1406

We take this opportunity to emphasise the completeness of the mortality follow-up.3 After careful rechecking of death registers and the employment of additional staff to find survivors, we estimate that death or survival has been established for more than 99% of men in all centres, and there is no significant difference between groups I and II in this respect. Royal Free Hospital,

J. A. HEADY

London NW3

throughout the period of primary immunisation). Groups were closely matched in terms of pre-immunisation antiPRP. Levels after the third dose are summarised in the table. No significant difference occurred in the pattern of responses between groups. Similarly, responses to pertussis and to tetanus and diphtheria toxoid were not enhanced in breastfed infants. Results were unchanged when infants were grouped more conservatively (breastfed for less than 1 or greater than 1 month), as in the earlier

study.3

London School of Hygiene and Tropical Medicine

J. N. MORRIS

Wynn Institute for Metabolic Research, 21 Wellington Road, London NW8 9SQ, UK

M. F. OLIVER

1. Committee of Principal Investigators. A co-operative trial in the primary prevention of ischaemic heart disease using clofibrate. Br Heart J 1978; 40: 1069-118. 2. Committee of Principal Investigators. WHO cooperative trial on primary prevention of ischaemic heart disease using clofibrate to lower serum cholesterol: mortality follow-up. Lancet 1980; ii: 379-85. 3. Committee of Principal Investigators. WHO cooperative trial on primary prevention of ischaemic heart disease with clofibrate to lower serum cholesterol: final mortality follow-up. Lancet 1984; ii: 600-04. 4. Muldoon M, Manuck S, Matthews K. Lowering cholesterol concentrations and mortality: a quantitative review of primary prevention trials. BMJ 1990; 301: 309-14. 5. Davey Smith G, Pekkanen J. Should there be a moratorium on the use of cholesterol lowering drugs? BMJ 1992; 304: 431-34. 6. Ravnskov U. Cholesterol lowering trials and coronary heart disease: frequency of citation and outcome. BMJ 1992; 305: 15-19. 7. Durrington PN, Laker MF, Keech A. Frequency of dtation and outcome of cholesterol lowering trials. BMJ 1992; 305: 420-21.

Our data do not support the conclusions of Pabst and Spady; we found no evidence of a significant difference in accepted serological correlates of immunity in breastfed infants at 7 months of age. Our analysis involved five times more infants and had sufficient power to detect a difference in response rates between groups of 15% or greater, with 80% probability (ex =0-05, two sided). Unlike the earlier analysis, we did not omit low antiPRP responders (< 100 J.1g/ml) from analysis. Our results would not have changed had we done so. Different haemophilus conjugate vaccines were used in the two studies but Decker et als found no influence of feeding method on responses to the four available haemophilus b conjugate vaccines in a controlled trial in American infants. Details of their analysis are not available. It seems that the earlier conclusions were incorrect and that breastfeeding does not enhance responses to haemophilus b conjugate vaccines, at least when assessed on completion of the primary series.

Vaccine Evaluation Center, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada

D. SCHEIFELE G. J. BJORNSON R. GUASPARINI B. FRIESEN W. MEEKISON

Breastfeeding and antibody responses to routine vaccination in infants SIR,—Breastfeeding offers infants advantages over formula feeding, including increased protection against some infections.1,2 Pabst and Spady3 indicated that breastfed compared with formulafed infants responded with higher antibody levels to a series of three doses of haemophilus b polysaccharide-C97 diphtheria toxin conjugate vaccine, which they regarded as "strong evidence that breastfeeding enhances the active immune response in the first year of life". They cautioned that feeding method should be taken into account in vaccine studies in infants. We have completed a large study of another haemophilus b conjugate vaccine. Feeding history was obtained for 408 infants at 7 months of age, 1 month after they completed three doses of haemophilus b polysaccharide-tetanus toxoid conjugate vaccine (PRP-T, Connaught Laboratories, Willowdale, Ontario). Participants were healthy infants attending immunisation clinics in the suburbs of Vancouver. Vaccinations were given at 2, 4, and 6 months of age, concurrently with diphtheria-pertussis-tetanus vaccine and oral poliovirus vaccine (omitted at 6 months). Blood was obtained at intervals; at 7 months sera were tested for antiPRP by radioimmunoassay, pertussis agglutinins by microassay, tetanus antitoxin by enzyme immunoassay, and diphtheria antitoxin by microneutralisation.4 Infants were grouped by feeding history. For maximum contrast compared those who were breastfed for less than 4 weeks or not all with those who were breastfed for at least 24 weeks (ie,

we

at

1. Kovar MG, Sordula MK, Marks JS, Frazer DW. Review of the epidemiologic evidence for an association between infant feeding and infant health. Pediatrics 1984; 74 (suppl): 615-38. 2. Dolan SA, Boesman-Finkelstein M, Finkelslein RA. Inhibition of enteropathogenic bacteria by human whey in vitro. Pediatr Infect Dis J 1989; 8: 430-36. 3. Pabst H, Spady DW. Effect of breastfeeding on antibody response to conjugate vaccine. Lancet 1990; 336: 269-70. 4. Scheifele DW, Barreto L, Meekison W, Guasparini R, Friesen B. Assessment of Haemophilus influenzae type b tetanus toxoid conjugate vaccine given concurrently or combined with diphtheria and tetanus toxoids and pertussis vaccine, to healthy infants. Can Med Asso J (in press). 5. Decker MD, Edward KM, Bradley R, Palmer P. Comparative trial in infants of four conjugate Haemophilus influenzae type b vaccines. J Pediatr 1992; 120: 184-89.

Bartter’s syndrome and

growth hormone replacement

SIR,-Dr Boer and Professor Soppi’s findings (Oct 3, p 860) are likely to be seen in Bartter’s syndrome, and it is good riews that growth hormone (GH) replacement was successful in their case. However, their observation is still inconclusive. First, normal adult height has been attained in children with Bartter’s syndrome, who are short when diagnosed.1,2 In our case, a 9-year-old boy was 117 cm ( -5 SD) on first admission and yet he is 175 cm (+10 SD) at 24 years of age despite prolonged hypokalaemia. We therefore speculate that the delayed bone age, despite improvement of linear growth after the institution of indomethacin, might allow more time to grow before the epiphyses close.

ANTI-PRP RESPONSES AT 7 MONTHS OF AGE AFTER THREE DOSES OF PRP-T VACCINE

Second, to assess GH secretion, most investigators do two or provocative tests, because failure to respond to a single

more

stimulus has been regarded as insufficient evidence for the diagnosis of GH deficiency.4Boer and Zoppi did only one test and the peak GH value was 98 ng/ml, which is very near to that regarded as a normal response. In our opinion, arginine is the least potent of GH provocative stimuli. Boer and Zoppi’s report should therefore be regarded with caution.

Department of Pediatrics, *Not

significant by t-test, p=0745 Data were normally distributed transformed to logarithms. Negatives were assigned value of 0 03 I1glml.

when

Nikko Memorial Hospital, Muroran 051, Japan

NORITOMO ITAMI NORIKO SATAKE MAKOTO YOSHIDA EIKI OHSHIKA YASUTSUGU KOGA

1407

1. Brouhard BH. Juxtaglomerular hyperplasia In: Rudolph AM, ed. Rudolph’s ed. London: Prentice-Hall, 1991: 1284-85. 2. Proesmans W, Massa G, Vanderschuerren-Lodeweycke M Growth from birth to adulthood in a patient with the neonatal form of Bartter’s syndrome. Pediatr Nephrol 1988; 2: 205. 3. Tamiya N, Yasuda K, Tochimaru H, et al. A case of Bartter’s syndrome associated with central pontine myelinolysis. Japan J Pediatr Nephrol 1991; 4: 277. 4. D’Ercole AJ, Underwood LE. Anterior pituitary gland and hypothalamus In: Rudolph AM, ed. Rudolph’s paediatrics, 19th ed. London: Prentice-Hall; 1991. 1566-77. 5. DiGeorge AM. Hypopituitarism. In: Berman RE, ed. Nelson’s textbook of pediatrics, 14th ed. Philadelphia: Saunders, 1992; 1398-402.

paediatrics, 19th

Muscling in on salbutamol S!R,—Dr Martineau and colleagues (Oct 31, p 1094) suggest that serious consideration should be given to adding salbutamol to the list of banned substances for athletes. This view is based on the results of a trial comparing controlled-release salbutamol with placebo in a small number of volunteers. The information presented does not allow an evaluation of the study design; neither salbutamol dosage nor the measurements used to assess muscle strength are described. They point out that there has been no published evidence about the effects of &bgr;z-agonists on muscle mass and function in man. However, evidence from in-vivo studies and the known kinetics of these drugs raises several points. First, Martineau et al point out that clenbuterol, the 0,-agonist that was reported to have been used by athletes at the Barcelona Olympics, has been compared with salbutamol in several studies. The short plasma half-life of 3-6 h (compared with 34-35 h for clenbuterol)l may account for the observations that salbutamol does induce the changes in skeletal muscle seen with clenbuterol in these in-vivo studies. Martineau and colleagues have themselves shown that, whereas high oral doses of salbutamol fed to rats had no effect on gastrocnemius muscle mass or other indices of muscle growth, continuous infusion of salbutamol did have an effect similar to that of clenbuterol This finding suggests that continuous exposure to high systemic concentrations of &bgr;z-agonists would be needed if any effect is to be seen in man. Second, slow-release salbutamol (Volmax) was developed as a convenient oral dosing regimen for those patients requiring continuous bronchodilation. A dose of 8 mg twice daily results in steady-state plasma concentrations of 10-20 ng/ml over the 12 h twice daily dosing period.3 The recommended dose for inhaled salbutamol (200 ug) results in plasma concentrations of drug that are only transiently detectable.4For example, in a study of asthmatic patients6 a single oral dose of 8 mg resulted in plasma concentrations of salbutamol that were 100 times greater than those after a single inhaled dose of 80 jg. Therefore, absorption and plasma concentrations relate closely to the dose of drug. An athlete would have to use doses vastly greater than those recommended by the inhaled route to achieve systemic values similar to those achieved after oral dosing. Such doses would result in increased side-effects such as fine tremor that would probably inhibit rather than improve athletic performance. For most patients with asthma, the banning of salbutamol and other inhaled &bgr;z-agonists by sporting bodies would be of little consequence. However, the elite athlete who has to maintain control of his or her disease while competing at the highest level should not be handicapped by being unable to use such an effective drug. Asthmatic athletes are not uncommon; the proportion of Olympic athletes who are asthmatic is similar to that of the general population? The International Olympic Committee prohibits the use of oral &bgr;-zagonists but allows metered-dose aerosols or dry-powder formulations. There is no evidence to support any change in this position. not

Clinical Research,

Glaxo Inc, Research Triangle Park, North Carolina, USA

J. B. D. PALMER

Department of Respiratory Medicine, International Medical Affairs,

G. L. SHEPHERD A. T. CIFELLI

Glaxo Group Research,

Abridge, Middlesex UB11 1. Morgan DJ 270-94.

Clinical

1BT, UK

pharmacokinetics

of

&bgr;-agonists.

Clin Pharmacokinet 1990; 18:

2. Choo JJ, Horan MA, Little RA, Rothwell NJ. Anabolic effects of clenbuterol on skeletal muscle are mediated by &bgr;2-adrenoceptor activation. Am J Physiol 1992; 263: E50-56. 3. Lipworth BJ, Clark RA, Dhillon DP, Charter MK, Palmer JBD, McDevitt DG. Single dose and steady state pharmacokinetics of 4 mg and 8 mg oral salbutamol controlled-release m patient with bronchial asthma. Eur J Clin Pharmacol 1989; 37: 49-52. 4. Martin LE, Hobson, JC, Page JA, Harrison C Metabolic studies of salbutamol-3H: a new bronchodilator, in rat, rabbit, dog and man. Eur J Pharmacol 1971; 14: 183-99. 5. Kennedy MCS, Simpson WT. Human pharmacologic and clinical studies on salbutamol: a specific beta-adrenergic bronchodilator. Br J Dis Chest 1969; 63: 165. 6. Evans ME, Walker SR, Brittain RT, Paterson JW. The metabolism of salbutamol in man. Xenobiotica 1973; 3: 113-20. 7. Morton AR, Papalia SM, Fitch KD. Is salbutamol ergogenic? The effects of salbutamol on physical performance in high-performance nonasthmatic athletes. Clin J Sports Med 1992; 2: 93-97.

SiR,—In your Aug 15 editorial you comment on the muscleenhancing properties of clenbuterol, and Dr Martineau and colleagues report substantial increases in muscle strength with a slow-release preparation of salbutamol. There seems to be some evidence of measurable increases in muscle strength (of the order of 20%) after longer term use of either of these drugs.l.2 We provide perioperative care for heart-lung and single-lung transplantation patients. Because of the severe chronic nature of their conditions—eg, cystic fibrosis, alpha1-antitrypsin deficiency-they often present for surgery with reduced muscle mass (despite the best efforts of the patient, their family, dietitian, and physicians). There is good evidence that this leads to increased perioperative risk,3,4 presumably because of the confounding with disease severity and reduced immunological and cardiorespiratory function. With their decreased respiratory muscle mass, they have reduced ventilatory reserve. This leads to difficulty in weaning from mechanical ventilation after transplantation, and so sets up a cascade of potential complications (sepsis, tracheal/bronchial anastamosis breakdown). Any way of improving muscle strength during the waiting period before transplantation may be beneficial to eventual outcome. The added benefit of 0,-mediate bronchodilation may also support respiratory function during this time. Further studies are certainly needed on the risk-benefit profile of clenbuterol or slow-release salbutamol before definitive statements can be made. Department of Anaesthesia, Alfred Hospital, Melbourne 3181, Australia

PAUL S. MYLES ANTHONY M. WEEKS

Yang YT, McElligot MA. Multiple actions of &bgr;-adrenergic agonists on skeletal muscle and adipose tissue. Biochem J 1989, 261: 1-10. 2. Martineau L, Horan MA, Little RA, Rothwell NJ. Effect of salbutamol on skeletal muscle functional capacity in man. Proc Nutr Soc 1991; 50: 237A. 3. Porayko MK, DiCecco S, O’Keefe SJ. Impact of malnutrition and its therapy on liver transplantation. Semin Liver Dis 1991; 11: 305-14. 4. Moore C, Chowdhury Z, Young JB. Heart transplant nutrition programs: a national survey. J Heart Lung Transplant 1991; 10: 50-55. 1.

in severe diabetic ketoacidosis

Spurious euglycaemia

SIR,-We report severe diabetic ketoacidosis in which diagnosis delayed because of spurious euglycaemia. The patient, an insulin-dependent male diabetic aged 32, presented to the emergency department with a short history of abdominal pain and dyspnoea. Examination showed tachycardia of 160/min and a respiratory rate of 40/min. Urinalysis revealed ketonuria and glycosuria. The clinical diagnosis of diabetic ketoacidosis was confounded by the fmding of a suspiciously normal glucometer reading, confirmed by a plasma glucose of 8-7 mmol/1. Hyponatraemia (plasma sodium 108 mmol/1) suggested the was

of After

interference with biochemical analysis. ultracentrifugation of the same sample of blood, plasma glucose was 24-1 mmol/1 and sodium was 138 mmol/1. Serum triglycerides were 130 mmoljl and cholesterol 25 mmol/1. Assay of plasma sodium with an indirect ion-selective electrode requires initial dilution of the sample. Sodium activity is then measured in the water phase and translated into a concentration

possibility

hyperlipidaemic