Patients with moderate-volume ascites can be treated as outpatients and do not require hospitalization unless they have other complications of cirrhosis. These patients have a positive sodium balance because their sodium excretion is low relative to their sodium intake. The goal of treatment of cirrhotic ascites is to achieve a negative sodium balance by two means: (1) a moderate restriction of sodium intake and (2) enhancement of renal sodium excretion by diuretics.
The leading current opinion is that in patients with cirrhosis who need diuretics to achieve a negative sodium balance, dietary salt intake should be moderately restricted (90 mmol/day of sodium, which is equivalent to approximately 5.2 g/day of NaCl).2
A rational approach to diuretic therapy should take into account the pathophysiology of renal retention in patients with cirrhosis and ascites. Renal sodium retention in patients with cirrhosis and ascites is mainly due to increased tubular sodium reabsorption rather than a decrease of filtered sodium load; however, it remains controversial which sites in the nephron are involved. For example, increased sodium reabsorption was observed in the proximal tubule in patients with cirrhosis and ascites when compared to controls. Distal sodium reabsorption, when evaluated as a percent of the distal sodium delivery, was also higher in patients with cirrhosis and ascites.3
Although the sympathetic nervous systems and angiotensin II can be potential mediators of the enhanced sodium reabsorption in proximal tubule, the increased release of aldosterone is the primary factor in increased reabsorption of sodium along the distal tubule.4 Accordingly, it was observed that the administration of an aldosterone antagonist to nonazotemic patients with cirrhosis with ascites is more effective than a loop diuretic.5 Likewise, antialdosteronic drugs were proven to be more effective than other distal potassium sparing diuretics—namely amiloride and triamterene, which act from the luminal surface to inhibit Na+ uptake by principal epithelial cells of the collecting duct.6 Thus, the core diuretic for the treatment of ascites in patients with cirrhosis should be an aldosterone antagonist that is given once per day at an initial dose of 100 to 200 mg/day. A stepwise sequential therapy with increasing oral doses of an aldosterone antagonists (up to 400 mg/day) may be effective in mobilizing ascites in 60% to 80% of nonazotemic patients with cirrhosis and ascites.7, 8 The highest rate of response to monotherapy with aldosterone antagonist was observed in patients with cirrhosis at their first episode of ascites.8
Even if most experts add a loop diuretic once a patient fails to respond to the aldosterone antagonist, combination therapy with an antialdosteronic drug plus furosemide at the beginning of treatment has been suggested as a possible alternative diuretic regimen. Combined diuretic treatment can be started with the administration of 40 mg/day of furosemide and 100-200 mg/day of an aldosterone antagonist. If there is no response within 4 to 5 days of treatment, the dosages can be increased to 80 mg/day of furosemide and 200 to 300 mg/day of aldosterone antagonist, eventually peaking at 160 mg/day and 400 mg/day, respectively (Table 3). Recently, it was observed in a controlled clinical trial that combined diuretic therapy is safer and cheaper than sequential diuretic therapy in patients with cirrhosis and recurrent ascites.9
Table 3. Seven General Recommendations for Rational Medical Therapy for Uncomplicated Ascites in Patients with Cirrhosis
|1||Most patients with moderate ascites can be managed as outpatients. The treatment can be started with a diet that is moderately low in sodium (90 mmol/day). A sequential diuretic treatment should be preferred in patients who have their first episode of ascites, starting with an antialdosteronic drug (100–200 mg/day). A loop diuretic should be added only in nonresponders to 400 mg/day of an antialdosteronic drug. Combination therapy from the beginning of treatment should be preferred in patients with recurrent ascites, starting with 40 mg/day of furosemide and 100 to 200 mg/day of an aldosterone antagonist.|
|2||In nonresponders, the dose of diuretics should be increased stepwise in either a sequential or combination treatment, every 4 to 5 days to a maximum of 400 mg/day of antialdosteronic drug and 160 mg/day of furosemide.|
|3||The goal of diuretic treatment should be to achieve a weight loss of 300 to 500 g/day in patients without peripheral edema and 1 kg/day in patients with peripheral edema. Patients should be instructed to reduce the dose of diuretics if a greater loss of weight occurs.|
|4||Once ascites has been reduced, sodium restriction should be maintained while the diuretic dosage is reduced.|
|5||Patients on diuretic treatment should undergo frequent clinical and biochemical monitoring.|
|6||Patients not responsive to top diuretic doses or patients who develop complications under diuretic treatment should be checked for refractory ascites. Patient compliance with a low-sodium diet should be checked by measuring urine sodium excretion. In addition, patients should be checked for the use of drugs that can interfere with diuretics (e.g., nonsteroidal anti-inflammatory drugs) and for bacterial infections.|
|7||Patients with grade 3 or tense ascites should by treated with therapeutic paracentesis.|
In either sequential or combined diuretic therapy, an insufficient diuretic response is defined by a weight loss of <1 kg in the first week or 2 kg every week thereafter, until ascites is adequately controlled.1, 2 The safe upper limit of the rate of weight loss is contentious, but most experts agree that the diuretic dosage should be adjusted to achieve a weight loss rate of <500 g/day in patients without peripheral edema or 1 kg/day in patients with edema10 (Table 3).
Following mobilization of ascites, diuretics should be adjusted to maintain patients with minimal or no ascites, thus avoiding diuretic-induced complications such as renal failure, hepatic encephalopathy, electrolyte and acid-base disorders, gynecomastia, and muscle cramps. In most studies, the average prevalence of diuretic-induced complications in patients with cirrhosis ranged between 20% and 40%.1, 2
Caution should be used when starting treatment with diuretics in patients with renal impairment, hyponatremia, or disturbances in serum potassium concentration, and patients should be submitted to frequent clinical and biochemical monitoring. There is no good evidence regarding the level of severity of renal impairment and hyponatremia at which diuretics should not be started.
Diuretics are generally contraindicated in patients with overt hepatic encephalopathy. All diuretics should be discontinued if there is severe hyponatremia (serum sodium concentration <120 mmol/L), progressive renal failure, worsening hepatic encephalopathy, or incapacitating muscle cramps. Aldosterone antagonists should be stopped if patients develop severe hyperkalemia (serum potassium >6 mmol/L). Furosemide should be stopped if there is severe hypokalemia (<3 mmol/L).