865 neither Party could excuse itself from the bureaucracy which was now gripping the N.H.S. and involving nurses in more administrative work and doctors in more committees. Mr John Cronin (Labour, Loughborough), a consultant surgeon, appealed to Mrs Castle not to alienate the consultants and to treat them with consideration. Although there must be no compromise on the principle of abolishing pay-beds, some financial compensation was needed for those consultants affected. Perhaps the most succinct view came from Mr Kenneth Baker (Conservative, St Marylebone): "Not enough money is being spent on the N.H.S. and the country can probably afford virtually no more". Demand was insatiable and the question was not only how much we could afford but also how much we were prepared to afford. Though the N.H.S. was one of Britain’s greatest post-war achievements, the time had now come to consider alternative sources of finance. Predictably, Labour M.p.s rallied to Mrs Castle’s defence (and the Prime Minister was beside his beleaguered Secretary of State as she made her speech). But one Labour M.P. gave her less than whole-hearted support. Mr William Hamilton (Central Fife) thought she was being used as a scapegoat by the doctors: "She is in my view the wrong person for this particularly sensitive job. She sometimes creates an unfavourable impression, not only among doctors but among nurses too, by her strident defence of the Labour Party manifesto". Conservatives were in no doubt that Mrs Castle had for the first time in medical history united the doctors, nurses, and administrators against her. Dr Gerard Vaughan (Conservative, South Reading), a front-bench Opposition spokesman, said the consultants were fed up and ready to explode on almost any issue, while nurses no longer felt the pride they did and hesitated to say that they were nurses. Many Labour Nt.P.s found this almost too much to take and it was left to Dr David Owen, Minister of State, winding up the debate, to plead "even at this late stage" for a better sense of proportion about the problems of the N.H.S. On resources, no-one could make the needed economies better than the medical profession. For instance, if in all areas the average length of stay in hospital was no higher than the average which applied in a quarter of the areas, the potential saving in marginal costs, mainly hotel costs, would be about 56 million. On agency nurses, Dr Owen claimed that there seemed to have been a reasonably smooth transition. With three exceptions, there had been no reports of bed or ward closures as a result of the Government’s phasing-out policy. As for private medical practice, neither he nor Mrs Castle would be prepared to contemplate total abolition. He, too, took a conciliatory line towards consultants and junior doctors. Undoubtedly, many part-time consultants worked long hours for the Service, far exceeding what could normally be considered as their open-ended contractual obligation. He would strongly reject any policy that started to be "anti-doctor"; there was a great deal of sympathy among Labour M.P.s for the cause of junior hospital doctors. But, Dr Owen declared, the 1948 compromise allowing private practice within N.H.S. hospitals had been a festering sore which had grown worse in the past few years. There was now a chance that a reasonably con-
ducted policy on pay-beds and a phased separation "could solve the problems of private practice for decades".
Letters
to
the Editor
ORAL HYPOGLYCÆMICS IN DIABETES MELLITUS
SiR,—Your otherwise well-balanced editorial (Sept. 13, p. 489) unfortunately ended with a well-turned non-sequitur. Having argued the uncertainty of the evidence for and against the use of oral agents in diabetes and having expressed regrets at the generalisation from the conclusions of the University Group Diabetes Program (U.G.D.P.), with two specific drugs, to all substances classed as oral agents, you conclude by condemning "the instant prescription of a potent and potentially dangerous drug". To which particular drug do you refer? With
general caveat about the use of all potent and potentially dangerous drugs we would concur, but that is hardly the implia
cation to be drawn from the context. U.G.D.P. stands alone among several reasonably conducted, double-blind, random-allocation trials of tolbutamide and phenformin in claiming excess cardiovascular mortality. You referred to our findings in Bedford which contained no hint of increased cardiovascular mortality in those treated with tolbutamide compared with placebo.’ In a similar study, we have observed no effect of phenformin upon mortality, nor have we, in contrast to U.G.D.P., found any effect on blood-pressure or pulse-rate. Similar findings are reported for tolbutamide2-4 and for phenformin.’ As for the "eagerly awaited" clinical studies, it was the authors of the U.G.D.P. report who, quite properly, stressed the dubious validity of conclusions drawn from comparisons made from retrospective analysis of nonrandomised clinical data. The Joslin Clinic data to which you referred have already been presented verbally both as supporting and as refuting U.G.D.P. conclusions!6 It is true that each prospective study has differed with respect to the kind of population observed and the dose of drug used, but this only adds to the complexity of interpretation and does not imply that the largest investigation (U.G.D.P.) provides the "right" answer. Furthermore, no trial has yet assessed the effects of oral antidiabetic drugs on mortality or morbidity of diabetics with ,
symptoms and/or significant
hyperglycaemia despite adequate
dieting. The effect of the oral agents on cardiovascular morbidity has excited less interest to date. As you rightly state (though without quoting our most recent analysis 7) we adduced some evidence for a "protective" effect of tolbutamide against arterial events (infarction, angina, claudication, stroke, and Minnesota-codable E.c.G. changes). The similar study of Carlstrom et al. supports our own. Furthermore, a preliminary analysis of data from the first five years of follow-up of our double-blind, random-allocation trial of phenformin (50 mg/day) in 204 newly detected8 "border-line diabetics" (male Civil Servants aged 40-65) showed significantly fewer individuals in the phenformin group suffering non-fatal myocardial infarction and codable E.c.. deterioration compared with the placebo group. Your editorial fails to draw attention to a new element which has, perhaps predictably, emerged on the American scene. There, it seems, the U.G.D.P. may cease simply to be one study among others, but will receive an exclusive seal of 1.
Keen, H., Jarrett, R. J., Chlouverakis, C., Boyns, D. R. Postgrad. med. J. 1968, 44, 960. 2. Carlstrom, S., Persson, G., Scherstèn, B. Diabetes, 1975, 24, 414 (abstract). 3. Paasikivi, J. Acta med. scand. 1970, suppl. 507. 4. Feldman, R., Crawford, D., Elashoff, R., Glass, A. in Proceedings of 8th Congress of International Diabetes Federation, (edited by W. J. Malaisse and J. Pirart). Excerpta med. int. Congr. Ser. 1974, no. 312, p. 574. 5. Tzagournis, M., Reynerston, R. Ann. intern. Med. 1972, 76, 587. 6. U.S. Food and Drug Administration Public Hearing on Proposed Labelling for Oral Hypoglycæmic Drugs, Rockville, Maryland, Aug. 20, 1975 (in the press). 7. Keen, H., Jarrett, R. J., Fuller, J. H. in Proceedings of 8th Congress of International Diabetes Federation, (edited by W. J. Malaisse and J. Pirart). Excerpta med. int. Congr. Ser. 1974, no. 312, p. 588. 8. Reid, D. D., Brett, G. Z., Hamilton, P. J. S., Jarrett, R. J., Keen, H., Rose, G. A. Lancet, 1974, i, 469.
866 official endorsement, for the Food and Drug Administration has proposed that an "unencumbered warning" of increased risk of cardiovascular death be prominently included in the "package insert" of all oral hypoglycaemic agents. This "unencumbered warning" would accept U.G.D.P. findings as established ; it would extend them to all other drugs and dosages; it would dismiss criticisms as invalid and it would make no reference to contradictory findings. In our view, this action would not only unfairly "slant" the evidence but would introduce, by selective promotion and suppression of evidence, something approximating to an official version of the truth. As well as being alien to the tradition of free scientific debate, it could have the effect of giving F.D.A. pronouncements the force of law. A physician departing from the officially sanctioned "correct" treatment of diabetes might well lay himself open
to
TABLE 11--COMPARISON OF CORRECTED WEIGHTS OF MALF AND OF FEMALE INFANTS WHO LATER DEVELOPED DIABETES WITH CONTROl INFANTS OF THE SAME SEX
malpractice litigation.
The oral
controversy is far from settled. Inthe agents are being overused and misused, more in some countries than in others, but this is the fate of all drugs in common use. It is a problem more likely to be solved by education than legislation. Of course, the public welfare is paramount, and legislative action is sometimes required, but when it is imposed on the basis of shaky evidence and in the face of bona-fide division of opinion it is unacceptable. H. KEEN Department of Medicine, R. J. JARRETT Guy’s Hospital Medical School, London SE1 9RT. J. H. FULLER
hypoglycaemic
contestably,
WEIGHT GAIN IN INFANCY AND SUBSEQUENT DEVELOPMENT OF DIABETES MELLITUS IN CHILDHOOD
SIR,-It has been shown that, at the time of onset of diabetes in childhood, diabetic boys may be taller than average for their age.’ This suggests that an endocrine disorder has preceded overt diabetes by a considerable time. There have also been case-reports of infants with hypoglycaemic episodes developing diabetes mellitus in later childhood.’ These observations led us to investigate the pattern of weight gain in infancy in a group of children who developed diabetes. The 105 families attending our children’s diabetic clinic were sent questionnaires asking them to retrieve information TABLE I.-STATE OF UNDRESS OF DIABETIC CHILDREN WHEN WEIGHED IN
INFANCY, AND WEIOHT DEDUCTED
6
AND
TO ACHIEVE CORRECTED WEIGHTS AT
12
weights of ihese diabetic children in infancy were com40 male and 40 female infants who were born with pared between 38 and 41 weeks of gestation and whose birth-weights were within two standard deviations of the mean. These 80 control infants were randomly selected from a larger group currently under study in Oxford for other purposes. The weights in infancy of the diabetic children and of the control infants are compared in table n. For the males the birth-weights of the two groups are similar; at 6 months the diabetic group is significantly heavier; at 1 year the diabetic group is heavier but this difference does not reach significance. The two groups of female infants are of similar birth-weight; at 6 months the weights are similar; at 1 year the diabetic group is significantly heavier. These data suggest that children who develop diabetes mellitus are heavier at certain stages in infancy. This could be the result of overfeeding. Alternatively it may be an early indication of hormonal imbalance-possibly a relative hyperinsulinism. This work
(J.D.B.) and
supported by the British Diabetic Association M.R.C. programme grant (M.O.).
was
an
Department of Pædiatrics, University of Oxford, John Radcliffe Hospital, Headington, Oxford.
J. D. BAUM M. OUNSTED M. A. SMITH
MONTHS
the weight of their diabetic children at birth, 6 months, and 12 months as recorded on their infant-welfare-clinic cards. We obtained information on the weights in infancy of 13 diabetic girls and 22 diabetic boys. We also asked the parents to record whether the infants had been weighed naked, partially dressed, or dressed when they were weighed, or alternatively to say they were uncertain. These replies are shown in table i. In order to compare these weights with control infants who were weighed naked, we substracted a correction factor 220 g (the weight of a good-quality terry-towelling napkin plus a vest) from the weight when the infant had been weighed partially dressed; and 380 g (a terry-towelling napkin, plus vest, plus a stretchable sleeping-suit) when the infant had been weighed dressed. Where the replies were uncertain we subtracted 380 g from the weight. All the diabetic children had been born "at term" according to their mother’s recollection.
on
1. 2.
The
Drayer, N. M. Archs Dis. Childh. 1974, 49, 616. Sperling, M., Drash, A. Am. J. Dis. Child. 1971, 121,
5.
BLOOD, PLASMA, OR SERUM? SIR,-A recent paper in your journal listing blood analyses for various constituents, mentioning them all as blood this and blood that, stimulates me to write to you, about an increasing carelessness of authors with regard to these tests and, forgive me, perhaps a little lapse on behalf of the editors who review their papers and correct them before publication. May I emphasise that blood samples for analysis for different things in the pathology laboratories mainly comprise three different sources: first, blood-that is, whole bloodwhich is used for substances mainly contained in the red cells (namely, haemoglobin, glutathione, lead) and also for one or two estimations for which there are special reasons for using whole blood not too obvious at first sight (sugar, that is, glucose, is often still done on whole blood, likewise alcohol). The anticoagulant is usually but not always heparin. Secondly, plasma, obtained from anticoagulated blood, is nearly always used now for routine determinations that go through the ’AutoAnalyzer’ system of analysis and this includes urea, electrolytes, cholesterol, and nearly all the common things. For years urea used to be determined on whole blood as it is freely diffusible and the blood urea is only a little less than the plasma urea. But blood has not been used for urea for years now and it is quite wrong, as is so frequently stated, that the blood urea was this or that because the estimation was not done on the blood but on the plasma. Thirdly, there is serum
ducted policy on pay-beds and a phased separation "could solve the problems of private practice for decades".
Letters
to
the Editor
ORAL HYPOGLYCÆMICS IN DIABETES MELLITUS
SiR,—Your otherwise well-balanced editorial (Sept. 13, p. 489) unfortunately ended with a well-turned non-sequitur. Having argued the uncertainty of the evidence for and against the use of oral agents in diabetes and having expressed regrets at the generalisation from the conclusions of the University Group Diabetes Program (U.G.D.P.), with two specific drugs, to all substances classed as oral agents, you conclude by condemning "the instant prescription of a potent and potentially dangerous drug". To which particular drug do you refer? With
general caveat about the use of all potent and potentially dangerous drugs we would concur, but that is hardly the implia
cation to be drawn from the context. U.G.D.P. stands alone among several reasonably conducted, double-blind, random-allocation trials of tolbutamide and phenformin in claiming excess cardiovascular mortality. You referred to our findings in Bedford which contained no hint of increased cardiovascular mortality in those treated with tolbutamide compared with placebo.’ In a similar study, we have observed no effect of phenformin upon mortality, nor have we, in contrast to U.G.D.P., found any effect on blood-pressure or pulse-rate. Similar findings are reported for tolbutamide2-4 and for phenformin.’ As for the "eagerly awaited" clinical studies, it was the authors of the U.G.D.P. report who, quite properly, stressed the dubious validity of conclusions drawn from comparisons made from retrospective analysis of nonrandomised clinical data. The Joslin Clinic data to which you referred have already been presented verbally both as supporting and as refuting U.G.D.P. conclusions!6 It is true that each prospective study has differed with respect to the kind of population observed and the dose of drug used, but this only adds to the complexity of interpretation and does not imply that the largest investigation (U.G.D.P.) provides the "right" answer. Furthermore, no trial has yet assessed the effects of oral antidiabetic drugs on mortality or morbidity of diabetics with ,
symptoms and/or significant
hyperglycaemia despite adequate
dieting. The effect of the oral agents on cardiovascular morbidity has excited less interest to date. As you rightly state (though without quoting our most recent analysis 7) we adduced some evidence for a "protective" effect of tolbutamide against arterial events (infarction, angina, claudication, stroke, and Minnesota-codable E.c.G. changes). The similar study of Carlstrom et al. supports our own. Furthermore, a preliminary analysis of data from the first five years of follow-up of our double-blind, random-allocation trial of phenformin (50 mg/day) in 204 newly detected8 "border-line diabetics" (male Civil Servants aged 40-65) showed significantly fewer individuals in the phenformin group suffering non-fatal myocardial infarction and codable E.c.. deterioration compared with the placebo group. Your editorial fails to draw attention to a new element which has, perhaps predictably, emerged on the American scene. There, it seems, the U.G.D.P. may cease simply to be one study among others, but will receive an exclusive seal of 1.
Keen, H., Jarrett, R. J., Chlouverakis, C., Boyns, D. R. Postgrad. med. J. 1968, 44, 960. 2. Carlstrom, S., Persson, G., Scherstèn, B. Diabetes, 1975, 24, 414 (abstract). 3. Paasikivi, J. Acta med. scand. 1970, suppl. 507. 4. Feldman, R., Crawford, D., Elashoff, R., Glass, A. in Proceedings of 8th Congress of International Diabetes Federation, (edited by W. J. Malaisse and J. Pirart). Excerpta med. int. Congr. Ser. 1974, no. 312, p. 574. 5. Tzagournis, M., Reynerston, R. Ann. intern. Med. 1972, 76, 587. 6. U.S. Food and Drug Administration Public Hearing on Proposed Labelling for Oral Hypoglycæmic Drugs, Rockville, Maryland, Aug. 20, 1975 (in the press). 7. Keen, H., Jarrett, R. J., Fuller, J. H. in Proceedings of 8th Congress of International Diabetes Federation, (edited by W. J. Malaisse and J. Pirart). Excerpta med. int. Congr. Ser. 1974, no. 312, p. 588. 8. Reid, D. D., Brett, G. Z., Hamilton, P. J. S., Jarrett, R. J., Keen, H., Rose, G. A. Lancet, 1974, i, 469.
866 official endorsement, for the Food and Drug Administration has proposed that an "unencumbered warning" of increased risk of cardiovascular death be prominently included in the "package insert" of all oral hypoglycaemic agents. This "unencumbered warning" would accept U.G.D.P. findings as established ; it would extend them to all other drugs and dosages; it would dismiss criticisms as invalid and it would make no reference to contradictory findings. In our view, this action would not only unfairly "slant" the evidence but would introduce, by selective promotion and suppression of evidence, something approximating to an official version of the truth. As well as being alien to the tradition of free scientific debate, it could have the effect of giving F.D.A. pronouncements the force of law. A physician departing from the officially sanctioned "correct" treatment of diabetes might well lay himself open
to
TABLE 11--COMPARISON OF CORRECTED WEIGHTS OF MALF AND OF FEMALE INFANTS WHO LATER DEVELOPED DIABETES WITH CONTROl INFANTS OF THE SAME SEX
malpractice litigation.
The oral
controversy is far from settled. Inthe agents are being overused and misused, more in some countries than in others, but this is the fate of all drugs in common use. It is a problem more likely to be solved by education than legislation. Of course, the public welfare is paramount, and legislative action is sometimes required, but when it is imposed on the basis of shaky evidence and in the face of bona-fide division of opinion it is unacceptable. H. KEEN Department of Medicine, R. J. JARRETT Guy’s Hospital Medical School, London SE1 9RT. J. H. FULLER
hypoglycaemic
contestably,
WEIGHT GAIN IN INFANCY AND SUBSEQUENT DEVELOPMENT OF DIABETES MELLITUS IN CHILDHOOD
SIR,-It has been shown that, at the time of onset of diabetes in childhood, diabetic boys may be taller than average for their age.’ This suggests that an endocrine disorder has preceded overt diabetes by a considerable time. There have also been case-reports of infants with hypoglycaemic episodes developing diabetes mellitus in later childhood.’ These observations led us to investigate the pattern of weight gain in infancy in a group of children who developed diabetes. The 105 families attending our children’s diabetic clinic were sent questionnaires asking them to retrieve information TABLE I.-STATE OF UNDRESS OF DIABETIC CHILDREN WHEN WEIGHED IN
INFANCY, AND WEIOHT DEDUCTED
6
AND
TO ACHIEVE CORRECTED WEIGHTS AT
12
weights of ihese diabetic children in infancy were com40 male and 40 female infants who were born with pared between 38 and 41 weeks of gestation and whose birth-weights were within two standard deviations of the mean. These 80 control infants were randomly selected from a larger group currently under study in Oxford for other purposes. The weights in infancy of the diabetic children and of the control infants are compared in table n. For the males the birth-weights of the two groups are similar; at 6 months the diabetic group is significantly heavier; at 1 year the diabetic group is heavier but this difference does not reach significance. The two groups of female infants are of similar birth-weight; at 6 months the weights are similar; at 1 year the diabetic group is significantly heavier. These data suggest that children who develop diabetes mellitus are heavier at certain stages in infancy. This could be the result of overfeeding. Alternatively it may be an early indication of hormonal imbalance-possibly a relative hyperinsulinism. This work
(J.D.B.) and
supported by the British Diabetic Association M.R.C. programme grant (M.O.).
was
an
Department of Pædiatrics, University of Oxford, John Radcliffe Hospital, Headington, Oxford.
J. D. BAUM M. OUNSTED M. A. SMITH
MONTHS
the weight of their diabetic children at birth, 6 months, and 12 months as recorded on their infant-welfare-clinic cards. We obtained information on the weights in infancy of 13 diabetic girls and 22 diabetic boys. We also asked the parents to record whether the infants had been weighed naked, partially dressed, or dressed when they were weighed, or alternatively to say they were uncertain. These replies are shown in table i. In order to compare these weights with control infants who were weighed naked, we substracted a correction factor 220 g (the weight of a good-quality terry-towelling napkin plus a vest) from the weight when the infant had been weighed partially dressed; and 380 g (a terry-towelling napkin, plus vest, plus a stretchable sleeping-suit) when the infant had been weighed dressed. Where the replies were uncertain we subtracted 380 g from the weight. All the diabetic children had been born "at term" according to their mother’s recollection.
on
1. 2.
The
Drayer, N. M. Archs Dis. Childh. 1974, 49, 616. Sperling, M., Drash, A. Am. J. Dis. Child. 1971, 121,
5.
BLOOD, PLASMA, OR SERUM? SIR,-A recent paper in your journal listing blood analyses for various constituents, mentioning them all as blood this and blood that, stimulates me to write to you, about an increasing carelessness of authors with regard to these tests and, forgive me, perhaps a little lapse on behalf of the editors who review their papers and correct them before publication. May I emphasise that blood samples for analysis for different things in the pathology laboratories mainly comprise three different sources: first, blood-that is, whole bloodwhich is used for substances mainly contained in the red cells (namely, haemoglobin, glutathione, lead) and also for one or two estimations for which there are special reasons for using whole blood not too obvious at first sight (sugar, that is, glucose, is often still done on whole blood, likewise alcohol). The anticoagulant is usually but not always heparin. Secondly, plasma, obtained from anticoagulated blood, is nearly always used now for routine determinations that go through the ’AutoAnalyzer’ system of analysis and this includes urea, electrolytes, cholesterol, and nearly all the common things. For years urea used to be determined on whole blood as it is freely diffusible and the blood urea is only a little less than the plasma urea. But blood has not been used for urea for years now and it is quite wrong, as is so frequently stated, that the blood urea was this or that because the estimation was not done on the blood but on the plasma. Thirdly, there is serum
