CARDIAC ARREST AFTER INTRAVENOUS

1265

epileptic,’18 and non-epileptic9 1319 patients to encourage investigation of a causal relationship 20 between them, especially in view of the high rate of protein turnover in the further

nervous

system. 21

The National Hospital, London W.C.1.

E. H. REYNOLDS.

Area Laboratory, West Park Hospital, Epsom.

J. PREECE.

M.R.C. Experimental Hæmatology Research Unit, St. Mary’s Hospital, London W.1.

Fig. 2-C.S.F.-folate in relation epileptic patients.

to

serum-folate in drug-treated

serum levels detected by all workers, except Weckman and Lehtovaara, are accompanied by changes in the C.S.F. The failure of Weckman and Lehtovaara to find differences in serum values may account for their similar c.s.F. levels in treated and untreated epileptics. Although these workers do not record the serum levels, their control neurological group appears to contain many patients with folate deficiency; 49 cases had C.S.F. values less than 5 ng. per ml., which we would regard as very abnormal. We have observed low c.s.F. levels (< 10 ng. per ml.) in a few patients with neurological disease (Wernicke’s encephalopathy, dementia, malignant neurological disease) but in none of these was the finding surprising. In view of the controversial nature of their findings, it would be pertinent to have some clinical information about their neurological controls and their FOLATE LEVELS IN RELATION TO PSYCHIATRIC ILLNESS

In c.s.F.: dementia v. psychosis, N.s.; dementia v. depression/retardation, P<0 001; dementia v. behaviour disorders, p
values

N.s. =not

are

otherwise the

same

for

gaussian or log-

significant.

untreated epileptic patients (which we rarely have the opportunity to study), in addition to some details of serum-folate levels, the duration of the study, the storage of the samples, and the use of preservatives. We have examined our results in epileptic.patients in relation to the presence of mental illness. The accompanying table shows that patients with dementia, psychosis, depression and/or retardation, and behaviour disorders had significantly lower c.s.p.-folate levels than those who were mentally normal, the lowest values being in patients with dementia. Similar, though less significant, trends were seen in the serum. Although the study of the complex relationship between folate and vitamin-B12 metabolism and neuropsychiatric illness

is

at an

CARDIAC ARREST AFTER INTRAVENOUS FRUSEMIDE 22 SIR,-Dr. Machtey reported the occurrence of sudden death in two adults within one minute after an intramuscular injection of frusemide. Although not specifically mentioned, it seems unlikely that the patients had been previously treated with this drug. I here report a similar unfortunate experience in a child who initially had tolerated oral and intravenous ’’ ’ frusemide without ill effect. A 7-year-old boy had developed a nephrotic syndrome 5 months before his admission to this hospital. He had been treated at another centre with prednisone 40 mg. daily for three weeks followed by 50 mg. daily for 18 days. (Edema persisted, as did proteinuria and microscopic haematuria. Chlorothiazide and spironolactone were without effect and he did not have a diuresis till he was given intravenous albumin. (Edema recurred, proteinuria and microscopic hasmaturia persisted, and he was transferred to this hospital for further "

lowering of

tribution is assumed. normal distribution.

I. CHANARIN.

early stage, there is sufficient evidence in both

investigation. He showed mild generalised oedema and oral moniliasis. His was 22-5 kg., height 121 cm. The blood-pressure was normal, the blood-urea-nitrogen 17 mg. per 100 ml., serumcholesterol 600 mg. per 100 ml., serum protein 4-5 and albumin 0-8 g. per 100 ml. The urine was grossly clear, was strongly positive for protein, and weakly positive for haemoglobin, and

weight

the sediment contained hyaline and granular

casts and few red blood-cells. I planned to treat the infection and reduce the oedema, obtain a renal biopsy, and then decide whether to continue or withdraw steroid treatment or commence an immunosuppressive agent. The patient was given prednisone 50 mg. daily in divided doses, and nystatin, but he developed more cedema and ascites and had intermittent diarrhoea. He had a tendency to low serum-electrolyte values and at times was given added sodium chloride and potassium chloride. Salt-poor albumin was given intravenously several times with some improvement in the oedema. At this time the prednisone was discontinued over two days and long-acting corticotrophin 40 units intramuscularly daily was started, for I have sometimes seen a good response in children with nephrotic syndrome who failed to respond to prednisone. Because of persistent oedema and his failure to respond to chlorothiazide and spironolactone, it was decided to try frusemide. Two oral doses of 100 mg. were given 12 hours apart, with some increase in urine volume but no loss of weight. In the next 4 days, no diuretic agent was used; thereafter 40 mg. frusemide was given every 12 hours, four doses orally and the remainder intravenously. On the morning of the last dose, he had a blood-urea- nitrogen of 20 mg. per 100 ml., serum sodium of 131, potassium 4-8, chloride 98, and total carbon dioxide of 23 meq. per litre. A few hours later the frusemide was given intravenously over a period of about 90 seconds, and 30 seconds later he complained of abdominal pain and was placed on a bedpan. He passed some flatus and then developed excruciating abdominal pain, at first generalised and then moving to the right side. Within 30 seconds, he collapsed and had cardiac 17. Reynolds, E. H. Brain, 1968, 91, 197. 18. Reynolds, E. H. Lancet, 1968, i, 398. 19. Strachan, R. W., Henderson, J. G. Q. Jl Med. 1967, 36, 189. 20. Reynolds, E. H. Excerpta med. int. Cong. Ser. 1966, no. 150, p. 1733. 21. Richter, D. Br. med. Bull. 1965, 21, 76. 22. Machtey, I. Lancet, 1968, ii, 1301.

1266 and respiratory arrest. Immediate resuscitation was successful in restoring cardiac action but he remained unconscious, had several subsequent cardiac arrests and intermittent generalised convulsions, and died 48 hours later following another arrest. At necropsy, the heart was normal apart from 20 ml. serous pericardial fluid, the lungs showed congestion, the bowel and mesenteric vessels were normal. The kidneys were large, swollen, boggy and had a granular appearance; microscopically the glomeruli showed increased mesangial matrix but no cellular proliferation, hyalinisation, or epithelial crescents, and there was no thickening of the capillary basement membranes. We concluded that he had a steroid-resistant nephrotic syndrome which most closely resembled the " minimal change " type, and that he had a cardiac arrest caused by hypersensitivity to frusemide. I have seen no other report of such an occurrence in childhood and have had no other such complication in a number of children who have received this diuretic

agent. The Hospital for Sick Children, Toronto 2, Ontario.

C. P. RANCE.

SURVIVAL-TIMES AFTER CARDIAC ALLOGRAFTS SiR,-Dr. Messmer and his colleagues (May 10, p. 954) ask: " Does cardiac transplantation at the present stage of development prolong the life of patients with advanced, therapyresistant heart-disease ? They conclude, with various qualiit believe that their paper gives a that does. We fications, misleading answer to their question. As Mr. Le Vay notes (May 24, p. 1048), only 2 of 15 transplanted patients were alive at the end of the observation period, while 15 of 42 were alive in the comparison group. Different periods of observation, incomplete follow-ups, and the contribution of preoperative survival to the total survival of the transplanted group question the validity of comparing mean survival-time of potential and actual recipients. A life-table analysis of the data affords a sounder comparison of survival with cardiac transplantation against survival without "

transplantation (see accompanying table). Taking all starters (column P in table), transplant patients appear to have an advantage in cumulative survival up to the end of the fourth month (after which only transplant patients died). This apparent advantage is entirely located in the first-month experience (column p in table). The lower first-month survival of non-transplant patients results from a skewed distribution of deaths: 70% occurred within the first month, half of them during the first week, whereas 50% of the transplant patients had a preoperative waiting-period of at least one week. For those who survived the first month, there is virtually no difference in the cumulative probability of survival (column P’ in table). This is an unavoidable bias, given the comparisons the authors have chosen to present. Of necessity transplant patients had to live until they were operated on; the comparison group was under no compulsion to survive a comparable period. A second problematic element of the comparisons presented

by the authors relates to age-distribution. The mean age of the transplant group was 49 years with a range of 5-62 years; the mean age of the potential recipient " group was 47 years, with a range of 7-60 years. The similarities conceal striking disparities. Among the 15 transplant patients, 1 5-year-old was in the age-group 45 years or less, and 14 were in the older age-group. Among potential recipients 12 of 42 were 45 or less, and 30 were older. These age differences, per se, probably exert a negligible influence on survival over an observation period of 9 months, but they do elaborate the question about the comparability of the transplanted group and the " potential recipient " comparison group. The question of prolongation of life is of course not the only issue to be weighed in the decision to operate. On that particular question, however, the evidence seems inadequate. "

Epidemiology Research Unit, N.Y.S. Department of Mental Hygiene, Division of Epidemiology, Columbia University, New York 10032.

FETAL/MATERNAL

LYMPHOCYTE TRANSFER Walknowska and Sm,-Dr. colleagues (June 7, p. 1119) suggest that "... it may be that the transplacental passage of fetal lymphocytes contributes to the acceptance of the fetus during gestation ". Before accepting this hypothesis, which was proposed in general terms five years ago, 1 it is necessary to demonstrate specific abrogation of transplantation immunity in the mother and to examine the possibility of a mutual effect in the fetus. It is possible that one cell-type of chimsrism in adult mammals may not be accompanied by diminished immunity towards different tissues from the same source as the chimaeric cells, as has been demonstrated in cattle twins3 Direct observations rather than inferences are desirable in such complex situations. Partly published studies 4in five mammalian species have shown that specific depression of immunity towards the histocompatibility antigens of the partner in viviparity exists in the armadillo and the rat, and to lesser degrees in man, dog, and sheep. This has been called " immunological inertia ", because it can be distinguished from similar states such as "paralysis", "tolerance", "antigen overload ", and " desensitisation ", by the characteristic features of partner-specificity, mutuality, evanescence and species-variation. The mechanism of inertia may be cellular transfer, but subcellular material would be equally acceptable for the exchange of information about the profiles of histocompatibility antigens that must occur. Artificial mimicry of the inertia is one method of testing this hypothesis that has 1. 2. 3.

Anderson, J. M., Benirschke, K. Br. med. J. 1964, i, 1534. Anderson, J. M. Nature, Lond. 1965, 206, 786. Stone, W. H., Cragle, R. G., Swanson, E. W., Brown, D. G. Science,

4. 5.

N.Y. 1965, 148, 1335. Anderson, J. M. Transpl. Proc. 1969, 1, 67. Anderson, J. M., Benirschke, K. Ann. N.Y. Acad. Sci. 1962, 99, Art3, 399.

PATIENTS, WITH AND WITHOUT CARDIAC TRANSPLANTATION REDUCING THE STARTING NUMBER BY HALF THE WITHDRAWALS)

SURVIVAL OF END-STAGE HEART-DISEASE

H. HANSEN F. MAROLLA Z. STEIN.

(MISSING

DEATHS ESTIMATED BY