669 number of schizophrenics and noted that no increase in schizophrenic symptoms occurred. We also suggested then that Horrobin’s present hypothesis "calls for clinical assessment if it is to acquire credibility." Therapeutic enthusiasm will be in order when this is done and the hypothesis confirmed.
Stone, Aylesbury, Bucks HP17 8PP
DAVID C. WATT
EPIDURAL ANALGESIA AND NEONATAL HYPERBILIRUBINÆMIA
SIR,-Dr Lewis and Miss Friedman (Feb. 10, p. 300) mar preliminary communication on phenazone (antipyrine) prophylaxis of neonatal hyperbilirubin2emia by some unfounded allegations. They cite a retrospective analysis of 12 461 births at Queen Charlotte’s Hospital between 1971 and 1975 as evidence that epidural analgesia causes neonatal jaundice.’ That study shows no such thing. As so often happens with retrospective studies, spurious conclusions are reached and confusion is caused by ignoring variables that are later shown to be important. That retrospective study omitted to their
record prenatal medications that might have influenced enzyme induction, and serum-bilirubin was not measured for all infants. It also ignored important non-anxsthetic variables that have been shown to affect fetal well-being and gas exchange during labour and delivery, such as maternal posture/.3 hydration 4,and oxygenation.6-8 Thus we do not know that nursing practices at Queen Charlotte’s Hospital rigorously avoided the harmful dorsal maternal posture throughout the first and second stages of labour. The three variables of maternal posture, hydration, and F02 at delivery profoundly affect fetal oxygenation and acid-base status, and no study of fetal outcome should ignore them.8.9 Some prospective studies have suggested a strong association between oxytocin and neonatal hyperbilirubinxmia,’O mainly in the context of prematurely induced labour.ll-13 Since epidural analgesia is often used as an adjunct to the planned induction of labour, it is not surprising that an association should exist between oxytocin and epidural analgesia in unripe labours; however, it is clearly erroneous to use this association to imply that epidural analgesia causes neonatal
jaundice. We are passing through a phase of popular enthusiasm for "natural childbirth" and a rejection of medical interference in labour. Perhaps this movement represents a deep biological call to more rugged and eugenic breeding than our ethics permit ; nonetheless, it runs counter to our commitment to nurture the weak and threatened offspring at all phases of its existence. Skilful epidural analgesia is a powerful tool for protecting the infant from the stresses of labour: any unfounded allegations against the method, such as those made by Lewis and Friedman, undermine the cause of safe childbirth. Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina 27710, U.S.A.
PHILIP R. BROMAGE
1 Friedman, L., Lewis, P. J., Clifton, P., Bulpitt, C. J. Br. med. J. 1978,
Humphrey, M., Hounslow, D., Morgan, S., Wood, C. J. Obstet. Gynœc. Br. Commonw. 1973, 80, 1075. 3. Humphrey, M. D., Chang, A., Wood, E. C., Hounslow, D. ibid. 1974, 81, 600.
4.Wollman, S. B., Marx, G. F. Anesthesiology, 1978, 29, 374. 5. Collins, K.M., Bevan, D. R., Beard, R. W. Br. med. J. 1978, ii, 1460. 6. Khazin, A. F., Hon, E. H., Hehre, R. W. Am. J. Obstet. Gynec. 1971, 109, 628. 7. Marx,G.F.,Mateo,C.V. Can.Anæsth. Soc. J. 1971, 18, 587. 8. Fox, G.S., Houle, G. L. ibid. 1971, 18, 60. 9.Fox, G. S., Smith, J. B., Namba, Y., Johnson, R. C. Am. J. Obstet. Gynec.
1979, 133, 15. Beazley, J.M., Alderman, B.Br. J.Obstet. Gynæc. 1975, 82, 265. 11. Davies, D. P., Gomersall, R., Robertson, R., Gray, O. P., Turnbull, A. C. Br med. J. 1973, iii, 476. 12 Calder, A. A., Moar, V. A., Ounsted, M. K., Turnbull, A. C. Lancet, 1974, ii, 1339. 13 Chew, W. C., Swann, I.L. Br. med. J. 1977, i,72. 10
*** This letter has been shown whose reply follows.-ED.L.
Dr Lewis and Miss
that we have not been calls" in our work on neonatal responding "deep biological jaundice. We have merely investigated the factors associated with this common condition and, latterly, evaluated antenatal phenazone treatment as a prophylactic. We stand by our conclusion that epidural anxsthesia is one of several obstetric practices contributing to the increased incidence of the condition.’ Bromage thinks the association of epidural anaesthesia and neonatal jaundice is spurious since epidural anaesthesia is often practised together with icterogenic factors such as oxytocin and pre-term delivery. However, our multivariate analysis determined the influence of each variable independently of the others and we found that epidural anxsthesia per se raised mean peak serum-bilirubin concentrations in neonates by 6.8 mol/1 (0-4mg/dl) Since certain bupivacaine metabolites are glucuronidated in man (J. Caldwell, personal communication) there is a possible mechanism for the effect. However, we do not suggest that epidural anaesthesia should be avoided because it is mildly icterogenic. It is one of several practices in modern obstetrics which contribute to an upward trend in neonatal jaundice, a trend which might persuade obstetricians to look with more interest at prophylactic antenatal therapy with inducing agents.
Department of Clinical Pharmacology, Royal Postgraduate Medical School, London W12 0HS
PETER J. LEWIS LOUISE A. FRIEDMAN
SIR,-Your editorial (Feb. 3, p. 249) combines IgE antibody with "other circulating antibodies", and this covers up clear differences between IgE-mediated reactions and those mediated by other circulating antibodies. Symptoms of IgE antibody food reactions consist of allergic conjunctivitis, allergic rhinitis, sneezing, nasal occlusion, and wheezing. The symptoms precipitated by other circulating antibodies are (as your editorial states) oedema and urticaria. Typical wheal-andflare skin reactions occur in IgE-mediated food allergy, but not in the "other circulating antibody" type. Eosinophilia is a frequent finding in the IgE type, but not in the other type. IgE levels are increased only in the IgE type of allergy. Skin testing is of considerable practical value in the IgEmediated type, in contrast to your statement that "skin testing has little value in diagnosis of food allergy", which would be true of the "other antibody" type. Skin testing has been a valuable routine procedure in the diagnosis of food allergy of the IgE type for the past 50 years. If properly done, diagnosis is quite accurate. The intradermal method is the most accurate and the concentration of the extract must be adequate without being strong enough to precipitate a constitutional reaction. Testing, therefore, is usually done in two dilutions with those allergens known to have produced constitutional reactions such as fish, nuts, mustard seeds, or eggs. Testing as well as the actual ingestion of the offending food seems to have a threshold or "all or none" action, similar to the stimulation of a frog’s muscle with a galvanic current. Below a certain concentration in the circulation there is no effect until a threshold has been reached. In food allergy the threshold varies with the individual and with conditions that regulate absorption from the gastrointestinal tract. Threshold amounts seem to be lower for dangerous allergens and higher for the more innocuous foods such as cereals, meat, and chocolate. This is true whether the food is ingested or injected in the form of an extract. Fruits and vegetables (except for beans and peas), although they do occasionally produce allergic reactions, are not skin tested 1.
Friedman, L., Lewis, P. J., Clifton, P., Bulpitt, C. J. 1235.
670 because their extracts are unstable and because the protein ingested is often modified by cooking. All this information was set out in 1931 in Coca, Walzer, and Thommen’s book Asthma and Hayfever in Theory and Practice IgE-mediated reactions apart, I agree that elimination diets offer the best means to detect the allergen, combined with the history. I find the Alvarez diet (lamb, rice, canned pears, sugar, salt, and water and nothing else for 3 days) to be most ’. valuable. Your editorial covers well the wide range of tissue injury that may result from food ingestion, but several conditions mentioned would not be considered "food allergy" by many
Hospital, Buffalo, N.Y., U.S.A.
VICTOR L. COHEN
came to see us some
later, all of them did satisfy Thorn’s
"three considerations"’ (not "criteria" as stated by Edwards and Dent). These are excessive weight gain and/or fluid retention, with a diurnal gain in weight in general of more than 1.4 kg, exclusion of organic disease, and psychological or emotional disturbance. While on diuretics our patients were having diurnal swings’in weight, sometimes associated with large ftuctuations in carbohydrate and sodium intake. When the diuretics were stopped under controlled conditions in hospital, oedema developed in nine out of the ten patients. In the paper by Thorn,’ cited by Edwards and Dent, it is not clear whether the diurnal fluctuations in weight are while the patients are on diuretics or after diuretics have been stopped, and in particular, if they have been stopped, how long after. This is an important point which is relentlessly confusing in published
of observations made on patients with "idiopathic" oedema. For instance, Edwards and Dent’s letter adds to the confusion by stating that in their published paper2"... diuretic therapy had been discontinued for at least one month prior to investigation". But the paper itself states that "... none of the patients took diuretics or other therapy for at least a week before being studied". In any case the results presented in our paper suggest that even one month after stopping diuretics many of the observations described by Edwards and Dent would be influenced by the previous administration of these drugs. Edwards and Dent then state that the cardinal feature of "idiopathic" oedema is an excessive fall in blood volume on standing. They state that the evidence in support of this speculation is contained in two of their papers, one of which is unpublished.3 There is no evidence in the published paper2 to justify this statement, though it is true that the summary claims that, "The rate of loss of isotopically labelled 1’ albumin from the intravascular compartment was greater in patients with ’idiopathic’ oedema than in control subjects". But in the body of the paper there are no results of administering 125I-albumin to controls. The reason is revealed in the sion : "... for ethical reasons we did not give isotopically labelled albumin to our control subjects". The results that are described, show that in the patients the rate of loss of 125I-albumin was less in the upright position (5.6% per hour compared to 10. 1 % per hour when supine). This anomalous finding was attributed to "technical difficulties of blood sampling in the upright position when tilted". It is clear therefore, that this paper2 does not support the contention that 1251-albumin leaks more freely from the capillaries of patients with "idiopathic" oedema. The additional claim that there was a fall in blood volume upon standing, which was greater in the patients than in tlie controls, was based on increases of packed-cell volume of 10.3% in 11 patients and 7.9% in an unspecified number of controls. In view of the difficulties of blood-sampling which occurred in the upright posture in six of the patients, these results, though they are significant, should perhaps be interpreted with some caution. We must also point out that Edwards and Dent’s statement in their letter that there was a good correlation between 125I-albumin loss from the circulation and packed-cell volume is contrary to the results detailed in the paper. The good correlation that did occur was between the rise in packed-cell volume and the increase in concentration of
SIR,-Dr MacGregor and his co-workers (Feb. 24, p. 397)
’idiopathic’ oedema is idiopathic" and suggested that a principal cause was diuretic abuse, abetted in some patients by self-imposed fluctuations of sodium and carbohydrate intake. There are several aspects of’this study we would like to comask if"
The most important point is that MacGregor et al. have studied a group of patients who would not be generally accepted as idiopathic oedema. Most investigators have taken their definition from Thorn,’ who stated that the condition was one of intermittent affecting adult females without evidence of cardiac, renal, hepatic, allergic, hypoproteinwmic, obstructive veqous, or lymphatic disease, or taking drugs known to cause sodium retention. We would addthat premyxoedema should also be excluded. Furthermore, we have followed the criterion of Thorn that to be considered a case of idiopathic oedema the patient must have diurnal weight gains in excess of 1.4 kg. None of the patients studied by et al. satisfied these criteria-indeed only three presented with oedema. Their findings are important but the title of their article should have been "A study of oedema in diuretic abusers". The cardinal feature of idiopathic oedema, as defined by Thorn and confirmed by us,2.3 is the excessive fall in blood volume on standing, with compensatory renal reabsorption of salt and water. In both these studies there was good correlation between measurements of 121 I-albumin loss from the circulation and packed-cell volume is assessing changes in blood volume on tilting, and in both any diuretic therapy had been discontinued for at least one month before the investigation. In our experience, in who fit the diagnostic criteria of idiopathic oedema, as outlined above, the discontinuation of diuretic therapy does not lead to a disappearance of the symptoms and signs of the syndrome. We do not feel that maintenance diuretics are the appropriate therapy for this syndrome since they will lead to a further reduction of an already low blood volume. The ideal treatment should be directed at the cause of the excessive capillary leak, and this remains unknown. i OWEN M. EDWARDS Addenbrooke’s Hospital, RICHARD G. DENT Cambridge CB2 2QQ
1211-albumin. await Edwards and Dent’s second paper with instill maintain that intermittent oedema of unknown cause in most if not all women is due to their use of diuretics, possibly abetted on some occasions by self-imposed fluctuations in sodium and carbohydrate intake-in other words, their oedema is not idiopathic.
***This letter has been shown to Dr MacGregor and Professor de Wardener, whose reply follows.-ED.L
SIR,-Dr Edwards and Dr Dent do not accept that our patients had "idiopathic" oedema because a careful history of the initial cause for their taking diuretics did not always reveal that it was oedema; more usually it was concern for their weight and appearance. However, by the time the patients 1. Thorn, G. W. J. Am. med. Ass. 1968, 206, 333. 2. Edwards, O. M., Bayliss, R. I. S. Q. Jl Med., 1976, 45, 125. 3. Dent, R. G., Edwards, O. M. Clin. Endocr. (in the press).
Charing Cross Hospital Medical School, Department of Medicine, London W6 8RF
G. G. A. A. MacGREGOR
MACGREGOR H. E. DE WARDENER
1. Thorn, G. W. J. Am. med. Ass. 1968, 206, 333 2. Edwards, O. M., Bayliss, R. I. S. Q.Jl Med. 1976, 45, 125. 3. Dent, R. G., Edwards, O. M. Clin. Endocr. (in the press).