Jaundice after Repeated Exposure to Halothane: An Analysis of Reports to the Committee on Safety of Medicines

Analysis of data derived from 130 reports of jaundice occurring after anaesthesia with halothane showed a significant relation between the number of exposures to this anaesthetic and the rapidity with which jaundice develops after exposure. This is considered to provide strong evidence of a cause-effect relationship between the use of halothane and jaundice. Out of 114 patients with complete anaesthetic histories 94 (82%) had been exposed more than once; of those so exposed 80% had been anaesthetized with halothane more than once within 28 days. Altogether 66 (51%) of the 130 patients died.     

Unexplained hepatitis following halothane.

Full clinical and laboratory details of 203 patients with postoperative jaundice were submitted to a panel of hepatologists. All patients whose jaundice may have had an identifiable cause were excluded, which left 76 patients with unexplained hepatitis following halothane anaesthesia (UHFH). Hepatitis in 95% of these cases followed multiple exposure to halothane, with repeated exposure within four weeks in 55% of cases. Twenty-nine patients were obese, 52 were aged 41-70, and 53 were women. Thirteen patients died in acute hepatic failure. Rapid onset of jaundice after anaesthesia, male sex, and obesity in either sex were poor prognostic signs. Of the clinical stigmata of hypersensitivity, only eosinophilia was impressive. The UHFH group had a much greater incidence of liver kidney microsomal (LKM) and thyroid antibodies and autoimmune complement fixation than those patients whose jaundice related to identifiable factors. Thirteen of the 19 patients with LKM antibodies also had thyroid antibodies. In six patients retested two to three years later LKM antibodies had disappeared, although thyroid antibodies persisted. Rapidly repeated exposure to halothane may cause hepatitis, but such a complication is probably rare. Possibly obese women with a tendency to organ-specific autoimmunity may be more at risk. Nevertheless, the comparative risks of rapidly repeated halothane or non-halothane anaesthesia cannot be determined from the present data. If alternative satisfactory agents are available halothane should be avoided in patients with unexplained hepatitis after previous exposure, although in three to five patients with UHFH who were re-exposed to halothane jaundice did not recur.     

Onset of Postoperative Jaundice Related to Anaesthetic History

A review of 182 cases from the U.S. National Halothane Study showed the interval to the onset of jaundice after one exposure to halothane (91 cases) to be slightly shorter than the interval for those having had multiple exposures to the agent. These findings are in sharp contrast to other recently published results. Thirty-three cases of jaundice after the use of other anaesthetic agents are also reported.     

Post-halothane Jaundice in Relation to Previous Administration of Halothane

The time interval since previous anaesthesia was compared in a surgical population in South Wales and in patients who developed jaundice after halothane. There was a significant difference in the pattern of time interval since previous general anaesthetics in the surgical population and in those patients who developed jaundice after halothane. In the group who developed jaundice there was an “excess” of patients who had had a previous halothane anaesthetic within four weeks. Halothane should if possible be avoided in patients who have had it before, particularly if this was within the previous four weeks. In the case of repeat halothane anaesthetics within four weeks, the risk seems to lie between 1 in 6,000 and 1 in 22,000.     

Halothane Hepatitis—A Preventable Disease?

Eleven patients with acute hepatitis following multiple anaesthetics with halothane have been seen at two hospitals during the last four years. Six had massive hepatic necrosis and died. Unexplained fever occurred in nine of the patients; two of these and one other had had previous episodes of jaundice after halothane anaesthesia. Thus, in ten patients the disease could have been avoided.     

Halothane hepatitis

This report describes five cases of hepatocellular injury following halothane anesthesia. Four patients had multiple exposures to the anesthetic. Three of the five died from submassive to massive liver cell necrosis. The two survivors developed jaundice and/or dark urine following each exposure to halothane; liver biopsy in one showed centrilobular and linear areas of necrosis. Fever, anorexia, nausea, vomiting, abdominal pain and jaundice were present in all cases. In the two survivors the prothrombin time was less than 20 seconds throughout the course of the disease, whereas in the three who died the prothrombin time was more than 20 seconds from the onset. The English literature to the end of 1971 is reviewed. Approximately 600 cases of halothane-related hepatitis have been reported     

Chronic exposure to inhaled anesthetics increases cholesterol content in Acholeplasma laidlawii

Acholeplasma laidlawii cells were grown in cholesterol-enriched medium and exposed continuously to either air (control), 4.0 vol.% halothane in air at 1 atm pressure (4% atm halothane), or 80% cyclopropane in oxygen for 24 h at 37°C. Cells grown in the presence of 4% atm halothane or 80% cyclopropane had approximately twice as much membrane cholesterol content/mg protein as the control cells. Cells grown in an anesthetic environment also tended to have a higher membrane cholesterol/phospholipid molar ratio compared to control cells. Membranes isolated from halothane-exposed cells grown in a cholesterol-enriched medium were more ordered at 37°C (measurements were made with no anesthetic present) than membranes from control cells grown in an identically enriched medium. This difference in membrane physical state between control and anesthetic-exposed cells decreased as the temperature decreased, and disappeared at approx. 23°C. Continuous exposure of A. laidlawii to 4% atm halothane or 80% cyclopropane for 24 h did not markedly affect membrane fatty acid composition, either in cells grown on an unsupplemented medium or in cells grown in a medium enriched in myristic, palmitic or stearic acids. These results further support the hypothesis that an increased membrane cholesterol content may play a role in the tolerance or dependence that develops after chronic exposure to anesthetic agents.     

The in vivo genotoxicity of cisplatin,isoflurane and halothane evaluated by alkaline comet assay in Swiss albino mice

The aim of this study was to evaluate the genotoxicity of repeated exposure to isoflurane or halothane and compare it with the genotoxicity of repeated exposure to cisplatin. We also determined the genotoxicity of combined treatment with inhalation anaesthetics and cisplatin on peripheral blood leucocytes (PBL), brain, liver and kidney cells of mice. The mice were divided into six groups as follows: control, cisplatin, isoflurane, cisplatin–isoflurane, halothane and cisplatin–halothane, and were exposed respectively for three consecutive days. The mice were treated with cisplatin or exposed to inhalation anaesthetic; the combined groups were exposed to inhalation anaesthetic after treatment with cisplatin. The alkaline comet assay was performed. All drugs had a strong genotoxicity (P < 0.05 vs. control group) in all of the observed cells. Isoflurane caused stronger DNA damage on the PBL and kidney cells, in contrast to halothane, which had stronger genotoxicity on brain and liver cells. The combination of cisplatin and isoflurane induced lower genotoxicity on PBL than isoflurane alone (P < 0.05). Halothane had the strongest effect on brain cells, but in the combined treatment with cisplatin, the effect decreased to the level of cisplatin alone. Halothane also induced the strongest DNA damage of the liver cells, while the combination with cisplatin increased its genotoxicity even more. The genotoxicity of cisplatin and isoflurane on kidney cells were nearly at the same level, but halothane caused a significantly lower effect. The combinations of inhalation anaesthetics with cisplatin had stronger effects on kidney cells than inhalation anaesthetics alone. The observed drugs and their combinations induced strong genotoxicity on all of the mentioned cells.     

Prevalence of antibodies to hepatitis C virus (HCV) in haemophiliacs

The prevalence of 1) hepatitis C virus (HCV), an agent likely to be responsible for parenterally transmitted hepatitis non-A, non-B, 2) hepatitis B virus (HBV) and 3) human immunodeficiency virus (HIV) infection was studied in 211 patients with clotting disorders (78% of the patients had residual factor activities of less than or equal to 2%). Of these patients 71% were positive for HBV markers and 44% for HIV markers. Using a new ELISA technique, 80% were anti-HCV-positive. The prevalence of anti-HCV was greater in patients with more severe clotting disorders and was related to the total amount of replacement therapy received; the prevalence was less in older patients. Seroconversion after a single exposure to dry heat-treated factor concentrates was documented in 3 patients 3-4 months after exposure.     

Influence of dose rate on survival time for 239PuO2-induced radiation pneumonitis or pulmonary fibrosis in dogs.

Beagle dogs were exposed once or repeatedly to 0.75-microns-diameter monodisperse aerosols of 239PuO2 by pernasal inhalation. The dogs that were exposed once received alveolar depositions (+/- standard deviation) of 3.9 +/- 1.9 kBq/kg body mass and accumulated doses of 23 +/- 8 Gy to the lung before death at 5.4 +/- 1.7 years after exposure. Dogs exposed repeatedly received a total alveolar deposition of 5.3 +/- 0.9 kBq/kg body mass during 7 to 10 semiannual exposures and accumulated doses of 22 +/- 5 Gy to the lung before death at 4.9 +/- 0.7 years after first exposure. Clearance of the plutonium from the lung in the dogs exposed repeatedly was slower than in the dogs exposed once. All dogs in the repeated-exposure study and all but one dog in the single-exposure study died from radiation effects. Pulmonary fibrosis accounted for 72% of the radiation-related deaths in the single-exposure study and 87% in the repeated-exposure study. The remaining dogs died with pulmonary cancer. Based on total cumulative radiation dose, the times after exposure to death from radiation pneumonitis and pulmonary fibrosis were not significantly different for single and repeated exposures. Thus dose rate does not appear to be an important factor in predicting death from radiation pneumonitis or pulmonary fibrosis for dogs inhaling 239PuO2.     

Congenital heart disease and prenatal exposure to exogenous sex hormones.

One-hundred and four infants with congenital heart disease were identified from their birth certificates and matched with normal controls. Their gestational histories were examined to see whether they had been exposed to exogenous sex hormones. Exposure was 8-5 times more common among the infants with malformations than among controls. A history of hormone exposure was more common among those patients with multiple malformations, and the exposed infants were also more likely to have died (and to have died earlier) than those who had not been exposed, which suggests that hormone exposure causes severe types of malformations. The commonest type of exposure was to hormone pregnancy tests, which was needless exposure. Only two of the mothers of malformed infants had inadvertently used oral contraceptives in the first trimester.     

A Halothane-Related Effect on Rat Brain Myelination: A Comparison of Chronic Prenatal or Postnatal Exposure

Rats were exposed to 0.5% halothane in air for 8 h per day during the intervals (1) 5 days postconception to birth, (2) birth to 5 days postnatal age, or (3) birth to 10 days postnatal age. Controls were exposed to an equivalent flow of air. Prenatal exposure had no significant effect on body or brain weight and no subsequent effect on the relative synthesis of brain subcellular membranes. Five days of postnatal exposure caused a 10% reduction in body and brain weight and a 10% relative reduction in the synthesis of brain myelin. The effect persisted throughout the period of rapid postnatal brain myelination. Ten days of postnatal exposure produced equivalent, more severe effects on body and brain weights and a more severe effect on myelin synthesis. Postnatal exposure had no apparent effect on the relative synthesis of non-myelin particulate proteins.     

Genetic monitoring of aluminum workers exposed to coal tar pitch volatiles

A group of 50 workers exposed to coal tar pitch volatiles (CTPV) in an aluminum reduction plant and a group of 50 non-exposed workers were selected to evaluate the genotoxic effects of CTPV exposure. A battery of tests was performed on 3 different body fluids; urine, blood and semen. Urine samples were evaluated for mutagenic constituents using the Ames/Salmonella assay. Cultured lymphocytes from blood samples were used to perform cytogenetic analysis. Semen samples were used to measure sperm count, percent abnormal sperm morphology and frequency of sperm carrying double fluorescent bodies (2-F). 14 of 28 (50%) exposed workers and 7 of 36 (19.4%) non-exposed workers had mutagenic urine. This difference was significant (p less than 0.01). Among the non-smokers a significantly higher percentage of workers who were exposed had positive urine (36%) compared to the non-exposed workers (5%) (p less than 0.05). Among the exposed group, more mechanics had mutagenic urine than did other types of workers. Overall chromosome aberration rates were similar in both exposed and non-exposed workers. Among exposed workers a significant inverse correlation (p less than 0.05) between age and chromatid aberration rate was observed. Results of semen analysis failed to detect differences between exposed and non-exposed workers. Results of these tests lend support to a battery approach to genetic monitoring and suggest a link between exposure to CTPV and genotoxic effects. Detection of exposure to mutagens at an early time offers an opportunity for disease prevention by the reduction of exposure.     

Adult Behavior in Male Mice Exposed to E-Cigarette Nicotine Vapors during Late Prenatal and Early Postnatal Life

Nicotine exposure has been associated with an increased likelihood of developing attention deficit hyperactivity disorder (ADHD) in offspring of mothers who smoked during pregnancy. The goal of this study was to determine if exposure to E-cigarette nicotine vapors during late prenatal and early postnatal life altered behavior in adult mice.

Methods

Timed-pregnant C57BL/6J mice were exposed to 2.4% nicotine in propylene glycol (PG) or 0% nicotine /PG once a day from gestational day 15 until delivery. After delivery, offspring and mothers were exposed to E-cigarette vapors for an additional 14 days from postnatal day 2 through 16. Following their last exposure serum cotinine levels were measured in female juvenile mice. Male mice underwent behavioral testing at 14 weeks of age to assess sensorimotor, affective, and cognitive functional domains.

Results

Adult male mice exposed to 2.4% nicotine/PG E-cigarette vapors had significantly more head dips in the zero maze test and higher levels of rearing activity in the open field test compared to 0% nicotine/PG exposed mice and untreated controls. In the water maze test after reversal training, the 2.4% nicotine/PG mice spent more than 25% of time in the new location whereas the other groups did not.

Conclusion

Adult male mice exhibited increased levels of activity in the zero maze and open field tests when exposed to E-cigarette vapor containing nicotine during late prenatal and early postnatal life. These findings indicate that nicotine exposure from E-cigarettes may cause persistent behavioral changes when exposure occurs during a period of rapid brain growth.     

Effects of protraction of the alpha dose to the lungs of mice by repeated inhalation exposure to aerosols of 239PuO2

To determine the long-term biological effects of protracted alpha irradiation of the lung, 84-day-old C57BL/6J mice were repeatedly exposed by inhalation to aerosols of 239PuO2 every other month for up to six exposures in 10 months to reestablish lung burdens of 20, 90, or 460 Bq. Other mice were exposed only once when either 84 or 460 days of age to achieve desired initial lung burdens of 20, 90, 460, or 2300 Bq. Suitable control groups were maintained. Groups of mice with similar cumulative alpha doses to the lung had 3.4 to 4.4 times greater incidence of pulmonary tumors (adenomas and adenocarcinomas) when the dose to the lung was protracted by the repeated inhalation exposures compared to mice that received a single inhalation exposure. Excess pulmonary tumors per unit dose to the lung were also greater in groups of repeatedly exposed mice compared to those exposed only once. Repeatedly exposed mice also died earlier with pulmonary tumors than did those exposed once. It appears that protraction of an alpha dose to lungs increases the carcinogenic risk of inhaled 239PuO2 in mice.     

Effect of insecticides on Tiphia vernalis (Hymenoptera: Tiphiidae) oviposition and survival of progeny to cocoon stage when parasitizing Popillia japonica (Coleoptera: Scarabaeidae) larvae

The effect of insecticides on oviposition of Tiphia vernalis Rohwer and subsequent survival of parasitoid progeny to the cocoon stage was determined in the laboratory by using larval Japanese beetle, Popillia japonica Newman, as the host. Insecticides tested were imidacloprid, thiamethoxam, halofenozide, chlorpyrifos, and carbaryl at labeled rates. Female T. vernalis were allowed 2 d to parasitize P. japonica larvae after the parasitoids had received a 4-d exposure to insecticide-treated soil. Another group of female T. vernalis were allowed 2 d to parasitize P. japonica larvae that had been exposed to insecticide-treated soil for 3-4 d. Percentage of parasitism of P. japonica larvae in these trials after exposure of adult parasitoids to carbaryl, chlorpyrifos, halofenozide, or imidacloprid-treated soil (23.3-50.0%) or adult parasitoids to chlorpyrifos, halofenozide, or imidacloprid-treated grubs (33.0-56.7%) was not negatively affected relative to the control treatment (21.7-54.2%). A third group of adult T. vernalis and P. japonica larvae were simultaneously exposed to chlorpyrifos or carbaryl treatments. Percentage parasitism in these trials was lower for T. vernalis adults exposed to the chlorpyrifos and carbaryl (15.0-25.0%) relative to the control (57.5-62.5%) with the exception of one trial with carbaryl (40.0%). However, exposure of the parasitoid and P. japonica to chlorpyrifos 0.5X, carbaryl 0.5X, imidacloprid, halofenozide, or thiamethoxam in several trials resulted in parasitism that was equivalent or greater than (45.0-80.0%) the untreated control (57.5-62.5%). Japanese beetle larval mortality in these trials was greater in the insecticide and parasitoid combination (97.5-100.0%) than with insecticides alone (45.0-100.0%). Percentage of survival of T. vernalis progeny to the cocoon stage was not negatively affected by a 4-d adult parasitoid exposure to carbaryl and chlorpyrifos treated soil (11.7-16.7% versus 18.3% control) or a 2-d exposure to P. japonica-treated larvae (16.7-18.3% versus 28.3% control). However, simultaneous exposure of T. vernalis progeny and P. japonica larvae to chlorpyrifos- and carbaryl-treated soil resulted in no parasitoids surviving to the cocoon stage. Between neonicotinoids, thiamethoxam had more adverse impact on percentage parasitism (52.5%) and survival to the cocoon stage (10.0%) than imidacloprid (80.0 and 32.5%, respectively). Results of this study indicate soil incorporation of imidacloprid and halofenozide had minimal effect on the number of P. japonica larvae parasitized by T. vernalis or survival of T. vernalis progeny to the cocoon stage; therefore, they are more suitable for use with T. vernalis. In contrast, chlorpyrifos, carbaryl, and thiamethoxam lowered the number of T. vernalis progeny surviving to the cocoon stage, and carbaryl and chlorpyrifos reduced the number of P. japonica larvae parasitized. The soil incorporation of insecticides is discussed as one explanation for the minimal effects of some insecticides on T. vernalis.     

Circulating immune complexes after repeated halothane anaesthesia.

A patient developed hepatitis after receiving three halothane anaesthetics in 22 days. Twenty-four hours after the onset of jaundice she developed an acute serum sickness syndrome with polyarthralgia, proteinuria, and transient impairment of renal function. Serum concentrations of complement components C1q, C4, and C3 were substantially reduced, and immune complexes capable of activating the complement system via the classical pathway were present in the serum and synovial fluid. A metabolite of halothane was associated with these complexes. Fourteen months after exposure to halothane her lymphocytes were stimulated in vitro by this metabolite. The conditions under which stimulation occurred were unusual--namely, a 7S fraction of the serum, presumably IgG, was necessary. Our results provide strong evidence that halothane may be immunogenic and that its immunogenicity is dependent on the non-covalent binding of one of its metabolites to plasma proteins.     

Cytogenetic damage in workers exposed to ethylene oxide

Sister-chromatid exchanges (SECs) and chromosomal aberrations (CAs) were detected in the peripheral lymphocytes of 41 sanitary workers exposed to ethylene oxide (EO) in the sterilizing units of 8 hospitals in the Venice Region. The first group (19 workers) was exposed to 10.7 +/- 4.9 ppm EO, expressed as the time-weighted average concentration for an 8-h working day (TWA/8 h conc.), and the second group (22 workers) to 0.35 +/- 0.12 ppm. Each exposed worker was paired with a control of similar age and smoking habits. A highly significant (P less than 0.001) increase in the mean frequency of SCEs was found in the higher exposure group, 14 (74%) exposed subjects having significantly increased levels of SCEs compared to their matched controls. In the lower exposure group, the increase in mean frequency of SCEs was lower, though still significant (P less than 0.05): 7 (33%) exposed subjects had higher and 1 (5%) had a lower SCE level than the matched controls. From the first group, 10 subjects, 7 of whom had increased SCE levels, were reanalysed 12-18 months after their exposure had been lowered or interrupted: in only 2 of them the SCE level was significantly decreased. A statistically significant correlation between SCE frequency and level of EO exposure (TWA/8 h conc.), as well as a multiple correlation between SCE level and EO exposure, smoking and age were found. However, no interaction could be detected between EO exposure and smoking in the induction of SCEs. In controls, SCE frequency was correlated with smoking and age. In the higher exposure group, the number of both chromatid- and chromosome-type aberrations, independent of gaps, was significantly increased, whereas in the lower exposure group only the frequency of chromosome-type aberrations, excluding gaps, was statistically higher than in controls. The level of CAs remained to a great extent unchanged in the 10 subjects re-examined at a later stage after lowering or halting exposure. Taking the group as a whole, the frequency of cells with total CAs was found to be weakly (P = 0.05) correlated with EO exposure, and was not correlated with smoking, age or SCE frequency.     

Hepatic reactions associated with ketoconazole in the United Kingdom.

Ketoconazole was introduced in the United Kingdom in 1981. By November 1984 the Committee on Safety of Medicines had received 82 reports of possible hepatotoxicity associated with the drug, including five deaths. An analysis of the 75 cases that had been adequately followed up suggested that 16, including three deaths, were probably related to treatment with the drug. Of the remainder, 48 were possibly related to treatment, five were unlikely to be so, and six were unclassifiable. The mean age of patients in the 16 probable cases was 57.9, with hepatotoxicity being more common in women. The average duration of treatment before the onset of jaundice was 61 days. None of these well validated cases occurred within the first 10 days after treatment. The results of serum liver function tests suggested hepatocellular injury in 10 (63%); the rest showed a mixed pattern. In contrast, the results of histological examination of the liver often showed evidence of cholestasis. The characteristics of the 48 patients in the possible cases were similar. Allergic manifestations such as rash and eosinophilia were rare. Hepatitis was usually reversible when treatment was stopped, with the results of liver function tests returning to normal after an average of 3.1 months. In two of the three deaths probably associated with ketoconazole treatment the drug had been continued after the onset of jaundice and other symptoms of hepatitis. Clinical and biochemical monitoring at regular intervals for evidence of hepatitis is advised during long term treatment with ketoconazole to prevent possible serious hepatic injury.