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Discussion Introduction
 
In patients who have underlying liver disease, development of fluid retention is a hallmark of liver decompensation and is associated with significant morbidity and mortality in cirrhotic patients. Successful treatment of ascites depends on identifying the correct cause, since some nonhepatic causes of ascites do not respond to sodium restriction and diuretic therapy. The following discussion will address the management of patients with ascites, including patients with refractory ascites. Estimating Prognosis As part of the initial plan for managing the patient's ascites, especially refractory ascites, the clinician should determine the patient's Child-Pugh-Turcotte score (Figure 1) and a Model for End-Stage Liver Disease (MELD) score[2,3]. The MELD score incorporates the patient's age, total bilirubin serum creatinine, and international normalized ratio (INR) for persons age 12 and older (Figure 2), but the actual calculation of the score is complex and requires log scale. Accordingly, several online resources, such as on the HRSA Organ Procurement and Transplantation Network MELD calculator, are available to provide an easy on-line method for calculating the MELD score. The MELD score and, to a lesser extent the Child-Pugh-Turcotte score, serve as strong predictors of 3-month mortality (Figure 3)[3].

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General Approach to the Treatment of Ascites

As part of the evaluation of the patient with ascites, the clinician should determine (or should have already determined) the serum-ascites albumin gradient (SAAG); the SAAG is calculated as the difference between the serum and ascitic fluid albumin values and helps guide the appropriate management of ascites. In essentially all cases, if the SAAG is less than 1.1, sodium restriction and diuretics are ineffective. On the other hand, in cases where the SAAG is 1.1 or greater, sodium restriction and diuretics are the primary treatment modalities, since these patients generally have portal hypertension-related ascites[1]. Patients with ascites should avoid taking prostaglandin inhibitors, such as nonsteroidal anti-inflammatory drugs, since they can precipitate renal failure in the setting of diuretic use for ascites.

Sodium Restriction

For patients with ascites caused by portal hypertension, the ascites results from avid renal retention of sodium and water. In this setting, the most critical aspect of ascites management is sodium (salt) restriction. All patients with ascites should receive thorough education on sodium restriction and many will benefit from dietary counseling. It is important to note that diuretics are less effective in patients who do not also restrict sodium intake. Patients should restrict their dietary sodium to approximately 2000 mg/day (88 meq/day)[1]. The more strict the sodium restriction, the quicker the ascites will respond, but dietary restrictions more stringent than 2000 mg/day can be very difficult for patients to tolerate and maintain. The general goal with ascites treatment is to restrict sodium intake and maintain a urinary sodium excretion greater than 78 mmol/day; only the 10 to 15% of patients who have spontaneous urinary excretion of sodium greater than 78 mmol/day will achieve this goal without the addition of a diuretic[1].

In order to precisely calculate the urinary sodium excretion, a 24-hour urine collection is necessary, which is cumbersome and in many cases impractical. Instead, a spot urine sodium that is greater than a spot urine potassium concentration correlates well with a sodium urinary excretion greater than 78 mmol/day[1]. Patients who have a urine sodium/potassium ratio greater than 1 and are not losing weight, are likely consuming too much sodium in their diet and should undergo dietary counseling. There is a common misconception that fluid restriction is an important treatment modality in managing ascites. Fluid restriction, however, is not generally a necessary part of the initial management of ascites. Indiscriminately applied fluid restriction can lead to dehydration and renal failure in cirrhotic patients who have intravascular volume depletion. Sodium restriction and diuretic use is much more effective in managing ascites than fluid restriction. Careful fluid restriction can be applied when the serum sodium is less than 120 to 125 mmol/L.

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Diuretics Sodium restriction alone may be adequate for the select group of patients who have a spontaneous urinary Na excretion greater than 75mmol/L, but most patients with ascites need sodium restriction and diuretic therapy. The recommended diuretic therapy consists of the combination of a loop diuretic and a potassium sparing diuretic[1,4]. Combination therapy is more effective than sequential therapy[5] and can better maintain serum potassium levels (since furosemide wastes potassium and spironolactone spares potassium).

The recommended initial regimen is furosemide 40 mg plus spironolactone 100 mg daily, both given as once daily doses in the morning. The doses can be increased simultaneously every 3 to 5 days, while maintaining the 40:100 mg ratio in a once-daily fashion. The maximum dose for furosemide is 160 mg daily and for spironolactone 400 mg daily. At the higher doses the total diuretic dose can be given once daily or divided as twice daily dosing, depending on patient preference. As dose adjustments are made, serum electrolytes and renal function tests should be carefully monitored. Once the discomfort from the tense ascites has resolved with initial diuresis, a maximal weight loss of about 0.5 kg per day due to fluid loss is a good target, ideally continuing at this rate until the patient has an abdomen without clinically apparent fluid. If there is a concern for inadequate diuresis, checking a spot urine sodium and potassium concentration can be helpful.

Some experts recommend use of spironolactone monotherapy initially for patients with first episode ascites that is mild to moderate, with addition of furosemide if the patient has an inadequate response to full dose spironolactone, or develops hyperkalemia[1,6]. For patients intolerant or allergic to furosemide, bumetanide can be used as an alternative; the recommended dose of bumetanide ranges from 0.5 mg to 2 mg once daily. To convert furosemide to a bumetanide, divide the furosemide dose by 40 to give you the equivalent bumetanide dose. Triamterene and amiloride are potassium-sparing diuretics that can be used as an alternative to spironolactone, particularly if gynecomastia develops with spironolactone. The patient should discontinue diuretic therapy if the serum sodium decreases to less than 120 mmol/L (despite fluid restriction), uncontrolled or recurrent encephalopathy develops, or the serum creatinine exceeds 2.0 mg/dL[1].

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Refractory Ascites

Refractory ascites is commonly understood as ascites that is not successfully managed by medical therapy[7]. Refractory ascites can further be divided into two categories: (1) ascites unresponsive to sodium-restricted diet and high-dose diuretic treatment (400 mg/day of spironolactone and 160 mg/day of furosemide) or (2) ascites that recurs rapidly after a therapeutic paracentesis and high-dose diuretic treatment[8]. Randomized trials involving patients with cirrhosis and ascites have shown that with standard medical therapy fewer than 10% of patients have refractory ascites[9,10]. The development of refractory ascites portends a very poor prognosis, with 21% of these patients dying within 6 months and approximately 70% dying within 2 year [1,7,11]. Options for patients refractory to routine medical therapy include serial therapeutic paracentesis, transjugular intrahepatic portasystemic shunt (TIPS), or liver transplantation. Placement of a peritoneovenous shunt, such as the Leveen or Denver Shunt, is no longer recommended as a routine initial approach, primarily because of the poor long-term patency, high complication rate, and lack of proven survival benefit in this setting[1]. The use of peritoneovenous shunt has been relegated to an option for patients who are not candidates for serial therapeutic paracentesis, liver transplantation, or TIPS procedure.

Serial Therapeutic Paracentesis

Serial therapeutic paracentesis is generally a safe and effective option for patients with refractory ascites. For patients with advanced liver disease who do not have an option for liver transplantation, serial therapeutic paracentesis may provide the only option for managing refractory ascites. Although one might expect therapeutic paracentesis to have a higher complication rate than diagnostic paracentesis, prospective studies have not borne this out[12]. Controversy has existed regarding the necessity for post-paracentesis volume replacement (with colloid solution) to prevent electrolyte and renal abnormalities. A prospective study has demonstrated that patients with diuretic-resistant, tense ascites can undergo a single 5-liter paracentesis without post-paracentesis colloid infusion, as long as baseline renal dysfunction is not present[13]. In addition, removal of volumes of fluid exceeding 5 liters has also been shown to be safe with the administration of intravenous albumin[14]. Based on available data, many experts do not recommend the use of albumin or other colloid expanders with removal of less than 5 liters of ascitic fluid, but would give albumin when ascitic fluid removal exceeds 5 liters (at a dose of 6.25 grams of 25% albumin for every 1 liter removed above the initial 5 liters).

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Transjugular Intrahepatic Portosystemic Shunt (TIPS)
 
In recent years, placement of a TIPS has emerged as an alternative treatment for refractory ascites. The TIPS is an artificial connection (stent) in the liver made between the lower pressure hepatic vein (which transports blood from the liver back to the heart) and the higher pressure portal vein (transports blood from the gastrointestinal tract) (Figure 4); the TIPS procedure creates a shunt that so that blood flows from the higher pressure portal vein directly into the lower pressure hepatic vein (Figure 5), thereby reducing the vascular resistance of the liver, decreasing portal venous pressure, and reducing the formation of ascites[15]. The TIPS procedure is usually performed by an interventional radiologist under conscious sedation, although sometimes general anesthesia is used[15]. Several meta-analyses have compared TIPS with large volume paracentesis and have found TIPS more effective in controlling ascites, but more likely to cause severe encephalopathy[15,16,17,18,19]. Overall, about a third of patients who receive a TIPS develop encephalopathy, with a minority of them developing severe encephalopathy that requires a TIPS revision, which is performed by narrowing or occluding the shunt. Although most studies report no difference in overall survival when comparing TIPS and repeated large volume paracentesis, a recent meta-analysis reported significant improved transplant-free survival with TIPS[17]. Patients who receive a TIPS may require diruretics following the procedure.

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For patients who have advanced liver dysfunction and high predicted 30-day mortality, as determined by a Child Class C or MELD score greater than 19, should be informed of their overall poor prognosis and a health professional should discuss the potential need for liver transplantation with them; in this setting, the patient should undergo placement of TIPS only if no other options exist7[15]. In addition, placement of TIPS in patients with advanced liver dysfunction has significant risk of causing hepatic dysfunction and liver failure (because the TIPS shunts portal blood flow away from the liver). Further, post-TIPS heart failure has also been described and most experts recommend not performing a TIPS in patients with an ejection fraction less than 60% or who have diastolic dysfunction. The ejection fraction cut-off of 60% may seem unreasonably high, but patients with cirrhosis typically have hyperdynamic circulation and usually have an ejection fraction greater than 65%[20]. Considering the significant risks associated with TIPS, this procedure should only be performed at centers with significant experience in performing the procedure and with risk stratification of patients with refractory ascites. The AASLD has published guidelines on the role of TIPS in the Management of Portal Hypertension, including a list of absolute and relative contraindications to placement of a TIPS (Figure 6)[15].

Liver Transplantation Finally, since approximately 20% of patients with refractory ascites die within 6 months, liver transplantation should be considered as one of the treatment options of patients with refractory ascites [1,11]. Therefore, liver transplantation evaluation should be considered a part of the management of patients with refractory ascites. Calculating a MELD score, as outlined above, is an essential component of the transplantation evaluation.