations of methoxyflurane, halothane, diethyl ether, fluroxene, cyclopropane, xenon and nitrous oxide in the dog. Anesthesiology 26:771-777, 1965. 19. Embrey, M. P., W. J. Garrett, and D. L. Pryer. Inhibitory action of halothane on contractility of human pregnant uterus. Lancet 2:1093-1094, 1958. 20. Epstein, R. M., S. Deutsch, L. H. Cooperman, A. J. Clement, and H. L. Price. Studies of the splanchnic circulation during halothane anesthesia in man. Anesthesiology 26:246, 1965. (abstr.) 21. Fink, B. R., S. H. Ngai, and E. C. Hanks. The central regulation of respiration during halothane anesthesia. Anesthesiology 23:200-206, 1962. 22. Gain, E. A., and S. G. Paletz. An attempt to correlate the clinical signs of Fluothane anaesthesia with the electroencephalo- graphic levels. Canad. Anaesth. Soc. J. 4:289-294, 1957. 23. Galindo, A., and M. Baldwin. Intracranial pressure and internal carotid blood flow during halothane anesthesia in the dog. Anesthesiology 24:318-326, 1963. 24. Galla, S. J., and E. P. Wilson. Hexose metab- olism during halothane anesthesia in dogs. Anesthesiology 25:96-97, 1964. (abstr.) 25. Gibson, J. A. Fluothane toxicity: Pathological studies of mouse liver and kidney. Canad. Anaesth. Soc. J. 6:148-152, 1958. 26. Haley, F. C. Comparison of the hepatotoxic effects of halothane and chloroform in hypoxic dogs. Canad. Anaesth. Soc. J. 10:352-356, 1963. 27. Haley, F. C., and G. M. Wyant. The effect of halothane on the liver of dogs exposed to mild hypoxia. Canad. Anaesth. Soc. J. 6:271-276, 1959. 28. Hoech, G. P.. Jr., R. S. Matteo, and B. R. Fink. Effect of halothane on oxygen con- sumption of rat brain, liver and heart and anaerobic glycolysis of rat brain. Anes- thesiology 27:770-777, 1966. 29. Johnstone, M. Halothane: The first five years. Anesthesiology 22:591-614, 1961. 30. Jones, W. M., G. Margolis, and C. R. Stephen. Hepatotoxicity of inhalation anesthetic drugs. Anesthesiology 19:715- 723, 1958. 31. Katz, R. L., R. S. Matteo, and E. M. Papper. The injection of epinephrine during gen- eral anesthesia with halogenated hydro- carbons and cyclopropane in man. 2. Halo- thane. Anesthesiology 23:597-600, 1962. 32. Larson, C. P., Jr., E. I. Eger, H, and J. W. Severinghaus. The solubility of halothane in blood and tissue homogenates. Anes- thesiology 23:349-355, 1962. 33. MacKay, I. M. Clinical evaluation of Fluo- thane with special reference to a con- trolled percentage vaporizer. Canad. Anaesth. Soc. J. 4:235-245, 1957. 34. Mahaffey, J. E., E. E. Aldinger, J. H. Sprouse, T. D. Darby, and W. B. Thrower. The cardiovascular effects of halothane. Anesthesiology 22:982-986, 1961. 35. Marshal1, F. N., C. B. Pittinger, and J. P. Long. Effects of halothane on gastrointestinal motility. Anesthesiology 22:363-366, 1961. 8
36. Marx, G. F., I. C. Andrews, and L. R. Orkin. Cerebrospinal fluid pressures during halothane anaesthesia. Canad. Anaesth. Soc. J. 9:239-245, 1962. 37. Mazze, R. I., F. D. Schwartz, H. C. Slocum, and K. G. Barry. Renal function during anesthesia and surgery. I. The effects of halothane anesthesia. Anesthesiology 24:279-284, 1963. 38. Merkel, G., and E. I. Eger, II. A compara- tive study of halothane and halopropane anesthesia including method for deter- mining equipotency. Anesthesiology 24:346-357, 1963. 39. Morris, L. E. A new vaporizer for liquid anesthetic agents. Anesthesiology 13:587- 593, 1952. 40. Morris, L. E. Comparison studies of hepatic function following anesthesia with the halogenated agents. Anesthesiology 21:109-110, 1960. (abstr.) 41. Morrow, D. H., and A. G. Morrow. The effects of halothane on myocardial con- tractile force and vascular resistance. Direct observations made in patients dur- ing cardiopulmonary bypass. Anesthe- siology 22:537-541, 1961. 42. Ngai, S. H. General anesthetics. Effects upon physiological systems, pp. 43-98. In W. S. Root and F. G. Hofmann, Eds. Phys- iological Pharmacology. Vol. I. New York: Academic Press, Inc., 1963. 43. Ngai, S. H., and P. Bolme. Effects of anes- thetics on circulatory regulatory mecha- nisms in the dog. J. Pharmacol. Exp. Ther. 153:495-504, 1966. 44. Ngai, S. H., E. C. Hanks, and S. E. Farhie. Effects of anesthetics on neuromuscular transmission and somatic reflexes. Anes- thesiology 26:162-167, 1965. 45. Ngai, S. H., R. L. Katz, and S. E. Farhie. Respiratory effects of trichlorethylene, halothane and methoxyflurane in the cat. J. Pharmacol. Exp. Ther. 148:123-130, 1965. 46. Norris, F. H., Jr., P. H. Geisler. W. L. Pritchard, and K. D. Hall. Lack of necro- sis in dog liver after anesthesia with halo- thane. Arch. Int. Pharmacodyn. 145:405- 412, 1963. 47. Papper, E. M., and R. J. Kitz, Eds. Uptake and Distribution of Anesthetic Agents. New York: McGraw-Hill Book Co., Inc., 1963. 321 pp. 48. Price, H. L., and P. J. Cohen, Eds. Effects of Anesthetics on the Circulation. Springfield, HI.: Charles C. Thomas, 1964. 293 pp. 49. Price, H. L., S. Deutsch, I. A. Davidson, A. J. Clements, M. G. Behar, and R. M. Epstein. Can general anesthetics produce splanchnic visceral hypoxia by reducing regional blood flow? Anesthesiology 27:24- 32, 1966. 50. Price, H. L., H. W. Linde, R. E. Jones, G. W. Black, and M. L. Price. Sympatho-adrenal responses to general anesthesia in man and their relation to hemodynamics. Anesthe- siology 20:563-575, 1959. 51. Price. H. L., H. W. Linde, and H. T. Morse. Central nervous actions of halothane affect- ing the systemic circulation. Anesthesiology 24:770-778, 1963. 52. Rackow, H., E. Salanitre, R. M. Epstein, G. L. Wolf, and W. Perl. Simultaneous uptake of N2 O and cyclopropane in man as a test of compartment model. J. Appl. Physiol. 20: 611-620, 1965. 53. Raventos, J. The action of Fluothane; a new volatile anaesthetic. Brit. J. Pharm. 11: 394-410, 1956. 54. Raventos, J., and P. G. Lemon. The impuri- ties in Fluothane: Their biological proper- ties. Brit. J. Anaesth. 37:716-737, 1965. 55. Sadove, M. S., and V. E. Wallace. Halothane. Philadelphia: F. A. Davis Co., 1962. 496 pp. 56. Saidman, L. J., and E. I. Eger, II. Effect of nitrous oxide and of narcotic premedication on the alveolar concentration of halothane required for anesthesia. Anesthesiology 25:302-306, 1964. 57. Sechzer, P. H., R. D. Dripps, and H. L. Price Uptake of cyclopropane by the human body. J. Appl. Physiol. 14:887-890, 1959. 58. Sechzer, P. H., H. W. Linde, R. D. Dripps, and H. L. Price. Uptake of halothane by the human body. Anesthesiology 24:779-783, 1963. 59. Seevers, M. H., and R. M. Waters. Pharma- cology of anesthetic gases. Physiol. Rev. 18:447-479, 1938. 60. Semino, L., G. Virdis, and A. Origone. Effetti dell'anestesia fluotanica sul parenchima epatico e renale. Studio speri- mentale morfologico e istochimico. Pathologica 56:123-144, 1964. 61. Sessler, A. D., and R. A. Theye. Metabolic and circulatory aspects of halothane anes- thesia. Anesthesiology 27:226-227, 1966. (abstr.) 62. Severinghaus, J. W., and S. C. Cullen. Depression of myocardium and body oxygen consumption with Fluothane. Anesthesi- ology 19:165-177, 1958. 63. Severinghaus, J. W., and C. P. Larson, Jr. Respiration in anesthesia, pp. 1219-1264. In W. O. Fenn and H. Rahn, Eds. Handbook of Physiology. Section 3, Vol. 2. Washing- ton, D.C.: American Physiological Society, 1965. 64. Shimosato, S., T. H. Li, and B. Etsten. Ven- tricular function during halothane anesthesia in closed chest dog. Circ. Res. 12:63-75, 1963. 65. Stephen, C. R., and D. M. Little, Jr. Halo- thane (Fluothane). Baltimore: Williams and Wilkins Co., 1961. 152 pp. 66. Theye, R. A., and G. F. Tuohy. Oxygen uptake during light halothane anesthesia in man. Anesthesiology 25:627-633, 1964. 67. Urban, H., and W. D. Erdmann. Vergleichende Priifung der Leberverfettung nach Chloro- form- und Halothan-Narkose an Ratten, Einfluss der Wechseldruck-Beatmung mit Sauerstoff. Anaesthesist 14:79-82, 1965. 68. van Dyke, R. A., and M. B. Chenoweth. Me- tabolism of volatile anesthetics. Anesthe-« siology 26:348-357, 1965. 69. Vasicka, A., and H. E. Kretchmer. Uterine dynamics. Clin. Obstet. Gynec. 4:17-46, 1961. 70. Watland, D. C., J. P. Long, C. B. Pittinger, and S. C. Cullen. Neuromuscular effects of ether, cyclopropane, chloroform and Fluo- thane. Anesthesiology 18:883-890, 1957.
71. Whitteridge, D. Effect of anaesthetics on liver in protein-deficient mice. Brit. J. mechanical receptors. Brit. Med. Bull. Anaesth. 37:103-110, 1965. 14:5-7, 1958. 74. Wollman, H., S. C. Alexander, P. J. Cohen, 72. Wilson, K. B., and S. L. Vandewater. Halo- P. E. Chase, E, Melman, and M. G, Behar. thane in obstetrics: Five years experience. Cerebral circulation of man during halo- Anesth. Analg. (Cleveland) 44:34-38, 1965. thane anesthesia: Effects of hypocarbia and 73. Wingard, D., H. S. Davis, and D. Leonard. of d-tubocurarine. Anesthesiology 25:180- Effects of halothane and chloroform on the 184, 1964. 10
CHAPTER I-3. HEPATIC EFFECTS OF HALOTHANE REVIEW OF THE LITERATURE S. H. Ngai Columbia University, College of Physicians and Surgeons, and Presbyterian Hospital, New York, New York Soon after halothane was introduced into clinical practice, a number of publications ap- peared describing experiences with it. The re- ports described series ranging from fewer than 100 to thousands of cases, and were primarily concerned with anesthetic techniques and the patients' responses during and after anesthesia. Few specifically mentioned the possible hepato- toxic effects of halothane. Before 1960, Little e-t aL (55) studied hepatic function in 10 patients before and after halothane anesthesia and compared the results with those in patients anesthetized with cyclopropane or diethyl ether. Transient hepatic dysfunction was observed, but there was no significant difference among these anesthetics. Stephen et al. (77) used the sulfobromophthalein (Bromsulphalein, BSP) retention test in 51 patients anesthetized with halothane and found no difference between this group and those anesthetized with other agents. Three fatal cases of hepatic necrosis after halothane anesthesia were reported - one after aortic valvuloplasty in a patient with severe congestive heart failure (16), one after cholecystectomy complicated by episodes of cardiovascular depression during anesthesia (86), and one after an uncomplicated inguinal hernior- rhaphy (87). These authors suspected halothane of contributing to the deaths, but obviously other factors could have played a role. Three cases of nonfatal postoperative hepatic complications after halothane anesthesia were also reported, but detailed information on hepatic function was not available (5,16). A number of case reports of hepatic necro- sis after halothane anesthesia appeared late in 1962 and early in 1963 (14,15,54,78,80). These reports raised the question of the safety of this anesthetic agent and served as the impetus for the National Halothane Study. Since then, addi- tional cases, both fatal and nonfatal, have been reported and many have cast suspicion on or implicated halothane as a hepatotoxin. Such a contention could hardly have been proved because of the multitude of factors leading to hepatic necrosis in patients undergoing operation. While the National Halothane Study was in progress, a number of retrospective surveys and prospective studies were carried out in an attempt to prove or disprove a causal relationship between halo- thane and hepatic necrosis and to estimate the incidence of postoperative hepatic complication as related to various anesthetic agents. The following section summarizes the pertinent literature to January 1966. RETROSPECTIVE STUDIES Retrospective studies of the incidence of postoperative hepatic necrosis vary considerably in the methods and case material used. Table 1 summarizes the total number of cases thus studied and the frequency of use of halothane and other anesthetics associated with fatal and non- fatal hepatic necrosis. Data were obtained from anesthesia registers, hospital charts, and ne- cropsy records. In some the total number of cases was approximate. Fatal cases were gathered from among those patients who died from 4 weeks to 4 months following anesthesia, although in a number of reports the time was not recorded. Performance of necropsy varied from 65 to 90 percent. In Table 1 the cases listed under the heading "Nonhalothane" include those involving anesthesia with all commonly used agents: thiopental- nitrous oxide, cyclopropane, diethyl ether, and other halogenated agents (trichloroethylene, methoxyflurane, and fluoroxene). Most authors excluded, or considered separately, those cases with preoperative hepatic disease. Detailed description of the liver pathology was not pro- vided in all reports. Thus, the incidence of hepatic necrosis after anesthesia as estimated from these data must be viewed with caution. It is unlikely that a significant number of patients who died of massive hepatic necrosis were over- looked in these surveys. Rather, the incidence of massive hepatic necrosis may have been over- estimated. In the series of Slater et al. (75) and Gingrich and Virtue (33), the extent of hepatic damage found at necropsy varied from fatty in- filtration to focal necrosis or massive necrosis. Additional pertinent information may be gathered from a few of these reports. Kee'ri- Szanto and Lafleur (48) found that, of approxi- mately 100 patients with pre-existing serious hepatic disease, seven died of hepatic complica- tions. Of these, two were given halothane anes- thesia, but that agent was administered to ap- proximately 52 percent of the patients in this selected group. In another series (46), 185 pa- tients with cirrhosis of the liver underwent portal-systemic venous anastomosis. Halothane anesthesia was administered to 44 patients and other agents to 141. The over-all mortality rate was 10.8 percent, but there was no significant difference in mortality between the two groups. Similar results were reported by Benke (8) in a series of 130 patients with pre-existing jaundice of diverse origin, 25 of whom were given halo- thane. In addition, Dawson et al. (25) analyzed 11
TABLE 1.âRETROSPECTIVE STUDIES IN THE LITERATURE COMPARING THE HEPATIC EFFECTS OF HA10THANE AND OTHER ANESTHETIC AGENTS Halothane Nonhalothane Reference Period of survey Total no. cases No. admin- istrations No. cases hepatic necrosis No. admin- istrations No. cases Necropsy rate, (*) hepatic necrosis 48 1959-1962 (48 months ) 50,000* 35,000* 6 15,000* 1 --. 2 1960-1963 (38 months ) 36,000* 13,024 0 23,000* 1 â 75 1959-1962 (48 months ) 46,923 14,685 3 32,238 7 65 22 1959-1963 (48 months) 13,176 6,509 0 6,667 0 64 1960-1962 (36 months) 26,844 16,684 0 10,160(2712) 1(0) 74.7 38 1960-1963 (48 months) 48,311 21,461 1 26,850 2 65 1958-1962 (60 months) 22,701 6,618 0 16,083 0 88 33 1953-1963 (10 years) 24, 112 3,073 1 21,039(717) 5(0) 90 27 1956-1963 (8 years) 102,342 20,232 1 82,110 0 75 Total and incidence of hepatic necrosis 370,409 137,286 12 233,147(3429) 17 1:13,715 1:11,440 *Estimated Numbers in parentheses indicate anesthesia with trichloroethylene, methoxyflurane, or fluoroxene, as mentioned in original report. their experience with operations on the biliary tract. In 1958, diethyl ether was used in 925 patients; in 1962, halothane was used in 749. About 2 percent of patients in both groups re- vealed preoperative evidence of hepatocellular disease. One patient in each group died of hepatic failure. Analysis of postoperative hepatobiliary complications or mortality, from known or un- known causes, revealed no significant difference between the groups. Thus, from these experiences it would appear that neither pre-existing hepatic disease nor operation on the biliary tract con- traindicates the use of halothane. Data from the National Halothane Study lend further support to this contention (see Chapters III-1 and IV-3). In addition to the aforementioned studies of postoperative death, Mushin et aL (64) and Henderson and Gordon (38) examined the frequency of postoperative hepatic dysfunction as indicated by abnormal hepatic function tests or jaundice. It was assumed that major hepatic damage oc- curring while the patient was in the hospital would have been observed by the attending clini- cian and that appropriate tests would have been performed. Data were obtained from the records of the biochemical laboratory. Reference to the clinical charts permitted analysis of anesthetic or surgical factors. Mushin et al. concluded from their survey of 26,844 cases that halothane differs little from other anesthetics in its effect on the liver. Again, in patients with pre-existing liver disease, halothane did not appear to result in greater degrees of hepatic dysfunction than other anesthetics. Henderson and Gordon (38) found that the incidence of postoperative jaundice (defined as a serum bilirubin greater than 1.5 van den Bergh units, preoperative jaundice being ex- cluded) increased from 1.1 per 1000 during the period 1953-1956 to 4.2 per 1000 during the period 1960-1963. These authors attributed the increase to the changing character of surgical practice and to more frequent use of blood transfusions and new therapeutic agents. During 1960-1963, how- ever, when halothane was compared with other anesthetics, there was no difference in abnormal hepatic function tests, the incidence being 4.1 and 4.2 per 1000 after halothane and other agents, respectively. Although retrospective surveys of this nature do not ensure identification of all cases of postoperative hepatic dysfunction, it is reasonably certain that most cases with 12
major hepatic complications must have been discovered. Two other retrospective studies are of interest in that they indicate the relative infre- quency of massive hepatic necrosis associated with anesthesia and operation. Caravati and Wootton (17) examined all necropsy records in three community hospitals during the 16-year period 1946-1961. Total hospital admissions numbered 662,252. Massive hepatic necrosis was found in nine of 9960 patients who came to ne- cropsy. Only three of these had been subjected to anesthesia and operation soon before the onset of hepatic complications and death. None of these patients received halothane. Rodgers et al. (69) reviewed all necropsy records of a large city hospital during the 10/2-year period 1953-1963. Eighteen instances of massive hepatic necrosis were found among 11,341 necropsies. Six of the 18 patients had undergone operation. The primary anesthetics administered were: cyclopropane, three cases; diethyl ether and cyclopropane, one case; and halothane, one case; the remaining patient was operated on without general anes- thesia. Clinical, laboratory, and necropsy find- ings of these cases are set forth in Tables 3 and 4. Although in some the etiologic factor was not ascertained, it appeared that viral hepatitis, prolonged hypotension treated with vasopressor drugs, septicemia, and reactions to therapeutic agents were causative in most instances. Anes- thesia did not seem to play a role, no matter the agent. The total number of administrations of general anesthesia during the period of survey was not mentioned in either of these reports, but Rodgers et al. estimated that, since 1958, 3000 to 4000 patients per year had been anesthetized with halothane in their hospital. Another form of retrospective survey was carried out by Green and Mungavin (35), who asked practicing anesthetists in England for information on cases of hepatic complications suspected of having occurred after halothane anesthesia. More than 1000 replies yielded 47 cases, of which 16 were fatalities. It is of interest that, in 10 of the 16 fatal cases, the cause of the hepatic com- plication was "indeterminate." The value of this type of survey is questionable in terms of inci- dence of complication and comparison with other anesthetics. There was no assurance that all pertinent cases were known or reported, and the frequency of use of the anesthetic was not indi- cated. These authors also searched for cases of fatal hepatic necrosis among necropsy records of six teaching hospitals. The survey was carried out for the years 1956 to 1963 and covered a cumulative total of 28 years of experience. There were 18 cases associated with halothane anes- thesia and 14 cases in which halothane was not used. Again, the total number of administrations of general anesthesia was not available, although it was estimated that 60 percent of the patients had received halothane. A number of reports dealt with halothane anesthesia alone and cited the incidence of post- operative hepatic complications or their absence (11,31,32,39,41,44,56,66,71,77,88). The numbers of cases in the reports ranged from 400 to 12,000. The incidence of postoperative jaundice ranged from 33 in 2700 cases (39) to none in 10,000 to 12,000 (31,66,88). It seems certain that there was little uniformity in the method of case searching; nor can it be assumed that etiologic factors other than anesthesia were not involved. Nevertheless, the report of Bentel (11) is of interest. Over a period of 4 years, Bentel regularly (approximately 20 times per week) used halothane, pentolinium (Ansolysen), and posture to induce hypotension (systolic arterial pressure, 60 to 70 mm Hg) for the performance of various surgical procedures. There were only three cases of jaundice that developed 6 months to 1 year after operation, presumably from causes other than anesthesia. From the large numbers of cases in the retrospective surveys, it may be concluded that massive hepatic necrosis after anesthesia and operation is indeed rare. The exact incidence cannot be ascertained from these data, but it appears that halothane differs little from other anesthetic agents, even if anesthesia were con- sidered a contributing etiologic factor. From limited experience it may be stated also that halothane is comparable with, and possibly supe- rior to, other anesthetic agents in its safety in the management of patients with hepatic disease or for operation on the biliary tract. PROSPECTIVE STUDIES Retrospective studies only partially answer the question of whether postoperative hepatic necrosis is associated with halothane more fre- quently than with other anesthetics, and may provide estimates of the incidence of fatal and nonfatal hepatic complications. However, the very nature of such studies leaves much to be de- sired. In institutions with large surgical case- loads, it is unlikely that close scrutiny and adequate postoperative examination are afforded all patients. It may also reasonably be assumed that the frequency with which a complication is found is directly related to the index of suspi- cion. Thus, bias on the part of the observer can- not be discounted. Although cases of serious and fatal hepatic necrosis are not likely to be missed in retrospective studies, the incidence of milder forms of hepatic dysfunction after halothane or other anesthetic agents would be generally unknown. Furthermore, choice of anesthetic agent may have been dictated not only by clinical circumstances but by the personal preference of the anesthetist. These variables are important in the final results, but are not apparent in statistical analyses such as those de- scribed above. 13
TABLE 2.--PROSPECTIVE STUDIES IN THE LITERATURE COMPARING THE HEPATIC EFFECTS OF HALOTHANE AND OTHER ANESTHETIC AGENTS Refer- ence Method of patient selection liver function tests used Time of tests No. of cases Results or conclusions Halothane Others 77 -- BSP retention (45 min) Postoperatively, 24 hr and 5 51 51 Comparable results in both groups days 55 Cholinesterase , cholesterol, choles- terol esterification, alkaline phospha- .tase, bilirubin, cephalin floccula- tion Preoperatively; postopera- tively, days 2 and 7 10 20 Comparable minor changes after anesthesia 36 Paired Bilirubin, SCOT, SGPT, BSP retention (45 min) Preoperatively; postopera- tively, 24 hr 27 30* Minor changes in hepatic function after anesthesia attributed to oper- ation rather than to anesthesia. No significant differ- ence between halo- thane and chloro- form 70 Random SGPT Preoperatively; postopera- tively, 24 hr 140 140 6 patients in each group had post- operative SGPT higher than 39; study in progress 7 OCT Preoperatively; postopera- tively, 2, 4, 6, 8 days 13 3 All values within normal limits 22 Random SGPT Preoperatively; postopera- tively, 2 or 6 164 104 No significant dif- ference between preoperative or postoperative values days 23 Liver biopsy, OCT Beginning and end of opera- tion 10 6 No change observed in liver biopsy; all OCT values with- in normal limit 76 SCOT, SGPT, LDH, MDH Preoperatively; during opera- tion; post- operatively, 24 hr 19 11 No abnormal values observed 50 Matched series Urobilinogen, Cholinesterase, SGPT Preoperatively; postopera- tively, 6 and 30 hr SGPT 84 84 Halothane group not different from non- halothane groups only 51 Matched series SGPT Preoperatively; postopera- tively, 6 and 30 hr 50 50 +50* No evidence of hepatic dysfunction after halothane or chloroform 67 BSP retention pro- thrombin time, guanase, OCT Preoperatively and postopera- tively, 1 and 5 days; pre- operatively and postopera- tively 1 and 3 days 21 21 BSP retention ele- vated postopera- tively; no signifi- cant difference between halothane and nonhalothane series 14
Table 2 (Cont'd) Refer- ence Method of Liver function tests used No. of cases Results or conclusions patient selection Time of tests Halothane Other 42 Paired Bilirubin, SCOT, ICD Preoperatively; postopera- tively, 1, 2, 3 days 46 30 36** 1 patient (halo thane) showed elevated SCOT (1260) and ICD (6260); no significant abnor- malities in remaining patients 27 Random I CD Preoperatively; postoperat i vely , 1 and 4 days 139 84 No significant dif- ference between the two groups Abbreviations: SCOT, serum glutamic oxalacetic transaminase; SGPT, serum glutamic pyruvic trans- aminase; OCT, ornithine carbamyl transferase; ICD, isocitrio dehydrogenase; 3J3H, lactic dehydrogenase; and MDH, malic dehydrogenase. *Chloroform. **Regional anesthesia. A well-designed prospective study may eliminate some of these discrepancies, but certain criteria must be considered. Depending on the incidence of postoperative hepatic com- plications, the size of the sample must be ade- quate to permit statistical analysis. Patients must be selected on a broad basis, with respect to age, sex, physical status, and type of opera- tion. If one anesthetic agent is to be compared with another without bias, patients must be randomly assigned to each group. Appropriate laboratory tests must be performed at the proper time to detect hepatic dysfunction. It may be difficult to execute such a study properly because of practical and ethical problems. Table 2 summarizes the results of published prospective studies comparing the effect of halothane and other anesthetic agents on hepatic functions. These studies vary considerably in the size of samples, the liver function tests applied, and the time of application of these tests postoperatively. With few exceptions, the samples were small. Only three studies randomly as- signed the anesthetic agent to be administered. In some, postanesthetic alterations in hepatic function were not followed beyond 30 hr. Despite these limitations, the general conclusion has been that there is no significant difference among halothane and other agents in their effects on the liver. Transient abnormalities, presumably attributable to the operation, were found with equal frequency. A number of reports have dealt with the effect of halothane alone. Lorentz and Henneberg (57) measured serum lactic dehy- drogenase in 16 patients 24 and 48 hr after halothane anesthesia for major surgical pro- cedures; there was no change of significance. Tracy and Heyman (81), Urso et al. (83), and Pichlmayr and Pichlmayr (66) studied hepatic functions in a total of 134 surgical patients who were anesthetized with halothane. Hepatic func- tion tests included sulfobromophthalein retention, serum transaminase levels, bilirubin concen- tration, flocculation, and alkaline phosphatase. Although transient abnormal values were ob- served in some patients, the role of pre-existing disease, concurrent drug therapy, and the opera- tive procedure was unknown. No comparable series of cases with other anesthetic agents were available for comparison. Keeri-Szantd (47) reported a prospective study involving 250 surgical patients anesthetized with halothane, methoxyflurane, or neuroleptanal- gesic mixtures. He observed a greater intra- operative sulfobromophthalein retention with halothane than with methoxyflurane. In another 100 patients, the degree of abnormal BSP reten- tion 5 days postoperatively was greater in those who received higher concentrations of halothane (2 percent) for induction than in those who re- ceived 1 percent of halothane. The possible significance of these results is obscure. McReynoldset al.. (61) compared halothane and chloroform in 763 patients; 548 patients re- ceived halothane and 215 chloroform. Distribu- tion of patients according to age, physical status, and site of operation was approximately the same for both groups. The over-all mortality rate was 3.7 percent in the chloroform group and 2.7 per- cent in the halothane group, not significantly different from the total hospital death rate after administration of other anesthetic agents in the same institution. One patient with severe pre- existing hepatic disease died with diffuse hepatic and kidney necrosis, 15 days after chloroform anesthesia and 22 days after halothane anesthesia for a previous operation. Three patients in each group incurred "minor" hepatic complications. The authors concluded that halothane and 15
chloroform are similar in clinical effect, use- fulness, and safety. CASE REPORTS The service of the National Library of Medicine was requested to ensure complete coverage of the literature during the period 1963- 1965. On the basis of its data-retrieval system and the sorting of a total of 350,000 references, a list of publications was compiled to include all papers pertaining to anesthesia, halothane, toxicologic reports, jaundice, hepatic disease, hepatitis, hepatic necrosis, and postoperative complications. In addition, the medical library of the Ayerst Laboratories kindly provided a complete bibliography on halothane for 1956 to 1965. These lists were screened and all perti- nent references perused for case histories of hepatic complications after anesthesia and operation. This process yielded 132 cases of post- operative death due to hepatic necrosis or asso- ciated with some degree of pathologic change in the liver but not necessarily massive necrosis. An additional 124 cases were selected in which evidence of postoperative hepatic dysfunction was presented. This evidence included clinical jaundice, abnormal hepatic function tests, and biopsies. Relevant clinical histories and labora- tory and pathologic findings, where available, are presented in Tables 3 and 4 (fatal cases) and 5 and 6 (nonfatal cases). Most but not all of the fatal cases mentioned in the section on retro- spective studies are included. In the retrospec- tive studies of Kee'ri-Szanto and Lafleur (48), Allen and Metcalf (2), and Henderson and Gordon (38), 11 patients incurred hepatic necrosis; of these, seven had received halothane anesthesia. The survey of Green and Mungavin (35) of six hospitals in England yielded 32 cases of hepatic necrosis, 18 associated with halothane and 14 with other agents. None of these 43 cases is included in Tables 3 and 4, because of lack of details. Slater et al. (75) presented histories of two of their 10 patients in whom necropsy revealed hepatic necrosis of various degrees of severity. A subsequent publication by the same authors (29) provided additional information on nine patients who showed evidence of acute parenchymatous hepatic disease at necrospy. Overlaps in re- porting are apparent in these publications, as well as in those by Virtue and Payne (86), Ging- rich and Virtue (33), Lindenbaum and Leifer (54), and Blackburn et al. (13). Obvious duplications are omitted from Tables 3 through 6. The preponderance (in Tables 3 through 6) of cases associated with halothane reflected the current interest in this problem. The degree of suspicion that each author held certainly played an important role in these reports. Thus, the majority of cases involving anesthetic agents other than halothane were reported in connection with retrospective surveys when the total experi- ence in a given institution was scrutinized. When this was done, the incidence of hepatic necrosis or dysfunction associated with halothane usually did not differ significantly from that associated with other agents (cf. the section on retrospective studies and Table 1). Case reports cited herein varied con- siderably in details of clinical histories, particu- larly regarding circulatory status during and after operation, transfusion, and concurrent drug therapy. Descriptions of pathologic changes in the liver were not always given in sufficient detail. For these reasons, no attempt will be made to discuss individual cases. Nevertheless, in a number of cases hepatic necrosis and dysfunc- tion can probably be explained on the bases of pre-existing hepatic disease, such cardiovascular disturbances as congestive heart failure and shock, prolonged treatment with vasopressor drugs, and overwhelming infection. Because it is not possible to review all reported cases in the same manner as was done for the cases collected in the National Halothane Study, it would not be fruitful or justifiable to render an opinion con- cerning the probable cause(s) of hepatic necrosis in any of the reported cases. The possibility of coincidental viral infection was repeatedly men- tioned, but this must remain conjectural, as shall be the contention of many other authors who implicated halothane. Thus, it appears that, even with such a large series of patients who incurred postoperative hepatic damage, any conclusion based on case reports concerning the causal relationship be- tween halothane and hepatic necrosis would be unwarranted. These reports cannot be taken to prove that halothane is or is not hepatotoxic. REFERENCES 1. Affolter, H., G. Hartmann, V. Kapfhammer, and S. Scheidegger. Akute Massennekrose der Leber nach mehrmaliger Halothane- Narkose. Schweiz. Med. Wschr. 94:396-400, 1964. 2. Allen, H. L., and D. W. Metcalf. A search for halothane liver complications. Anesth. Analg. (Cleveland) 43:159-162, 1964. 3. Armstrong, C. A., and W. G. Wade. Fatal jaundice after halothane. Lancet 2:393, 1965. 4. Ashton, J. W., K. J. O'Connor, and G. L. Williams. Jaundice after halothane and radiotherapy. Brit. Med. J. 2:811, 1963. 5. Barton, J. D. Jaundice and halothane. Lancet 1:1097, 1959. 6. Beddard, J. R. Jaundice after halothane and radiotherapy. Brit. Med. J. 2:1529, 1963. 7. Belgeri, R., and A. Ferrero. Comportamento della ornitina carbamil transferasi (OCT) del siero dopo narcosi con Fluothane in ostetricia e ginecologia. Ann. Ostet. Ginec. 86:763-770, 1964. 16
8. Benke, A. Uber einige Ursachen des Coma hepaticum. Anaesthesist 13:302-304, 1964. 9. Bennike, K.-A., and J. O. Hagelsten. Cyclo- propane hepatitis: A Danish disease? Lancet 2:355, 1964. 10. Bennike, K. A., J. O. Hagelsten, and E. P. Hansen. Leberstorungen nach Halothane- narkose--post oder propter? Anaesthesist 13:289-293, 1964. 11. Bentel, H. Halothane and liver damage. Anaesthesia 19:143, 1964. 12. Birt, R. C., and T. B. Boulton. Post-operative jaundice: A case history. Anaesthesia 20:79-85, 1965. 13. Blackburn, W. R., S. H. Ngai, and J. Linden- baum. Morphologic changes in hepatic necrosis following halothane anesthesia in man. Anesthesiology 25:270-283, 1964. 14. Brody, G. L., and R. B. Sweet. Halothane anesthesia as a possible cause of massive hepatic necrosis. Anesthesiology 24:29-37, 1963. 15. Bunker, J. P., and C. M. Blumenfeld. Liver necrosis after halothane anesthesia. Cause or coincidence? New Eng. J. Med. 268:531-534, 1963. 16. Burnap, T. K., S. J. Galla, and L. D. Vandam. Anesthetic, circulatory and respiratory effects of Fluothane. Anesthesiology 19:307-320, 1958. 17. Caravati, C. M., and P. Wootton. Acute mas- sive hepatic necrosis with fatal liver failure. Southern Med. J. 55:1268-1277, 1962. 18. Chadwick, D. A., and R. C. Jennings. Massive hepatic necrosis associated with halothane anaesthesia. Lancet 1:793-795, 1964. 19. Chamberlain, G. Liver damage after halothane anaesthesia. Brit. Med. J. 1:1524-1525, 1963. 20. Chambers, J. S., P. F. Sewell, and H. B. Young. Jaundice after halothane and radio- therapy. Brit. Med. J. 1:562, 1964. 21. Clements en, H. J., G. Wolff, and W. Hugin. Die Funktionsveranderungen des E.M.O. Inhalers durch Kombination mit dem Ambu- Beatmungsbeutel und Ruben-Ventil. Anaes- thesist 13:15-21, 1964. 22. Collins, W. L., and L. W. Fabian. Transam- inase studies following anesthesia. Southern Med. J. 57:555-559, 1964. 23. Costa, J., and C. da Silva. Contribuicao ao estudo da toxicidade hepatica do halotano. Rev. Esp. Anest. 12:51-57, 1965. 24. Davies, C. K. Jaundice following halothane anaesthesia (a case report). Anaesthesia 20:245-249, 1965. 25. Dawson, B., R. R. Jones, N. Schnelle, V. B. Hartridge, J. A. Paulson, M. A. Adson, and W. H. Summerskill. Halothane and ether anesthesia in gallbladder and bile duct surgery: A retrospective study into mor- tality and hepatobiliary complications. Anesth. Analg. (Cleveland) 42:759-770, 1963. 26. Deacon, A. L. Liver damage after halothane. Brit. Med. J. 2:56-57, 1963. 27. DeBacker, L. J., and D. S. Longnecker. Pros- pective and retrospective searches for liver necrosis following halothane anesthesia. Serum enzyme study and case report. J.A.M.A. 195:157-160, 1966. 28. Defalque, R. J., and V. K. Stoelting. Hepatic failure after halothane. Anesthesiology 25:868-869, 1964. 29. Dykes, M. H., S. G. Walzer, E. M. Slater, J. M. Gibson, and D. S. Ellis. Acute paren- chymatous hepatic disease following general anesthesia: Clinical appraisal of hepatotoxi- city following administration of halothane. J.A.M.A. 193:339-344, 1965. 30. Fono, R. Fluothane ikterus gyermekkorban. Orv. Hetil. 105:557-558, 1964. 31. Frey, R., and H. Oehmig. Halothan und Leberschaden. Anaesthesist 13:315-316, 1964. 32. Calvin, H. J. Liver damage and halothane. Irish J. Med. Sci. 6:479-480, 1964. 33. Gingrich, T. F., and R. W. Virtue. Post- operative liver damage: Is anesthesia in- volved? Surgery 57:241-243, 1965. 34. Gordon, J. Jaundice associated with halothane anaesthesia. Anaesthesia 18:299-301, 1963. 35. Green, K. G., and J. M. Mungavin. Halothane and the liver: Retrospective studies. Proc. Roy. Soc. Med. 57:311-314, 1964. 36. Griffiths, H. W., and L. Ozguc. Effects of chloroform and halothane anaesthesia on liver function in man. Lancet 1:246-247, 1964. 37. Heidenberg, W. J. Halothane hepatitis. Lancet 1:1424, 1963. 38. Henderson, J. C., and R. A. Gordon. The in- cidence of postoperative jaundice with special reference to halothane. Canad. Anaesth. Soc. J. 11:453-459, 1964. 39. Henke, D., and R. Schuster. Zur Frage der Hepatotoxizitat von Fluothane aus klinischer Sicht. Bruns1 Beitr. Klin. Chir. 208:162-174, 1964. 40. Herber, R., and R. Specht. Liver necrosis following anesthesia. Arch. Intern. Med. 115:266-272, 1965. 41. Hilscher, A. Noch einmal: Akute Massen- nekrose der Leber nach mehrmaliger Halothanenarkose. Schweiz. Med. Wschr. 95:138-139, 1965. 42. Holmes, A. W., J. R. Torgerson, and W. S. Cline. The acute effects of anesthesia with halothane on liver function in man. Gastro- enterology 48:515, 1965. (abstr.) 43. Howard, E. R. Halothane. Lancet 2:541, 1965. 44. Hutchinson, B. R. Halothane in closed circuit anaesthesia. New Zeal. Med. J. 63:647-653, 1964. 45. Johnson, C. C. Hepatitis associated with halothane. Northwest Med. 63:611-616, 1964. 46. Jones, R. R., B. Dawson, M. A. Adson, and W. H. Summerskill. Halothane and nori- halogenated anesthetic agents in patients with cirrhosis of the liver: Mortality and morbidity following portal-systemic venous anastomoses. Surg. Clin N. Amer. 45: 983-990, 1965. 47. Keeri-SzinW, M. Halothane and the liver. Brit. J. Anaesth. 37:368, 1965. 48. Kee'ri-Szantd, M., and F. Lafleur. Postanes- thetic liver complications in a general hospital: A statistical study. Canad. Anaesth. Soc. J. 10:531-538, 1963. 49. Kerbel, N. C., and I. M. Hilliard. Halothane hepatotoxicity. Canad. Med. Assoc. J. 89:944-946, 1963. 17
50. Kirwan, M. J., J. W. Dundee, R. S. Clarke, 70. E. S. Mitchell, and D. W. Neill. Halothane hepatotoxicity; an investigation of the effects of short exposure. Anaesthesia 20:59-65, 71. 1965. 51. Kirwan, M. J., J. W. Dundee, and D. W. Neill. 72. A comparison of the effects of chloroform and halothane on liver function. Anaesthesia 20:66-69, 1965. 52. Klinge, O. Toxische Hepatose bei Halothan- 73. Narkose. Klin. Wschr. 43:1042-1049, 1965. 53. Lehner, T. Systemic candidiasis and renal involvement. Lancet 1:1414-1416, 1964. 74. 54. Lindenbaum, J., and E. Leifer. Hepatic necrosis associated with halothane anes- thesia. New Eng. J. Med. 268:525-530, 1963. 55. Little, D. M., Jr., C. M. Barbour, and J. B. 75- Given. The effects of Fluothane, cyclopro- pane, and ether anesthesias on liver func- tion. Surg. Gynec. Obstet. 107:712-718, 1958. 56. Lomaz, J. G. Halothane and jaundice in paedi- 76. atric anaesthesia. Anaesthesia 20:70-78, 1965. 57. Lorentz, J., and U. Henneberg. Das Verhalten der leberspezifischen Lactat-dehydrogenase 77. nach Halothan-Narkosen. Anaesthesist 13:234-235, 1964. 58. Lorhan, P. H., and H. E. Keigh. Was it halo- thane? A case report. Canad. Anaesth. Soc. J. 13:68-70, 1966. 78. 59. Louw, J., H. N. Aaron, and J. W. Mostert. Halothane jaundice. Report of a case. S. Afr. Med. J. 38:387-388, 1964. 60. Marx, G. F., Y. Kikkawa, and L. R. Orkin. 79. Delayed chloroform poisoning: Report of a case. Anesth. Analg. (Cleveland) 41:575- 581, 1962. 80. 61. McReynolds, E. C., A. Thorogood, and L. E. Morris. Clinical comparison of halothane (Fluothane) and chloroform. Arch. Surg. 81. 86:633-640, 1963. 62. Minuck, M., and R. S. Lambie. Hepatic com- plications and halothane anesthesia. Mani- toba Med. Rev. 43:577, 1963. 82. 63. Morgenstern, L., H. J. Sacks, and M. J. Marmer. Postoperative jaundice associated 83. with halothane anesthesia. Surg. Gynec. Obstet. 121:728-732, 1965. 64. Mushin, W. W., M. Rosen, D. J. Bowen, and H. Campbell. Halothane and liver dysfunc- 84. tion: A retrospective study. Brit. Med. J. 2:329-341, 1964. 65. Perry, L. B., and J. A. Jenicek. Massive he- patic necrosis associated with general anes- 85. thesia. Milit. Med. 129:1148-1151, 1964. 66. Pichlmayr, I., and R. Pichlmayr. Zur Frage der Leberschadigung durch Halothan. Uberblick iiber Literatur and eigene 86. Untersuchungen. Anaesthesist 13:293-302, 1964. 67. Prince, L. C., H. M. Rowe, and G. T. 87. Passananti. The effect of anesthesia upon liver enzymes, guanase and ornithine carbamyl transferase, reflecting cellular damage. Anesthesiology 26:258-259, 1965. (abstr.) 88. 68. Robinson, J. Fluothane and jaundice. Brit Med. J. 2:1268-1269, 1963. 69. Rodgers, J. B., G. K. Mallory, and C. S. Davidson. Massive liver cell necrosis; a retrospective study. Arch. Intern. Med. 89. 114:637-646, 1964. Rollason, W. N. Chloroform, halothane, and hepatotoxicity. Proc. Roy. Soc. Med. 57:307-311, 1964. Samrah, M. E. Liver damage after halothane. Brit. Med. J. 1:1736-1737, 1963. Schmid, M., M. L. Hefti, R. Gattiker, H. J. Kistler, and A. Senning. Benign postopera- tive intrahepatic cholestasis. New Eng. J. Med. 272:545-550, 1965. Schneider, I. Akute Leberdystrophie bei einem Saugling nach Halothan-Narkose. Deutsch. Gesundh. 20:465-467, 1965. Schoeffel, M. E., V. M. Arean, and J. S. Gravenstein. Liver and kidney damage after anesthesia. Southern Med. J. 58:198-204, 1965. Slater, E. M., J. M. Gibson, M. H. Dykes,and S. G. Walzer. Postoperative hepatic necro- sis. Its incidence and diagnostic value in association with the administration of halo- thane. New Eng. J. Med. 270:983-987, 1964. Stark, G., and B. Claude. Der Einfluss der Narkose auf die Transaminasen (GOT, GPT) und Dehydrogenasen (LDH, MDH) im Serum. Anaesthesist 13:38-40, 1964. Stephen, C. R., J. H. Lawrence, L. W. Fabian, M. Bourgeois-Gavardin, S. Dent, and D. C. Grosskreutz. Clinical experience with Fluothane; 1,400 cases. Anesthesiology 19:197-207, 1958. Temple, R. L., R. A. Cote, and S. W. Gorens. Massive hepatic necrosis following general anesthesia. Anesth. Analg. (Cleveland) 41:586-592, 1962. Thije, O. J. ten, C. Pearce, and W. J. Heyen- brok. Leverbeschadiging door halothaan. Nederl. T. Geneesk. 109:1069-1072, 1965. Tornetta, F. J., and H. T. Tamaki. Halothane jaundice and hepatotoxicity. J.A.M.A. 184: 658-660, 1963. Tracy, E., and J. Heyman. Combined effects of halothane and long-term tranquilizer treatment on liver function. J. Amer. Assoc. Nurse Anesthetists 32:302, 1964. Tygstrup, N. Halothane hepatitis. Letters to the Editor. Lancet 2:466-467, 1963. Urso, L., P. R. Dal Monte, F. Breschi, and A. Tura. Studio funzionale e bioptico del fegato in pazienti sottoposti ad anestesia fluotanica. Minerva Anest. 30:204-206, 1964. Verdena1, J., A. Marzet, and J. Delarue. Un cas d'ictere grave dans les suites d'une anesthesie a 1'halothane. Anesth. Analg. (Paris) 20:597-602, 1963. Vickers, M. D., and O. P. Dinnick. Post- operative hepatic morbidity with special reference to the role of halothane. Anaes- thesia 20:29-58, 1965. Virtue, R. W., and K. W. Payne. Case re- ports. Postoperative death after Fluothane. Anesthesiology 19:562-563, 1958. Vourc'h, G., E. Schnoebelen, F. Bucke, and L. Fruhling. Hepatonephrite aigue mortelle apres anesthesie comportant de 1'halothane (Fluothane). Anesth. Analg. (Paris) 17: 466-475, 1960... Wilson, R. D., A. B. Tarrow, and S. Garvin. Hepatic effects of halothane: A clinical and laboratory evaluation of 10,129 admin- istrations. Anesth. Analg. (Cleveland) 43:40-43, 1964. Winkler, K., P. Sejersen, and H. Rask. Halo- thane. Lancet 2:902-903, 1965. 18
TABLE 3.âHEPATIC DAMAGE AFTER ANESTHESIA AND OPERATIONâFATAL CASES IN THE LITERATURE (1958-1966), CLINICAL HISTORIES* Case Reference Sex and age, years Pre-existing hepatic disease Operation Anesthetic agent (duration, rnin)» Trans- fusion Complications Drug therapy Qaset of postoperative J aund ice, days Cause and day of death after operation 1 16 U Chronic passive congestion Aortic valvulo- plasty H (60) Yes Hypotension during opera- tion -- ? Hepatic failure 6 48 C (120) 2 86 F Jaundice Cholecystectomy, choledochotomy H No Hypotension and Penicillin streptomycin, erythromycln, tetracycline " Hepatic failure 11 39 respiratory depression dur- ing operation 3 87 U None Inguinal herniorrhaphy H (60) No â Penicillin, edrenoxyl, vitamin K 4 Hepatic 35 failure 4 4 78 U Alcoholism (1) Stin graft, leg H (30) No -- (24) 44 (2) Thyroidectomy H (180) Yes Penicillin, steroids 2 Hepatic failure 3 5 17 U None Appendectomy Non-H Yes Penicillin, strep tomy c In, chlorampheni- oolr sulfa- methoxypyri- dine, FUra- dantin 2 Hepatic failure 23 16 6 17 U None Lobectomy Non-H Yes Isoniazid, para-amlno salicylic acid, pyrazin- amide, strep- tomycin 14 Hepatic failure 23 41 (6 weeks previ- ously) 7 17 U None Prostatic biopsy Non-H No Septicemia Sulfieoxazole 7 2 Septicemia 9 69 8 60 U 48 None Lamineotomy Ch (300) Yes Hypotension during opera- tion Imipramine (preopera- tively) No Jaundice Sudden death; ? cardiac 2 9 61 H 72 Alcoholism, Jaundice, enlarged liver (1) -- H â â â â (22) (2) â Ch â â mm Progressive Hepatic failure , . 10 25 U Cirrhosis Cholecystectomy, choledochotomy I Transient hypotension during opera- tion Prochlor- perazine 7 Hepatic failure 32 48 11 25 F (1) &ophagoscopy H - Atrial fibril- lation -- 58 (2) Cholecystec- tomy, repair of diaphragmatic hernia H Dehlscence Prochlorpera- zine (25) (28) (3) Wound repair H â Dehiscence â (6) (9) (4) Wound repair H â â â 2 Hepatic failure 5 12 25 F 74 ~ Cholecystectomy, gastrostomy E Yes - Prochlorpera- zine ? 24 Leukemia 34 13 1 4 F 70 Abnormal hepatic function tests Cholecystectomy, liver biopsy H (170) No ~~ " 15 Hepatic failure 20 14 14 F 74 Episodes of dark urine and light- colored stools Cholecystectomy, choledochotomy, liver biopsy H (180) No Cholangitis, stapliylococcal Bunamiodyl, antibiotics ? 26 Hepatic failure 43 15 14 U 63 None (1) Repair of ret- inal detachment H (160) No None -- (2) Same H (150) No None â â (72) (3) Same H (165) No None ? 6 Hepatic failure 16 *H, halothane; N, nitrous oxide; C, cyclopropane; E, diethyl ether; V, divinyl ether; Ch, chloroform; V, methoxyflurane; Tri tri ethylene; and R, regional anesthesia. ichloro- 19
Table 3 (Cont'd) Case Reference ;;cx and age, years Pre-existing hepatic disease Operation Anesthetic agent (duration, min)» Trans- fusion Complications Drug therapy Onset of postoperative Jaundice, days Cause and day of death after operation 16 15 F 16 None Repair lacerated wrist H (280) No None - No Jaundice Hepatic failure 14 17 15 U Alcoholism (1) Plication of perforated duode- nal ulcer H (85) No None - (19) 67 (2) Gastrectomy H (285) Yea Hypotension - 6 Hepatic failure 9 18 54 U Alcoholism (1) Plications of perforated duode- nal ulcer H (80) No None â (59) 49 (2) Gastrectomy U (235) No None Neomycin, hydrocortisone, vitaInin K 2 Hepatic failure 10 19 80 F 68 None (1) Radical mastectomy H (135) Yes None -- -- (52) (2) Skin graft H (30) No None Tetracycline, prochlorpera- zine, isopro- p amide 11 (43) (3) Exploratory laparotomy C No None â Progressive Hepatic failure 17 20 80 F 62 None Cholecystectomy, choledochotomy H No None Tetracylcine, novobiocin, promethazine 21 Hepatic failure 38 21 19 F None (1) D & 0 H No None â (18) (25) 55 (2) Hysterectomy H (90) No G.U. tract infection Sulfadimidine 11 Hepatic failure 18 22 26 F None (1) Pelvic exami- nation H No None -- -- (63) 55 (2) Hysterectomy H (125) No Wound infection Penicillin, streptomycin, tetracycline 19 (56) (3) Radium im- plantation H (10) No None Neomycin, prednisone Progressive Hepatic failure 21 23 34 F 55 None (1) Cholecystec- tomy, choledochot- omy H No Trans ection hepatic duct, reanastomosis promethazine 17 (27) (2) Exploratory laparotomy H No None â Continued (10) (3) Exploratory laparotomy Non-H- No None -- Continued Hepatic failure 6 24 84 F 82 None Colectomy, herniorrhaphy ll Yes None Penicillin, streptomycin 5 Hepatic failure 7 25 6 F 68 None (1) Radium implantation H, Tr No None â (23) (46) (2) Same H, Tr No None â (16) (39) (3) Same H, Tr No None â 2 ? Hepatic failure 25 26 62 F 67 None (1) Cholecystot- omy U (60) No None Oxytetracy- cline (23) (26) (2) Keller's operation H (90) No None -- 3 (6) (3) Choledocbot- N No None -- Continued Hepatic failure 3 omy 27 20 F 40 None (1) Cervical biopsy N No None â (28) (2) Radium implantation H No None -- (15) (18) (3) Radical hysterectomy H, R Yes None Neomycin, steroid 1 Hepatic failure 4 (140) 28 75 U None (1) Gastrectomy C (240) Yes Hypothermia, hypotension Norepinephrine infusion, pro- longed 2 (9) 70 (2) BCploratory laparotomy, colon resection None Moribund Continued ? Siock 1 20
Table 3 (Cont'd) Case Reference Sex and Pre-existing hepatic disease Operation Anesthetic agent (duration, min)« Trans- fusion Complications Drug therapy Onset of postoperative Jaundice, days Cause and day of death after operation age, years 29 75 U 54 (1) Craniotomy H (570) Yes Status epilepticus Barbiturates, diphenyl- hydantoin -- (23) (2) Craniotomy H (330) Yes Transient hypotension during opera- tion Prochlorpera- zine 8 Hepatic failure 10 30 64 F 68 Reduction frac- tured tibia and fibula H Yes Ni trof urantoin, oxytetracyc- line, phenindlone, neomycin Jaundice ? 54 31 64 F (1) Slgmoidoscopy H No â Phthalylsulfa- thiazole, neomycin (15) (32) 52 (2) Colectomy Non-H Yes -- ~ (1) Hepatic failure 8 32 1 F 49 None ( 1 ) Biopsy, vulva H (65) No Cystitis Azo-gantrisin â (57) (2) Vulvectomy H (60) Yes None Chloramphenicol (22) (35) (3) Inguinal node dissection H (70) Yes None Penicillin, streptomycin, neornycin, Solucortef , Konakion 2 Hepatic failure 6 33 18 r None Cl) Sigmoidoecopy H No None â (26) 56 (2) Oolostomy H (100) No None Neomyoin, (11) (17) promethazine (3) Oolectomy H (165) Yes None Tetracycline ''trichloryl" 5 Hepatic failure 11 34 53 F 68 â Cys tec tomy H ~ ~ ~ Not stated Renal failure 14 35 9 F 75 None Gastrectomy, pyloroplasty C Yes -- ~ 5 Pulmonary infarction 8 36 9 F None Hemicolectomy C Yes None â No Jaundice Not stated 21 74 37 28 U Alcoholism, cirrhosis (1) /taputation, foot R No None Oral anti- diabetic drugs, tetracycline, chloramphenicol " (23) 54 (2) Same R No None â ~ (16) (3) Laminectomy H (225) Yes None Aureomycin, chloramphenicol 2 Hepatic failure 8 38 13 F 59 None Tonsillectomy H (90) No hVpotension ~ ? 14 Hepatic failure 40 39 13 F 23 Pre -eclamp- sia, mild Cholecystectomy H (105) No None Antibiotics 1 Hepatic failure 12 40 13 F 39 None (1) Breast biopsy H (75) No None â â (17) (2) Radical mastectomy H (180) No Convulsion, postopera- tively Penicillin, -i. 6 Hepatic failure 6 tetracycline, chloramphenicol 41 13 H 73 None (1) Cystoscopy H (15) No None â â UO) (2) Pros tatec tomy R (80) No None - - (36) (3) Cystoecopy H (30) No None - - (12) (4) Excision renal cyst H (75) No None â 1 Hepatic failure 8 42 10 F 54 None (1) Carotid arte- riogram H (75) No None Diatrizoate (2) Craniotomy H (270) Yes None (3) Carotid arte- riogram H (75) No None Diatrizoate 5 (4) Arteriogram and craniotomy H (270) Yes None Urograf in 8 ? 7 mos. 334-553 O-69â3 21
Table 3 (Cont'd) Sex Pre-existing hepatic disease Anesthetic agent (duration, min)» Trans- fusion Drug therapy Onset of postoperative Jaundice, days Cause and day of death after operation Case Reference and age, years Operation Complications 43 69 F 53 Jaundice Exploratory laparotomy C Yes (4 mos. pre- opera- tive- Isoniazid, . I para-amino- salicylic acid, sulfisoxazole, diphenyl- hydantoin, primidone Continued 1y) 44 69 U 66 Alcoholism Debridement and skin grafts x 5 E, C, N Yes â -- 2 months 69 45 69 T 69 Jaundice Exploratory laparotomy C No None ~ Continued -- 46 69 F 55 Chronic hepatitis Bowel resection ( infarction ) None Yes Hypo tension Vesopressors Shock 5 (8 mos. pre- opera- tive- 1y) 47 69 F 60 Jaundice Exploratory laparotomy (ca of pancreas) C No Hypo tens ion Vasopressors Continued Shock 4 48 69 U Alcoholism (1) debridement and skin graft ? C or N Yes None Antibiotics (42) (42) 50 (2) Same H No None â (29) (29) (3) Same ? C or N No None ~ 10 ? Shock 10 49 74 F None Cholecystectomy, choledochotomy H (180) No None Chlorampheni- col, neomycin steroids 9 Hepatic failure 24 34 50 74 F None (1) Dressing, for burns V, K Yes None Penicillin (44) (44) (2) Same (7 days) V, E Yes None â (35) (35) (3) Same (16 days) V, E Yes None 26 Q.I. bleed- ing; ? hepatic failure 8 51 73 U None Pyloromyotomy H (30) Yes None Terramycin, steroid, 5 Hepatic failure 8 5 wks. levulose 52 3 F None (1) Vsin ligation H No None -- - (72) (2) Same H No None -- 21 Hepatic failure 30 53 63 M 44 None Herniorrhaphy H (120) No None - 8 Hepatic failure 12 54 63 M Jaundice (1) Excision sali- vary cyst H No None - - 69 (2) Cholecystec- tomy H (330) No None â Progressive Hepatic failure 36 55 63 F None (1) Nephrectomy H (120) No None â â (35) (2) Pneumonectomy H (240) Yes None -- 3 Hepatic failure 16 56 63 F None (1 ) Glossectomy H (105) No None ~ - (55) (2) Radical neck dissection H (180) Yes None â¢â¢ 4 Hepatic failure 17 57 63 F 42 None (1) Cervical node Non-H No None -- -- biopsy (2) Thyroidectomy, radical neck dis- section H (240) No None 10 Staphylo- coccal septicemla 3C 58 85 F 56 None (1) Radium implan- tation H No None -- - (33) (2) Same H No None - - (26) (3) Radical hys- terectomy H No None â 3 Hepatic failure 5 59 40 F Cirrhosis Liver biopsy H No Hypo tension Corticoids, 3 Hepatic failure ? 60 Vasopressors 22
Table 3 (Cont'd) Case Reference Sex and age, years Pre-existing hepatic disease Operation Anesthetic agent (duration, min)» Trans- fusion Complications Drug therapy Onset of postoperative Jaundice, days Cause and day of death after operation 60 40 F 45 History of Jaundice (1) ttysterectomy H No (2) Cholecystec- tomy H No Hypotension Corticoids, vasopressors 14 Hepatic failure ? 61 40 F 23 None D & C, colpotomy H No -- - 7 Hepatic failure 1 62 33 M None Small bowel re- section C (150) â typo tens ion before opera â tion Norepinephrine infusion 2 Hepatic failure ? 57 63 33 F 87 None Nailing of hip fracture N -- -- -- No Jaundice ? 12 64 33 F 35 â Mitral valve prosthesis N (420) Yes â â 3 tyocardial infarction 27 65 33 F None Hysterectomy C (120) Yea Shock Norepinephrine 10 Uremia 21 41 66 33 H 74 None Choleoystectomy, drainage of ab- scess R â -- -- â Bronchopneu- monia, hepatic necrosis ? 67 33 F 54 Metastatic tumor of liver Exploratory lapa- rotomy, resection of liver (rt. lobe) C (555) ~- ~â ~~ 2 ? Hepatic failure 12 68 72 U None Gas trec tomy H (265) Yea None - 1 0.1. bleeding ? 59 69 72 H 54 None ? Resection of urinary bladder H (200) Yes Uremia - 1 Uremia ? 70 72 F 63 None Gastrectomy, splenectomy, pan- createctoay H (210) Yes Peritonitis, portal venous thrombosis â 2 Peritonitis T 71 72 M None Hemicolectomy H (215) Yes Peritonitis â 1 Peritonitis ? 59 72 72 M None Colostomy H (135) Yes Uremia, peritonitis -- 1 Uremia ? 70 73 72 U None Oestrectomy H (250) Yes -- ~ 2 Pulmonary embolus ? 51 74 29 74 None esophagoscopy H (25) No Mediastinitis -- 1 ? ? 75 29 65 Cirrhosis Prosthesis, hip B (230) Yes -- -- ? 8 ? ? 76 29 None lliofemoral endar- terectomy Z, N, H No â â 2 1 ? 60 (305) 77 29 r None (1) Cystoscopy, D & C, cervical biopsy C (30) No â -- â 47 (2) Pelvic exen- teration C (3080) ? Hypotension, staphylococcal respiratory in- fection, en- terocolitis Succinylsul- fathiazole, sulf isoxazole ? 8 ? ? 78 29 75 None Gastrectomy B (250) " Hypotension, subhepatic abscess â ? 3 ? T 79 29 43 None lliofemoral 0 (205) -- Septicemla -- 4 Septicemia ? enibo lec tomy 80 29 78 None Colectomy 0 (330) â Pneumonia Chlorpromazine, phthalylsulfa- thiazole 4 ? » 81 29 81 None (1)' Abdominal perineal resection and prostatectomy B (300) - Hypotension Phthalylsulfa- thiazole (2) Gastrectomy C (240) 4 ? ? 23
Table 3 (Cont'd) Case Reference Sex and age, years Pre-existing hepatic disease Operation Anesthetic agent (duration, min)» Trans- fusion Complications Drug therapy Onset of postoperative Jaundice, days Cause and day of death after operation 82 79 U 46 None (1) & (2) Excision tumor of cheek H No None - (3) Same H No None - 7 (4) Same H No None Prednisone 2 (5) Carotid cathe- terization H No Vomiting Methotrexate 1 (6) Radical neck dissection N, E No None â (7) Wound closure N, S No G.I. hemor- rhage, shock (31 days post- ope ratively) 2 G. I. hemor- rhage 34 83 27 U None ( 1 ) Craniotomy H (300) â None Isoniazid (13) 21 (2 ) Craniotomy H (150) " None Isoniazid No Jaundice Intra ventric- ular bleed- ing 3 84 58 F 20 None Cholecys tec tomy H (240) No None Acetaminophen, trimethoben- zamide, chlor- promazine 9 Hepatic failure 15 85 52 F 23 ? None Craniotomy, pos- terior fossa H (300) Yes Postoperative respiratory distress â No Jaundice Respiratory failure 6? 86 52 F 55 ? None (1) Craniotomy H (330) Yes Brain edema â 1 (2) (2) (2) Craniotomy ? â â Sudden death 1 87 52 f 66 ? None Craniotomy, pos- terior fossa H (270) Yes -- 1 Bronchopneu- monia 2 88 52 U ? None Gastrectomy H (90) Yes Preoperative hemorrhage and shock â 1 Hepatic failure 8 61 89 52 M ? None Craniotomy H (240) Yes Acute circula- tory failure (5 days post- operatively ) " No Jaundice Circulatory failure 5 33
TABLE 4.--HEPATIC DAMAGE AFTER ANESTHESIA AND OPERATIONâFATAL CASES IN THE LITERATURE (1958-1966), LABORATORY AND NECROPSY FINDINGS* Serum billrubin, ADtaline phos- phatase, units Pro- Albumin, Other laboratory findings Case UK * SOOT SOFT OF TT throm- bin time g % Pathologic findings Author's remarks or conclusions Total Direct 1 44.8 Chronic passive congestion, central lobular necrosis of liver Changes in liver could have resulted from heart failure 2 Clotting time, 3O min. Massive hepatic necrosis, pancre- atic necrosis Course and hepatic changes similar to delayed chloroform poisoning 3 3 Urea nitrogen 63 mg * Acute degenerative hepatitis, renal tubular necrosis Implicating halothane 4 11.9 6.7 14.3 (B) 244 10* Bili rub in - uria Massive hepatic necrosis, pancre- atic and renal necrosis Circumstantial evi- dence was provocative but no proof of halo- thane poisoning 9 23.2 12.2 7.7 (?) 27,000 14,000 8 Massive centrilo- bular hepatic necrosis, cholemic nephrosis Not possible to deter- mine etiology of liver necrosis, viral or drug induced units 6 12.6 4.7 520 3+ 5 15* Massive hepatic necrosis Drug or serum hepatitis 7 81 51 5.8 (B) 180 3+ units 12* Centrilobular hepatic necrosis Hepatic necrosis prob- ably due to drug sen- sitivity or septicemia 8 Massive centrilo- bular hepatic necrosis, marked fatty metamorphosis Hepatic damage similar to that in chloroform poisoning 9 Diffuse hepatic and renal necrosis Possibility that halo- thane and chloroform caused toxic effects in a patient with pre- existing hepatic dis- ease 10 5.6 1.4 2.5 -~ Cause of hepatic necro- sis unexplained by operation 11 6.1 1.9 35.6 (KA) 111.5 nmy'hr/] 2.75 Acute hepatic necrosis Cause of hepatic necro- sis unexplained by operation 12 6.8 1.6 ? Atypical myelo- cytic leukemia Cause of hepatic de- terioration not ex- plained by operation 13 19 9.4 5.9 (KA) 1100 <10* Acute yellow atro- phy Strong implication that halothane induced hepatic necrosis 14 52 26 (KA) 330 4+ Neg 14 BSP reten- tion, 77% Massive central and midzonal coagula- tion necrosis, cholestasis Strong implication that halothane induced hepatic necrosis 15 Early postnecrotic cirrhosis, wide areas of recent necrosis and regen- eration, cholesta- sis Strong implication that halothane induced hepatic necrosis 16 <10* Central and mid- zonal hyaline hepa- tic necrosis, bile stasis, renal tubu- lar necrosis Strongly suggest that halothane may be responsible »KA, King-Arnstrong units; B, Bodansky units; S, Shlnowara units; SGOT, serum glutamic oxaloacetic transaminase; SGPT, serum glutamic pyruvic transamlnase; CF, cephalln flocoulation; TT, thymol turbidity; IDH, lactic dehydrogenase; and ICD, isocitric dehydrogenase. 25
Table 4 (Cont'd) Case Serum billrubln, mg % Alkaline phos- phatase, units SOOT SOFT CF TT Pro- tarcm- bin time Albumin, f * Other laboratory findings Pathologic findings Aithor's remarks or conclusions 17 Total Direct BUN, 96 Massive hepatic Strongly suggest that halothane may be responsible mg * necrosis, renal tubular necrosis, coronary occlusion 18 29.5 17 (KA) 720 600 2+ + 44 sec Massive hepatic necrosis, choleeta- sis, renal tubular necrosis, focal pancreatitis Implicating halothane as the responsible agent 19 13.2 26 (B) 190 4+ Neg 46* Centrllobular hepatic necrosis, cholestasis Strong likelihood that halothane caused Jaundice and death 20 36 25 20 (B) 1260 NPN 209 Massive hepatic necrosis, mild cholestaais, nephro- sis Strong likelihood that halothane caused Jaundice and death *e % 21 21.3 7.9 18 (?) >800 >800 3 51 sec 3.6 Zinc sul- f ate 3 Total necrosis of all liver cells Hard to prove causal relationship between halothane and hepatic damage 22 12 >1000 units 3.3 units floc- culation Subacute hepatic necrosis, G.I. hemorrhage Implying causal rela- tionship between halothane and hepatic necrosis 19.5 23 13 >150 Acute yellow atror phy, biliary tract normal "Conjectures regarding causal relationship are valueless." 24 BUN, 142 n«* Bc tensive periportal degeneration of liver "Typical toxic degen- erative hepatitis." 25 11.4 35 100 Widespread centrilo- bular focal necrosis of liver, early postnecrotic cir- rhosis Implicating halothane and radiotherapy 26 9.4 4.3 11 (?) 1250 + 3+ 25 sec Massive hepatic necrosis Aitiblotics and viral hepatitis are possible causes of hepatic necrosis 27 24.8 13.4 220 540 Massive hepatic necrosis, no cellu- lar infiltration or proliferation 28 25.6 Focal areas of centrilobular necro- sis of liver Suggest that prolonged shock and sepsis were responsible for hepatic necrosis 29 13.6 6.8 (B) 650 4+ 2.6 2.9 Evidence highly sug- gestive of toxic hepatitis units 30 39 (KA) 54 34 2+ Liver pale, fatty and friable, sup- purative pyelone- phritis, pulmonary infarction 26
Table * (Cont'd) Case Serum bllirubin, OK % Alkaline phos- phatase, units SOOT SOFT OF TT Pro- throm- bln Albumin, 8 * Other laboratory Pathologic findings Author's remarks or conclusions Total Direct time findings 31 Acute hepatic necro- sis, septic spleen, bronchopneumonia 9.2 44 (KA) 2 Zinc sul- fate tur- bidity, 3 units 32 1.4 Massive hepatic necrosis, no inflam- matory Infiltration "A clear cut case of hepatic necrosis caused by halothane. " 14.4 5.6 (?) 1940 2400 Neg Nog -C1O* 2.5 BUN 26 mg* 33 Advanced hepatic necrosis, minimal mixed cellular in- filtration, renal tubular degeneration "Possible halothane induced hepatitis." 18.0 20 (KA) 1200 860 3 units Zinc tur- bidity 4 units 34 Hepatic necrosis, renal candidiasis Toxic hepatic necrosis could not be ruled out 35 6.0 "1.8" Subacute hepatitis with fatty degenera- tion "Cyclopropane hepati- tis" 36 Interstitial sub- acute hepatitis "Cyclopropane hepati- tis." 37 28 (KA) 23 sec Advanced Laennec's cirrhosis, no necro- sis or fatty change, G.I. hemorrhage "Precipitating cause of fatal liver failure was not known." 38 23.2 26 (KA) 1800 748 4+ 3+ 10* Central and midzonal coagulation necrosis of liver, chole- statis, renal tubu- lar necrosis Halothane may have acted as a hepatotoxin 39 3.4 3 (B) 1260 Neg Neg 10* Central and Midzonal coagulation necrosis of liver, renal tubular necrosis, pancreatitis Halothane may have acted as a hepatotoxin 40 58 Massive hepatic necrosis, renal tubular necrosis Halothane may have acted as a hepatotoxin 41 10 20 (KA) 35 Neg Neg Massive hepatic necrosis, renal tubular necrosis Halothane may have acted as a hepatotoxin 42 22 17 (B) 374 406 4+ Neg 11* Liver biopey after 3rd and 4th opera- tions: focal hepatic necrosis, mixed cel- lular infiltration; autopsy: parenchy- ma tous degeneration of liver, dilated sinusoids Causal relationship between halothane and hepatic damage is possible 20 24.8 (KA) 41.9 17.6 nn/hr/1 nn/hr/1 0.2 14.5 35.1 (KA) 7.4 nm/hr/1 7.1 un/hr/1 0.27 BSP reten- tion (45 min), 36* 43 24.0 3.8 (B) 4+ 15 sec Massive hepatic Probably viral hepa- titis, questionably drug toxicity necrosis, focal periportal mixed cellular Infiltra- tion
Table 4 (Cont'd) Serum bllirubin, »g * Alkaline phos- phatase. Pro- Other laboratory findings Case Total Direct units SOOT SOFT OF TT throm- bin time Albumin, g * Pathologic findings Author's remarks or conclusions 44 10.0 6.4 (a) 23 sec Massive hepatic necrosis, moderate periportal fibrosis Probably viral hepa- titis 45 30.0 12.3 (B) 4+ 16 sec Massive hepatic necrosis, moderate mononuclear infil- tration Etiology unknown 46 4.2 (B) 3+ 27 Cirrhosis of liver, massive parenchymal necrosis Hepatic necrosis due to prolonged shock and vasopressor ther- apy, chronic hepatic disease sec 47 38 11.8 (B) 155 2+ 45 sec Massive centri- lobular hepatic necrosis Prolonged shock and vasopressor therapy 48 3.9 4.5 (B) 16 sec Massive hepatic necrosis, lympho- cytic infiltration with broad bands of connective tissue ? Viral hepatitis, ? halothane hepatitis 49 31 7.5 2150 52 sec Massive central and mid zonal hepatic necrosis, renal tubular degenera- tion "Toxic hepatic necro- sis . " 50 Massive hepatic necrosisj minimal inflammation; renal tubular necrosis "Toxic hepatic necro- sis and nephritis." 2150 43 I CD 3280 units 51 30.9 21.8 ' 590 sec Acute hepatic dys- trophy, endemic nephrosis Suspicious of 'causal relationship between halothane and necrosis but no proof 52 Massive hepatic ne- crosis, pulmonary edema Cause of hepatic necrosis not indicated by histology 26. 19.2 23 (KA) 430 2 BUN, 30 rag % 53 5 702 1872 units Pro- longed Massive hepatic necrosis, minimal cellular infiltra- tion Suggest causal rela- tionship between halothane and hepatic necrosis 54 28 110 Pro- longed Moderate centri- lobular hepatic necrosis, marked cholestasis Suggest causal rela- tionship between halothane and hepatic necrosis 55 37 1230 2200 Massive centri- lobular hepatic necrosis, chole- stasis, active regenerative proc- ess Suggest causal rela- tionship between halothane and hepatic necrosis 56 Massive centri- lobular hepatic Suggest causal rela- tionship between halothane and hepatic necrosis 57 22 2320 Pro- longed necrosis Suggest causal rela- tionship between halothane and hepatic necrosis, liver status improved before onset of septicemia 58 34 1400 Massive hepatic necrosis "Inexplicable by other causes. " 9.4 26 (KA) 1880 11500 28
Table 4 (Cont'd) Case Serum bilirubin, 5 * Alkaline phos- phatase, SCOT SOFT CF TT Pro- throm- bln Albuminj « * Other laboratory findings Pathologic findings Author's remarks or conclusions Total Direct units time » 10 (KA) 29* 3.3 Icteric index, 63 Extensive necrosis of hepatic tumor cells, atrophy of central cords Implicating halothane 60 10.6 15 (KA) 700 Implicating halothane 56 1 4 (KA) 1005 <5* 61 3.7 2175 12* 3.2 Extensive oentri- lobular hepatic necrosis Implicating halothane 62 Acute diffuse hepa- titis, lower nephron nephrosis Specific etiologic factor not stated 63 Early postnecrotic scarring Specific etiologic factor not stated (A Focal hepatic necro- sis and fatty infil- tration Specific etiologic factor not stated 65 Messy fatty infil- tration of liver, lower nephron nephrosis Specific etiologic factor not stated 66 Massive subscapular hepatic necrosis, pancreatic fistula Specific etiologic factor not stated 67 Necrosis of liver, left lobe; severe fatty infiltration, splenic infarcts Specific etiologic factor not stated 66 20.8 6.8 (B) 83 29 Intrahepatic chole- stasis Benign syndrome re- sulting from operation, not related to so- called halothane Jaundice 69 13.6 10.4 (B) 114 30 Intrahepatic chole- stasis Benign syndrome re- sulting from operation, not related to so- called halothane Jaundice 70 27.6 18.1 (B) 33 20 Intrahepatic chole- stasis Benign syndrome re- sulting from operation, not related to so- called halothane Jaundice 71 17.3 4.3 (B) 84 23 Intrahepatic chole- stasis Benign syndrome re- sulting from operation, not related to so- called halothane Jaundice 72 11.5 2.4 (B) Intrahepatic chole- stasis Benign syndrome re- sulting from operation, not related to so- called halothane Jaundice 73 17.1 3.1 (B) Intrahepatic chole- stasis Benign syndrome re- sulting from operation, not related to so- called halothane Jaundice 7* 9.8 7.7 550 2.4 Moderate acute con- gestion of liver No evidence to prove that halothane is or is not hepatotcocic 75 M.1 4.7 (B) 4+ 2.2 Lsennec's cirrhosis with marked necro- sis and inflamma- tion No evidence to prove that halothane is or is not hepatotoxic 76 33.9 11 (B) 141 4+ 4+ 1.7 Slight fatty change and congestion of liver No evidence to prove that halothane is or is not hepatotoxic 29
Table 4 (Cont'd) Case Serum bilirubin, mg % Alkaline phofl- SCOT SOFT CF TT FTo- throm- bin time Albumin, Other laboratory findings Pathologic findings Author's remarks or conclusions 77 Ibtal Direct unlts g * Severe fatty change No evidence to prove that halothane is or Is not hepatotoxic 0.8 8.1 (B) 2+ 2+ 3.1 78 2.8 1.8 (B) 3.4 Subhepetic abscees with adJacent necro- sis, marked chole- stasis No evidence to prove that halothane is or is not hepatotoxic 79 6.4 12.8 (B) 50 2.6 ~~ No evidence to prove that halothane is or is not hepatotoxic 80 5.8 6.0 (B) 25 3.6 Nutritional cirrho- sis, moderate fatty change No evidence to prove that halothane is or is not hepatotoxic 81 19.0 14.0 (B) 45 2.9 No evidence to prove that halothane is or Is not hepatotoxic 82 4.2 1.6 t ->- Uver biopsy after 4th operation: cholangitis, fatty change, no necrosis; autopsy: cholangi- tis, centrllobular hepatic necrosis, fibrosis, fatty change; metastatic tumor In lung and liver, bleeding duodenal ulcer, cholelithiasis "It appears likely that Jaundice after 4th and 5th operations was due to halothane; cholangl- Us differs from the picture found in moet reported cases of post- halothane liver dam- age." 14.0 30 (KA) 2360 1060 4 unite 10.0 30 (KA) 500 83 9.0 -30 (KA) 4 units Pro- longed Massive hepatic necrosis Etiology of hepatic necrosis not clear 84 5.5 21 (KA) 7000 Massive hepatic necrosis No opinion offered 85 Scattered focal hepatic necrosis, fatty change at pe- riphery of lobules; pulmonary Infarc- tion, atelectaale, and edema Death was due to pul- monary changes; fatty change in liver may be toxic in origin 86 Centrllobular focal hepatic necrosis, diffuse fatty change, cholestasis; meningeal hemor- rhage, brain edema Suggesting allergic reaction 87 8.02 Increase Centrllobular fatty change in liver with cholestasis, severe bronchopneumonia, slight toxic nephrosis Compatible with toxic hepatosis 88 in urine urobilin- ogen Diffuse fatty change, cholestasis, and focal necrosis in liver; Intra- abdominal hemorrhage Toxic hepatosis in addition to hemorrhage and shock 89 Dlffuae fatty change, cholestasis, and focal necrosis of liver; hernia- tion of brain stem Death was due to brains tern hern i at ion; toxic hep at os is 30
TABLE 5.âHEPATIC DAMAGE AFTER ANESTHESIA AND OPERATION--NONFATAL CASES IN THE LITERATURE (1958-1966), CLINICAL HISTORIES Case Reference Sex &nd age, years Pre-existing hepatic disease Operation Anesthetic agent (dur- ation, min)» Trans- fusion Complications Drug therapy Onset of postoperative Jaundice, days Remarks 1 16 U None Frontal ainusotomy H No Hypotension during operation -- ? 70 46 2 5 U None (1) Prostatectomy H â ~ -- Yes, onset not stated (2) Exploratory laparotomy ? " " Laparotomy for cause of Jaundice; none found 3 5 11 None tepair, fracture of patella H -- -- - Yes, onset not stated 4 14 F 51 None [1) Excision of breast cyst H (90) No None Bunamiodyl Fever, RUQ pain, 1 day postopera- (2) Cholecystec- tomy, choledocho- Lomy H (210) No None Penicillin 11 tively s 54 F 52 None (1) Arthrodesis, ankle H No None -- - (2) Joint fusion, foot H No None -- 3 Fever, imne - diately after operation (3) Arthrodesis, toes H No None - 6 6 54 F 50 None (1) Transabdcminal polypectomy C, H No Hypo tension Metaraminol -- '2 ) Exploratory laparotomy C Yes Hypotension Metaraminol, tetracycline 22 (3) Repair, incl- sional hernia H No None â 8 1 year later 7 54 F 62 None (1) Radical mast- ectomy H (540) Yes None - " (2) Skin graft H No None -- 4 (3) Excision, renal cyst H (100) No None -- 5 8 54 F 60 None Radical vulvectomy H (600) Yes None Streptomycin isoniazid, bis- hydroxycou- marin No Jaundice RUQ pain, hepatomegaly, x-ray; shooed gall- stones 9 V, M None [1) Cystoscopy, proctoscopy H No Perforated ulcer (6 days postopera ti vely ) â -- 59 \2) Gastrectomy H Yes Thrombophle- bitis - -- (3) Colectomy H Yes â Bie-hydroxycou- marin 2 10 54 F 72 None |1) Breast biopsy H (180) No None -- -- '2) Simple mastec- tomy H (125) No Chills, fever -- 13 '.3) Exploratory, laparotomy, ehole- eystectomy, liver biopsy C, N (175) No " " Subsiding No biliary tract obstruc tion found 11 54 M None '!) Aspiration of knee Joint H No None â 16 !2) Arthrotomy Enee H No None â No Jaundice Splenomegaly, lethargy 12 54 M None Appendectomy H No None -- U Hepatomegaly 34 *H. halothane; N. nitrous oxide; C, cyclopropane; E. diethyl ether; V, divinyl ether; Ch, chloroform; M. methoxyflurane; Tr, trichloro- ethylene; and R, regional anesthesia. 31
Table 5 (Cont'd) Case Reference Sex and age, years Pre-existing hepatic disease Operation Anesthetic agent (dur- ation, min)« Trans- fusion Complications Drug therapy Onset of postoperative Jaundice, days Remarks 13 37 U 57 None (1) Hemiorrhaphy H (120) No None â (2) Phlebectomy H (169) No Pneumonia, staphylococcal Tetracycline, chloramphenl- col, penicil- lin, diphenhy- dramine 12 Chills, fever, skin rashes 5 days postopera- tively 14 34 F 41 None (1) D. 4 C. H No None Promethazine (2) Spine fusion H No Hypotension ~ 7 15 4 F 42 None (1) Cervical biopsy H No None - (2) Radium inser- tion H No None - 6 (3) Same H No None - (4) Same H No None - lmmed late Hepatomegaly 16 4 F 58 None (1) Cervical biopsy H No None ~ (2) Radium inser- tion H No None â (3) Same H No None - (4) Same H No None â Yes, onset not stated Hepatomegaly 17 i. F 59 None (1) D. & C., radium insertion H No None -- (2) Radium inser- tion H No None â (21) (3) Hysterectomy H Yes None - 1 Hepatomegaly 18 15 U " Cholecys tec tomy , choledochotomy, appendectomy E No " " 3 63 19 25 U " Cholecystectomy, repair umbilical hernia E No " Prochlorpera- zine 3 48 20 25 F mm (1) Cholecysteo- tomy H No Dehiscence -- 5 58 (2) Wound repair H No - - 21 25 F 56 -- Choleoys tec tomy H No -- - 49 22 19 F 47 â (1) D. & C. H No - - (26) (2) Hysterectomy H No -- - 5 23 68 F 34 None (1) Peripheral nerve operation H â â â (2) Peripheral nerve operation H - ~ Steroids 7 24 49 F 39 Childhood Jaundice (1) Delivery H No None - (2) Phlebectomy H No None - Several days 25 49 F 23 None (1) Dilatation of Wharton's duct H (25) No None â (2) Excision sub- mandibular gland H No None - 7 26 82 F 54 None (l) Carotid ar- teriogram H (60) No None Diatrizoate (19) (2) Cranlotomy H (240) Yes None Penicillin, tetracycline, salicylates 16 Fever (3) Carotid ar- teriogram H (60) No None Urographin 7 2 years after second opera- tion (4) Craniotomy H (240) Yes None Penicillin, Streptomycin, salicylates 7 32
Table 5 (Cont'd) Case Reference Sex and age, years Pre-existing hepatic disease Operation Anesthetic agent (dur- ation, min)* Trans- fusion Complications Drug therapy Onset of postoperative Jaundice, days Remarks 27 62 F 57 None (l) Bunionectomy H (150) No Wound Infection Erythromycin (33) (2) Amputation, toe H No None Tetracycline 5 28 62 U None Gas trec tomy H (360) Yes Transient hypo- tension during operation â 4 58 29 21 -- -- Gastrectomy H Yes Hypotension during oper- ation Chlorpromazine, promazine 5 30 21 â â Gastrectomy R Yes Hypotension during opera- tion â 5 31 59 M None Gastroenterostomy H (75) No None -- 3 63 32 9 H 57 None Pyloroplasty C Yes None Bis-hydroxy- coumarin 5 Lung infarc- tion 33 45 F 51 None (1) Cholecystec- tomy H -- ~ ~ (2) Thyroidec- tomy H No None - 5 Mentally confused 34 13 M None (1) Cecostomy H No None ~ 4 74 (2) Colectomy, liver biopsy E No None -- 35 64 U â Gastrectomy, vagotomy H Yes Intraperitoneal hemorrhage Penicillin, streptomycin, promethazine 5 40 36 64 U -- Gastrectomy H Yes - Chlorpromazine 3 32 37 64 U Nailing of femur H Yes Hematuria None ? 12 1 previous operation & 2 subsequent operations all with halo thane , uneventful 49 38 64 U â Appendectomy H No Ileus Oxytetracy- cHne, chlor- promazine ? 8 28 39 64 U 69 -- Amputation, leg H No None None 15 40 64 F 20 -- D. t C. H No ~ None 1 41 64 U 59 â (1) Nephrectomy Non-H Yes - None ? 3 (2) Hound repair H No - None No Jaundice 42 64 U ~ Appendectomy Non-H No -- None 3 Cholecysto- gram: gall- stones 37 43 64 M 65 -- Pneumonectomy Non-H Yes - Qulnldine, streptomycin 6 44 64 M 38 -- Appendectomy Non-H No - Streptomycin 5 45 64 F 14 - Appendectomy Non-H No â None 4 46 64 F 60 (1) Gastroenter- ostomy Non-H No Intestinal obstruction None ? (21) (2) Reconstruction, gastroenterostomy Non-H Yes None None ? 1 47 64 F 76 Hepatomegaly Colectomy Non-H No ? Coronary in- farction Chlorproma- zine, neomycin, streptomycin, meprobamate, imipramine 6 33
Table 5 (Cont'd) Cue Reference Sex and age, Pre-existing hepatic disease Operation Anesthetic agent (dur- ation, min)» Trans- fusion Complications Drug therapy Onset of postoperative Jaundice, days Remarks years 48 64 F 29 â Colectomy Non-H Yea -- Chlorproma- zine, neomycin, phthalyl- sulfathiazole 1 49 39 U -- Herniorrhaphy H (40) â ~ â 1 (mild) 26 5O 39 H 19 -- Appendectomy H (30) - - -- 1 (mild) 51 39 M -- Colectomy H (135) -- - - 5 (mild) 73 52 39 F 14 -- Appendectomy H (30) - - ~ 1 (mild) 53 39 U -- Plastic repair, penis H (30) - - -- 2 (mild) 46 54 39 U â Appendectomy H (65) â â ~ 2 (moderate) 27 55 39 F 38 â Gastrectomy, Appendectomy H (105) ~ â ~ 2 (mild) 56 39 U -- Appendectomy H (60) - ~ -- 1 (mild) 24 57 39 U -- Gastrectomy, appendectomy H (150) -- - -- 3 (mild) 27 58 39 U -- Gastrectomy, appendectomy H (195) - - ~ 3 (moderate) 61 59 39 M -- Appendectomy H (50) ~ - - 2 (mild) IS 60 39 U -- Appendectomy H (30) - -- - 4 (mild) 31 61 39 11 29 ~ Herniorrhaphy H (50) â â â 1 (mild) 62 39 F 19 -- Appendectomy H (50) ~ - ~ 2 (mild) 63 39 T 32 -- Appendectomy H(30) - - - 1 (mild) 64 39 U 59 - Herniorrhaphy H (50) ~ -- - 4 (mild) 65 39 U - Appendectomy H (30) - - ~ 2 (mild) 23 66 39 U ~ Herniorrhaphy H (50) - â -- 1 (mild) 48 67 39 U -- Gastrectomy H (120) ~ -- - 6 (mild) 54 68 39 U -- Appendectomy H (30) -- -- -- 2 (mild) 24 69 39 M 37 -- Appendectomy H (45) ~ - ~ 1 (moderate) 70 39 M 25 -- Appendectomy H (75) - - - 4 (mild) 71 39 U 45 -- Gastrectomy H (140) ~ -- -- 3 (moderate) 72 39 F 20 -- Appendectomy H (25) - - - 8 (mild) 73 39 U â Qaetrectomy, appendectomy H (105) ~ â â 4 (moderate) 64 74 39 F -- Cholecystectomy H (90) ~ - - 1 (moderate) 42 75 39 M ; Gastrectomy, appendectomy H (225) " 2 (mild) 59 ⢠34
Table 5 (Cont'd) Case Reference Sex and age, years Pre-existing hepatic disease Operation Anesthetic agent (dur- ation, min)« Trans- fusion Complications Drug therapy Onset of postoperative Jaundice, days Remarks 76 39 F 15 -- Appendectomy H (50) - - -- 2 (mild) 77 39 a - Herniorrhaphy H (270) â â ~ 4 (mild) 60 78 39 u -- Herniorrhaphy H (135) -- - - 7 (moderate) 53 79 39 M 20 -- Appendectomy H (15) - - - 1 (severe) 00 39 F 26 -- Appendectomy H (65) ~ -- -- 1 (mild) 81 39 U -- Herniorrhaphy H (70) ~ ~ - 2 (moderate) 40 82 30 F Hepatitis (2 years pre- viously Ligation patent ductus arteriosus H (60) No None ~ 3 6 83 10 M Cholestasis (1) Cystoscopy H (50) No None Nitrofurantoin, tetracycline 8 67 (2) Prostatectomy C No None ~ (3) Cystoscopy H(45) No - - 84 10 U None (1) Carotid ar- teriogram, cranio- tomy H (270) Yes None Chlorpromazine, urografin 6 Transfusion 16 days before oper- ation 44 (2) Pneumoence- phalogram H (75) No None â 85 56 H None (1) Ventriculogram H (35) No None ~ 5 days (2) Craniotonv H (75) Yes Septicemla - 3 86 56 U 3 days None ( 1} Craniotomy H Yes Septicemia - V, (2) Laparotomy, liver biopsy H (60) No None 87 56 F 3 days None (1) Cystoscopy H (45) No None - (2) Nephrectomy H (50) No None ~ 12 Diarrhea 88 12 M 59 History of Jaundice (34 years pre- viously) ( 1) Esophagoscopy H No None - Hepatomegaly (2) Esophagoscopy H No None -- 3 (3) Esophagogas- trectomy, liver biopsy N â â â â 89 24 U Alcoholism Hemorrholdectomy H (20) No None Prome thazine 15 44 90 43 U None (1) Appendectomy H No None Tetracycline 2 82 (2) Transurethral resection, pros- tate H No None -- 1 91 63 F 53 None Gastrectomy H (300) - None â 9 92 63 M None ( 1) Bronchoscopy H (55) ~ -- - (H) 72 (2) Pneumonectamy H (330) 7- - - 7 93 63 F 55 History of obstructive Jaundice Cholecystectomy, choledochotomy H (290) No None None 12 Chills, fever 94 63 F 34 None (1) Cervical node biopsy H (60) No None - (2) Total thyroid - ectoonr 1 H - â -- 5 Tetany, chills fever 95 85 U None Total parotidec- H (225) NO â - " 3 Hypo tensive anesthesia 77 tomy 35
Table 5 (Cont'd) Sex Pre-existing hepatic disease Anesthetic agent (dur- ation, min)» Onset of postoperative Jaundice, days Case Reference and age, years Operation Trans- fusion Complications Drug therapy Remarks 96 85 F 60 None (1) Radium implan- tation H No None - (2) Same H No None â (3) Same H No None â (4) Cystoscopy H No None - (5) Radical hys- terectomy H No None - 4 97 85 M None ( 1) Arteriogram H No None - 48 (2) Arteriogram H No None - (3) Craniotomy H ~ None - 11 98 85 M None (1) Gastrectomy H No HUQ pain (12 days postopera- tively) " 50 (2) Laparotomy N No None -- (15) 99 85 H None (1) Burr hole H No None -- (18) 22 (2) Burr hole H No None - 11 100 40 M Nutritional deficiency Colectomy H, C Yes None - 4 75 101 40 M Nutritional deficiency (1) Colectomy H Yes None - 11 24 (2) Sinus tract excision H No None ~ No Jaundice 102 40 F 22 Nutritional deficiency Colectomy N Yes None â 10 103 40 M None Vagotomy and pyloroplasty H No Hypotension Corticoids (preopera- tively) , vaso- pressors 5 41 104 40 F 41 Previous Jaundice Rhizotomy H Yes None Corticoids (preopera- tively) 1 105 40 M None Esophagogas trec tomy H Yes None -- 4 75 106 40 M 40 Nutritional deficiency Colectomy H Yes None - 6 107 40 f 54 Alcoholism (1) Repair, retinal detachment H No None - (2) Same H No None â 6 (3) Same H No None -- No Jaundice 108 40 y Alcoholism (l) Repair mesen- teric artery H No None Corticoids 12 36 (2) laparotomy C No None - 1 109 29 52 None Craniotomy H (246) No -- Chlorpromazine , diphenylhydan- toin No Jaundice 110 29 45 None Land nec tomy H (110) No - Sulfisoxazole ? No Jaundice 111 29 F 56 None Radical Mastectomy H (160) No None -- ? 13 112 29 55 None (1) Craniotomy H (250) Yes Shock, wound infection Chlorpromazine , diphenylhydan- toin ( 2) Craniotomy H (163) Yes -- - ? 7 113 29 64 None Craniotomy H (340) No â Diphenylhydan- toin ? 1 114 29 57 None (1) Incision & drainage, hip H (64) Yes -- - (2) Skin graft, thigh H (75) ? -- ~ ? 10 36
Table 5 (Cont'd) Case Reference Sex and age, years Pre-existing hepatic disease Operation Anesthetic agent (dur- ation, min)* Trans- fusion Complications Drug therapy Onset of postoperative Jaundice, days Remarks 115 29 None Laminectomy N (180) No â 1 No Jaundice 20 116 29 None Gastrectomy C, E (300) No â â ? 3 37 117 29 None Colectomy C (330) No Phthalylsulfa- 1 56 thlazole 113 72 M None Lobectomy H (280) Yes 1 35 119 72 M None Esophagectomy H (290) Yes Penicillin 1 58 120 72 M None Segmental resec- H (250) Yes Hypotension 2 21 tion, lung 121 72 F None Exploratory H (185) Yes .. .. 1 24 laparotomy 122 72 M None Craniotomy Neurolept- Yes 2 65 analgesia (295) 123 72 F None I leotransversos - Neurolept- Yes 5 42 tomy analgesia (200) 124 89 M None (1) Dressing, burns H (90) Yes None Penicillin All operations (2) Dressing, burns H (60) Yes None polymyxin (3) Dressing, bums H (240) Yes None 10 (4) Dressing, burns H (150) Yes None 2 334-553 O-69â4 37
TABLE 6.âHEPATIC DAUAGE AFTER ANESTHESIA AND OPERATIONâNONFATAL CASES IN THE LITERATURE (1958-1966), LABORATOfff FINDINGS* Serum bilirubin, â¢g * Alkaline phospha- tase, units Pro- Albumin, If Other laboratory findings Pathologic findings Author's remarks or conclusions Case Total Direct SOOT SGPT CF TT throm- bln time 1 Postnecrotic cirrhosis ? Natural progression of pre-existing liver disease 2 3 4 13.3 7.0 18 (KA) 1160 Strong implication that halothane induced hepatic necrosis 5 33.5 38 <KA) 146 2+ Neg Implicating halothane as the responsible agent 6 1.2 33 (KA) 597 380 Meg Neg Implicating halothane as the responsible agent 5.8 57 (KA) 2+ -i 7 4.2 54 (KA) 1000 Neg Neg 16 sec Implicating halothane as the responsible agent 4.0 55 (KA) 59 -i Neg 20 sec 18 (KA) 340 340 ft 0.8 14 (KA) 480 380 Neg + 2.3 Implicating halothane as the responsible agent 9 20.8 42 (KA) 800 1500 + + 67 sec Implicating halothane as the responsible agent 10 18.0 45 (KA) 2800 Neg Neg 21 sec Extensive area of hepatic necrosis, most prominent in central zone; gall bladder normal Implicating halothane as the responsible agent 11 1.0 34 (KA) 540 Neg Neg 19 sec Implicating halothane as the responsible agent 12 8.2 33 (KA) 1730 1270 . 3+ 3+ 15 sec Implicating halothane as the responsible agent 13 4.0 1.7 17 (S) 260 470 4+ 14.7 units 80* 2.7 BSP reten- tion (45 mln), 69% Considerable necro- sis, collapse of parenchyma, extensive inflammation, fatty infiltration «KA King-Amstrong units; B, Bodansky units; S, Shinowara units; SOOT, serum glutamic oxaloacetic transaminase, SOFT, serum glutamic pyruvic transaminase; CF, cephalin flocculation; TT, thymol turbidity; LDH, lactic dehydrogenase; and ICD, isocitric dehydrogenase. 38
Table 6 (Cont'd) Case Se bill ng rum rubln, < Alkaline phospha- tase, units SOOT SOFT CF TT Pro- throm- bln Albumin Other laboratory Pathologic findings Author's remarks or conclusions 1 4 Total Direct time z% findings ? Viral hepatitis 15 5.9 450 1000 Wondering If combina- tion of halothane and radium therapy is re- sponsible for hepatic damage 16 Wondering if combina- tion of halothane and radium therapy is responsible for hepatic damage 17 21 310 Wondering if combina- tion of halothane and radium therapy is re- sponsible for hepatic damage IS 4.1 0.9 -- 19 7.6 1.6 -- 20 3.5 1.5 -- 21 1.9 0.3 17 (U) 4+ 4 3.7 Probably viral hepatitis 22 3 2.4 20.8 (?) 560 1 4.0 Zinc tur- bidity, 4 units 23 "Abnormal liver func- tion tests" â 24 5.8 48.5 (KA) 3600 4+ Mild healing focal hepatic necrosis Hepatic lesions com- patible with damage by exogenous agent 25 2.2 8.5 (KA) 1120 3+ Focal centrilobular hepatic necrosis, not significantly different from changes in viral hepatitis 26 1 Inflammatory changes indistinguishable from those seen in viral hepatitis of moderate severity Hepatitis was probably secondary to halothane 27 l l May be coincidental but there does seem to be some evidence of possible halothane hepato toxic i ty 19.0 9.0 29 (?) 1700 4- 2+ 100 sec 28 3.3 1.4 26 (?) 108 Neg Neg 93 sec Possible causes in- clude prolonged oper- ation hemo lysis, viral infection, and anti- biotics 39
Table 6 (Cont'd) Serum bilirubin, Alkaline phospha- lase, units Pro- Other laboratory findings Case ml SOOT SGPT CF TT throm- bin time Albumin, 8* Pathologic findings Author's remarks or conclusions Total Direct 29 5.9 2.5 (?) 100 88 Centrilobular cholestasis, diffuse fatty change Difficult to Judge cause of hepatic damage 30 1.4 10.4 (?) 40 20 Neg Centrilobular cholestasis, no necrosis, no inflam- mation Difficult to Judge cause of hepatic changes 31 4.0 1.8 9.2 (KA) 72 54 4+ 3.5 2.6 Zinc tur- bidity 12.8; IDH, 200 Patchy necrosis, fatty change Hepatotoxic reaction to halothane 32 8.5 48.2 (KA) 8.9i»V hr/1 5.2 nU/hr/ BSP reten- tion (45 min), 33* ~ 33 18 5.1 (?) 240 1 4+ 9.5 26* 3.0 Severe hepatitis due to halothane 34 3.6 10 (KA) 40 40 Neg Neg 86* Iflld centrilobular hepatic necrosis, cholestasis Halothane may have acted as a hepatotoxin 39 5.9 7.5 (KA) 1 Zinc tur- bidity, 2 units -- 36 6.2 12.0 (KA) 3 Zinc tur- bidity, 3 units â 37 5.5 37.0 (KA) 1100 700 12.5 Zinc tur- bidity, 18.4 units -- 38 4.3 â 39 2.0 3.0 (KA) 4 Zinc tur- bidity, 12 units -- 40 2.8 21.5 (KA) 1 Zinc tur- bidity, 7 units â 41 3.1 14.8 (KA) 36 1.0 13.8 (KA) 18 42 2.0 16.0 (KA) 3.5 Zinc tur- bidity, 7.5 units â 43 1.4 45.0 (KA) 2 Zinc tur- bidity, 5 units â 44 2.4 5.3 (KA) 19 29 ~ 45 2.6 29.0 (KA) 85 325 19 Zinc tur- bidity, 19 units Clinical diagnosis: viral hepatitis 46 5.0 10.4 (KA) 1 -- 47 10.0 116.0 (KA) 93 67 3 Zinc tur- bidity, 3 units â 48 13.3 90 82 ~ 49 1.5 23 19 - 50 0.6 25 38 -- 51 1.8 - 52 1.3 76 63 -- 40
Table 6 (Cont'd) Case Serum bllirubin, «« 4 Alkaline phoapha- SCOT SGPT CF TT Pro- throm- bin time Albumin, g* Other laboratory findings Pathologic findings Author's remarks or conclusions Total Direct 53 23 101 76 ~ 54 1.0 23 16 - 55 1.1 8 11 -- 56 1.7 75 60 -- 57 2.0 703 250 -- 58 3.3 -- 59 0.4 -- 60 2.8 35 38 -- 61 1.0 -- 62 1.1 -- 63 2.2 -- 64 1.4 44 28 -- 65 1.3 -- 66 1.2 - 67 0.8 83 45 -- 68 1.8 50 95 -- 69 1.8 50 95 -- 70 0.4 50 38 - 71 2.5 121 170 - 72 1.0 60 23 - 73 1.2 -- 74 2.8 113 234 ~ 75 1.4 ~ 76 0.9 48 8 â 77 1.0 â 78 4.8 370 601 â 79 9.2 2174 3629 â 80 1.4 23 15 â 81 6.6 249 556 â 82 5.4 3.3 19 (?) 14 units Suggested causal rela- tionship between halo- thane and Jaundice 83 1.2 16.9 (KA) 4.9mM/ hr/1 49mH/ hr/1 Neg It cannot be excluded that halothane has caused hepatic damage 84 1.8 14.2 (KA) 3.9n*(/ hr/1 7.6n*4/ .hr/1 6.1 It cannot be excluded that halothane has caused hepatic damage 85 units No definite association between halothane and Jaundice can be estab- lished, although it cannot be excluded 13.6 6.6 107.0 (KA) 84 3 units 86 14.4 9.0 17.0 (KA) 87 57 2 units Intrahepatic cho1ce - tasis, no necrosis, early obstructive biliary cirrhosis No definite association between halothane and Jaundice can be estab- lished, although It cannot be excluded 87 8.0 5.0 No definite association between halothane and Jaundice can be estab- lished, although it cannot be excluded 41
T«ble 6 (Cont'd) Serum bilirubin, â¢t-% Alkaline Pro- Albumin, If Other laboratory findings Pathologic findings Author's remarks or conclusions Case phospha- tase, units SOOT SGPT CF TT throm- bln time Total Direct 88 'Normal" "Normal" 66 Neg Neg ICD, 8.6 Recent centrllobular hepatic necrosis with regeneration, cholestasis Not possible to draw conclusion, but halo- thane may cause or aggravate liver dam- age 4.I "Normal" 252 ICD, 6.5 89 20 31.2 (KA) 492 >500 7 units Possible causes of hepatitis : halo thane , promethazine, viral hepatitis, pre- existing liver disease 90 2.0 4.5 (KA) 31 21 15.3 (KA) >60 >60 Zinc tur- bidity, 10 units 91 2.3 1025 1630 Suggest causal rela- tionship between halo- thane and Jaundice 92 3.0 590 Suggest causal rela- tionship between halo- thane and Jaundice 93 1.5 710 520 Variable degrees of eosinophilic degen- eration of hepatic cells, diffuse in- flammation Viral hepatitis 94 6 1420 860 Suggest causal rela- tionship between halo- thane and Jaundice 95 6 t 210 200 Neg Neg .. 96 3.3 "Time of onset of Jaundice too late to incriminate halothane as a direct hepato- toxln. " 97 3.3 Normal Meg Neg "Etiology: halothane or viral hepatitis." 98 2000 30* "Probably viral hepatitis." 99 9.4 3980 2130 + + "Likely viral hepatitis." 100 4.4 48* Implicated halothane 101 4.4 5 (KA) 135 65* Implicated halothane 102 6.7 65 2.7 Implicated halothane 103 3.4 5 (KA) 89 77* Implicated halothane 104 6.3 40 85* Implicated halothane 105 3.9 4 (KA) 48 Implicated halothane 106 10.5 10 (KA) 460 2.6 Implicated halothane 107 16.5 27 (KA) 2260 48* Implicated halothane 108 5.1 26 (KA) 4300 5* 2.8 Implicated halothane 109 1.5 10.3 (B) Neg 4.0 BSP reten- tion (45 mln), 24* Recognition of etio- logic factors is con- jectural 110 0.5 M.6 (B) 185 Neg BSP reten- tion (45 min), 23* Recognition of etio- logic factors is con- jectural 111 13.2 9.0 (B) 375 3+ Recognition of etio- logic factors is con- jectural 112 4.0 7.4 (B) 125 4+ 2.7 Recognition of etio- logic factors is con- jectural 42
Table 6 (Cont'd) Case Serum billrubin, °8 * Alkaline phoepha- tase, units SCOT SGPT CF TT Pro- thraa- bin time Albumin, g% Other laboratory findings Pathologic findings Author's remarks or conclusions Total Direct 113 5.3 8.6 (B) 73 + Recognition of etio- logic factors is con- jectural 114 2.9 13.0 (B) 220 3+ BSP reten- tion (45 min), 38% Recognition of etio- logic factors is con- jectural 119 1.4 13.7 (B) 180 2+ 4.7 BSP reten- tion (45 min), 5% Recognition of etio- logic factors Is con- jectural 116 3.8 20.6 (B) 630 4+ 3.8 BSP reten- tion (45 min), 31% Recognition of etio- loglc factors is con- jectural 117 30.0 17.3 (B) 20 + 3.3 BSP reten- tion (45 min), 17% Recognition of etio- logic factors is con- jectural 118 11.0 6.8 (B) 83 29 Choleetasis, steatosis "Jaundice is believed to be the result of transient hepatic insufficiency from operation." 119 10.8 18.5 (B) 78 40 C hole stasis "Jaundice is believed to be the result of transient hepatic Insufficiency from operation. " 120 9.2 16.5 (B) Cholestasis "Jaundice is believed to be the result of transient hepatic insufficiency from operation." 121 10.8 13 (B) 57 16 Choleetasis Jaundice is believed to be the result of transient hepatic insufficiency from operation." 122 5.7 3.6 (B) 30 25 Cholestasis "Jaundice is believed to be the result of transient hepatic insufficiency from operation. " 123 5.4 4.2 (B) 28 27 "Jaundice is believed to be the result of transient hepatic insufficiency from operation. " 124 6.1mH/hr/l 30ail/ hr/1 2.2 Icterus Index, 40 units "Allergic hepatic damage was probably caused by halothane." 7.70*^hr/1 30nttf hr/1 3.5 16* 2.5 Icterus index, 130 units units 43
PART II. DESIGN OF THE STUDY
![National Halothane Study: a Study of the Possible Association Between Halothane Anesthesia and Postoperative Hepatic Necrosis; Report. Edited by John P. Bunker [and Others]](data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAAEAAAABCAYAAAAfFcSJAAAAAXNSR0IArs4c6QAAAARnQU1BAACxjwv8YQUAAAAJcEhZcwAADsQAAA7EAZUrDhsAAAANSURBVBhXYzh8+PB/AAffA0nNPuCLAAAAAElFTkSuQmCC)