LIVER-CIRRHOSIS WITH ASCITES - PATHOGENESIS OF RESISTANCE TO DIURETICS AND LONG-TERM EFFICACY AND SAFETY OF TORASEMIDE

In a prospective randomized short-term study, the efficacy and safety of xipamide and a combination of spironolactone and furosemide were co mpared in the treatment of hepatic cirrhotic ascites. Twenty-two patie nts were randomized to either xipamide, 20 mg/day (group I), or spiron olactone, 200 mg/day, combined with furosemide, 40 mg on alternate day s (group II). During the first 4 days of treatment, adequate diuresis, measured as loss of body weight greater than 1.6 kg, occurred in 7 pa tients in group I and in 3 in group II. In the latter group, another 4 patients responded satisfactorily after a further 4 days of treatment . Four patients in group I who failed to respond to xipamide with an a dequate loss of body weight were subsequently treated with the spirono lactone-furosemide combination, but only one responded. Two patients i n group II who failed to respond to the combination of spironolactone and furosemide also failed to respond to xipamide. In both groups, a p ositive diuretic response occurred only when the pretreatment fraction al sodium excretion exceeded 0.2%. Diuretic resistance was overcome on ly by additional treatments which reduced proximal tubular sodium reab sorption. Xipamide commonly induced hypokalaemia; in contrast hyperkal aemia was seen following treatment with the spironolactone-furosemide combination. Renal function remained stable in all patients during bot h diuretic treatments. An open ongoing 6-month trial of torasemide, 10 -40 mg/day, in combination with spironolactone, 50-400 mg/day, has als o been undertaken in 117 patients with cirrhotic ascites who showed in adequate responses to salt and water restriction and spironolactone al one. Twenty-seven patients have been withdrawn from the study, 9 for t he complications of hepatic coma, bleeding oesophageal varices, or hyp onatraemia. Twenty-two patients are still being treated and 68 have co mpleted the trial on a mean dose of torasemide, 15 mg/day. Body weight was reduced by a mean of 2.3 kg at 6 weeks, 2.6 kg at 14 weeks and 3. 2 kg after 6 months. Loss of body weight was primarily associated with reduction of ascites and secondarily with reduction of peripheral oed ema. There were no untoward adverse reactions with torasemide, and no significant changes in serum electrolytes, liver, renal, or haematolog ical variables.