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.     

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.     

Recurrence of Venous Thromtoembolic Disease and Use of Oral Contraceptives

In 1969 this department reported on 42 women who had developed “idiopathic” venous thromboembolism while using oral contraceptives and 42 women who had developed the disease in the absence of such exposure. We have traced the subsequent history of these women to obtain information about recurrence of the disease.During the follow-up period the risk of recurrence of thromboembolism during pregnancy or the puerperium appeared to be much the same irrespective of whether or not oral contraceptives had been in use at the time of the index attack. Recurrences unassociated with childbearing however, occurred about four times more often among women who had not been using oral contraceptives at the time of the index attack than among women who had been doing so. None of these findings was influenced by the use of oral contraceptives during the follow-up period, since exposure to the preparations was negligible after the index attack.     

Non-Tuberculous Chest Disease Found in a Mass X-Ray Survey in Vancouver,B.C

In 1964, 219,085 persons were examined during a tuberculosis survey in Vancouver, B.C. One hundred and fifteen new cases of tuberculosis and 929 cases of significant non-tuberculous lung disease were found. In a four-month follow-up of the non-tuberculous cases it was found that of the 742 patients who had named a physician when examined 26.6% had not made contact with him. Of those who did contact the physician, the follow-up was considered “poor” in only 30 patients (2.1%). Seventeen patients had died in the four-month interval and 81 who could not be located after the initial survey were considered “lost”. Rates were determined for 37 diagnoses per 1000 patients screened. The most common diagnosis was localized pulmonary fibrosis (1.69/1000). Carcinoma was found in 0.30/1000 and solitary lung density in 0.17/1000 population screened.     

Antenatal prophylaxis of Rh isoimmunization: 28-weeks'-gestation service program

Two (0.18%) of 1086 Rh-negative primigravidas or multigravidas treated similarly in all previous pregnancies, who were given a single injection of Rh immune globulin (300 μg) at 28 weeks'' gestation and subsequently were delivered of Rh-positive babies, had demonstrable Rh isoimmunization at the time of that injection and must be considered “logistic” failures of antenatal prophylaxis. The remaining 1084 (who were treated again after delivery) had no evidence of Rh isoimmunization at delivery and none of the 512 screened at 6 months after delivery appeared to be immunized. If the 28th-week injection had not been protective, one would have expected 14 of the 1084 to have been demonstrably Rh isoimmunized and evidence of Rh isoimmunization to have persisted in 6 of the 512 observed 6 months after delivery.Six of 719 Rh-negative multigravidas who had not received Rh immune globulin after previous pregnancies or had been treated only after delivery showed evidence of Rh isoimmunization despite a single injection of Rh immune globulin at 28 weeks in a subsequent pregnancy. In three of the six the cause was most likely “sensibilization” due to previous exposure to Rh-positive blood or an untreated Rh-positive pregnancy. in 3 of the remaining 716 (0.42%) there may have been true failure of antenatal Rh prophylaxis administered at the 28th week. One would have expected this figure to be 12 of 716 if antenatal Rh prophylaxis at 28 weeks'' gestation were totally unsuccessful.It is concluded that a single intramuscular injection of Rh immune globulin, 300 μg, is 88% effective in preventing Rh isoimmunization during pregnancy in Rh-negative primigravidas and in multigravidas treated antenatally in all previous pregnancies, and is 75% effective in preventing Rh isoimmunization in Rh-negative multigravidas untreated during previous pregnancies. The majority of failures are due to Rh isoimmunization during pregnancy prior to antenatal prophylaxis at 28 weeks.     

Jaundice after repeated exposure to halothane: a further analysis of reports to the Committee on Safety of Medicines.

Aanalysis of data derived from 170 reports of jaundice developing after anaesthesia with halothane received after January 1974 confirmed the relations between multiple exposure to halothane and jaundice and between the number of exposures and the rapidity with which jaundice develops after exposure. When these reports were combined with 130 received earlier complete anaesthetic histories were available for 251 patients, 205 (82%) of whom had been exposed to halothane more than once; of these patients, 154 (75%) had been exposed more than once within 28 days. Altogether 139 (46%) of the 300 patients died.     

Breast-milk Jaundice and Oral Contraceptives

Among breast-fed infants in the normal lying-in wards of a maternity hospital a significantly higher incidence of “idiopathic” jaundice was found in infants of mothers who had been receiving the contraceptive pill before the present pregnancy than in the infants whose mothers never had the pill. The pill became widely used in society at about the same time as breast-milk jaundice was first reported.     

The Probability of Death Following a Fracture of the Hip

All patients 45 years of age and over admitted with fractures of the hip to hospitals in the Atlantic Health Region of Nova Scotia were followed up over a two-year period. Actuarial methods were used to estimate survivorship from the date of fracture in 202 patients.Over-all, it was estimated that only 63.8% would be alive by one year post-fracture. This is 70% of the survival rate expected in the general population of corresponding age and sex. The period of greatest mortality was within the first 12 weeks. Patients surviving to one year could be considered “cured”, for after that their survivorship was at least as favourable as that of the “normal” population.Mortality was greatest in males in those 75 years of age and over and especially in patients who were relatively immobilized prior to their fracture. In this “dependent” group the relative survival ratio at one year was only 38%.     

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.     

Effect of Immunotherapy on Seizure Outcome in Patients with Autoimmune Encephalitis: A Prospective Observational Registry Study

Objective

To evaluate the seizure characteristics and outcome after immunotherapy in adult patients with autoimmune encephalitis (AE) and new-onset seizure.

Methods

Adult (age ≥18 years) patients with AE and new-onset seizure who underwent immunotherapy and were followed-up for at least 6 months were included. Seizure frequency was evaluated at 2–4 weeks and 6 months after the onset of the initial immunotherapy and was categorized as “seizure remission”, “> 50% seizure reduction”, or “no change” based on the degree of its decrease.

Results

Forty-one AE patients who presented with new-onset seizure were analysed. At 2–4 weeks after the initial immunotherapy, 51.2% of the patients were seizure free, and 24.4% had significant seizure reduction. At 6 months, seizure remission was observed in 73.2% of the patients, although four patients died during hospitalization. Rituximab was used as a second-line immunotherapy in 12 patients who continued to have seizures despite the initial immunotherapy, and additional seizure remission was achieved in 66.6% of them. In particular, those who exhibited partial response to the initial immunotherapy had a better seizure outcome after rituximab, with low adverse events.

Conclusion

AE frequently presented as seizure, but only 18.9% of the living patients suffered from seizure at 6 months after immunotherapy. Aggressive immunotherapy can improve seizure outcome in patients with AE.     

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.     

Long term management of duodenal ulcer in general practice: How best to use cimetidine?

Two hundred and sixty seven patients with duodenal ulceration were entered into a five year study of two strategies of treatment with cimetidine. Two thirds were treated continuously with 400 mg at bedtime supplemented by temporary increases in dosage if they had symptomatic relapses (group 1), and the remaining third were given intermittent “healing” doses for four to eight weeks if a symptomatic recurrence was judged to have occurred (group 2). Life table analysis showed that the probability of remaining free of clinically important symptoms five years after the start of treatment was 24% (95% confidence interval (CI) 15·5% to 32·6%) in group 1 compared with nil in group 2 (p<0·0001). The median values for the longest periods free from relapse for each patient were 108 weeks in group 1 and 32 weeks in group 2, respectively (p<0·0001; 95% CI of the median difference 36 to 76). Over the five years 10 patients suffered major complications, two requiring emergency surgery, while a further nine had elective surgery because of the failure of medical treatment. There were no deaths that could be attributed either to ulceration or to treatment with cimetidine.Medical management was therefore very satisfactory for most patients, though those treated continuously with cimetidine suffered considerably less from their ulcer symptoms. As 80% of patients studied relapsed during the two years after a healing course of cimetidine, continuous treatment will benefit many patients treated in general practice.     

Risk factors for development of flucloxacillin associated jaundice.

OBJECTIVES--To identify risk factors predisposing to the development of flucloxacillin associated jaundice. DESIGN--Case-control study. Medical records of cases and controls were reviewed and information recorded on standard data collection forms. SETTING--Alfred Hospital recruiting subjects from Melbourne, Sydney, and Brisbane. SUBJECTS--Cases were defined as patients who had developed jaundice within eight weeks of stopping flucloxacillin, biochemical test results suggesting cholestasis, normal calibre bile ducts, and not been taking recognised hepatotoxic drugs. 51 of the 53 patients referred were included in the study. Four controls for each case were randomly selected from the patient register of the prescribing doctor. These were defined as patients who had been prescribed flucloxacillin without developing jaundice. MAIN OUTCOME MEASURES--Demographic characteristics, medical history, indication for flucloxacillin, dose, route and duration of treatment, other drugs, smoking, and previous drug allergies or use of flucloxacillin. RESULTS--Increasing age and a prolonged duration of flucloxacillin treatment were found to be risk factors for the development of jaundice. Patients aged over 55 years had an odds ratio of 18.61 (95% confidence interval 5.16-67.17) compared with patients under 30. The odds ratio for patients prescribed flucloxacillin for over 14 days was 7.13 (2.90 to 17.58) compared with patients treated for 14 days or less. Dose and route of administration were not related to the risk of jaundice. CONCLUSIONS--Older patients and those receiving flucloxacillin for longer than two weeks are at a substantially greater risk of jaundice. Careful consideration of the risk-benefit ratio is required when flucloxacillin is used in these settings.     

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     

Secondary Respiratory Infection in Hospital Patients: Effect of Antimicrobial Agents and Environment

A prospective study of 358 medical and 234 postoperative patients with clinical evidence of secondary chest infection showed that previous administration of antimicrobial agents greatly reduced the chance of obtaining a clear-cut laboratory report. In patients with radiographical evidence of pneumonia this led to a fourfold decrease in the overall rate of isolation of potential pathogens. Furthermore, 81 diverse “coliforms” were isolated from 258 medical and surgical patients who had received previous antimicrobial therapy while only four coliforms (all Escherichia coli) were isolated from 334 untreated patients. Thus the general hospital environment on its own seemed to have a negligible influence in promoting the growth of coliform flora in sputum. Any unique effect of underlying disease in this regard was masked by that of previous therapy. Finally, the results raised the possibility that previous antimicrobial therapy might have increased the risk of secondary pneumonia in hospital patients.     

Superinfections of the Lung: An Evaluation for Serial Transtracheal Aspirations

A prospective evaluation of cephaloridine, cephalothin, and lincomycin was conducted in 85 patients with pneumonia. None of the 50 with previous history of allergic sensitivity to penicillin had an allergic reaction. All cases of pure “pneumococcal pneumonia” were cured, regardless of the drug. Eight patients with polymicrobial pneumonia were cured by the cephalosporins, while lincomycin was ineffective in four patients who had polymicrobial pneumonia.Although expectorated sputum and exudates from the nasopharyngeal and oropharyngeal areas contained large concentrations of Staphylococcus aureus and various Gram-negative bacillary species during and at the end of therapy, serial cultures of transtracheal aspirate and the clinical course failed to confirm “superinfection” of the lung.     

Liver Transplantation in Man—III,Studies of Liver Function,Histology, and Immunosuppressive Therapy

The experience gained from 13 hepatic transplant operations is described, with particular reference to the findings in nine patients who survived the immediate operative period. A major problem was found to be infection. Fulminant pneumonia caused death in two adults, at a time when liver function was virtually normal. Infection related to bile fistula and sepsis may be overcome by an improved method of biliary drainage by cholecyst-dochostomy, which was carried out in the last two patients. Jaundice in the second week due to rejection was observed in several patients. The striking histological change was centrilobular cholestasis. The jaundice, which was not prevented by administration of antilymphocyte globulin, was rapidly controlled by temporarily increasing die dose of prednisone. One patient who survived for four and a half months and who had a poor tissue match subsequently developed chronic rejection with progressive cholestatic jaundice. Five of the patients were able to go home and at time of publication two are alive and well 14 and 20 weeks after treatment.     

Vagotomy and Pyloroplasty for Gastric Ulcer

In a series of 68 patients with gastric ulcer who were treated by vagotomy and pyloroplasty there were no operative deaths, though one patient who received massive transfusions died 14 weeks later from hepatic necrosis probably associated with serum hepatitis. Four patients developed recurrent peptic ulceration requiring further surgical treatment. The clinical condition of all but three of the remainder was satisfactory after an average follow-up period of three years and two months. Of the 14 patients who presented with an acutely bleeding gastric ulcer, one subsequently required gastrectomy for continued bleeding; in all the others the immediate and long-term results were satisfactory. Of 21 patients with a “high” ulcer and 29 with combined gastric and duodenal ulceration one (4·8%) and three (10%) respectively suffered recurrences. We conclude that vagotomy and pyloroplasty is a satisfactory form of treatment for a high or bleeding gastric ulcer, but that for all other gastric ulcers some form of gastric resection is preferable.     

Conditional Probability Analyses of the Spike Activity of Single Neurons

With the objective of separating stimulus-related effects from refractory effects in neuronal spike data, various conditional probability analyses have been developed. These analyses are introduced and illustrated with examples based on electrophysiological data from auditory nerve fibers. The conditional probability analyses considered here involve the estimation of the conditional probability of a firing in a specified time interval (defined relative to the time of the stimulus presentation), given that the last firing occurred during an earlier specified time interval. This calculation enables study of the stimulus-related effects in the spike data with the time-since-the-last-firing as a controlled variable. These calculations indicate that auditory nerve fibers “recover” from the refractory effects that follow a firing in the following sense: after a “recovery time” of approximately 20 msec, the firing probabilities no longer depend on the time-since-the-last-firing. Probabilities conditional on this minimum time since the last firing are called “recovered probabilities.” The recovered probabilities presented in this paper are contrasted with the corresponding poststimulus time histograms, and the differences are related to the refractory properties of the nerve fibers.     

The course of untreated epilepsy.

As little is known about the course of untreated epilepsy the time intervals between untreated tonic clonic seizures were examined retrospectively in a series of 183 patients presenting to a neurological department having had two to five seizures. After the first seizure a second attack had occurred within one month in 56 patients, within three months in 93, and within one year in 159. The median interval between the first two seizures was 12 weeks (95% confidence interval 10 to 18 weeks), between the second and third eight weeks (four to 12 weeks), between the third and fourth four weeks (two to 20 weeks), and between the fourth and fifth three weeks (one to four weeks). When patients who had had three, four, or five untreated seizures were considered separately a similar pattern of decreasing intervals was seen. Successive intervals between seizures could be compared in 82 patients. In 48 the interval decreased, in 16 it did not change, and in 18 it increased. These results suggest that in many patients there is an accelerating disease process in the early stages of epilepsy.