Treatment of ascites in patients with portal hypertension

Article reviews the current recommendations for the treatment of ascites, including hepatorenal syndrome and spontaneous bacterial peritonitis.


Introduction

Ascites is the most common complication of cirrhosis, developing in over half of cirrhotic patients within 10 years of diagnosis (11. Ginés P, Quintero E, Arroyo V, Terés J, Bruguera M, Rimola A, et al. Compensated cirrhosis: natural history and prognostic factors. Hepatology. 1987;7:122-8. [PMID: 3804191]). The onset of ascites marks a progression from compensated to decompensated cirrhosis. This progression portends a poor outcome, as it is associated with an increase in mortality (22. Planas R, Montoliu S, Ballesté B, Rivera M, Miquel M, Masnou H, et al. Natural history of patients hospitalized for management of cirrhotic ascites. Clin Gastroenterol Hepatol. 2006;4:1385-94. [PMID: 17081806]). Ascites is also the most common complication of cirrhosis requiring hospitalization (33. Lucena MI, Andrade RJ, Tognoni G, Hidalgo R, De La Cuesta FS; Spanish Collaborative Study Group On Therapeutic Management In Liver Disease. Multicenter hospital study on prescribing patterns for prophylaxis and treatment of complications of cirrhosis. Eur J Clin Pharmacol. 2002;58:435-40. [PMID: 12242604]). This article will review current recommendations for the treatment of ascites, including hepatorenal syndrome and spontaneous bacterial peritonitis.

Pathophysiology of cirrhotic ascites

Cirrhotic ascites formation begins with the development of portal hypertension (PHTN) (44. Ginés P, Fernández-Esparrach G, Arroyo V, Rodés J. Pathogenesis of ascites in cirrhosis. Semin Liver Dis. 1997;17:175-89. [PMID: 9308123]). Through complex mechanisms mediated in part by nitric oxide, PHTN results in splanchnic arterial vasodilation, which leads to decreased systemic vascular resistance and lower effective arterial volume (55. Vallance P, Moncada S. Hyperdynamic circulation in cirrhosis: a role for nitric oxide? Lancet. 1991;337:776-8. [PMID: 1706450], 66. Solà; E, Ginés P. Renal and circulatory dysfunction in cirrhosis: current management and future perspectives. J Hepatol. 2010;53:1135-45. [PMID: 20850887]). In early stages of cirrhosis, the body compensates by increasing cardiac output (66. Solà; E, Ginés P. Renal and circulatory dysfunction in cirrhosis: current management and future perspectives. J Hepatol. 2010;53:1135-45. [PMID: 20850887]). As liver disease advances and PHTN worsens, the decrease in effective arterial volume becomes more pronounced and increases in cardiac output are no longer able to compensate. Underfilling of the arterial circulation in the decompensated state leads to vasoconstriction via the renin-angiotensin-aldosterone system and sympathetic nervous system, which results in sodium and free water retention by the kidneys (77. Ginés P, Cárdenas A, Schrier RW. Liver disease and the kidney. In: Schrier RW, ed. Diseases of the Kidney and Urinary Tract. Philadelphia: Lippincott Williams & Wilkins; 2007:2179-2205.). Given the elevated hydrostatic pressure in the portal venous system, the retained fluid collects in the peritoneal cavity as ascites (88. Moore KP, Aithal GP. Guidelines on the management of ascites in cirrhosis. Gut. 2006;55 Suppl 6:vi1-12. [PMID: 16966752]).

Management of cirrhotic ascites

Over its natural history, cirrhosis progresses from a compensated state to diuretic-responsive ascites to refractory ascites and finally to hepatorenal syndrome (HRS). The new onset of ascites in a patient with previously compensated cirrhosis should prompt referral to a gastroenterologist or hepatologist. Ascites should be initially managed with oral diuretics (99. Garcia-Tsao G, Lim JK, Lim J; Members of Veterans Affairs Hepatitis C Resource Center Program. 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. 2009;104:1802-29. [PMID: 19455106]). Intravenous (IV) diuretics should be avoided, as they can acutely exacerbate the already decreased effective arterial volume of cirrhosis, leading to hyponatremia and renal impairment (1010. Garcia-Tsao G. Current management of the complications of cirrhosis and portal hypertension: variceal hemorrhage, ascites, and spontaneous bacterial peritonitis. Gastroenterology. 2001;120:726-48. [PMID: 11179247]). Tense ascites can be safely managed with large-volume paracentesis accompanied by IV albumin. This provides immediate symptomatic improvement and may expedite discharge from the hospital (99. Garcia-Tsao G, Lim JK, Lim J; Members of Veterans Affairs Hepatitis C Resource Center Program. 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. 2009;104:1802-29. [PMID: 19455106]). However, diuretics and paracentesis should both be avoided in the presence of conditions that further decrease the effective arterial volume, such as variceal hemorrhage, spontaneous bacterial peritonitis, and acute renal failure (ARF) (99. Garcia-Tsao G, Lim JK, Lim J; Members of Veterans Affairs Hepatitis C Resource Center Program. 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. 2009;104:1802-29. [PMID: 19455106]).

Diuretic-responsive ascites

All patients with ascites due to cirrhosis should restrict their dietary sodium intake to less than 2 g/d (1010. Garcia-Tsao G. Current management of the complications of cirrhosis and portal hypertension: variceal hemorrhage, ascites, and spontaneous bacterial peritonitis. Gastroenterology. 2001;120:726-48. [PMID: 11179247]). Although restriction to even lower levels of sodium intake may be more effective, it is not usually feasible and may negatively impact nutritional status due to poor palatability (1111. Runyon BA. Management of Adult Patients with Ascites Due to Cirrhosis: Update 2012. American Association for the Study of Liver Diseases Practice Guidelines. Available online. ). Most patients will require diuretics in addition to sodium restriction. These modalities work synergistically, and therefore diuretics should not replace sodium restriction (99. Garcia-Tsao G, Lim JK, Lim J; Members of Veterans Affairs Hepatitis C Resource Center Program. 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. 2009;104:1802-29. [PMID: 19455106]).

Spironolactone is an aldosterone antagonist and is the diuretic of choice for cirrhotic ascites (88. Moore KP, Aithal GP. Guidelines on the management of ascites in cirrhosis. Gut. 2006;55 Suppl 6:vi1-12. [PMID: 16966752], 1010. Garcia-Tsao G. Current management of the complications of cirrhosis and portal hypertension: variceal hemorrhage, ascites, and spontaneous bacterial peritonitis. Gastroenterology. 2001;120:726-48. [PMID: 11179247]). The initial dosage should be 100 mg/d (88. Moore KP, Aithal GP. Guidelines on the management of ascites in cirrhosis. Gut. 2006;55 Suppl 6:vi1-12. [PMID: 16966752], 1010. Garcia-Tsao G. Current management of the complications of cirrhosis and portal hypertension: variceal hemorrhage, ascites, and spontaneous bacterial peritonitis. Gastroenterology. 2001;120:726-48. [PMID: 11179247]). Since the effect of spironolactone persists for greater than 24 hours, multiple daily doses are not necessary or beneficial (99. Garcia-Tsao G, Lim JK, Lim J; Members of Veterans Affairs Hepatitis C Resource Center Program. 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. 2009;104:1802-29. [PMID: 19455106]). The dose can be titrated upward every 3 to 5 days to a maximum of 400 mg/d (88. Moore KP, Aithal GP. Guidelines on the management of ascites in cirrhosis. Gut. 2006;55 Suppl 6:vi1-12. [PMID: 16966752]). If hyperkalemia develops or if effective diuresis cannot be achieved at the maximum dose, furosemide may be added to spironolactone and sodium restriction (99. Garcia-Tsao G, Lim JK, Lim J; Members of Veterans Affairs Hepatitis C Resource Center Program. 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. 2009;104:1802-29. [PMID: 19455106]). Furosemide should be initiated at 40 mg/d and titrated as needed to a maximum dose of 160 mg/d (88. Moore KP, Aithal GP. Guidelines on the management of ascites in cirrhosis. Gut. 2006;55 Suppl 6:vi1-12. [PMID: 16966752]). Although it provides additional benefit when added to spironolactone, furosemide should not be used as the sole diuretic agent for ascites because it is ineffective at blocking the sodium-retaining effects of aldosterone on the distal tubule and collecting system (99. Garcia-Tsao G, Lim JK, Lim J; Members of Veterans Affairs Hepatitis C Resource Center Program. 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. 2009;104:1802-29. [PMID: 19455106], 1111. Runyon BA. Management of Adult Patients with Ascites Due to Cirrhosis: Update 2012. American Association for the Study of Liver Diseases Practice Guidelines. Available online. ). There is minimal evidence for the use of other diuretic agents in the management of ascites due to cirrhosis (99. Garcia-Tsao G, Lim JK, Lim J; Members of Veterans Affairs Hepatitis C Resource Center Program. 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. 2009;104:1802-29. [PMID: 19455106]).

Refractory ascites

Ascites may become refractory to diuretic therapy in one of two ways. Maximal doses of spironolactone and furosemide may fail to achieve adequate diuresis. Alternatively, it may become impossible to further increase diuretic doses due to complications of therapy such as ARF, hyponatremia, or hepatic encephalopathy (HE) (99. Garcia-Tsao G, Lim JK, Lim J; Members of Veterans Affairs Hepatitis C Resource Center Program. 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. 2009;104:1802-29. [PMID: 19455106], 1111. Runyon BA. Management of Adult Patients with Ascites Due to Cirrhosis: Update 2012. American Association for the Study of Liver Diseases Practice Guidelines. Available online. ). Before the diagnosis of refractory ascites is made, use of NSAIDs should be excluded, as they limit the effectiveness of diuretic therapy (88. Moore KP, Aithal GP. Guidelines on the management of ascites in cirrhosis. Gut. 2006;55 Suppl 6:vi1-12. [PMID: 16966752], 99. Garcia-Tsao G, Lim JK, Lim J; Members of Veterans Affairs Hepatitis C Resource Center Program. 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. 2009;104:1802-29. [PMID: 19455106]). Other than liver transplantation, the only effective treatments for refractory ascites are serial paracentesis and transjugular intrahepatic portosystemic shunt (TIPS) (1212. European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol. 2010;53:397-417. [PMID: 20633946]).

Serial paracentesis is as effective as diuretic therapy with no increase in the risk of complications (88. Moore KP, Aithal GP. Guidelines on the management of ascites in cirrhosis. Gut. 2006;55 Suppl 6:vi1-12. [PMID: 16966752]). It is reserved for patients who become refractory to diuretics because it requires more resources, both human and financial. When serial paracentesis is initiated, as much ascites as possible should be removed during each session (1111. Runyon BA. Management of Adult Patients with Ascites Due to Cirrhosis: Update 2012. American Association for the Study of Liver Diseases Practice Guidelines. Available online. ). If more than 5 L of ascites is removed, IV albumin should be administered to combat the resulting decrease in effective atrial volume. Seven g of albumin is administered for each L of ascites removed (99. Garcia-Tsao G, Lim JK, Lim J; Members of Veterans Affairs Hepatitis C Resource Center Program. 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. 2009;104:1802-29. [PMID: 19455106], 1111. Runyon BA. Management of Adult Patients with Ascites Due to Cirrhosis: Update 2012. American Association for the Study of Liver Diseases Practice Guidelines. Available online. ). This is usually achieved by infusing one to two 100-mL bottles of 25% albumin (25 g/100 mL) during or shortly following the paracentesis (1111. Runyon BA. Management of Adult Patients with Ascites Due to Cirrhosis: Update 2012. American Association for the Study of Liver Diseases Practice Guidelines. Available online. ). IV albumin in this setting prevents hyponatremia and ARF and may slow the reaccumulation of ascites (99. Garcia-Tsao G, Lim JK, Lim J; Members of Veterans Affairs Hepatitis C Resource Center Program. 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. 2009;104:1802-29. [PMID: 19455106]). In general, it is safe to continue diuretics during serial paracentesis (88. Moore KP, Aithal GP. Guidelines on the management of ascites in cirrhosis. Gut. 2006;55 Suppl 6:vi1-12. [PMID: 16966752]); they also help slow the reaccumulation of fluid (1010. Garcia-Tsao G. Current management of the complications of cirrhosis and portal hypertension: variceal hemorrhage, ascites, and spontaneous bacterial peritonitis. Gastroenterology. 2001;120:726-48. [PMID: 11179247]). The frequency of serial paracentesis is determined by patient symptoms. Indwelling peritoneal catheters should be avoided due to concerns about massive fluid losses and infection.

If paracentesis is required more often than every 2 weeks or if the removal of large volumes is limited by loculation, TIPS should be considered (99. Garcia-Tsao G, Lim JK, Lim J; Members of Veterans Affairs Hepatitis C Resource Center Program. 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. 2009;104:1802-29. [PMID: 19455106]). The connection created between the portal and systemic venous systems reduces portal pressure, making it an effective second-line treatment. However, the severity of HE is increased in patients with TIPS (1111. Runyon BA. Management of Adult Patients with Ascites Due to Cirrhosis: Update 2012. American Association for the Study of Liver Diseases Practice Guidelines. Available online. ).

Hepatorenal syndrome

Hepatorenal syndrome is the result of severely decreased effective arterial volume leading to renal vasoconstriction and, ultimately, prerenal ARF (99. Garcia-Tsao G, Lim JK, Lim J; Members of Veterans Affairs Hepatitis C Resource Center Program. 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. 2009;104:1802-29. [PMID: 19455106]). It is important to rule out other causes of renal failure, such as ATN, before diagnosing HRS. HRS typically occurs in patients with refractory ascites, but the development of ARF in any patient with cirrhosis should raise the suspicion of HRS (99. Garcia-Tsao G, Lim JK, Lim J; Members of Veterans Affairs Hepatitis C Resource Center Program. 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. 2009;104:1802-29. [PMID: 19455106]). HRS is associated with a high mortality, so treatment must be considered a bridge to liver transplantation (1010. Garcia-Tsao G. Current management of the complications of cirrhosis and portal hypertension: variceal hemorrhage, ascites, and spontaneous bacterial peritonitis. Gastroenterology. 2001;120:726-48. [PMID: 11179247]). Diuretics should be discontinued, and paracentesis should not be performed (99. Garcia-Tsao G, Lim JK, Lim J; Members of Veterans Affairs Hepatitis C Resource Center Program. 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. 2009;104:1802-29. [PMID: 19455106]). Treatment of HRS combines volume expansion with agents that decrease vasodilation. A typical regimen includes IV albumin in combination with off-label use of subcutaneous octreotide and oral midodrine (99. Garcia-Tsao G, Lim JK, Lim J; Members of Veterans Affairs Hepatitis C Resource Center Program. 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. 2009;104:1802-29. [PMID: 19455106], 1111. Runyon BA. Management of Adult Patients with Ascites Due to Cirrhosis: Update 2012. American Association for the Study of Liver Diseases Practice Guidelines. Available online. ). Hemodialysis is often problematic in patients with advanced cirrhosis but can be life-saving when employed as a bridge to liver transplantation (1111. Runyon BA. Management of Adult Patients with Ascites Due to Cirrhosis: Update 2012. American Association for the Study of Liver Diseases Practice Guidelines. Available online. ). Histologically, HRS kidneys are normal and combined liver-kidney transplantation is typically not needed.

Other therapeutics

Nonselective beta-blockers are used as prophylaxis against variceal bleeding but are not routinely used in the management of ascites. Nonselective beta-blockers prevent variceal bleeding through a reduction in portal pressure (1010. Garcia-Tsao G. Current management of the complications of cirrhosis and portal hypertension: variceal hemorrhage, ascites, and spontaneous bacterial peritonitis. Gastroenterology. 2001;120:726-48. [PMID: 11179247]), which should theoretically benefit patients with ascites. While there is some evidence that beta-blockers decrease the risk of developing ascites (1313. Abraldes JG, Tarantino I, Turnes J, Garcia-Pagan JC, Rodés J, Bosch J. Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis. Hepatology. 2003;37:902-8. [PMID: 12668985], 1414. Hernández-Gea V, Aracil C, Colomo A, Garupera I, Poca M, Torras X, et al. Development of ascites in compensated cirrhosis with severe portal hypertension treated with ##beta;-blockers. Am J Gastroenterol. 2012;107:418-27. [PMID: 22334252]), other studies have identified beta-blocker use as an independent risk factor for death (1515. Sersté T, Melot C, Francoz C, Durand F, Rautou PE, Valla D, et al. Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites. Hepatology. 2010;52:1017-22. [PMID: 20583214]). These conflicting findings will need to be investigated further before beta-blocker use can be recommended for the management of ascites. Clonidine, midodrine, and their combination may have utility in treating refractory ascites but also require further study (1616. Singh V, Singh A, Singh B, Vijayvergiya R, Sharma N, Ghai A, et al. Midodrine and clonidine in patients with cirrhosis and refractory or recurrent ascites: a randomized pilot study. Am J Gastroenterol. 2013;108:560-7. [PMID: 23419385]).

Spontaneous bacterial peritonitis

Spontaneous bacterial peritonitis is an infection of ascites in the absence of a surgically treatable intra-abdominal source. It is the most common infectious complication of cirrhosis (1717. Such J, Runyon BA. Spontaneous bacterial peritonitis. Clin Infect Dis. 1998;27:669-74; quiz 675-6. [PMID: 9798013]), with a prevalence of 10% to 30% in hospitalized cirrhotic patients with ascites (88. Moore KP, Aithal GP. Guidelines on the management of ascites in cirrhosis. Gut. 2006;55 Suppl 6:vi1-12. [PMID: 16966752]). Although outcomes have improved significantly with prompt diagnosis and treatment, the in-hospital mortality rate is still 20% (1010. Garcia-Tsao G. Current management of the complications of cirrhosis and portal hypertension: variceal hemorrhage, ascites, and spontaneous bacterial peritonitis. Gastroenterology. 2001;120:726-48. [PMID: 11179247]).

Clinical manifestations of this disorder are often nonspecific and subtle. The most common signs and symptoms are listed in Table 1. Approximately 10% of patients will be asymptomatic (1717. Such J, Runyon BA. Spontaneous bacterial peritonitis. Clin Infect Dis. 1998;27:669-74; quiz 675-6. [PMID: 9798013]), so a high index of suspicion is required for early diagnosis.

Microbiology and pathogenesis

Approximately 60% of spontaneous bacterial peritonitis cases are caused by enteric gram-negative bacteria, most commonly Escherichia coli and Klebsiella pneumoniae. Gram-positive cocci, primarily streptococcal species, account for approximately 25% of episodes. Patients receiving spontaneous bacterial peritonitis prophylaxis are more likely to develop infections from gram-positive organisms, including methicillin-resistant Staphylococcus aureus (1919. Campillo B, Dupeyron C, Richardet JP, Mangeney N, Leluan G. Epidemiology of severe hospital-acquired infections in patients with liver cirrhosis: effect of long-term administration of norfloxacin. Clin Infect Dis. 1998;26:1066-70. [PMID: 9597225]).

The development of spontaneous bacterial peritonitis is thought to be the result of complex physiologic changes found in cirrhotic patients. These include intestinal dysmotility (2020. Madrid AM, Cumsille F, Defilippi C. Altered small bowel motility in patients with liver cirrhosis depends on severity of liver disease. Dig Dis Sci. 1997;42:738-42. [PMID: 9125642]), intestinal bacterial overgrowth (2121. Chang CS, Chen GH, Lien HC, Yeh HZ. Small intestine dysmotility and bacterial overgrowth in cirrhotic patients with spontaneous bacterial peritonitis. Hepatology. 1998;28:1187-90. [PMID: 9794900]), increased intestinal permeability (2222. Scarpellini E, Valenza V, Gabrielli M, Lauritano EC, Perotti G, Merra G, et al. Intestinal permeability in cirrhotic patients with and without spontaneous bacterial peritonitis: is the ring closed? Am J Gastroenterol. 2010;105:323-7. [PMID: 19844200]), bacterial translocation (2323. Cirera I, Bauer TM, Navasa M, Vila J, Grande L, Taurá P, et al. Bacterial translocation of enteric organisms in patients with cirrhosis. J Hepatol. 2001;34:32-7. [PMID: 11211904], 2424. Such J, Francés R, Muñoz C, Zapater P, Casellas JA, Cifuentes A, et al. Detection and identification of bacterial DNA in patients with cirrhosis and culture-negative, nonneutrocytic ascites. Hepatology. 2002;36:135-41. [PMID: 12085357]), and immune system abnormalities (2525. Runyon BA. Bacterial infections in patients with cirrhosis. J Hepatol. 1993;18:271-2. [PMID: 8228117]).

In addition to severity of liver disease, low ascites total protein (<1.0 g/dL) (2626. Llach J, Rimola A, Navasa M, Ginés P, Salmerón JM, Ginés A, et al. Incidence and predictive factors of first episode of spontaneous bacterial peritonitis in cirrhosis with ascites: relevance of ascitic fluid protein concentration. Hepatology. 1992;16:724-7. [PMID: 1505916]) and elevated bilirubin (>2.5 mg/dL) are predictive of spontaneous bacterial peritonitis (2727. Andreu M, Sola R, Sitges-Serra A, Alia C, Gallen M, Vila MC, et al. Risk factors for spontaneous bacterial peritonitis in cirrhotic patients with ascites. Gastroenterology. 1993;104:1133-8. [PMID: 8462803]). Recurrence is common, approaching 70% at 1 year. Other predisposing factors are listed in Table 2.

Diagnosis

Clinical impression is a poor predictor of spontaneous bacterial peritonitis (2929. Chinnock B, Hendey GW, Minnigan H, Butler J, Afarian H. Clinical impression and ascites appearance do not rule out bacterial peritonitis. J Emerg Med. 2013;44:903-9. [PMID: 23473819]), so diagnostic paracentesis should be performed on all cirrhotic patients with ascites at the time of admission (2828. Runyon BA. Pathogenesis of spontaneous bacterial peritonitis. In: Lindor KD, ed. UpToDate. 2013., 3030. Rimola, A, García-Tsao, G, Navasa, M, Piddock, L J, Planas, R, Bernard, B, Inadomi, J M. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.). Additionally, any hospitalized patient with ascites demonstrating local or systemic signs or symptoms of infection (such as those in Table 1) should undergo diagnostic paracentesis. Spontaneous bacterial peritonitis is diagnosed when the ascites absolute neutrophil count is above 250 cells/mm3. Ascites fluid should be inoculated into blood culture bottles at the bedside to improve diagnostic yield (88. Moore KP, Aithal GP. Guidelines on the management of ascites in cirrhosis. Gut. 2006;55 Suppl 6:vi1-12. [PMID: 16966752], 3030. Rimola, A, García-Tsao, G, Navasa, M, Piddock, L J, Planas, R, Bernard, B, Inadomi, J M. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.). Even with this technique, cultures may remain negative in up to half of patients with an elevated ascites neutrophil count. This situation, referred to as “culture-negative neutrocytic ascites” (CNNA), is thought to be due to the low concentration of bacteria in ascites fluid. CNNA is considered a variant of spontaneous bacterial peritonitis and should be treated the same as culture-positive spontaneous bacterial peritonitis (3030. Rimola, A, García-Tsao, G, Navasa, M, Piddock, L J, Planas, R, Bernard, B, Inadomi, J M. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.). Most patients respond well to appropriate therapy and do not require repeat paracentesis. Repeat paracentesis should be considered if clinical response is delayed or atypical organisms are cultured (2828. Runyon BA. Pathogenesis of spontaneous bacterial peritonitis. In: Lindor KD, ed. UpToDate. 2013.).

Treatment

Antibiotics should be started immediately after spontaneous bacterial peritonitis is diagnosed. Empiric therapy should cover the most common causative organisms, as described above. Cefotaxime, a third-generation cephalosporin, is the best-studied drug. It achieves high ascites concentrations and provides coverage for most organisms that cause spontaneous bacterial peritonitis (88. Moore KP, Aithal GP. Guidelines on the management of ascites in cirrhosis. Gut. 2006;55 Suppl 6:vi1-12. [PMID: 16966752]). Current guidelines recommend intravenous cefotaxime, 2 g every 8 hours (2828. Runyon BA. Pathogenesis of spontaneous bacterial peritonitis. In: Lindor KD, ed. UpToDate. 2013.). Other third-generation cephalosporins (e.g., ceftriaxone and ceftazidime) and amoxicillin-clavulanic acid are effective alternative agents (3030. Rimola, A, García-Tsao, G, Navasa, M, Piddock, L J, Planas, R, Bernard, B, Inadomi, J M. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.). Oral ofloxacin may be used as initial treatment for uncomplicated spontaneous bacterial peritonitis in patients tolerating oral intake and without previous exposure to fluoroquinolones (2828. Runyon BA. Pathogenesis of spontaneous bacterial peritonitis. In: Lindor KD, ed. UpToDate. 2013.). Patients previously taking a fluoroquinolone for spontaneous bacterial peritonitis prophylaxis should be treated with cefotaxime (2828. Runyon BA. Pathogenesis of spontaneous bacterial peritonitis. In: Lindor KD, ed. UpToDate. 2013., 3030. Rimola, A, García-Tsao, G, Navasa, M, Piddock, L J, Planas, R, Bernard, B, Inadomi, J M. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.). The recommended duration of therapy is 5 days (2828. Runyon BA. Pathogenesis of spontaneous bacterial peritonitis. In: Lindor KD, ed. UpToDate. 2013.).

Renal dysfunction occurs in one-third of patients with spontaneous bacterial peritonitis and is a strong predictor of mortality (3131. Follo A, Llovet JM, Navasa M, Planas R, Forns X, Francitorra A, et al. Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis. Hepatology. 1994;20:1495-501. [PMID: 7982650]). There is evidence that volume expansion with albumin may improve these outcomes. IV albumin (1.5 g/kg in the first 6 hours, followed by 1 g/kg on day 3), when added to antibiotic therapy, significantly reduces rates of renal impairment and mortality (3232. Sort P, Navasa M, Arroyo V, Aldeguer X, Planas R, Ruiz-del-Arbol L, et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med. 1999;341:403-9. [PMID: 10432325], 3333. Salerno F, Navickis RJ, Wilkes MM. Albumin infusion improves outcomes of patients with spontaneous bacterial peritonitis: a meta-analysis of randomized trials. Clin Gastroenterol Hepatol. 2013;11:123-30.e1. [PMID: 23178229]). Patients with bilirubin above 4 mg/dL and preexisting renal impairment (blood urea nitrogen >30 mg/dL and/or creatinine >1.0 mg/dL) are more likely to benefit from the addition of albumin, and some evidence suggests that it is safe to restrict albumin use to these patients (3434. Sigal SH, Stanca CM, Fernandez J, Arroyo V, Navasa M. Restricted use of albumin for spontaneous bacterial peritonitis [Letter]. Gut. 2007;56:597-9. [PMID: 17369392]). Interventions that lower effective arterial volume and therefore increase the risk of renal failure, such as diuretic therapy and large-volume paracentesis, should be avoided in spontaneous bacterial peritonitis.

Prophylaxis

Primary prevention

Patients with cirrhosis and upper gastrointestinal bleeding are at high risk for developing bacterial infections, including spontaneous bacterial peritonitis. A meta-analysis of short-term antibiotic prophylaxis in this group of patients found significant improvement in infection rates and mortality (3535. Bernard B, Grangé JD, Khac EN, Amiot X, Opolon P, Poynard T. Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: a meta-analysis. Hepatology. 1999;29:1655-61. [PMID: 10347104]). This evidence supports recommendations that all cirrhotic patients with upper gastrointestinal bleeding receive a 7-day course of prophylactic antibiotics. Oral norfloxacin, 400 mg twice a day, is preferred, but IV ceftriaxone may be used for patients unable to tolerate oral intake (1010. Garcia-Tsao G. Current management of the complications of cirrhosis and portal hypertension: variceal hemorrhage, ascites, and spontaneous bacterial peritonitis. Gastroenterology. 2001;120:726-48. [PMID: 11179247], 2828. Runyon BA. Pathogenesis of spontaneous bacterial peritonitis. In: Lindor KD, ed. UpToDate. 2013., 3030. Rimola, A, García-Tsao, G, Navasa, M, Piddock, L J, Planas, R, Bernard, B, Inadomi, J M. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.).

For cirrhotic patients with ascites but no gastrointestinal bleeding, there is no consensus on antibiotic prophylaxis for primary prevention of spontaneous bacterial peritonitis. Total ascites protein is a strong predictor of incident spontaneous bacterial peritonitis, and few patients with ascites total protein above 1.0 g/dL develop it (2626. Llach J, Rimola A, Navasa M, Ginés P, Salmerón JM, Ginés A, et al. Incidence and predictive factors of first episode of spontaneous bacterial peritonitis in cirrhosis with ascites: relevance of ascitic fluid protein concentration. Hepatology. 1992;16:724-7. [PMID: 1505916]). Studies examining the impact of spontaneous bacterial peritonitis prophylaxis based solely on ascites total protein, however, have been inconclusive (1010. Garcia-Tsao G. Current management of the complications of cirrhosis and portal hypertension: variceal hemorrhage, ascites, and spontaneous bacterial peritonitis. Gastroenterology. 2001;120:726-48. [PMID: 11179247]). Other studies combining predictive laboratory data have found reductions in spontaneous bacterial peritonitis, HRS, and mortality with prophylaxis (3636. Fernández J, Navasa M, Planas R, Montoliu S, Monfort D, Soriano G, et al. Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology. 2007;133:818-24. [PMID: 17854593]). Recent guidelines recommend that patients at high risk for their first episode of spontaneous bacterial peritonitis be considered for chronic prophylaxis. Patients are considered high risk if they have an ascitic protein of <1.5 and advanced liver disease (Childs-Pugh ≥9 and total bilirubin >3 mg/dL) or an ascitic protein of <1.5 and renal dysfunction (creatinine ≥1.2 mg/dL, BUN ≥25 mg/dL, or plasma sodium ≤130 mEq/L) (2828. Runyon BA. Pathogenesis of spontaneous bacterial peritonitis. In: Lindor KD, ed. UpToDate. 2013.). Norfloxacin, 400 mg/d, is the recommended prophylactic antibiotic, with trimethoprim/sulfamethoxazole, 1 double-strength tablet daily, as an alternative agent (2828. Runyon BA. Pathogenesis of spontaneous bacterial peritonitis. In: Lindor KD, ed. UpToDate. 2013., 3030. Rimola, A, García-Tsao, G, Navasa, M, Piddock, L J, Planas, R, Bernard, B, Inadomi, J M. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.).

Secondary prevention

Patients with a previous episode of spontaneous bacterial peritonitis have a recurrence rate of 70% at 1 year, with a median survival of 9 months (3737. Titó; L, Rimola A, Ginés P, Llach J, Arroyo V, Rodés J. Recurrence of spontaneous bacterial peritonitis in cirrhosis: frequency and predictive factors. Hepatology. 1988;8:27-31. [PMID: 3257456]). Long-term prophylactic antibiotics lower the risk of recurrence and should be initiated after the first episode. Norfloxacin, 400 mg/d, is recommended (1010. Garcia-Tsao G. Current management of the complications of cirrhosis and portal hypertension: variceal hemorrhage, ascites, and spontaneous bacterial peritonitis. Gastroenterology. 2001;120:726-48. [PMID: 11179247], 2828. Runyon BA. Pathogenesis of spontaneous bacterial peritonitis. In: Lindor KD, ed. UpToDate. 2013., 3030. Rimola, A, García-Tsao, G, Navasa, M, Piddock, L J, Planas, R, Bernard, B, Inadomi, J M. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.) with ciprofloxacin, 500 mg/d, or trimethoprim/sulfamethoxazole, 1 double-strength tablet daily, as acceptable alternatives (2828. Runyon BA. Pathogenesis of spontaneous bacterial peritonitis. In: Lindor KD, ed. UpToDate. 2013.). Less frequent dosing strategies have been reported but are not currently recommended (2828. Runyon BA. Pathogenesis of spontaneous bacterial peritonitis. In: Lindor KD, ed. UpToDate. 2013.). The possibility of liver transplantation should be explored in all patients who survive an episode of spontaneous bacterial peritonitis (88. Moore KP, Aithal GP. Guidelines on the management of ascites in cirrhosis. Gut. 2006;55 Suppl 6:vi1-12. [PMID: 16966752]).

Antibiotic resistance

The emergence of fluoroquinolone-resistant enteric bacteria has been reported in cirrhotic patients on prophylactic norfloxacin (3838. Dupeyron C, Mangeney N, Sedrati L, Campillo B, Fouet P, Leluan G. Rapid emergence of quinolone resistance in cirrhotic patients treated with norfloxacin to prevent spontaneous bacterial peritonitis. Antimicrob Agents Chemother. 1994;38:340-4. [PMID: 8192461]). Furthermore, multidrug-resistant organisms, including extended-spectrum beta-lactamase-producing Enterobacteriaceae, Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, and Enterococcus faecium, are responsible for a growing number of infections in cirrhotic patients (3939. Fernández J, Acevedo J, Castro M, Garcia O, de Lope CR, Roca D, et al. Prevalence and risk factors of infections by multiresistant bacteria in cirrhosis: a prospective study. Hepatology. 2012;55:1551-61. [PMID: 22183941]). These findings emphasize the importance of limiting prophylactic antibiotics to those patients with a guideline-based indication for them.

Conclusion

Ascites is common in patients with cirrhosis, and its management frequently requires hospitalization. Sodium restriction and diuretic therapy form the foundation of management. Given the high incidence of spontaneous bacterial peritonitis and its nonspecific presentation, all cirrhotic patients admitted to the hospital should have diagnostic paracentesis. Immediate initiation of antibiotics and IV albumin is key to treatment of spontaneous bacterial peritonitis. Liver transplantation should be considered for cirrhotic patients with refractory ascites or those who survive an episode of spontaneous bacterial peritonitis.