1535

Very low density lipoproteins (VLDL) and triglyceride are consistently raised in patients taking either &bgr;-blockers or thiazide diuretics.1 Whether these changes are atherogenic remains controversial,z but preliminary analysis of prospective data from the Lipid Research Clinics Prevalence Study3 has shown triglyceride concentrations to be a strong predictor of CHD mortality. In addition, &bgr;-blockers reduce high density lipoprotein (HDL) concentrations, regarded by many workers as another important CHD risk indicator.’ The effects of drug treatment on carbohydrate metabolism have account.

concentrations

also been overlooked. Thiazide diuretics and &bgr;-blockers have each been associated with impaired glucose tolerance, which is known to be an independent risk factor for CHD, irrespective of duration.5 Both thiazide diuretics and &bgr;-blockers increase insulin resistance, causing hyperinsulinaemia.5 Furthermore, raised fasting glucose and insulin concentrations, which are associated with these treatments, are the strongest predictors of progression to noninsulin-dependent diabetes (NIDDM).6 In drug-treated hypertensive patients the frequency of NIDDM was six times higher than it was in untreated controls.’ Insulin resistance is probably an important cause of both hypertension and premature CHD8 and has been linked to abnormal thrombolysis (Hamsten A., personal communication). Changes in lipid metabolism seen in insulin resistance states9 resemble those induced by either &bgr;-blockers or thiazide diuretics. The metabolic effects of treatment with &bgr;-blockers and diuretics may be additive. Indeed the Oslo studylO showed that this combination gave a more significant increase in serum glucose and triglyceride than any other antihypertensive combination. These effects on lipid and carbohydrate metabolism cannot be considered separately. It is inappropriate to discount metabolic effects on the development of CHD by considering total cholesterol changes alone. RAYMOND BRUCE JOHN C. STEVENSON MICHAEL F. OLIVER

Wynn Institute for Metabolic Research, London NW8 9SQ, UK

VICTOR WYNN

1. Krone

W, Nagele H. Effects of antihypertensives on plasma lipids and lipoprotein metabolism. Am Heart J 1988; 116: 1729-34. 2. Brunzell JD, Austin MA. Plasma triglyceride levels and coronary disease N Engl J Med 1989; 320: 1273-74. 3 Criqui MH, Heiss G, Cohn R, Cowan LD, Suhindran CM, Bagdiwala S. Triglycerides and coronary heart disease mortality: the Lipid Research Clinics Follow-up Study CVD Epidemiol Newsl 1987; 41: 13 (abstr). 4. Miller NE. Associations of high-density lipoprotein subclasses and apolipoproteins with ischaemic heart disease and coronary atherosclerosis. Am Heart J 1987; 112: 589-97. 5. Houston MC. The effects of antihypertensive drugs on glucose intolerance in hypertensive non-diabetics and diabetics. Am Heart J 1988; 115: 640-56. 6. Haffner SM, Stem MP, Mitchell BD, Hazuda HP, Patterson JK. Incidence of type 2 diabetes in Mexican Americans predicted by fasting insulin and glucose levels, obesity and body fat distribution. Diabetes 1990, 39: 283-88. 7. Skarfors ET, Lithell HO, Selinus I, Aberg H. Do antihypertensive drugs precipitate diabetes in predisposed men? Br Med J 1989; 298: 1147-52. 8. Reaven GM. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595-607. 9. Abbott WGH, Lillioja S, Young AA, et al. Relationships between plasma lipoprotein concentrations and insulin action in an obese hyperinsulinaemic population. Diabetes 1987; 36: 897-904. 10. Helgeland A, Leren P, Foss OP, Hjermann I, Holme I, Lund-Larsen PG. Serum glucose levels during long-term observation of treated and untreated men with mild hypertension: the Oslo study. Am J Med 1984; 76: 802-05.

Brachioradial delay and severity of aortic stenosis SIR,-Dr Leach and Dr

McBrien (May

19, p 1199) report increased

brachioradial delay in patients with severe aortic stenosis. The wave speed in an artery is given by c

=

1 / pDwhere p is the

blood density and D is the distensibility of the artery defined as the fractional change of cross-sectional area with pressure (dA/AdP).1 The speed of propagation of the pulse wave is c + U where U is the blood velocity. Since the velocity of the blood is typically an order of

magnitude smaller than the wave speed, the time-delay between the brachial and the radial pulse depends mainly on the wave speed. The reported time-delay in patients with severe aortic stenosis is nearly double that in controls and must be the result of a near

of the wave speed. A decrease in arterial blood pressure is associated with a decreased wave speed but Leach and McBrien do not provide blood pressure values for their patients. However, other workers suggest that despite the large pressure differences across the aortic valve, mean arterial pressure in patients with severe aortic stenosis is not grossly abnorma1.2.3 Since blood density does not change significantly, the lowering of the wave speed must result from a change in the distensibility of the arteries in these patients. It would be of interest, therefore, to establish whether the dimensions, structure, and mechanical properties of the arteries in such patients are abnormal. The arterial wall undergoes changes which lead to a decreased compliance in patients with hypertension.4,5 It is possible that the opposite changes develop in the presence of severe aortic stenosis. The incomplete return of the pulse-wave velocity to normal after successful surgery is consistent with that suggestion.

halving

Centre for Biological and Medical Systems, Imperial College of Science. Technology and Medicine, London SW7 2BY, UK

C. G. CARO K. H. PARKER

1. Caro 2. 3. 4.

5

CG, Pedley TJ, Schroter RC, Seed WA. The mechanics of the circulation. Oxford: Oxford University Press, 1978: chapter 12. Hoffman JIE, Spaan JAE. Pressure-flow relations in coronary circulation. Physiol Rev 1990; 70: 331-90. O’Rourke MF. Influence of ventricular ejection on the relationship between central aortic and brachial pressure pulse in man. Cardiovasc Res 1970; 4: 291-300. Jones CJH, Singer DRJ, Watkins NV, MacGregor GA, Caro CG. Abnormal arterial flow pattern in untreated essential hypertenion. possible link with the development of atherosclerosis. Clin Sci 1990; 78: 431-35. Simon ACh, Levenson JA, Laurent SP, Safar ME. Estimation of forearm compliance in essential hypertension: a preliminary report. Clin Sci 1982; 63: 87s-88s.

Aprotinin for bleeding after cardiopulmonary bypass SIR,-Dr Angelini and colleagues (March 31, p 799) describe the use of aprotinin to control bleeding after cardiopulmonary bypass (CPB)—they use an antifibrinolytic agent with specific action against plasmin to treat hyperfibrinolysis. Tice1 was probably the first to describe the use of aprotinin in cardiac surgery for the treatment of hyperfibrinolytic haemorrhages. He used aprotinin in increasing doses, with resolution of biochemical evidence of fibrinolysis and cessation of bleeding. The prophylactic use of aprotinin advocated now has evolved partly through serendipity, when a dose regimen intended to inhibit complement activation was devised on theoretical grounds. Complement activation was not reduced but bleeding was.2 Prophylactic aprotinin has been tried in many situations, but in lower doses than is currently suggested. Investigations showed some reduction in blood loss, but not such that blood use could be avoided altogether, as should be our aim in cardiac surgery. 3,4 In 23 centres surveyed in the UK the mean red cell use in patients having open heart surgery was 5 units.s At a recent workshop on blood conservation (Royal Postgraduate Medical School) 20 % of all open heart surgery patients were reported to have received a haemostatic pack of blood components, exposing the patient to 17 donors. All Angelini and colleagues’ patients received large quantities of blood as well as component therapy, with little effect. Donor exposure was high in every case. The use of aprotinin was only indicated in these circumstances when the cause of the bleeding "unorthodox"

apparent. Whether hyperfibrinolysis resulted from the effects as is so often the case, was secondary to activation of all components of the haemostatic and fibrinolytic systems by active bleeding cannot be established. It seems logical to consider a policy that will prevent such situations from arising rather than have to adopt unorthodox methods to treat them. Whether aprotinin will be effective if given after CPB has ended is not known. The use of desmopressin, given after bypass, showed promise in one study where the blood loss was inordinately high. Other workers have not confirmed this finding.’ was

of CPB or,

The

prophylactic

use

of high-dose

aprotinin,

now

shown

to

be

effective in this regimen in many patients (not all having open heart surgery), can reduce blood use by 40-80%. Many receive no blood

1536

products at all.8 Prophylactic use may prevent uncontrollable bleeding after open heart surgery, which arises in a few patients. Its routine prophylactic use during cardiac surgery can be recommended. 66 Harley Street, London W1 N 1AE, UK

BEN BIDSTRUP

1. Tice DA, Worth MH, Clauss RH, Reed GH. The inhibition of Trasylol of fibrinolytic activity associated with cardiovascular operations. Surg Gynec Obstet 1964; 119: 71-74. 2. van Oeveren W, Janssen N, Bidstrup B, et al. Effects of aprotinin on haemostatic mechanisms in cardiopulmonary bypass. Ann Thorac Surg 1987; 44: 640-45. 3. Popov-Cenic S, Murday H, Kirchhoff P, Hack G, Fenyes J. Anlage und zusammenfassendes Ergebnis einer klinischen Doppelblindstudie bei aortokoronaren Bypass Operationen. In: Dudziak AR, Kirckhoff PG, Reuter HD, Schumann F, eds. Proteolyse und Proteinaseninhibition in der Herz- und Gefa&bgr;chirurgie. Stuttgart: Schattauer Verlag, 1985: 171-86. 4. Hannekum A, Reuter HD, Dalichau H, Horpáscy G, Selbeherr J. Anlage und zusammenfassendes Ergebnis einer klinischen Doppelblindstudie bei Operationen am offenen Herzen. Einflu&bgr; von Aprotinin auf Thrombozytenzahl und -funktion. In: Dudziak AR, Kirckhoff PG, Reuter HD, Schumann F, eds. Proteolyse und Proteinaseninhibition in der Here- und Gefa&bgr;chirurgie. Stuttgart: Schattauer Verlag, 1985: 221-33. 5. Russell G, Peterson S, Harper S, Fox M. Homologous blood use and conservation techniques for cardiac surgery in the United Kingdom Br Med J 1988; 297: 1390-91. 6. Salzman E, Weinstein M, Weintraub R, et al. Treatment with desmopressin acetate to reduce blood loss after cardiac surgery. N Engl J Med 1986; 314: 1402-06. 7. Hackmann T, Gascoyne RD, Naiman SC, et al. A trial of desmopressin (1-desamino8-D-arginine vasopressin) to reduce blood loss in uncomplicated cardiac surgery. N Engl J Med 1989; 312: 1437-43. 8. Bidstrup BP, Royston D, Sapsford RN, Taylor KM. Reduction on blood loss and blood use after cardiopulmonary bypass using high dose aprotinin (Trasylol). J Thorac Cardiovasc Surg 1989; 97: 364-72.

patients younger than 20 were retained because BCG vaccination (with Pasteur Institute freeze-dried vaccine) has been common since 1970. The diagnosis was checked by a leprosy specialist and skin biopsy was done in doubtful cases. The 50 cases were classified either lepromatous (including borderline and polar as lepromatous4) or non-lepromatous. 50 controls were matched by age within 2 years, sex, and socioeconomic status. The presence of a BCG scar was taken to indicate a positive exposure. 50% of cases and 66% of controls had a BCG scar (not significant). However, lepromatous patients had a proportion of BCG scars very close to that of their controls (21/34 vs 23/34), whereas non-lepromatous patients had a BCG scar less often than their controls (4/16 vs 10/16; p=0’03). For non-lepromatous leprosy, BCG efficacy, computed as 1 minus the estimated relative risk/ was 80% but the 95% confidence interval was wide

(13-96%). BCG seems to be protective against non-lepromatous leprosy in southern Vietnam, as observed in other areas. The efficacy (80%) is close to that reported in the Uganda study;’ however, more patients are needed for a reliable estimate. BCG had no protective efficacy against lepromatous leprosy, which is consistent with the immunological status of the two subtypes of leprosy patients considered; BCG is not expected to be effective in lepromatous patients, who have defective antimycobacterial cellular immunity. These conclusions have important implications for the control of leprosy in countries with a high proportion of lepromatous cases and indicate that the distinction between lepromatous and nonlepromatous is important in the evaluation of the protective role of BCG. We thank Dr J.

Ice

hockey lung and NO2 poisoning

SIR,-Nitrogen dioxide is known to be responsible for silofillers’ (with some deaths) and, as your May 19 editorial suggests, ice-hockey lung. Some solutes react with NOz fast enough to greatly assist the absorption of the gas from air into water.’ At physiological pH, ascorbic acid is most effective (unpublished). The gas is well absorbed by the lung, but it seems possible that a 1 g oral dose of ascorbic acid would temporarily protect against the subsequent toxic effects, by competing with the sensitive sites for freshly absorbed gas. Any protection thus afforded would depend on raising the ascorbic acid blood concentration from the normal low disease

value to

an

effective level.

12 Lenthay Court, Sherborne, Dorset DT9 6BQ, UK

1. Nash T. Absorption of A3023.

nitrogen

T. NASH dioxide

by

aqueous

solutions. J

Chem Soc 1970;

Leprosy and BCG in southern Vietnam SIR,-Dr Fine and Dr Rodrigues (April 28, p 1016) discuss the protective role of BCG vaccines in mycobacterial diseases. The efficacy of BCG against tuberculosis is difficult to assess because the variation in vaccine efficacy seen in different trials seems to be dependent more on geography than on vaccine strain.l However, in leprosy, five prospective studies have provided consistent results, showing a protective effect of BCG in Uganda, Burma, New Guinea, and south India, and in Malawi.2 Vaccine efficacy varied from 20% to 80%. In these trials non-lepromatous forms constituted the large majority of incident cases. Case-control methods have been widely used to evaluate the efficacy of BCG in tuberculosis3 and seem to be a cheap and useful tool for the assessment of vaccination programmes in developing countries. In leprosy, only one case-control study has been done,2providing results consistent with the prospective trials. In Vietnam the prevalence of leprosy is about 15 per 1000, 30-70% of cases (depending on the region) being lepromatous, the most infectious form. We have done a case-control study of the protective efficacy of BCG in southern Vietnam. Cases were taken at random from a file of leprosy cases being followed up at the Dermatology Hospital, Ho Chi Minh City. Only

Feingold and Dr E. Bois for helpful discussion.

Genetic

Epidemiology Research Unit (INSERM U155) and Department of Biomathematics, Hôpital de la Pitié-Salpêtrière, 75013 Paris, France, Dermatology Hospital, Ho Chi Minh City, Vietnam; Microbiology and Antibacterial Immunology Unit (INSERM U65), Montpellier, Institute of Dermatology, Hanoi, Department of Bacteriology, Hôpital de la Pitié-Salpêtrière, and Department of Microbiology, Hôpital Hôtel-Dieu, Paris

L. ABEL V. V. CUA J. OBERTI V. D. LAP L. K. DUE J. GROSSET P. H. LAGRANGE

1. Fine PEM. BCG vaccination against tuberculosis and leprosy. Br Med Bull 1988; 44: 691-703. 2. Fine PEM, Ponnighaus JM, Maine N, Clarkson JA, Bliss L. Protective efficicacy of BCG against leprosy in northern Malawi. Lancet 1986; ii: 499-502. 3. Comstock GW. Vaccine evaluation by case-control or prospective studies. Am J

Epidemiol 1990; 131: 205-07. Ridley DS, Jopling WH. Classification of leprosy according to immunity: a five group 1966; 34: 255-73. J system. Int Lepr 5. Smith PG. Retrospective assessment of the effectiveness of BCG vaccination against tuberculosis using the case-control method. Tubercle 1982; 62: 22-35. 4.

BCG vaccination and nutrition SiR,—Dr Fine and Dr Rodrigues (April 28, p 1016) discuss the efficacy and impact conundrums surrounding the use of BCG in mycobacterial diseases. These issues are of growing importance because of the resurgence of tuberculosis in conjunction with HIV infection and the implications for a vaccine against HIV, where stimulation of cellular immunity is critical. Little attention is given, however, to the connection between nutrition and immunity in the evaluation of BCG efficacy. The impact of malnutrition on T helper cells and on complement levels is well understood, yet none of the major clinical trials of BCG have adequately controlled for the nutritional levels of the recipients. Both the "take" of vaccinations and the duration of protective immunity may be affected. Chandra’ showed a response continuum of tuberculin conversion, when tested 3-4 months after BCG vaccination. In healthy infants there is an 85% conversion rate; in those with slight malnutrition (greater than 70% of standard) 70% convert; with moderate malnutrition (61-70% of standard) 55% convert; and with severe malnutrition (less than 60%), only 23% convert. In a study of Cree Indians in Canada,