Elaine Yeung, MD; Florence S. Wong, MD, FRCP(C)

Medscape General Medicine 4(4), 2002. © 2002 Medscape

Posted 10/22/2002

Ascites occurs in 50% of patients within 10 years of diagnosis of compensated cirrhosis.^[1] It is a poor prognostic indicator, with a 50% 2-year survival,^[2] worsening significantly to 20% to 50% at 1 year when the ascites becomes refractory to medical therapy.^[3,4] Ascites also predisposes patients to life-threatening complications such as spontaneous bacterial peritonitis and hepatorenal syndrome, and therefore is a major indication for liver transplantation. Effective management of ascites requires a thorough understanding of the pathophysiology of ascites formation and the rationale for various treatment modalities.

The pathophysiology leading to ascites formation is complex. Subtle sodium and water retention develops early in cirrhosis, and this becomes more avid as the cirrhotic process progresses. The presence of cirrhosis is associated with hemodynamic changes. Systemic and splanchnic vasodilatation occurs due to an imbalance of vasoactive substances, favoring vasodilators. The latter results in a decrease in effective circulating blood volume. The perceived hypovolemia in turn activates various vasoconstrictor systems, including the sympathetic nervous system, the renin-angiotensin-aldosterone system, and arginine vasopressin, producing renal vasoconstriction with a decrease in glomerular filtration rate (GFR), as well as an increase in renal sodium and water reabsorption.^[5] Independent of the hemodynamic changes, hepatic dysfunction also enhances renal sodium retention through some yet undefined mechanism, as sodium excretion has been shown to be related to a threshold of hepatic function.^[6,7] The presence of portal hypertension then preferentially localizes the excess fluid to the peritoneal cavity.

Treating Reversible Causes of Cirrhosis

In 1997, alcoholic liver disease accounted for 40% of deaths from cirrhosis in the United States.^[8] One prospective study^[9] has shown reduction of portal pressures in some patients following a period of abstinence from alcohol, with possible resolution of ascites or greater responsiveness to medical therapy. Irrespective of the etiology of cirrhosis, all patients should be advised to abstain from alcohol completely, including avoidance of alcohol-containing medications and so-called "nonalcoholic" beers.^[10]

Bedrest

Bedrest has traditionally been recommended for patients with ascites on the basis that upright posture increases aldosterone levels, which is associated with sodium retention.^[11] Although bedrest has been shown to increase natriuresis in cirrhotics,^[12] there are no data available to support improvement in clinically relevant outcomes in ascites.^[10] Furthermore, prolonged bedrest is impractical, expensive, and difficult to enforce.

Sodium Restriction

Sodium retention is central to the formation of ascites. The typical North American diet contains 200-300 mmol of sodium per day, whereas a no-added-salt diet contains 100-150 mmol of sodium per day. Nonurinary sodium excretion in afebrile cirrhotic patients without diarrhea is approximately 10 mmol/day.^[13] Patients with ascites on no diuretics commonly have renal sodium excretion of < 20 mmol/day. Such a patient on a no-added-salt diet will retain at least 100 mmol of sodium per day and 10 L of fluid in 2 weeks (100 mmol/day x 14 days/140 mmol/L = 10 L).

All patients with ascites should receive counseling regarding the importance of a low-sodium diet. A diet containing 88 mmol/day is currently recomm ended for patients with ascites.^[14] Diets that have even lower salt contents are not well tolerated. Potassium-containing salt substitutes should be avoided because of the risk of hyperkalemia, especially in those receiving potassium-sparing diuretics. In 10% of patients, sodium restriction alone may be adequate in the control of ascites.^[14] Only patients who have urinary excretions of > 78 mmol/day should be treated with sodium restriction alone. In patients with severely impaired natriuresis and difficult-to-control ascites, sodium restriction of 44 mmol per day or even 22 mmol per day may be required.

Most experts believe that dietary sodium restriction is essential to the effective management of ascites. Trials of sodium restriction vs unrestricted diet among patients on diuretics have not shown significant benefits, but have been shown to decrease the time to complete resolution of ascites.^[15] One study has shown that compliance with a low-sodium diet can significantly decrease diuretic requirements.^[16]

Fluid Restriction

Fluid loss usually follows sodium loss; therefore, fluid restriction in patients with ascites is usually not required. Cirrhotic patients with ascites often have hyponatremia, which is a reflection of severe intravascular volume contraction. In most instances, hyponatremia responds to volume replacement with colloid, and fluid restriction should only be used in patients with serum sodium < 120 mmol/L.

Diuretics

Diuretics that block aldosterone receptors in the distal convoluted tubule are preferred because of the presence of hyperaldosteronism in patients with cirrhosis. Loop diuretics may be used in combination, but are ineffective when used alone. The initial starting dose of spironolactone is 100 mg once daily and can be titrated up to a maximum of 400 mg once a day. Absorption of spironolactone is improved if administered with food. The diuretic effect can be seen within 48 hours, but the peak onset of action is 2 weeks, due to impaired metabolism in cirrhotic persons and a half-life of up to 5 days.^[17] Therefore, the dose should be adjusted only once a week. Side effects include hyperkalemia and painful gynecomastia. Amiloride can be used instead of spironolactone, starting at 5 mg per day. The latter is sometimes preferred because of its shorter half-life and quicker onset of action. However, it is much more expensive than spironolactone and has also been shown to be less effective in a randomized, controlled trial.^[18]

Both spironolactone and amiloride are weak diuretics and often require the addition of a loop diuretic such as furosemide. Furosemide effects are evident within 30 minutes of oral administration, with a peak effect within 1-2 hours and a duration of action of 4 hours. It is a potent diuretic but is not as effective as spironolactone alone.^[19] Furosemide prevents reabsorption of sodium in the loop of Henle; without spironolactone, however, sodium delivered to the distal collecting duct is rapidly reabsorbed due to unopposed aldosterone action. Side effects of furosemide include hypokalemia, hypovolemia, hyponatremia, and increased renal ammonia production. Hypokalemia is usually not a problem when furosemide is combined with a potassium-sparing diuretic. Intravenous administration of furosemide is not recommended because of good oral availability and because of the potential for causing acute reductions in GFR.^[20,21] There is no advantage to using other loop diuretics. The usual starting doses of diuretics are 100 mg of spironolactone and 40 mg furosemide.^[14] Doses can be titrated up to a maximum of 400 mg of spironolactone and 160 mg of furosemide. A ratio of 100:40 usually maintains normokalemia.

Monitoring Response to Sodium Restriction and Diuretics

Compliance with and response to sodium restriction and diuretics can be evaluated by daily weights and 24-hour urine collection for sodium. Completeness of urine collection is indicated by urinary creatinine levels of 15-20 mg/kg in males and 10-15 mg/kg in females.^[10] Weight loss should be limited to 0.5 kg per day. More rapid weight loss can cause hypovolemia and renal insufficiency, as fluid resorption from the peritoneal cavity is limited to 700 mL per day.^[22] Patients with massive edema can tolerate more rapid fluid loss until the edema has resolved.

In order for a patient with a serum sodium concentration of 140 mmol/L on an 88-mmol/day diet to lose 0.5 kg/day or 0.5 L of fluid, the 24-hour urine collection should contain approximately 150 mmol of sodium (140 mmol/Lx 0.5 L + 78 mmol/day). If a 24-hour urine collection is not possible, a random urine sodium-to-potassium ratio of > 1 predicts a > 78-mmol/day sodium excretion in 90% of patients.^[23] Noncompliance with a low-sodium diet is reflected by an adequate sodium excretion but with the patient not losing weight. Inadequate sodium excretion, on the other hand, necessitates increasing the doses of diuretics as tolerated up to the maximum recommended level. Diuretics should be discontinued and consideration should be given to the use of second-line therapy if there is evidence of encephalopathy, if serum sodium is < 120 mmol/L despite fluid restriction, or if serum creatinine is > 2.0 mg/dL (180 micromoles [mcmol]/day).^[10]

Large-volume paracentesis, if performed for tense nonrefractory ascites, should be followed by diuretics to prevent reaccumulation of fluid. In a study of 36 patients treated by total paracentesis plus intravenous albumin randomized to receive spironolactone 225 mg/day vs placebo, only 18% of those receiving spironolactone had recurrence of ascites compared with 93% of those in the placebo group (P < .0001).^[24] The use of 225 mg/day of spironolactone was shown to be effective and safe in most cases, without increased incidence of postparacentesis circulatory dysfunction. Patients should also continue to observe sodium restriction.

Refractory ascites is subdivided into diuretic-resistant and diuretic-intractable ascites (Table 1).^[25] Diuretic-resistant ascites usually requires a period of observation on maximal medical therapy to ensure diuretic resistance, which may take up to several weeks. A recent study showed that a single dose of 80 mg of intravenous furosemide and a subsequent random urine sodium of < 50 mmol/L is indicative of refractory ascites, compared with those cases of diuretic-responsive ascites, where the serum sodium is always > 80 mmol/L, with no overlap between the 2 groups.^[26] Refractory ascites portends a poor prognosis and requires second-line therapy, such as large-volume paracentesis, transjugular intrahepatic portosystemic shunts (TIPS), or liver transplantation.

Large-Volume Paracentesis

Several large randomized, controlled trials have shown that repeated large-volume paracentesis (4 L-6 L) is safer and more effective for the treatment of tense ascites compared with larger-than-usual doses of diuretics. ^[27-30] Incidence of systemic and hemodynamic disturbance, electrolyte abnormalities, renal impairment, and encephalopathy is lower in patients treated with repeated large-volume paracentesis compared with diuretic therapy.^[27] Improvement in cardiac output^[31]; lung volumes^[32]; and reductions in intra-abdominal, portal,^[33] intra-thoracic, and pulmonary pressures^[32] was also observed. Shortened duration of hospitalization was observed with large-volume paracentesis, but the rates of hospital readmission and survival were similar to those associated with use of diuretic therapy.^[27]

Total paracentesis has also been shown to be as safe as repeated partial paracentesis and to shorten the period of hospitalization -- and may even be performed on an outpatient basis.^[34] However, even in the most sodium-avid of all ascitic patients, paracentesis > 10 L should not be performed more often than every 2 weeks. More frequent need for paracentesis implies dietary noncompliance.

Procedure-associated risks include a 1% chance of significant abdominal-wall hematoma, 0.01% chance of hemoperitoneum, and a 0.01% chance of iatrogenic infection related to paracentesis.^[35,36] The only absolute contraindication to paracentesis is clinically evident fibrinolysis and disseminated intravascular coagulation.^[10] Severe coagulopathy and thrombocytopenia (INR > 2 or platelet count < 50) may need correction prior to the procedure to minimize the risk of bleeding, although there are no data supporting specific cut-offs. Leakage of ascitic fluid occasionally occurs and can be managed by placing a purse-string suture around the opening and by instructing the patient to lie on the side opposite to the puncture site.^[37] Permanent indwelling catheters should not be left in the peritoneal cavity, as this significantly increases the risk of peritonitis. The attachment of a colostomy bag to collect the ascitic fluid is also not recommended.

An important potential complication of paracentesis is postprocedure circulatory dysfunction characterized by renal impairment and activation of neurohormonal factors.^[38] In one randomized, controlled study of patients with tense ascites, intravenous albumin infusion was shown to lower the rates of hyponatremia, elevations in serum creatinine, and activation of neurohormonal factors (increased levels of renin and aldosterone) after paracentesis.^[39] However, the group that did not receive albumin did not suffer any greater morbidity or mortality. Another study found that patients with postparacentesis rise in plasma renin had decreased survival at 1 year,^[38] but it is unclear whether circulatory dysfunction is a consequence of the procedure or merely a marker of more advanced disease. Runyon,^[14] in his recent review of ascites, suggests that there are no adequate survival data to justify the expense of routine human albumin infusion and the possibility of infection with noneradicated and undefined viruses.

Despite the lack of evidence, albumin is still commonly used for intravenous plasma expansion after large-volume therapeutic paracentesis (> 5 L-6 L). Six to 8 g of albumin/L of ascitic fluid removed is administered intravenously during or after the procedure to prevent relative hypovolemia, which usually occurs 3-6 hours later.^[40] Another area of controversy relates to the use of nonalbumin plasma expanders. Four studies have compared nonalbumin plasma expanders with albumin. Although 3 of the 4 studies^[41-43] showed that synthetic plasma expanders were as effective in preventing hyponatremia and renal impairment, Gines and coworkers^[38] showed that postparacentesis circulatory dysfunction was more frequent in patients treated with dextran 70 or polygeline than in patients receiving albumin. Once again, more studies are necessary before definite recommendations can be made regarding the use of plasma expanders after paracentesis.

Peritoneovenous Shunts

A peritoneovenous shunt is a surgically inserted tube that connects the peritoneal cavity to the superior vena cava along subcutaneous tissue, allowing one-way passage of ascitic fluid from the peritoneal cavity back into the circulation.

Poor long-term patency and other technical problems such as shunt dislodgement and kinking, and the lack of a survival advantage, have all led to near abandonment of this procedure. Furthermore, shunt-fibrous adhesions and so-called "cocoon" formation can make subsequent liver transplantation difficult.^[44] The most recent guidelines from the American Association for the Study of Liver Diseases recommend peritoneovenous shunting only for diuretic-resistant patients who are not transplant candidates and who are not candidates for serial therapeutic paracentesis because of multiple abdominal surgical scars, or when a physician is unavailable to perform serial paracentesis.^[14]

Transjugular Intrahepatic Portal Systemic Shunt

TIPS is a side-to-side portocaval shunt initially designed to relieve portal hypertension for patients with refractory variceal bleeding.^[45] Because patients who had ascites were noted to have a reduction or disappearance of ascites after TIPS insertion, TIPS has become another option for the treatment of refractory ascites. A flexible metal prosthesis is used to bridge a branch of the hepatic and portal veins and is effective in reducing sinusoidal pressure.^[46] The procedure is performed percutaneously under radiologic guidance and obviates the need for surgery. It is recommended that coagulopathy (INR > 2 and platelet count < 50 x10⁹/L) be corrected first if indicated, and that paracentesis be performed in patients with tense ascites prior to the procedure.

Four randomized, controlled studies have compared TIPS with large-volume paracentesis in refractory ascites.^[47-50] All 4 studies showed better control of ascites with TIPS, but only 1 study showed a survival benefit.^[48] The mechanism for improvement in ascites with TIPS begins with decompression of portal circulation with improvement in splanchnic hemodynamics.^[51] The resulting refilling of the circulatory volume and decrease in plasma levels of renin and aldosterone results in an increase in creatinine clearance and natriuresis. Without diuretic therapy, the onset of natriuresis is delayed for up to 4 weeks.^[51] Once begun, natriuresis continues to improve, so that at 6 months after TIPS insertion, most patients are in a negative sodium balance on a 22-mmol/day diet, allowing elimination of ascites.^[52] Natriuretic response correlated significantly with baseline pre-TIPS renal function^[53-56] and inversely with the patient's age.^[51] Child-Pugh class C patients with ascites are less likely to respond to TIPS, and are generally not recommended for TIPS insertion.^[57-59]

Procedure-related complications and long-term difficulties with TIPS have prevented TIPS from being recommended in all patients with refractory ascites.^[56] The rate of procedure-related complications is 10% and of procedure-related mortality is 2%.^[59] Procedure-related complications include neck hematomas, hemobilia, puncture of the liver capsule causing intra-abdominal bleeding, and shunt occlusion. Reported rates of shunt occlusion range from 23% to 87% within the first year.^[57] It is recommended that ultrasonographic screening be performed at 24 hours after TIPS insertion, at 6 weeks, 3 months, 6 months, and every 6 months thereafter.^[46] In patients with a successful TIPS placement, there is resolution of ascites, improved renal function, patient well-being, and positive nitrogen balance during long-term follow-up.^[60]

In the early post-TIPS period, deterioration of liver function may occur as blood flow is shunted away from the liver. Deterioration in renal function may occur in patients with prior renal dysfunction (creatinine > 2.5 x upper limit of normal) and may be exacerbated by exposure to radiographic dye. In patients with pre-existing cardio-pulmonary disease, sudden portal decompression with return of the splanchnic volume to the systemic circulation can lead to an immediate and significant increase in cardiac output precipitating cardiac failure and pulmonary hypertension.^[61] The presence of a metal stent may also cause hemolysis.^[62]

Late TIPS complications include encephalopathy in 30% of cases,^[63] endothelial hyperplasia causing shunt stenosis in 40%, and reappearance of ascites in noncompliant patients. Encephalopathy is more frequent in patients older than age 60 years and in patients with a history of spontaneous encephalopathy.^[63] In most patients, chronic encephalopathy improves with time and can be controlled with lactulose. Chronic incapacitating encephalopathy can be reversed by balloon occlusion of the stent.^[64] Shunt infection is uncommon but may be difficult to eradicate. Therefore, dental clearance and treatment of spontaneous bacterial peritonitis are recommended before considering patients for TIPS insertion.

Absolute contraindications^[56] for TIPS insertion include serum bilirubin > 85 mcmol/L (5 mg/dL), INR > 2, functional renal disorder with serum creatinine > 250 mcmol/ (2.8 mg/dL), intrinsic renal disease with urine protein > 500 mg/24 hr or active urinary sediment, Grade III or IV hepatic encephalopathy, cardiac disease, portal vein thrombosis, noncompliance with sodium restriction, or the presence of carcinoma that is likely to limit the patient's lifespan to less than 1 year. Relative contraindications include dental sepsis, spontaneous bacterial peritonitis, and active infection (pneumonia or urinary tract infection).

Liver Transplantation

Liver transplantation is the only definitive treatment for ascites and the only treatment that has been clearly shown to improve survival.^[65] Patients with cirrhosis who develop ascites should be assessed for possible liver transplantation because of their poor prognosis. Patients who develop renal dysfunction (GFR < 50 mL/min) do much worse after liver transplantation (80% vs 50% survival at 15 months, P < .05).^[66,67] Therefore, given the latter, every effort should be made to transplant patients prior to the onset of renal dysfunction. Other poor prognostic indicators include mean arterial pressure < 82 mmHg, urinary sodium excretion of < 1.5 mEq/day, plasma norepinephrine levels of > 570 pg/mL, poor nutritional state, presence of hepatomegaly, and serum albumin < 25 g/L.^[68] Long waiting lists for cadaveric organs mean that only a small proportion of patients can benefit from this therapy. Living-related donor transplants are offered at a few centers, but careful selection of both donor and recipient is necessary because of significant risks to the donor.^[69]

Spontaneous bacterial peritonitis (SBP) is defined as an ascitic fluid infection associated with a positive bacterial culture and an ascitic fluid polymorphonuclear cell count of > 250/mm³, in the absence of a surgically treatable abdominal source of infection.^[70] In hospitalized patients with cirrhosis, 10% to 25% will have an episode of SBP with a mortality rate of 17% to 50%,^[71] with outcome dependent on the association with a recent gastrointestinal bleed,^[72] the severity of infection, and degree of renal and liver failure.^[73] Clinically, certain factors predispose patients with cirrhosis to developing ascites (Table 2).^[70,74] Patients who already have had 1 episode of SBP are at high risk for recurrence, with rates of 43% at 6 months, 69% at 1 year, and 74% at 2 years.^[75] Patients with SBP are also at particularly high risk for renal complications,^[76,77] likely related to systemic hemodynamic changes and the increased cytokine levels that are part of the systemic inflammatory response to infection.

Pathogenesis

Cirrhotic patients often have bacteremia and high levels of endotoxin levels without clinically significant infection.^[78] Bacteremia is most often from intestinal bacterial overgrowth,^[79] but may also result from bacteriuria or intravascular catheters.^[70] Intestinal permeability from vascular congestion and edema secondary to portal hypertension and malnutrition can cause increased bacterial translocation from the intestinal lumen to the bloodstream and seeding of ascitic fluid. Despite this, infection occurs only in those patients with decreased levels of complement factors (ascitic fluid third component of complement [C3] < 13 mg/dL and/or protein level < 1g/dL), severely impaired neutrophil chemotaxis, and poor phagocytic activity of neutrophils and macrophages.^[74,80] Deficiency in complements may be due to decreased synthesis or increased consumption.^[74,80] In addition, neutrophil response is worse in ascitic fluid than in serum, and worse in patients with Child-Pugh class C cirrhosis and in those with previous episodes of bacterial infections, including SBP. Furthermore, intrahepatic and extrahepatic shunts that prevent circulating bacteria from encountering Kupffer cells in the reticuloendothelial system also contribute to the development of SBP.^[70] In cirrhotic rats with hemorrhagic shock,^[81] increased bacterial translocation and intestinal permeability, as well as decreased effectiveness of the reticuloendothelial system, have been demonstrated, which could explain the higher rates of SBP among patients hospitalized with gastrointestinal bleeds.^[80,82]

Types of SBP

The most common form of SBP involves ascitic fluid with a positive bacterial culture and a polymorphonuclear (PMN) cell count of >/= 250/mm³. About two thirds of ascitic fluid infections belong to this subgroup and are almost invariably monomicrobial.^[83] Other variants of SBP include culture-negative neutrocytic ascites (CNNA) characterized by PMN cell count of >/= 250/mm³ with negative ascitic fluid cultures, and monomicrobial nonneutrocytic bacterascites (MNB), characterized by isolation of bacteria in cultures but with a PMN cell count of </= 250 mm³. The differential diagnosis of CNNA includes peritoneal carcinomatosis, pancreatitis, and tuberculous peritonitis. CNNA has the same prognosis as SBP and should therefore be treated similarly. Asymptomatic MNB usually signifies colonization and does not require antibiotic therapy unless there are clinical signs and symptoms suggestive of infection.

Polymicrobial bacterascites occurs when ascitic fluid contains multiple organisms and the PMN cell count is < 250/mm³. The latter usually results from inadvertent puncture of the intestines during attempted paracentesis and occurs in about 1/1000 paracenteses.^[70] Risk factors include ileus, presence of multiple surgical scars, and operator inexperience. If the ascitic fluid contains > 1 g/dL of protein and the opsonic activity of fluid is adequate, colonization usually resolves spontaneously. Secondary bacterial peritonitis is also polymicrobial but has a PMN cell count of > 250/mm³. The latter can be distinguished from SBP by a total protein > 1 g/dL, glucose concentration < 50 mg/dL, and a lactate dehydrogenase level > 225 U/mL. Prompt diagnosis through imaging is necessary because without surgical correction, death is the usual outcome.

Clinical Signs and Symptoms

Symptoms of SBP are outlined in Table 3.^[70] A rigid abdomen is not necessary for diagnosis, especially in patients with large-volume ascites, which prevents the contact of visceral and parietal peritoneal surfaces to elicit the spinal reflex that causes rigidity. Ten percent of patients are asymptomatic.^[70] Patients with ascites and unexplained deterioration clinically or in terms of laboratory parameters should have a diagnostic paracentesis. Other indications for diagnostic paracentesis are outlined in Table 4.^[84] Ascitic fluid should always be sent for determination of white blood cell count and differential, serum albumin levels, and culture. About 10 mL of ascitic fluid should be injected directly into blood culture bottles at the bedside because there is evidence that the yield increases from less than 50% to approximately 80%.^[85] Other tests, such as protein, glucose, lactate dehydrogenase, acid-fast smear and culture, cytology, triglyceride, and bilirubin levels should only be sent when clinically indicated.[70]

Treatment of SBP

Treatment should be started empirically if SBP is suspected clinically, regardless of the availability of laboratory results. In community-acquired SBP and in patients not on SBP prophylaxis, Escherichia coli and Klebsiella pneumoniae are seen in up to 60% of isolates. About 25% are Gram-positive cocci, mostly streptococcal species. Anaerobes are rarely seen. Intravenous cefotaxime is the empiric antibiotic of choice and has been shown to cure SBP episodes in 85% of patients compared with in 56% of those receiving ampicillin and tobramycin. The optimal cost-effective dosage is 2 g every 12 hours for a minimum of 5 days.^[84] Intravenous amoxicillin-clavulanic acid followed by oral therapy has been shown to be as effective as cefotaxime, but may not be widely available.^[86] Intravenous ciprofloxacin followed by oral treatment has also been shown to be effective.^[87] Trials of oral ofloxacin vs intravenous cefotaxime in patients without septic shock, encephalopathy, azotemia, gastrointestinal bleed, or ileus showed an SBP resolution rate of 84% in the ofloxacin group vs 85% in the cefotaxime group. Survival rate was 81% in both groups.^[88] Although oral antibiotics are promising as a form of outpatient therapy, monitoring of patient compliance is necessary and the duration of therapy must be evaluated before this option can be recommended. Once culture results are available, antibiotic modifications may be necessary, but aminoglycosides should still be avoided because of the risk of renal failure. Patients who develop SBP while on norfloxacin prophylaxis are more likely to have infections caused by Gram-positive cocci or quinolone-resistant Gram-negative bacilli.^[89,90] Cefotaxime is effective even in these latter cases.^[90,91] See Table 5.

In terms of other adjunctive therapies, one randomized trial of intravenous albumin in addition to antibiotics reduced renal impairment from 33% to 10% and hospital mortality from 29% to 10%.^[92] Despite these impressive results, the high cost of using albumin would require further studies to confirm efficacy before intravenous albumin can be recommended.

Prevention of SBP

Prevention of SBP involves treatment of the ascites and underlying liver disease, prophylaxis in high-risk patients, and eliminating potential sources of bacteremia.^[70] Patients should be counseled to avoid alcohol. Diuretics, by decreasing the amount of ascites, have been shown to lead to improved ascitic fluid opsonic activity.^[93] Gastrointestinal bleeding should be treated aggressively, including consideration for TIPS. Treatment and eradication of local infections should be undertaken before dissemination. Bacteriuria is common, especially in women. All patients should be screened and treated for urinary tract infections even in the absence of symptoms. Urinary catheters should be avoided. Intravascular catheters cause between 4% and 20% of bacteremic episodes and their use should also be minimized.^[70]

Patients who have had previous episodes of SBP should receive long-term antibiotic prophylaxis because of high rates of recurrence. It has been shown that norfloxacin 400 mg once daily decreases the recurrence rate of SBP at 1 year (from 68% to 20%).^[89] In a group of patients with low ascitic fluid protein concentration, with or without previous episodes of SBP, ciprofloxacin 750 mg weekly has been shown to decrease the incidence of SBP from 22% to 4% at 6 months.^[94] One meta-analysis of 4 randomized, controlled trials for SBP prophylaxis using quinolones or trimethoprim-sulfamethoxazole suggested increased survival at 5 months (82% with SBP prophylaxis vs 73% with placebo), but the analysis included patients with and without prior episodes of SBP.^[95] Economic analyses also suggest that SBP prophylaxis is associated with reduced cost compared with a "diagnose and treat" strategy in high-risk patients, and even reduces total antibiotic burden.^[96,97] Indications for SBP prophylaxis and various recommended antibiotic regimens are listed in Table 6.^[84]

In patients who have active gastrointestinal bleeding, norfloxacin is traditionally recommended for SBP prophylaxis because of its ability to selectively eliminate Gram-negative intestinal bacteria without having an impact on anaerobic flora; therefore, it can prevent problems with bacterial overgrowth. In a randomized, controlled trial, norfloxacin 400 mg twice daily administered for 7 days significantly reduced the incidence of bacteremia and/or SBP in patients with gastrointestinal hemorrhage.^[82] Other antibiotic regimens that have been investigated include ofloxacin 400 mg/day (initially intravenously then orally) plus amoxicillin-clavulanic acid (1 g intravenous, before each endoscopy),^[98] ciprofloxacin plus amoxicillin-clavulanic acid (first intravenously and then orally once bleeding is controlled),^[99] and oral ciprofloxacin (500 mg twice daily for 7 days).^[100] The incidence of bacterial infections was significantly lower among patients in the treated groups (10% to 20%) compared with those in the control groups (45% to 66%). Furthermore, a meta-analysis has shown that short-term survival is improved significantly with antibiotic prophylaxis in patients with cirrhosis and gastrointestinal hemorrhage, with no difference between oral vs intravenous antibiotics.^[101] Regardless of the antibiotic regimen used, SBP must be ruled out before starting prophylaxis.

Long-term norfloxacin administration reduces the risk of Gram-negative infections but increases the risk of severe hospital-acquired staphylococcal infections and resistance to antibiotics.^[102] There is currently insufficient evidence to use prophylaxis in low-protein ascites (< 1 g/dL), but some groups advocate the use of norfloxacin 400 mg once daily during hospitalization to reduce the incidence of SBP and extraperitoneal infections.^[70] However, others have routinely stopped norfloxacin prophylaxis in patients who are admitted to hospital.^[102] At present, quinolone-resistant bacteria do not seem to be a problem because there is no cross-resistance between quinolones and third-generation cephalosporins.^[70]

Prognosis

Despite effective antibiotic therapy for episodes of SBP, long-term prognosis is still extremely poor, with probabilities of survival at 1 and 2 years of 30% and 20%, respectively.^[70] An episode of SBP is an indication for liver transplantation. Previous SBP, however, is associated with greater incidence of infectious complications and higher mortality rate after liver transplantation.^[103]

Effective treatment of ascites remains one of the most important aspects in the management of patients with decompensated cirrhosis, especially in those who are not candidates for liver transplantation. Currently existing therapies, aside from liver transplantation, have not been shown to have a significant impact on survival. Living-related organ donation may be an attractive option for many patients, but can only be performed in specialized centers. As our understanding of the pathophysiology of ascites improves, new therapies may become available to enhance survival while awaiting liver transplantation.