MARCH 9, 1957 GLUTETHIMIDE IN LABOUR MFnWCARITRNAL 565 able in the 16 infants born within three hours after admini- stration of the drug. All the 16 infants were classed as A. Medical Memoranda Discussion In this series of cases treated with glutethimide there were no maternal or foetal deaths and no significant untoward effects attributable to the drug. Four patients complained Chronic Bromism of nausea and a further five vomited within three hours of Although there are four mixtures containing potassium administration of the drug. These figures are more striking bromide in the National Formulary 1955, the drug is not so when one considers that the corresponding incidence of frequently prescribed as previously. Barbour, Pilkington, vomiting in the chloral hydrate group was 77. and Sargant (1936) found that 14% of 200 consecutive Sleep ensued about 30 minutes after administration of the prescriptions contained potassium bromide. For the year drug in 65 cases, and in 17 of these the level of the systolic 1949, in England, the figure of 5.8% has been quoted by blood pressure fell by 10 mm. Hg and the diastolic by 5 mm. Dunlop, Inch, and Paul (1953). These authors, in a survey This drop in blood pressure was maintained for three hours. of prescribing in Scotland in 1951, found a further decline Table IV shows that the total amount of pethidine needed in the use of bromide; in that year 1% of prescriptions con- for additional sedation and analgesia in the glutethimide tained potassium bromide. This 1%, however, represents an group was substantially below that required in the control appreciable number of prescriptions, since in the month of October, 1951, alone 4,000 prescriptions containing bromide TABLE IV and chloral hydrate were dispensed in Scotland. A personal scrutiny of 10,000 prescriptions issued by general practi- Amount of Pethidine Glutethimide Chloral Hydrate tioners in Aberdeen between January and December, 1954, Required Group Group revealed 1.1% with potassium bromide as a constituent. None 9 2 It is well known that the long-continued use of bromide 100 mg. .. 78 63 " 200 ,, I.. II 28 may produce symptoms of intoxication," but because of Over 200 mg. 2 7 the decline in its use chronic bromism may be forgotten and the insidious onset For the purpose of the X2 test, two classes only were formed: (1) none and overlooked. Attention is again drawn to 100 mg.; and (2) 200 mg. and over. x' corrected for continuity results as 12-08, and clinical picture of that condition. which, on pure chance, would arise less often than about I in 1,000. It is there- foreregarded as highly significant ofa real difference in the amount ofpethidine required. CASE REPORT series. In the glutethimide group, 87 patients required 100 mg. or less of pethidine, while 13 required 200 mg. or A housewife aged 52 was admitted to hospital in October, more. In the control group, 65 patients required 100 mg. 1953, suffering from mitral stenosis and congestive heart or less, whilst 35 required 200 mg. or more. failure, manifest by dyspnoea, venous congestion, hepato- Glutethimide was well tolerated by all patients, and none megaly, and slight oedema. She was successfully treated, showed any allergic reaction. The normal course of labour and was discharged a few weeks later on a regime which in the glutethimide series was unaffected, the average dura-- included digitalis, 2 ml. of a mercurial diuretic intra- tion of each stage of labour (see Table I) being slightly less muscularly once a week, and a diet of ordinary food with -though not significantly so-than in the control group, and no added salt. the general management of the first stage was greatly facili- On October 13, 1954, she was readmitted at the request tated by the mental and physical relaxation induced by the of her general practitioner on account of dysarthria, ataxia, drug. All patients who initially were apprehensive lost their and fatigue. After leaving hospital in 1953 she had com- fear and became fully co-operative shortly after administra- plained of increasing tiredness. In August, 1954, progressive tion of the drug. slurring of speech was noted by the patient and by her There was no significant difference in the incidence of post- friends. At no time was there weakness of any one limb, partum haemorrhage between the two groups (see Table II). but she complained of generalized stiffness, and in September her gait became unsteady. By this time she was spending most of the day in bed, rising at 9 a.m. and returning to bed Conclusion and Summary again at 11 a.m. because of overwhelming fatigue. When she Administered in early labour, glutethimide was found was readmitted in October she was unable to stand without to be an effective sedative, and was more easily adminis- support and was complaining of inability to expiess her tered and showed less evidence of gastric irritation than thoughts in words; she also had difficulty in using her arms chloral hydrate. because of tremor. for On examination she was drowsy, lethargic, and uncoopera- It greatly reduced the requirements of pethidine tive. She wept frequently, and was completely disinterested analgesia and additional sedation, the difference being in her surroundings, but at no time were hallucinations or statistically significant. delusions noted. Speech was slurred, but there was no It alleviated apprehension, thereby encouraging relaxa- nominal aphasia. There was a coarse tremor of the hands tion and co-operation, and produced no evidence of any and some apraxia was present. The gait was grossly ataxic maternal or foetal hazard. and she was quite unable to stand without support. There were no other abnormal neurological signs. The mouth was I am indebted to Ciba Laboratories, Ltd., for the supply of dry and salivation scanty. There was no skin rash. Mitral doriden employed in this trial and to their medical adviser, Dr. stenosis was present, associated with mild congestive heart A. K. Pittman. I thank the sisters in charge of the labour ward distended and the liver palpable; for their assistance during this clinical trial. I am also indebted failure, the neck veins being to Dr. G. Hurden for his statistical analysis of this paper. I am there was no oedema. grateful to Professor G. G. Lennon for helpful advice and Further inquiry revealed that for a year she had been criticism. taking a dose of a mixture containing, in each fluid ounce REFERENCES (30 ml.), 30 gr. (2 g.) of potassium bromide, 30 gr. (2 g.) of tincture of Gromss F., Tripod, J.. and Meier, R. (1955). Schweiz. med. Wschr., 85, 305. chloral hydrate, and 30 minims (1.8 ml.) of opium Hoffmann, K., and Kebrle, J. (1952). Helv. chim. Acta, 35, 1235, 1541. every night. She regularly took + oz. (15 ml.) of this mix- Ladwig, H. A. (1955). A.M.A. Arch. Neurol. Psychiat., 74, 351. ture, but on many occasions repeated the dose. During this Matlin, E. (1956). Med. Tins (N.Y.), U4, 68. period she was having a diet low in sodium chloride and was Rushbrookc, M.. Wilson, Ez. S. B1., Acland, J. D., and Wilson, G. M. (1956). British Medical Journal, 1. 139. being given a mercurial diuretic, 2 ml. weekuly by intramuscuw 566 MARCH 9, 1957 MEDICAL MEMORANDA lar injection. Latterly she had been eating very little food. It seemed likely that these factors, which tend to decrease Lactosuria following Burns the chloride content of body fluids, would lead to retention of bromide. A clinical diagnosis of chronic bromism was Baar and Bull (1952) reported lactosuria in severely burned confirmed by a serum bromide estimation of 175 mg. per patients treated with a local application of penicillin lactose 100 ml. (17 mEq). powder. The following report of a similar case illustrates The bromide mixture was discontinued on October 14, and again the absorptive capacity of " raw " cutaneous areas and sodium chloride, 1 g. daily, was given by mouth. The signs indicates the danger of applying toxic substances to such of congestive cardiac failure increased and the sodium damaged surfaces. In this case, however, the absorbed sub- chloride was discontinued six days later. On October- 19 stance was harmless. there was some improvement in speech, but she was still drowsy, querulous, and ataxic; tremor was still present. By CASE REPORT October 26 she was more alert and taking an interest in her- A woman aged 56 was admitted with burns of the back, self and her surroundings. On November 2 the serum buttocks, and thighs-approximately 2% of the surface area bromide level was 100 mg. per 100 ml. (9.7 mEq). At this of the body. Her general condition was found to be time she was much improved, although still drowsy and satisfactory and the bums were dressed. The following unable to walk unaided. Five weeks after discontinuing the day routine ward-testing of the urine with Benedict's reagent bromide mixture she had recovered and was transferred to showed the presence of a reducing substance. In addition, a convalescent hospital. Her personality had reverted to it was noticed that both Rothera's test and Gerhardt's (ferric normal; she- was alert and co-operative, and no longer had chloride) reaction were positive. tremor, ataxia, or slurring of speech. On December 2 the The presence of glycosuria in the first 36 hours after serum bromide level was 10 mg. per 100 ml. (0.97 mEq). burning is not an uncommon occurrence, but, in order to Subsequently a mitral valvotomy was performed, resulting eliminate the possibility of a coincident diabetes mellitus, in improvement in exercise tolerance. a glucose-tolerance test was undertaken, the blood-sugar method of Kingsley and Reinhold (1949), with tungstic acid filtrates, being used. COMMENT Several aspects of the diagnosis of chronic bromism men- Glucose-tolerance Test. tioned by Barbour et al. (1936) can usefully be re-emphasized. Of their five cases, ataxia occurred in three, and tremor, Venous Blood Urine Memory speech difficulty, and depression in two. impair- Blood- Reducing ment and hallucinations were common symptoms. None of Specimen sugar Substance Rothe Grhardt the five had a skin rash. Patients with atherosclerosis, Level (ApproxV. Rtea Grrd anaemia, impaired renal function, and organic heart disease (mg.lOOmi.) as Gluo are more susceptible to bromide intoxication. There is a Fasting .. .. 105 05 Positive Positive I hour after 50 g. wide individual variation in the level at which symptoms glucose .. 150 0-5 to to appear-for example, a patient suffering from one of the 2 hours after 50 g. above conditions may develop symptoms of bromism with a glucose 105 0-5 serum bromide level of 150 mg. per 100 ml. (14.5 mEq), whereas a healthy young man is able to tolerate the same level with no symptoms at all. The test showed no impairment of glucose tolerance, so Barbour et al. point out that bromide acts by replacing the condition was obviously not diabetes mellitus. The chloride in the body and that the rate of substitution depends positive Gerhardt (ferric chloride) reaction resulted from the on the quantity of bromide given, the fluid and electrolyte administration of tab. codein. co. The positive Rothera intake, and the renal efficiency of the patient. Therefore a reaction was explained by the mild ketosis that might be patient on a low-fluid and low-chloride regime will develop expected from the patient's condition. a higher level of bromide in the serum more quickly than a The presence of a reducing substance in approximately patient on a normal diet receiving the same amount of constant concentration in all the urine samples prompted bromide. Rosenheim (1951) and Holt and Litchfleld (1951) investigation into the nature of this substance. point out the dangers of giving a low-salt diet to patients Paper chromatography of the urine showed the following: with hypertension receiving hexamethonium bromide. A fasting, lactose; at 1 hour, lactose and glucose; at 2 hours, high ratio of bromide to chloride in the body fluids will lactose. The solvent used was n-butanol 60%, acetic acid also develop in a patient taking bromide and little or no 15%, distilled water 25% ; the spray reagent was 3.: 5 dinitro- food (Nabarro, 1954). salicylic acid. Chronic bromism of slight or moderate degree is easily The lactosuria was found to be associated with the use of overlooked because of the insidious development of the clini- lactose as a bland dressing for the burned areas. It was cal picture. Vague symptoms such as fatigue, depression, and thought, at first, that the urine samples had been contami- memory impairment may be attributed to senility, mental nated with lactose at the time of collection, but a catheter disorder, cerebral atherosclerosis, or the cerebral anoxaemia specimen of the urine again showed the presence of lactose. of congestive heart failure. The dangers of giving bromides Lactose was absent from a specimen of urine obtained one to patients taking a diet low in sodium chloride or under- week after cessation of the lactose dressings. going treatment with mercurial diuretics cannot be too There is no doubt that the lactose had been absorbed strongly emphasized. from the burned areas and excreted by the kidney. I am I thank Dr. Ian Gordon for permission to publish this case unaware of any evidence suggesting that such a temporary report. lactosuria is at all harmful. E. M. SPENCE, M.B., M.R.C.P., My thanks are due to Mr. D. H. Patey for permission to Lately Medical Registar, Aberdeen Royal Infirmary. publish this case. REFEREN E. T. KNUDSEN, M.B., B.S., Barbour, R. F., Pilkinaton, F., and Sargant. W. (1936). British Medical Senior Lecturer in Chemical Pathology, Journal, 2. 957. Courtauld Institute of Biochemistry, Dunlop. D. M., Inch, R. S., and Paul, J. (1953). Ibid., 1. 694. MIddlesex Hospital, London. Holt, M. C.. and Litchfleld, J. W. (1951). Lancet, 1. 347. Nabarro. J. D. N. (1954). BiochemIcal Investigations In Diagnosis and RErENCES Treatment. Lewis. London. Baar, S.. and Bull. J. P. (1952). Lancet. 1, 978. Roseaheim. M. L. (1951). Lancet, 1, 347. Kingsley, G. R., and Rednhold, J. 0}. (1949). J. Lab. clII,. Med., 34. 713