How can I be sure that the patient has ascites?

The most common cause of ascites is portal hypertension secondary to cirrhosis. This accounts for 90% of cases. In 10% of cases, there is a nonhepatic cause, such as malignancy, heart failure, constrictive pericarditis, tuberculosis, nephrotic syndrome, hemodialysis, pancreatitis, bile leak, and other rare causes. (See Table I.)

A tabular or chart listing of features and signs and symptoms

History and exam

Ascites usually develops insidiously over the course of weeks. The main symptoms are increased abdominal girth with lower extremity edema. In patients with large and tense ascites, the respiratory function and physical activity may be impaired. Dyspnea occurs as a consequence of increasing abdominal distention or due to pleural effusions. Patients with ascites and spontaneous bacterial peritonitis (SBP) can present with fever, chills, abdominal pain, hepatic encephalopathy, and rebound abdominal tenderness. However, only a minority of patients with SBP present with these symptoms. The diagnosis of SBP always requires an examination of the peritoneal fluid.

In addition to examining the patient for stigmata of chronic liver disease, a detailed physical exam needs to be performed. Jugular venous distension can be seen in patients with heart failure. Kussmaul’s sign is seen in patients with constrictive pericarditis. Anasarca can be associated with nephrotic syndrome and congestive heart failure. Firm lymphadenopathy is found in patients with an underlying malignancy.

Patients have to have at least 1500 mL of peritoneal fluid for ascites to be detected reliably by physical examination. Ultrasonography can detect as little as 100 mL of abdominal fluid and should be used for obese individuals and for patients in whom the physical examination is unreliable.

There are several techniques available for diagnosing ascites on physical examination, with the most accurate being flank dullness; without this, the patient has a less than 10% likelihood of having ascites.

How can I confirm the diagnosis?

Diagnosis

A diagnostic paracentesis of at least 30 mL should always be performed to elucidate the cause of ascites. It should also be done in those patients requiring hospitalization and those with fever, abdominal pain, hypotension, or new onset hepatic encephalopathy. The paracentesis should be done regardless of the INR (international normalized ratio) of the patient.

Baseline tests that need to be ordered are cell count, culture in blood culture bottles, albumin, and protein. Glucose, lactate dehydrogenase, amylase, bilirubin, triglyceride level, tuberculosis culture and smear, and cytology are optional and should be ordered if causes other than portal hypertension are considered.

The cell count is the most useful test because it determines the presence of infection. The diagnosis of SBP is made when the ascitic fluid has more than 250/mm polymorphonuclear cells (PMN, also called neutrophils).

The difference between serum albumin and ascites albumin (serum ascites-albumin gradient) in patients with cirrhosis and portal hypertension is usually more than 1.1 g/dL. Values below 1.1 suggest a cause other than portal hypertension. Patients with cirrhosis and a protein value below 1.5g/dL have a greater risk of developing SBP.

An abdominal ultrasound with Doppler should be done to evaluate the liver parenchyma, rule out liver cancer or other masses, and evaluate the patency of the portal vein. In addition, it allows simultaneous visualization of the kidneys.

Echocardiography should be done if there is suspicion of cardiac disease.

Standard electrolyte, hematological, liver, and coagulation tests should be ordered. A urine sodium (UNa) is of key importance in directing therapy because patients with severe sodium retention (UNa <10meq/L) have poor response to diuretics.

What other diseases, conditions, or complications should I look for in patients with ascites?

Therapy of ascites

As discussed earlier, the most common cause of ascites is cirrhosis and portal hypertension. The recommendations for the management of ascites in cirrhosis are discussed below. A mainstay of therapy is a sodium-restricted diet of approximately 90 mmol/day (2-3 g/day). Fluid restriction is not necessary unless patients have dilutional hyponatremia (serum sodium <125 meq/L). An important aspect in the management of patients with cirrhosis and ascites is evaluation for liver transplantation in suitable candidates.

The current classification of ascites divides patients in three groups. Patients with grade 1 ascites are those in whom ascites is detected only by ultrasonography; these patients do not require any specific treatment, but they should be warned about avoiding foods with large amounts of salt. Patients with grade 2 ascites are those in whom ascites causes moderate distension of the abdomen, associated with mild/moderate discomfort. Patients with grade 3 ascites have large amounts of ascitic fluid, causing marked abdominal distension and associated with significant discomfort. Patients with refractory ascites are those that do not respond to high doses of diuretics or develop side effects that preclude their use.

Recommendations for the management of ascites are summarized in Table II.

What is the right therapy for the patient with ascites?

Grade 2 ascites

These patients typically can be managed as outpatients unless other complications of cirrhosis are present. A negative sodium balance with loss of ascites is quickly and easily obtained in most cases with diuretics. Patients with new onset ascites respond to spironolactone of 50 to 100 mg/day, and the dose may be increased progressively if needed.

Patients with prior episodes of ascites should receive the combination of spironolactone of 100 mg/day with furosemide (20–40 mg/day). If there is no response, compliance with diet and medications should be confirmed and diuretics may then be increased in a stepwise fashion every 5 to 7 days by doubling doses to a maximal dose of spironolactone of 400 mg/day and a maximal dose of furosemide of 160mg/day.

Diuretic therapy is effective in the elimination of ascites in 80% to 90% of all patients, a percentage that may increase to 95% when only patients without renal failure are considered. Spironolactone-induced gynecomastia may cause patients to stop the drug. In these cases, amiloride (5-10 mg/day) may be useful, although its potency is lower than that of spironolactone. Eplerenone, another aldosterone antagonist, has fewer endocrine adverse effects compared with spironolactone and could be a good alternative to spironolactone in patients with spironolactone-induced gynecomastia, but there is limited data.

The goal of diuretic therapy is to achieve an average weight loss of 300 to 500 g per day in patients without edema, and 800 to 1000 g per day in those with peripheral edema. A greater degree of weight loss may induce volume depletion and renal failure. After minimizing ascites, sodium restriction should be maintained while the dose of diuretics may be reduced as needed.

What is the most effective initial therapy?

Grade 3 ascites

These patients are best managed by therapeutic paracentesis. Complete removal of ascites in one tap (as many liters as possible) with intravenous albumin (6-8 g per liter tapped) has been shown to be quick, effective, and associated with a lower number of complications than conventional diuretic therapy. After a therapeutic tap, post-paracentesis circulatory dysfunction may develop; this is a circulatory derangement with marked activation of the renin-angiotensin system that occurs 24 to 48 hours after the procedure. This disorder is clinically silent, not spontaneously reversible, and associated with hyponatremia and renal impairment in up to 20% of patients. In addition it is associated with decreased survival.

Post-paracentesis circulatory dysfunction may be prevented with the administration of albumin (6-8 g/L tapped), with evidence available showing that albumin reduces morbidity and mortality among those undergoing large volume paracentesis.

Patients with known histories of cirrhosis and without any complications can be managed as outpatients. However, patients in whom tense ascites is the first manifestation of cirrhosis or those with associated hepatic encephalopathy, gastrointestinal bleeding, or bacterial infections require hospitalization. Most of these patients have marked sodium retention and need to be started or continued on relatively high doses of diuretics after paracentesis.

Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.

Refractory ascites

Up to 10% of patients with ascites can be refractory to treatment with diuretics. In refractory ascites, sodium excretion cannot be achieved either because patients do not respond to high doses of diuretics (spironolactone 400 mg/day and furosemide 160 mg/day) or because they develop side effects that prohibit their use. These patients in general have features of advanced liver disease, high recurrence rates of ascites after large-volume paracentesis, increased risks of hepatorenal syndrome, and poor prognoses.

Current treatment strategies include repeated therapeutic paracentesis, plus intravenous albumin, and transjugular intrahepatic portosystemic shunts (TIPS). Therapeutic paracentesis is the accepted initial therapy for refractory ascites. Patients, on average, require a tap every 2 to 4 weeks, and the majority may be treated as outpatients, making this option easy to perform and cost-effective.

TIPS, a nonsurgical method of portal decompression, reduces sinusoidal and portal pressure and decreases ascites and diuretic requirements in these patients. A disadvantage with TIPS is the development of side effects that include hepatic encephalopathy and impairment in liver function. Additionally, uncovered TIPS may be complicated by a high rate of stenosis of the prosthesis. Newer polytetrafluoroethylene-covered prostheses seem to improve TIPS patency and decrease the number of clinical relapses and reinterventions without increasing the risk of encephalopathy.

Randomized studies comparing TIPS with repeated paracentesis demonstrate that TIPS is associated with a lower rate of ascites recurrence, but hepatic encephalopathy occurred in up to 50% of patients treated with TIPS. The studies report discrepant findings with respect to survival: two studies showed a survival benefit with TIPS and two other studies demonstrated no difference in survival. Meta-analyses of these randomized controlled studies conclude that TIPS is better at controlling ascites but does not improve survival compared to paracentesis and increases the risk of hepatic encephalopathy.

Thus, the preferred initial treatment for refractory ascites is large-volume paracentesis with albumin replacement. TIPS as initial therapy should be evaluated on a case-by-case basis and reserved for patients less than 70 years old, with preserved liver function, without hepatic encephalopathy or severe cardiopulmonary disease, who require very frequent paracentesis, or in whom ascites cannot be adequately eliminated by paracentesis.

A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies

Spontaneous bacterial peritonitis

Bacterial infections in patients with cirrhosis occur at admission or during hospitalization in 20% to 60% of patients. Of these, most are secondary to SBP (30%); other common causes are urinary tract infection, pneumonia and bacteremia secondary to invasive procedures. Among all these patients, nearly 50% are due to gram negative bacteria and 48% are due to aerobic Gram-positive bacteria. The prevalence of SBP in hospitalized cirrhotic patients is approximately 10% to 30%. The 1-year survival probability after an episode is around 40%. The clinical spectrum of SBP is variable and ranges from no symptoms to fever, chills, abdominal pain, hepatic encephalopathy, severe peritonitis, shock, worsening liver failure, and/or the development of hepatorenal syndrome.

Listing of these, including any guidelines for monitoring side effects.

Therapy of spontaneous bacterial peritonitis

Once the diagnosis is secured, empiric antibiotic therapy is started with an intravenous third-generation cephalosporin (cefotaxime 2 g every 8-12 hours; ceftriaxone 1 g/24 hours) for at least 5 to 7 days. It is recommended that patients have a repeat tap 2 days after to ensure a drop in neutrophil count by at least 25% of the pretreatment value. If it fails to drop, antibiotic resistance should be suspected and modification in therapy be implemented. Antibiotics are changed depending on results from cultures.

Response to therapy should be monitored by clinical signs, white blood count and PMN (polymorphonuclear leukocyte) count in the ascitic fluid. Therapy can be stopped when clinical signs of infection have disappeared and the PMN count in the ascitic fluid has normalized. Given the high prevalence of nosocomial infections in patients with cirrhosis, the current empirical therapeutic approach may need to be altered in such patients as they may have multiresistant bacteria, mainly, Extended Spectrum Beta-Lactamase bacteria, Pseudomona aeruginiosa, and methicillin resistant Staphylococcus aureus. Thus, in patients with nosocomial infections and according to every hospital’s data on resistant bacteria, empirical therapy should include antibiotics that cover such microorganisms.

The most important predictor of survival in patients with SBP is the development of renal failure during the infection. Administration of albumin at a dose of 1.5 g/kg at the diagnosis and 1 g/kg 48 hours later prevents hepatorenal syndrome and reduces mortality from 30% to 10%. Since recurrence of SBP occurs in 70% of cases and constitutes a major cause of death in these patients, prophylaxis is recommended, particularly for listed patients. Because most cases are caused by gram-negative bacteria from the intestinal flora, long-term use of norfloxacin (400 mg/day) or ciprofloxacin (750 g/ week) or co-trimoxazole (800 mg sulfamethoxazole and 160 mg trimethoprim daily, orally) are recommended as secondary prophylaxis.

There are two conditions associated with an increased risk of the first episode of SBP in which primary prophylaxis is recommended. The first is in patients with GI hemorrhage. Multiple studies have shown that short-term (7 days) administration of oral norfloxacin 400 mg twice a day or intravenous ceftriaxone 1 g/day reduces the incidence of SBP, bacteremia, and rebleeding. The second is in patients with advanced cirrhosis (serum creatinine >1.2 mg/dL, Child-Pugh score >9, and/or serum sodium <130 mEq/L and ascitic fluid protein levels <1.5 gm/L). These patients benefit from norfloxacin (400 mg/day) because it not only reduces the probability of developing SBP but also reduces the risk of developing HRS and improves survival. Recommendations for the management of SBP are outlined below (i.e., Recommendations for the management of SBP).

How should I monitor the patient with ascites?

Recommendations for the management of spontaneous bacterial peritonitis

After diagnosis is made, start with third-generation cephalosporins (i.e., cefotaxime 2 g/8–12 hourly intravenously or ceftriaxone 1 g/24 hours intravenously). In nosocomial spontaneous bacterial peritonitis, consider the addition of an antibiotic active against Gram-positive cocci and/or multiresistant bacteria.
Give albumin 1.5 g/kg intravenously at the time of diagnosis of the infection and 1 g/kg 48 hours later.
A repeat diagnostic tap 2 days after the start of treatment may help guide the antibiotic therapy.
Maintain antibiotic therapy until disappearance of signs of infection and the reduction of polymorphonuclear cells in ascitic fluid below 250/mm3.
After resolution of infection, start long-term prophylactics.

What's the evidence?

Moore, KP, Wong, F, Ginès, P. “The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club”. Hepatology. vol. 38. 2003. pp. 258-66.

Ginès, P, Cárdenas, A. “The management of ascites and dilutional hyponatremia in cirrhosis”. Semin Liver Dis. vol. 28. 2008. pp. 43-58.

Santos, J, Planas, R, Pardo, A. “Spironolactone alone or in combination with furosemide in the treatment of moderate ascites in nonazotemic cirrhosis: a randomized comparative study of efficacy and safety”. J Hepatol. vol. 39. 2003. pp. 187-92.

Angeli, P, Fasolato, S, Mazza, E. “Combined versus sequential diuretic treatment of ascites in nonazotemic patients with cirrhosis: results of an open randomized clinical trial”. Gut. vol. 59. 2010. pp. 98-104.

Ginès, P, Arroyo, V, Quintero, E. “Comparison of paracentesis and diuretics in the treatment of cirrhotics with tense ascites: results of a randomized study”. Gastroenterology. vol. 93. 1987. pp. 234-41.

Ginès, P, Tito, L, Arroyo, V. “Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis”. Gastroenterology. vol. 94. 1988. pp. 1493-502.

D’Amico, G, Luca, A, Morabito, A. “Uncovered transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis”. Gastroenterology. vol. 129. 2005. pp. 1282-93.

Runyon, BA. “American Association for the Study of Liver Diseases. Management of adult patients with ascites due to cirrhosis: an update 2012”. Hepatology. vol. 57. 2013 Apr. pp. 1651-3.

Garcia-Tsao, G, Lim, JK. “Management and treatment of patients with cirrhosis and portal hypertension: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program”. Am J Gastroenterol. vol. 104. 2009. pp. 1802-29.

Bernardi, M, Caraceni, P, Navickis, RJ, Wilkes, MM. ” Albumin infusion in patients undergoing large-volume paracentesis: a meta-analysis of randomized trials”. Hepatology. vol. 55. 2012. pp. 1172

“EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis”. J Hepatol.. vol. 53. 2010. pp. 397-417.

Rimola, A, Garcia-Tsao, G, Navasa, M. “Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club”. J Hepatol. vol. 32. 2000. pp. 142-53.

Saab, S, Hernandez, JC, Chi, AC, Tong, MJ. “Oral antibiotic prophylaxis reduces spontaneous bacterial peritonitis occurrence and improves short-term survival in cirrhosis: a meta-analysis”. Am J Gastroenterol. vol. 104. 2009. pp. 993-1001.

Chavez-Tapia, NC, Barrientos-Gutierrez, T, Tellez-Avila, FI. “Antibiotic prophylaxis for cirrhotic patients with upper gastrointestinal bleeding”. Cochrane Database Syst Rev. 2010 Sep 8. pp. CD002907

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