CAPTOPRIL AND RESISTANT ASCITES

405 CAPTOPRIL AND RESISTANT ASCITES

137±12 to 114±16 mm Hg. In patients 1, 2, and 5, who were on the captopril/diuretic combination, renal function deteriorated within 2 weeks (figure). When diuretic and captopril in case 1 or diuretic only

SIR,-In reply to the letter from Dr Shepherd and colleagues (June 18, p 1391) we report here side-effects of captopril in combination

(with reduced captopril dose) in cases 2 and 5 were stopped renal function rapidly improved. In patients 3 and 4 renal function did not change on captopril alone but the introduction of a diuretic resulted in rapid deterioration. When the diuretic was stopped renal function improved whether (case 3) or not (case 4) captopril was

with diuretics in the treatment of resistant ascites in patients with alcoholic cirrhosis. Ascites in cirrhotic patients is caused by hyperaldosteronism with sodium retention, portal hypertension, and hypoalbuminaemia. 1,2 The cirrhosis’patient cannot excrete sufficient sodium in his urine. To reverse the sodium retention in two cirrhotic patients with resistant ascites we added captopril to conventional therapy. A 64-year-old man with a non-functioning LeVeen peritoneovenous shunt was given captopril 6-25 mg three times daily in addition to frusemide and spironolactone. After 5 days without weight reduction or increased natriuresis the captopril dose was doubled. Subsequently severe confusion developed. No signs of hypotension, electrolyte disturbance, or hepatic or renal failure

continued. In case 5 renal function deteriorated rapidly on captopril and diuretic, but despite continued therapy it showed no further change for many weeks. The final severe deterioration in renal function was readily reversed by stopping diuretic and correcting the sodium and water deficits while continuing with captopril. There were no consistent changes in the pattern of urinary sediment. Blood pressure control deteriorated when either diuretic alone or captopril and diuretic were withdrawn, increasing to 129±17 mm

Hg. Renal function thus deteriorated significantly in all of five patients with bilateral renal artery stenosis when a combination of captopril and diuretic was used to control blood pressure. However, in the four patients treated at some stage with captopril in the absence of diuretic renal function either did not deteriorate or improved. Lowering of blood pressure might itself impair renal function by reducing renal perfusion pressure but in both this and other studies4-6 blood pressure levels achieved on captopril and diuretic had been obtained intermittently on other therapy, without deterioration in renal function. The maintenance of recovery of renal function despite continued captopril suggests that neither direct nephrotoxicity7 nor a hypersensitivity reactionto captopril are likely explanations. The diuretic may have caused the deterioration in function by inducing sodium and water depletion, this almost certainly being so in case 5. However, in cases 3 and 4, only small doses of diuretic were used (40 mg frusemide and 5 mg bendrofluazide, respectively) and it is unlikely that there was a large deficit of sodium and water. Perhaps even mild sodium and water depletion can impair renal function when activity of the reninangiotensin system is blocked. Studies in animals suggest that the renin-angiotensin system has an important role in regulating renal efferent arteriolar tone,9 this dependency of autoregulation of glomerular filtration rate on the renin-angiotensin system being most marked during sodium depletion Inhibition of angiotensin ii synthesis under these conditions might be expected to inhibit this autoregulation. Patients with bilateral renovascular disease have reduced renal perfusion pressure and antihypertensive therapy may reduce this still further. But GFR is usually maintained in the sodium replete state. However, mild sodium depletion induced by diuretics might increase the dependency of autoregulation on the renin-angiotensin system so that, when captopril is given, renal perfusion pressure falls inducing a large drop in GFR. Department of Medicine, Royal Infirmary, Edinburgh EH3 9YW

M. L. WATSON G. M. BELL A. L. MUIR

Department of Radiology, Royal Infirmary, Edinburgh

T. A. S. BUIST

Department of Medicine, Eastern General Hospital, Edinburgh

R. J. KELLETT

Department of Medicine, Western General Hospital, Edinburgh

P. L. PADFIELD

* laparocentesis Clinical and laboratory findings in

patient 2.

recorded. When captopril was stopped the confusion disappeared immediately. A 59-year-old man with resistant ascites and severe oedema was treated with diuretics for 9 days and a laparocentesis (8 litres) was done. Because diuresis was unsatisfactory despite spironolactone 100 mg and frusemide 240 mg daily we decided to add captopril 6 -25 mg three times daily. A marked natriuresis was induced with concomitant weight reduction (see figure). The patient improved in a few days and was discharged. During the outpatient period the patient’s weight rose by 6 kg because he failed to take his drugs correctly. He was readmitted. After 3 days the captopril dose was doubled to 12 -5mg three times daily. On this dose he became very confused without signs of hypotension, electrolyte disturbance, or hepatic or renal failure. As in the other patient the confusion disappeared when captopril was stopped. Our treatment differs from that of Shepherd et al, in that we used captopril in combination with conventional therapy, but in small doses. However, we have used this treatment in only two patients in both of whom severe confusion developed and disappeared when captopril was withdrawn. We urge caution when captopril is used in were

cirrhotic ascites. 7. Farrow PR, Wilkinson R. Reversible renal failure during treatment with captopril. Br Med J 1979; i: 1680. 8. Luderer JR, Schoolwerth AC, Sinicrope RA, Ballard JO, Lookingbill DP, Hayes AH. Acute renal failure, hemolytic anemia and skin rash associated with captopril therapy AmJ Med 1981; 71: 493-96. 9. Hall JE, Guyton AC, Jackson TE, Coleman TG, Lohmeir TE, Trippoddo NC. Control of glomerular filtration rate by renin-angiotensin system. Am J Physiol 1977; 233: F366-72. 10. Hall JE, Guyton AC, Cowley AW. Dissociation of renal blood flow and filtration rate autoregulation by renin depletion. Am J Physiol 1977; 232: F215-21.

FRANK JØRGENSEN JØRN BADSKJAER

Department of Medicine, Sundby Hospital, DK-2300 Copenhagen S, Denmark

1.

Epstein M. Deranged

sodium homeostasis in cirrhosis.

HENRIK NORDIN

Gastroenterology 1979;

76:

622-35. 2. Wilkinson SP, Williams R. 1980; 21: 545-54.

Renin-angiotensin-aldosterone

system in cirrhosis Gut

406

SIR,-Dr Ring (July 16, p 165) suggested that captopril might severely compromise renal function as a result of a reduction in glomerular filtration rate (GFR) from a loss of resistance in the efferent arterioles. It has been suggested that an increase in angiotensin 11 might be initially beneficial in preserving GFR by efferent arteriole vasoconstriction, particularly in predominantly heart failure. If, as has been suggested, the renin-angiotensin system is activated, then intrarenal angiotensin 11 concentration may rise excessively, resulting in the constriction at or proximal to the glomerular capillaries, which in turn would cause a marked decline in GFR with resultant retention of urea, together with

hyponatracmia 1,2

similar

to

that

seen

in

our

case

report.3

A

reduction in angiotensin II by captopril in patients with retention of urea and hyponatraemia should improve renal function rather than, as Ring suggests, severely compromise it. Whether intravascular expansion requires to be provided simultaneously to offset the potential reduction in arterial pressure does not detract from the potential use of the angiotensin-converting enzyme inhibitors in resistant ascites. Department of Medicine, Ninewells Hospital and Medical School, Dundee DD1 9SY

A. N. SHEPHERD P. NELIGAN P. C. HAYES

MASS CONTROL OF CORONARY RISK FACTORS p 37) uses data from the US Risk Factor Intervention Trial (MRFIT) as evidence for his argument that mass interventions to reduce risk factors have not worked and ought to be given up. The data from MRFIT, in fact, show just the opposite.The rates of coronary mortality were much reduced in both groups, the half given special interventions (SI) and the half returned to their usual sources of medical care (UC). The designers of the study assumed that the risk factors among the UC group would change very little, preserving the statistical likelihood that 187 coronary deaths would occur among them. They calculated that a much greater reduction in risk factors among the SI group would reduce their projected number of coronary deaths to 137, thus providing a 27% difference that would be statistically significant. What then happened proved that risk factor intervention does work, contrary to Oliver’s interpretation. Since the American public and their physicians have so widely accepted the value of stopping smoking, of treating hypertension, and of reducing dietary saturated fat, the level of risk factors among the UC half fell much beyond that projected by the study designers. As a result, only 104 coronary deaths occurred, not significantly more than the 92 among the SI group. Thus, coronary mortality was markedly reduced in both groups, with a reduction in the various risk factors measured in both groups. Obviously, the design of the study was flawed so that it failed to show a difference in mortality, but by no means does this lack of difference between the two groups signify a lack of efficacy of risk factor intervention. The trial failed in its original purpose but it succeeded admirably in demonstrating the value of risk factor reduction. Though I agree with Oliver’s call for selectivity in applying interventions that may have some inherent risks, such as antihypertensive drug therapy,5 the idea of only "focusing on the top few percent at really high risk" implies that we will leave the 15-20% who are hypertensive and the even larger number who are hypercholesterolaemic to die prematurely from coronary disease, without applying those preventive measures that are risk-free.

SIR,-Professor Oliver (July 2,

Multiple

1. Atkinson AB, Robertson JIS. Captopril in the treatment of clinical hypertension and cardiac failure. Lancet 1979; ii: 836-39. 2. Brown JJ, Davis DL, Johnstone VW, Lever AF, Robertson JIS. Renin relationships in congestive cardiac failure, treated and untreated. Am Heart J 1970; 80: 329-42. 3. Shepherd AN, Neligan P, Hayes PC. Captopril and resistant ascites. Lancet 1983; i: 1391-92. 4. Multiple Risk Factor Intervention Trial Research Group: Multiple risk factor intervention trial. JAMA 1982; 248: 1465-77. 5. Kaplan NM. Therapy for mild hypertension. JAMA 1983; 249: 365-67.

Moderation of dietary sodium, saturated fats, and calories does impose, in Oliver’s words, "a calvinistic life-style for us all", but rather tries to break some of the unnatural and unhealthy dietary habits we have so recently adopted. not

Department of Internal Medicine, University of Texas Southwestern Medical School, Dallas, Texas 75235, USA

NORMAN M. KAPLAN

SIR,-Professor Oliver’s reference to the North Karelia project merits comment since our conclusions differ from his. At five yearsl,2a reduction in risk factor levels was indeed noted. During this period CHD rates did start to decrease in North Karelia (in contradiction to Oliver’s statement), but no significant difference could then be observed in CHD mortality trends between North Karelia and the reference area.33 ’After ten years of the programme, risk factor levels fell further (unpublished), and when we analysed the latest CHD mortality trends (1969-79)4 for North Karelia, the reference county, and all other counties-since the project might also have special influence on the reference area-the decline in CHD mortality in North Karelia had continued. For 1969-79, which includes eight years of intervention, Oliver gives the reductions in age-standardised male CHD mortality as 24% in North Karelia, 21% in the reference area, and 12% in Finland outside North Karelia. But.he should have cited our paper futher: since the intervention programme started only after the spring of 1972, it is important to note that most of the reduction in North Karelia took place after 1973, while the reference area had a substantial reduction already before the programme started. The table shows that the reduction in agestandardised CHD mortality in men in 1974-79, based on smoothing the curve by linear regression, was about twofold in North Karelia compared with the reference area or the rest of Finland (p<0’05, compared with North Karelia). The reductions in agestandardised male CHD mortality from 1974 to 1979 were 22% in North Karelia, 12% in the reference area, and 11% in the whole country. We think that this is more than "a little difference"-both in percentage and in absolute number of reduced premature CHD deaths in the area. AVERAGE ANNUAL REGRESSION BASED DECLINE IN AGE-STANDARDISED CHD MORTALITY IN 1974-79 IN NORTH

KARELIA,

THE REFERENCE AREA AND FINLAND LESS NORTH KARELIA

(±95% CONFIDENCE INTERVALS)4

*Difference from North Karelia in relation

to

random

variation

p<0’05.

These results do not prove a causal association but they do suggest that a comprehensive risk factor reduction programme can lead to reduced disease rates in the community. Public health decisions on risk factor reduction must be based on broad information about the overall expected favourable and harmful consequences of such activity. Community studies investigate several questions relevant to prevention and community 1. Puska P, Tuomilehto J, Salonen J, Neittaanmäki L, Mäki J, Virtamo J, Nissinen A. Koskela K, Takalo T. Changes in coronary risk factors during comprehensive fiveyear community programme to control cardiovascular diseases (North Karelia

project). Br Med J 1979;

ii:

1173-78.

2. Salonen J, Puska P, Kottke T, Tuomilehto J. Changes in smoking, serum cholesterol and blood pressure levels during a community-based cardiovascular disease

prevention program-the North Karelia project. Am J Epidemiol 1981; 114: 81-94. 3. Salonen J, Puska P, Mustamemi H. Changes in morbidity and mortality during comprehensive community programme to control cardiovascular diseases during 1972-77 in North Karelia. Br Med J 1979; ii: 1178-83. 4. Salonen J, Puska P, Kottke T, Tuomilehto J, Nissinen A. Decline in mortality from coronary heart disease in Finland from 1969 to 1979. Br Med J 1983; 286: 1857-60.