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EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis

  • European Association for the Study of the Liver
    Author Footnotes
    1 Correspondence: 7 rue des Battoirs, CH-1205 Geneva, Switzerland. Tel.: +41 22 807 0360; fax: +41 22 328 07 24.Contributors: Chairman: Pere Ginès; Clinical Practice Guidelines Members: Paolo Angeli, Kurt Lenz, Søren Møller, Kevin Moore, Richard Moreau; Journal of Hepatology Representative: Carlo Merkel; EASL Governing Board Representatives: Helmer Ring-Larsen and Mauro Bernardi; Reviewers: Guadalupe Garcia-Tsao, Peter Hayes.
  • Author Footnotes
    1 Correspondence: 7 rue des Battoirs, CH-1205 Geneva, Switzerland. Tel.: +41 22 807 0360; fax: +41 22 328 07 24.Contributors: Chairman: Pere Ginès; Clinical Practice Guidelines Members: Paolo Angeli, Kurt Lenz, Søren Møller, Kevin Moore, Richard Moreau; Journal of Hepatology Representative: Carlo Merkel; EASL Governing Board Representatives: Helmer Ring-Larsen and Mauro Bernardi; Reviewers: Guadalupe Garcia-Tsao, Peter Hayes.
      Ascites is the most common complication of cirrhosis, and ∼60% of patients with compensated cirrhosis develop ascites within 10 years during the course of their disease [
      • Ginès P.
      • Quintero E.
      • Arroyo V.
      • et al.
      Compensated cirrhosis: natural history and prognostic factors.
      ]. Ascites only occurs when portal hypertension has developed [
      • Ripoll C.
      • Groszmann R.
      • Garcia-Tsao G.
      • et al.
      Hepatic venous gradient predicts clinical decompensation in patients with compensated cirrhosis.
      ] and is primarily related to an inability to excrete an adequate amount of sodium into urine, leading to a positive sodium balance. A large body of evidence suggests that renal sodium retention in patients with cirrhosis is secondary to arterial splanchnic vasodilation. This causes a decrease in effective arterial blood volume with activation of arterial and cardiopulmonary volume receptors, and homeostatic activation of vasoconstrictor and sodium-retaining systems (i.e., the sympathetic nervous system and the renin–angiotensin–aldosterone system). Renal sodium retention leads to expansion of the extracellular fluid volume and formation of ascites and edema [
      • Schrier R.W.
      • Arroyo V.
      • Bernardi M.
      • et al.
      Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis.
      ,
      • Møller S.
      • Henriksen J.H.
      The systemic circulation in cirrhosis.
      ,
      • Henriksen J.H.
      • Møller S.
      Alterations of hepatic and splanchnic microvascular exchange in cirrhosis: local factors in the formation of ascites.
      ]. The development of ascites is associated with a poor prognosis and impaired quality of life in patients with cirrhosis [
      • Tandon P.
      • Garcia-Tsao G.
      Bacterial infections, sepsis, and multiorgan failure in cirrhosis.
      ,
      • Guevara M.
      • Cárdenas A.
      • Uriz J.
      • Ginès P.
      Prognosis in patients with cirrhosis and ascites.
      ]. Thus, patients with ascites should generally be considered for referral for liver transplantation. There is a clear rationale for the management of ascites in patients with cirrhosis, as a successful treatment may improve the outcome and symptoms.
      A panel of experts was selected by the EASL Governing Board and met several times to discuss and write these guidelines during 2008–2009. These guidelines were written according to published studies retrieved from Pubmed. The evidence and recommendations made in these guidelines have been graded according to the GRADE system (Grading of Recommendations Assessment Development and Evaluation). The strength of evidence has been classified into three levels: A, high; B, moderate; and C, low-quality evidence, while that of the recommendation into two: strong and weak (Table 1). Where no clear evidence existed, the recommendations were based on the consensus advice of expert opinion(s) in the literature and that of the writing committee.
      Table 1Grading evidence and recommendations (adapted from the GRADE system).
      NotesSymbol
      Grading of evidence
       High quality evidenceFurther research is very unlikely to change our confidence in the estimate of effectA
       Moderate quality evidenceFurther research is likely to have an important impact on our confidence in the estimate of effect and may change the estimateB
       Low or very low quality of evidenceFurther research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Any estimate of effect is uncertainC
      Grading recommendation
       Strong recommendation warrantedFactors influencing the strength of the recommendation included the quality of evidence, presumed patient-important outcomes, and cost1
       Weaker recommendationVariability in preferences and values, or more uncertainty: more likely a weak recommendation is warranted2
      Recommendation is made with less certainty: higher cost or resource consumption

      1. Uncomplicated ascites

       1.1. Evaluation of patients with ascites

      Approximately 75% of patients presenting with ascites in Western Europe or the USA have cirrhosis as the underlying cause. For the remaining patients, ascites is caused by malignancy, heart failure, tuberculosis, pancreatic disease, or other miscellaneous causes.

       1.2. Diagnosis of ascites

      The initial evaluation of a patient with ascites should include history, physical examination, abdominal ultrasound, and laboratory assessment of liver function, renal function, serum and urine electrolytes, as well as an analysis of the ascitic fluid.
      The International Ascites Club proposed to link the choice of treatment of uncomplicated ascites to a classification of ascites on the basis of a quantitative criterion (Table 2). The authors of the current guidelines agree with this proposal.
      Table 2Grading of ascites and suggested treatment.
      Grade of ascitesDefinitionTreatment
      Grade 1 ascitesMild ascites only detectable by ultrasoundNo treatment
      Grade 2 ascitesModerate ascites evident by moderate symmetrical distension of abdomenRestriction of sodium intake and diuretics
      Grade 3 ascitesLarge or gross ascites with marked abdominal distensionLarge-volume paracentesis followed by restriction of sodium intake and diuretics (unless patients have refractory ascites)
      A diagnostic paracentesis with an appropriate ascitic fluid analysis is essential in all patients investigated for ascites prior to any therapy to exclude causes of ascites other than cirrhosis and rule out spontaneous bacterial peritonitis (SBP) in cirrhosis. When the diagnosis of cirrhosis is not clinically evident, ascites due to portal hypertension can be readily differentiated from ascites due to other causes by the serum–ascites albumin gradient (SAAG). If the SAAG is greater than or equal to 1.1 g/dl (or 11 g/L), ascites is ascribed to portal hypertension with an approximate 97% accuracy [
      • Runyon B.A.
      Practice Guidelines Committee, American Association for the Study of Liver Diseases (AASLD)
      Management of adult patients with ascites due to cirrhosis.
      ,
      • Runyon B.A.
      • Montano A.A.
      • Akriviadis E.A.
      • et al.
      The serum–ascites albumin gradient is superior to the exudate–transudate concept in the differential diagnosis of ascites.
      ]. Total ascitic fluid protein concentration should be measured to assess the risk of SBP since patients with protein concentration lower than 15 g/L have an increased risk of SBP [
      • Rimola A.
      • Gracia-Tsao G.
      • Navasa M.
      • et al.
      Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.
      ].
      A neutrophil count should be obtained to rule out the existence of SBP [
      • Rimola A.
      • Gracia-Tsao G.
      • Navasa M.
      • et al.
      Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.
      ]. Ascitic fluid inoculation (10 ml) in blood culture bottles should be performed at the bedside in all patients. Other tests, such as amylase, cytology, PCR and culture for mycobacteria should be done only when the diagnosis is unclear or if there is a clinical suspicion of pancreatic disease, malignancy, or tuberculosis [
      • Runyon B.A.
      Practice Guidelines Committee, American Association for the Study of Liver Diseases (AASLD)
      Management of adult patients with ascites due to cirrhosis.
      ,
      • Runyon B.A.
      • Montano A.A.
      • Akriviadis E.A.
      • et al.
      The serum–ascites albumin gradient is superior to the exudate–transudate concept in the differential diagnosis of ascites.
      ,
      • Rimola A.
      • Gracia-Tsao G.
      • Navasa M.
      • et al.
      Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.
      ,
      • Moore K.P.
      • Wong F.
      • Ginès P.
      • et al.
      The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club.
      ].
      Recommendations A diagnostic paracentesis should be performed in all patients with new onset grade 2 or 3 ascites, and in all patients hospitalized for worsening of ascites or any complication of cirrhosis (Level A1).
      Neutrophil count and culture of ascitic fluid (by inoculation into blood culture bottles at the bedside) should be performed to exclude bacterial peritonitis (Level A1).
      It is important to measure ascitic total protein concentration, since patients with an ascitic protein concentration of less than 15 g/L have an increased risk of developing spontaneous bacterial peritonitis (Level A1) and may benefit from antibiotic prophylaxis (Level A1).
      Measurement of the serum–ascites albumin gradient may be useful when the diagnosis of cirrhosis is not clinically evident or in patients with cirrhosis in whom a cause of ascites different than cirrhosis is suspected (Level A2).

       1.3. Prognosis of patients with ascites

      The development of ascites in cirrhosis indicates a poor prognosis. The mortality is approximately 40% at 1 year and 50% at 2 years [
      • Guevara M.
      • Cárdenas A.
      • Uriz J.
      • Ginès P.
      Prognosis in patients with cirrhosis and ascites.
      ]. The most reliable factors in the prediction of poor prognosis include: hyponatremia, low arterial pressure, increased serum creatinine, and low urine sodium [
      • Guevara M.
      • Cárdenas A.
      • Uriz J.
      • Ginès P.
      Prognosis in patients with cirrhosis and ascites.
      ,
      • Llach J.
      • Ginès P.
      • Arroyo V.
      • et al.
      Prognostic value of arterial pressure, endogenous vasoactive systems and renal function in cirrhotic patients admitted to the hospital for the treatment of ascites.
      ]. These parameters are not included in the Child-Turcotte-Pugh score (CTP score) and among them, only serum creatinine is included in the Model for end-stage liver disease (MELD score). Furthermore, since serum creatinine has limitations as an estimate of glomerular filtration rate in cirrhosis [
      • Caregaro L.
      • Menon F.
      • Angeli P.
      • et al.
      Limitations of serum creatinine level and creatinine clearance as filtration markers in cirrhosis.
      ], these scores probably underestimate the mortality risk in patients with ascites [
      • Heuman D.M.
      • Abou-assi S.G.
      • Habib A.
      • et al.
      Persistent ascites and low sodium identify patients with cirrhosis and low MELD score who are at high risk for early death.
      ]. Since allocation for liver transplantation is based on the MELD score in several countries, patients with ascites may not receive an adequate priority in the transplant lists. Therefore, there is a need for improved methods to assess prognosis in patients with ascites.
      Recommendations Since the development of grade 2 or 3 ascites in patients with cirrhosis is associated with reduced survival, liver transplantation should be considered as a potential treatment option (Level B1).

       1.4. Management of uncomplicated ascites

      Patients with cirrhosis and ascites are at high risk for other complications of liver disease, including refractory ascites, SBP, hyponatremia, or hepatorenal syndrome (HRS). The absence of these ascites-related complications qualifies ascites as uncomplicated [
      • Moore K.P.
      • Wong F.
      • Ginès P.
      • et al.
      The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club.
      ].

       1.4.1. Grade 1 or mild ascites

      No data exist on the natural history of grade 1 ascites, and it is not known how frequently patients with grade 1 or mild ascites will develop grade 2 or 3 ascites.

       1.4.2. Grade 2 or moderate ascites

      Patients with moderate ascites can be treated as outpatients and do not require hospitalization unless they have other complications of cirrhosis. Renal sodium excretion is not severely impaired in most of these patients, but sodium excretion is low relative to sodium intake. Treatment is aimed at counteracting renal sodium retention and achieving a negative sodium balance. This is done by reducing the sodium intake and enhancing the renal sodium excretion by administration of diuretics. Whilst the assumption of the upright posture activates sodium-retaining systems and slightly impairs renal perfusion [
      • Ring-Larsen H.
      • Henriksen J.H.
      • Wilken C.
      • et al.
      Diuretic treatment in decompensated cirrhosis and congestive heart failure: effect of posture.
      ], forced bed rest is not recommended because there are no clinical trials assessing whether it improves the clinical efficacy of the medical treatment of ascites.

       1.4.2.1. Sodium restriction

      A negative sodium balance can be obtained by reducing dietary salt intake in approximately 10–20% of cirrhotic patients with ascites, particularly in those presenting with their first episode of ascites [
      • Gatta A.
      • Angeli P.
      • Caregaro L.
      • Menon F.
      • Sacerdoti D.
      • Merkel C.
      A pathophysiological interpretation of unresponsiveness to spironolactone in a stepped-care approach to the diuretic treatment of ascites in nonazotemic cirrhotic patients with ascites.
      ,
      • Bernardi M.
      • Laffi G.
      • Salvagnini M.
      • et al.
      Efficacy and safety of the stepped care medical treatment of ascites in liver cirrhosis: a randomized controlled clinical trial comparing two diets with different sodium content.
      ]. There are no controlled clinical trials comparing restricted versus unrestricted sodium intake and the results of clinical trials in which different regimens of restricted sodium intake were compared are controversial [
      • Bernardi M.
      • Laffi G.
      • Salvagnini M.
      • et al.
      Efficacy and safety of the stepped care medical treatment of ascites in liver cirrhosis: a randomized controlled clinical trial comparing two diets with different sodium content.
      ,
      • Gauthier A.
      • Levy V.G.
      • Quinton A.
      Salt or not salt in the treatment of cirrhotic ascites: a randomized study.
      ]. Nevertheless, it is the current opinion that dietary salt intake should be moderately restricted (approximately 80–120 mmol of sodium per day). A more severe reduction in dietary sodium content is considered unnecessary and even potentially detrimental since it may impair nutritional status. There are no data to support the prophylactic use of salt restriction in patients who have never had ascites. Fluid intake should be restricted only in patients with dilutional hyponatremia.
      Recommendations Moderate restriction of salt intake is an important component of the management of ascites (intake of sodium of 80–120 mmol/day, which corresponds to 4.6–6.9 g of salt/day) (Level B1). This is generally equivalent to a no added salt diet with avoidance of pre-prepared meals.
      There is insufficient evidence to recommend bed rest as part of the treatment of ascites. There are no data to support the use of fluid restriction in patients with ascites with normal serum sodium concentration (Level B1).

       1.4.2.2. Diuretics

      Evidence demonstrates that renal sodium retention in patients with cirrhosis and ascites is mainly due to increased proximal as well as distal tubular sodium reabsorption rather than to a decrease of filtered sodium load [
      • Angeli P.
      • Gatta A.
      • Caregaro L.
      • et al.
      Tubular site of renal sodium retention in ascitic liver cirrhosis evaluated by lithium clearance.
      ,
      • Angeli P.
      • De Bei E.
      • Dalla Pria M.
      • et al.
      Effects of amiloride on renal lithium handling in nonazotemic ascitic cirrhotic patients with avid sodium retention.
      ]. The mediators of the enhanced proximal tubular reabsorption of sodium have not been elucidated completely, while the increased reabsorption of sodium along the distal tubule is mostly related to hyperaldosteronism [
      • Bernardi M.
      • Servadei D.
      • Trevisani F.
      • et al.
      Importance of plasma aldosterone concentration on natriuretic effect of spironolactone in patients with liver cirrhosis and ascites.
      ]. Aldosterone antagonists are more effective than loop diuretics in the management of ascites and are the diuretics of choice [
      • Pérez-Ayuso R.M.
      • Arroyo V.
      • Planas R.
      • et al.
      Randomized comparative study of efficacy of furosemide versus spironolactone in nonazotemic cirrhosis with ascites.
      ]. Aldosterone stimulates renal sodium reabsorption by increasing both the permeability of the luminal membrane of principal cells to sodium and the activity of the Na/K ATPase pump in the basolateral membrane. Since the effect of aldosterone is slow, as it involves interaction with a cytosolic receptor and then a nuclear receptor, the dosage of antialdosteronic drugs should be increased every 7 days. Amiloride, a diuretic acting in the collecting duct, is less effective than aldosterone antagonists and should be used only in those patients who develop severe side effects with aldosterone antagonists [
      • Angeli P.
      • Dalla Pria M.
      • De Bei E.
      • et al.
      Randomized clinical study of the efficacy of amiloride and potassium canrenoate in nonazotemic cirrhotic patients with ascites.
      ].
      A long-standing debate in the management of ascites is whether aldosterone antagonists should be given alone or in combination with a loop diuretic (i.e., furosemide). Two studies have assessed which is the best approach to therapy, either aldosterone antagonists in a stepwise increase every 7 days (100–400 mg/day in 100 mg/day steps) with furosemide (40–160 mg/day, in 40 mg/day steps) added only in patients not responding to high doses of aldosterone antagonists or combined therapy of aldosterone antagonists and furosemide from the beginning of treatment (100 and 40 mg/day increased in a stepwise manner every 7 days in case of no response up to 400 and 160 mg/day) [
      • Angeli P.
      • Fasolato S.
      • Mazza E.
      • et al.
      Combined versus sequential diuretic treatment of ascites in nonazotemic patients with cirrhosis: results of an open randomized clinical trial.
      ,
      • Santos J.
      • Planas R.
      • Pardo A.
      • et al.
      Spironolactone alone or in combination with furosemide in the treatment of moderate ascites in nonazotemic cirrhosis. A randomized comparative study of efficacy and safety.
      ]. These studies showed discrepant findings which were likely due to differences in the populations of patients studied, specifically with respect to the percentage of patients with the first episode of ascites included in the two studies [
      • Bernardi M.
      Optimum use of diuretics in managing ascites in patients with cirrhosis.
      ]. From these studies it can be concluded that a diuretic regime based on the combination of aldosterone antagonists and furosemide is the most adequate for patients with recurrent ascites but not for patients with a first episode of ascites. These latter patients should be treated initially only with an aldosterone antagonist (i.e., spironolactone 100 mg/day) from the start of therapy and increased in a stepwise manner every 7 days up to 400 mg/day in the unlikely case of no response. In all patients, diuretic dosage should be adjusted to achieve a rate of weight loss of no greater than 0.5 kg/day in patients without peripheral edema and 1 kg/day in those with peripheral edema to prevent diuretic-induced renal failure and/or hyponatremia [
      • Shear L.S.
      • Ching S.
      • Gabuzda G.J.
      Compartimentalization of ascites and edema in patients with cirrhosis.
      ]. Following mobilization of ascites, diuretics should be reduced to maintain patients with minimal or no ascites to avoid diuretic-induced complications. Alcohol abstinence is crucial for the control of ascites in patients with alcohol-related cirrhosis.

       1.4.2.3. Complications of diuretic therapy

      The use of diuretics may be associated with several complications such as renal failure, hepatic encephalopathy, electrolyte disorders, gynaecomastia, and muscle cramps [
      • Angeli P.
      • De Bei E.
      • Dalla Pria M.
      • et al.
      Effects of amiloride on renal lithium handling in nonazotemic ascitic cirrhotic patients with avid sodium retention.
      ,
      • Bernardi M.
      • Servadei D.
      • Trevisani F.
      • et al.
      Importance of plasma aldosterone concentration on natriuretic effect of spironolactone in patients with liver cirrhosis and ascites.
      ,
      • Pérez-Ayuso R.M.
      • Arroyo V.
      • Planas R.
      • et al.
      Randomized comparative study of efficacy of furosemide versus spironolactone in nonazotemic cirrhosis with ascites.
      ,
      • Angeli P.
      • Dalla Pria M.
      • De Bei E.
      • et al.
      Randomized clinical study of the efficacy of amiloride and potassium canrenoate in nonazotemic cirrhotic patients with ascites.
      ,
      • Angeli P.
      • Fasolato S.
      • Mazza E.
      • et al.
      Combined versus sequential diuretic treatment of ascites in nonazotemic patients with cirrhosis: results of an open randomized clinical trial.
      ,
      • Santos J.
      • Planas R.
      • Pardo A.
      • et al.
      Spironolactone alone or in combination with furosemide in the treatment of moderate ascites in nonazotemic cirrhosis. A randomized comparative study of efficacy and safety.
      ,
      • Bernardi M.
      Optimum use of diuretics in managing ascites in patients with cirrhosis.
      ,
      • Shear L.S.
      • Ching S.
      • Gabuzda G.J.
      Compartimentalization of ascites and edema in patients with cirrhosis.
      ,
      • Marchesini G.
      • Bianchi G.P.
      • Amodio P.
      • et al.
      Factors associated with poor health-related quality of life of patients with cirrhosis.
      ,
      • Angeli P.
      • Albino G.
      • Carraro P.
      • et al.
      Cirrhosis and muscle cramps: evidence of a causal relationship.
      ]. Diuretic-induced renal failure is most frequently due to intravascular volume depletion that usually occurs as a result of an excessive diuretic therapy [
      • Shear L.S.
      • Ching S.
      • Gabuzda G.J.
      Compartimentalization of ascites and edema in patients with cirrhosis.
      ]. Diuretic therapy has been classically considered a precipitating factor of hepatic encephalopathy, yet the mechanism is unknown. Hypokalemia may occur if patients are treated with loop diuretics alone. Hyperkalemia may develop as a result of treatment with aldosterone antagonists or other potassium-sparing diuretics, particularly in patients with renal impairment. Hyponatremia is another frequent complication of diuretic therapy. The level of hyponatremia at which diuretics should be stopped is contentious. However, most experts agree that diuretics should be stopped temporarily in patients whose serum sodium decreases to less than 120–125 mmol/L. Gynaecomastia is common with the use of aldosterone antagonists, but it does not usually require discontinuation of treatment. Finally, diuretics may cause muscle cramps [
      • Marchesini G.
      • Bianchi G.P.
      • Amodio P.
      • et al.
      Factors associated with poor health-related quality of life of patients with cirrhosis.
      ,
      • Angeli P.
      • Albino G.
      • Carraro P.
      • et al.
      Cirrhosis and muscle cramps: evidence of a causal relationship.
      ]. If cramps are severe, diuretic dose should be decreased or stopped and albumin infusion may relieve symptoms [
      • Angeli P.
      • Albino G.
      • Carraro P.
      • et al.
      Cirrhosis and muscle cramps: evidence of a causal relationship.
      ].
      A significant proportion of patients develop diuretic-induced complications during the first weeks of treatment [
      • Angeli P.
      • Fasolato S.
      • Mazza E.
      • et al.
      Combined versus sequential diuretic treatment of ascites in nonazotemic patients with cirrhosis: results of an open randomized clinical trial.
      ]. Thus, frequent measurements of serum creatinine, sodium, and potassium concentration should be performed during this period. Routine measurement of urine sodium is not necessary, except for non-responders in whom urine sodium provides an assessment of the natriuretic response to diuretics.
      Recommendations Patients with the first episode of grade 2 (moderate) ascites should receive an aldosterone antagonist such as spironolactone alone, starting at 100 mg/day and increasing stepwise every 7 days (in 100 mg steps) to a maximum of 400 mg/day if there is no response (Level A1). In patients who do not respond to aldosterone antagonists, as defined by a reduction of body weight of less than 2 kg/week, or in patients who develop hyperkalemia, furosemide should be added at an increasing stepwise dose from 40 mg/day to a maximum of 160 mg/day (in 40 mg steps) (Level A1). Patients should undergo frequent clinical and biochemical monitoring particularly during the first month of treatment (Level A1).
      Patients with recurrent ascites should be treated with a combination of an aldosterone antagonist plus furosemide, the dose of which should be increased sequentially according to response, as explained above (Level A1).
      The maximum recommended weight loss during diuretic therapy should be 0.5 kg/day in patients without edema and 1 kg/day in patients with edema (Level A1).
      The goal of long-term treatment is to maintain patients free of ascites with the minimum dose of diuretics. Thus, once the ascites has largely resolved, the dose of diuretics should be reduced and discontinued later, whenever possible (Level B1).
      Caution should be used when starting treatment with diuretics in patients with renal impairment, hyponatremia, or disturbances in serum potassium concentration and patients should be submitted to frequent clinical and biochemical monitoring. There is no good evidence as to what is the level of severity of renal impairment and hyponatremia in which diuretics should not be started. Serum potassium levels should be corrected before commencing diuretic therapy. Diuretics are generally contraindicated in patients with overt hepatic encephalopathy (Level B1).
      All diuretics should be discontinued if there is severe hyponatremia (serum sodium concentration <120 mmol/L), progressive renal failure, worsening hepatic encephalopathy, or incapacitating muscle cramps (Level B1).
      Furosemide should be stopped if there is severe hypokalemia (<3 mmol/L). Aldosterone antagonists should be stopped if patients develop severe hyperkalemia (serum potassium >6 mmol/L) (Level B1).

       1.4.3. Grade 3 or large ascites

      Large-volume paracentesis (LVP) is the treatment of choice for the management of patients with grade 3 ascites. The main findings of studies comparing LVP with diuretics in patients with grade 3 ascites are summarized as follows [
      • Ginès P.
      • Arroyo V.
      • Quintero E.
      • et al.
      Comparison of paracentesis and diuretics in the treatment of cirrhotics with tense ascites. Results of a randomized study.
      ,
      • Ginès P.
      • Tito L.V.
      • Arroyo V.
      • et al.
      Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis.
      ,
      • Salerno F.
      • Badalamenti S.
      • Incerti P.
      • et al.
      Repeated paracentesis and i.v. albumin infusion to treat “tense ascites” in cirrhotic patients: a safe alternative therapy.
      ,
      • Fassio E.
      • Terg R.
      • Landeira G.
      • Abecasis R.
      • Salemne M.
      • Podesta A.
      • et al.
      Paracentesis with dextran 70 vs. paracentesis with albumin in cirrhosis with tense ascites. Results of a randomized study.
      ,
      • Acharya S.K.
      • Balwinder S.
      • Padhee A.K.
      • et al.
      Large-volume paracentesis and intravenous dextran to treat tense ascites.
      ,
      • Solà R.
      • Vila M.C.
      • Andreu M.
      • et al.
      Total paracentesis with dextran 40 vs. diuretics in the treatment of ascites in cirrhosis: a randomized controlled study.
      ,
      • Ginès A.
      • Fernandez-Esparrach G.
      • Monescillo A.
      • et al.
      Randomized controlled trial comparing albumin, dextran-70 and polygelin in cirrhotic patients with ascites treated by paracentesis.
      ]: (1) LVP combined with infusion of albumin is more effective than diuretics and significantly shortens the duration of hospital stay. (2) LVP plus albumin is safer than diuretics, the frequency of hyponatremia, renal impairment, and hepatic encephalopathy being lower in patients treated with LVP than in those with diuretics, in the majority of studies. (3) There were no differences between the two approaches with respect to hospital re-admission or survival. (4) LVP is a safe procedure and the risk of local complications, such as hemorrhage or bowel perforation is extremely low [
      • Pache I.
      • Bilodeau M.
      Severe hemorrhage following abdominal paracentesis for ascites in patients with liver disease.
      ].
      The removal of large volumes of ascitic fluid is associated with circulatory dysfunction characterized by a reduction of effective blood volume, a condition known as post-paracentesis circulatory dysfunction (PPCD) [
      • Ginès P.
      • Tito L.V.
      • Arroyo V.
      • et al.
      Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis.
      ,
      • Ginès A.
      • Fernandez-Esparrach G.
      • Monescillo A.
      • et al.
      Randomized controlled trial comparing albumin, dextran-70 and polygelin in cirrhotic patients with ascites treated by paracentesis.
      ,
      • Pozzi M.
      • Osculati G.
      • Boari G.
      • et al.
      Time course of circulatory and humoral effects of rapid total paracentesis in cirrhotic patients with tense, refractory ascites.
      ]. Several lines of evidence indicate that this circulatory dysfunction and/or the mechanisms activated to maintain circulatory homeostasis have detrimental effects in cirrhotic patients. First, circulatory dysfunction is associated with rapid re-accumulation of ascites [
      • Solà R.
      • Vila M.C.
      • Andreu M.
      • et al.
      Total paracentesis with dextran 40 vs. diuretics in the treatment of ascites in cirrhosis: a randomized controlled study.
      ]. Secondly, approximately 20% of these patients develop HRS and/or water retention leading to dilutional hyponatremia [
      • Ginès P.
      • Tito L.V.
      • Arroyo V.
      • et al.
      Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis.
      ]. Thirdly, portal pressure increases in patients developing circulatory dysfunction after LVP, probably owing to an increased intrahepatic resistance due to the action of vasoconstrictor systems on the hepatic vascular bed [
      • Ruiz del Arbol L.
      • Monescillo A.
      • Jimenez W.
      • et al.
      Paracentesis-induced circulatory dysfunction: mechanism and effect on hepatic hemodynamics in cirrhosis.
      ]. Finally, the development of circulatory dysfunction is associated with shortened survival [
      • Ginès A.
      • Fernandez-Esparrach G.
      • Monescillo A.
      • et al.
      Randomized controlled trial comparing albumin, dextran-70 and polygelin in cirrhotic patients with ascites treated by paracentesis.
      ].
      The most effective method to prevent circulatory dysfunction after LVP is the administration of albumin. Albumin is more effective than other plasma expanders (dextran-70, polygeline) for the prevention of PPCD [
      • Ginès A.
      • Fernandez-Esparrach G.
      • Monescillo A.
      • et al.
      Randomized controlled trial comparing albumin, dextran-70 and polygelin in cirrhotic patients with ascites treated by paracentesis.
      ]. When less than 5 L of ascites are removed, dextran-70 (8 g/L of ascites removed) or polygeline (150 ml/L of ascites removed) show efficacy similar to that of albumin. However, albumin is more effective than these other plasma expanders when more than 5 L of ascites are removed [
      • Ginès A.
      • Fernandez-Esparrach G.
      • Monescillo A.
      • et al.
      Randomized controlled trial comparing albumin, dextran-70 and polygelin in cirrhotic patients with ascites treated by paracentesis.
      ]. Despite this greater efficacy, randomized trials have not shown differences in survival of patients treated with albumin compared with those treated with other plasma expanders [
      • Ginès A.
      • Fernandez-Esparrach G.
      • Monescillo A.
      • et al.
      Randomized controlled trial comparing albumin, dextran-70 and polygelin in cirrhotic patients with ascites treated by paracentesis.
      ,
      • Sola-Vera J.
      • Miñana J.
      • Ricart E.
      • et al.
      Randomized trial comparing albumin and saline in the prevention of paracentesis-induced circulatory dysfunction in cirrhotic patients with ascites.
      ,
      • Moreau R.
      • Valla D.C.
      • Durand-Zaleski I.
      • et al.
      Comparison of outcome in patients with cirrhosis and ascites following treatment with albumin or a synthetic colloid: a randomised controlled pilot trail.
      ]. Larger trials would be required to demonstrate a benefit of albumin on survival. Although there are no studies on how fast and when albumin should be given to patients treated with LVP, it seems advisable to administer it slowly to avoid a possible cardiac overload due to the existence of a latent cirrhotic cardiomyopathy and at the end of LVP when the volume of ascites removed is known and the increasing cardiac output begins to return to baseline [
      • Panos M.Z.
      • Moore K.
      • Vlavianos P.
      • Chambers J.B.
      • Anderson J.V.
      • et al.
      Single, total paracentesis for tense ascites: sequential hemodynamic changes and right atrial size.
      ].
      As far as alternative plasma volume expanders are concerned, it should be noted that polygeline is no longer used in many countries because of the potential risk of transmission of prions. Despite some evidence of the fact that the use of saline is not associated with an increased risk to develop PPCD after small volume paracentesis [
      • Sola-Vera J.
      • Miñana J.
      • Ricart E.
      • et al.
      Randomized trial comparing albumin and saline in the prevention of paracentesis-induced circulatory dysfunction in cirrhotic patients with ascites.
      ], there are no randomized controlled studies comparing saline versus albumin in patients who require LVP of less than 5 L. Few data exist on the use of starch as a plasma expander in patients with cirrhosis and grade 3 ascites treated with LVP, while there are some concerns about the possibility for starch to induce renal failure [
      • Brunkhorst F.M.
      • Angel C.
      • Bloos F.
      • et al.
      Intensive insulin therapy and pentastarch resuscitation in severe sepsis.
      ] and hepatic accumulation of starch [
      • Christidis C.
      • Mal F.
      • Ramos J.
      • et al.
      Worsening of hepatic dysfunction as a consequence of repeated hydroxyethylstarch infusions.
      ].
      Furthermore, a recent health economic analysis suggested that it is more cost-effective to use albumin after LVP compared with alternative but cheaper plasma volume expanders since the administration of albumin post-paracentesis is associated with a lower number of liver-related complications within the first 30 days [
      • Moreau R.
      • Valla D.C.
      • Durand-Zaleski I.
      • et al.
      Comparison of outcome in patients with cirrhosis and ascites following treatment with albumin or a synthetic colloid: a randomised controlled pilot trail.
      ].
      Although LVP is the treatment of choice for large ascites in patients with cirrhosis, it is important to realise that LVP does not address the underlying cause of the condition, namely renal sodium and water retention. Therefore, patients treated with LVP require diuretic treatment after the removal of ascitic fluid to prevent the re-accumulation of ascites [
      • Fernández-Esparrach G.
      • Guevara M.
      • Sort P.
      • et al.
      Diuretic requirements after therapeutic paracentesis in non-azotemic patients with cirrhosis. A randomized double-blind trial of spironolactone versus placebo.
      ].
      LVP should be performed under strict sterile conditions using disposable sterile materials. It is generally agreed that there are no contraindications to LVP other than loculated ascites, although studies have excluded several subsets of patients. Hemorrhagic complications after LVP are infrequent. In one study, which also included patients with INR >1.5 and platelet count <50,000/μl, only two patients experienced minor cutaneous bleedings out of 142 paracenteses [
      • Lin C.H.
      • Shih F.Y.
      • Ma M.H.
      • Chiang W.C.
      • Yang C.W.
      • Ko P.C.
      Should bleeding tendency deter abdominal paracentesis?.
      ]. The frequency of bleeding complications in patients with coagulopathy after LVP are also reported to be low in other studies and do not support a relation between risk of bleeding and the degree of coagulopathy [
      • Pache I.
      • Bilodeau M.
      Severe hemorrhage following abdominal paracentesis for ascites in patients with liver disease.
      ]. Thus, there are no data to support the use of fresh frozen plasma or pooled platelets before LVP, yet in many centers these products are given if there is severe coagulopathy (prothrombin activity less than 40%) and/or thrombocytopenia (less than 40,000/μl). Nevertheless, caution should be exercised in patients with severe coagulopathy and LVP should be avoided in the presence of disseminated intravascular coagulation.
      Recommendations Large-volume paracentesis (LVP) is the first-line therapy in patients with large ascites (grade 3 ascites) (Level A1). LVP should be completed in a single session (Level A1).
      LVP should be performed together with the administration of albumin (8 g/L of ascitic fluid removed) to prevent circulatory dysfunction after LVP (Level A1).
      In patients undergoing LVP of greater than 5 L of ascites, the use of plasma expanders other than albumin is not recommended because they are less effective in the prevention of post-paracentesis circulatory dysfunction (Level A1). In patients undergoing LVP of less than 5 L of ascites, the risk of developing post-paracentesis circulatory dysfunction is low. However, it is generally agreed that these patients should still be treated with albumin because of concerns about use of alternative plasma expanders (Level B1).
      After LVP, patients should receive the minimum dose of diuretics necessary to prevent the re-accumulation of ascites (Level A1).

       1.5. Drugs contraindicated in patients with ascites

      The administration of non-steroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, ibuprofen, aspirin, and sulindac to patients with cirrhosis and ascites is associated with a high risk of development of acute renal failure, hyponatremia, and diuretic resistance [
      • Boyer T.D.
      • Reynolds T.B.
      Effect of indomethacin and prostaglandin A1 on renal function and plasma renin activity in alcoholic liver disease.
      ]. The impairment in glomerular filtration rate is due to a reduced renal perfusion secondary to inhibition of renal prostaglandin synthesis. Thus, NSAIDs should not be used in patients with cirrhosis and ascites. This represents an important therapeutic limitation for these patients when analgesis are needed. Preliminary data show that short-term administration of selective inhibitors of cyclooxygenase-2 does not impair renal function and the response to diuretics. However, further studies are needed to confirm the safety of these drugs [
      • Clària J.
      • Kent J.D.
      • Lopez-Parra M.
      • et al.
      Effects of celecoxib and naproxen on renal function in nonaziotemic patients with cirrhosis and ascites.
      ].
      Angiotensin-converting enzyme inhibitors, even in low doses, should be avoided in patients with cirrhosis and ascites since they can induce arterial hypotension [
      • Pariente E.A.
      • Bataille C.
      • Bercoff E.
      • Lebrec D.
      Acute effects of captopril on systemic and renal hemodynamics and on renal function in cirrhotic patients with ascites.
      ] and renal failure [
      • Gentilini P.
      • Romanelli R.G.
      • La Villla G.
      • et al.
      Effects of low-dose captopril on renal haemodynamics and function in patients with cirrhosis of the liver.
      ]. Likewise, α1-adrenergic blockers, such as prazosin, should be used with great caution because despite a reduction in portal pressure, they can further impair renal sodium and water retention and cause an increase in ascites and/or edema [
      • Albillos A.
      • Lledo J.L.
      • Rossi I.
      • et al.
      Continuous prazosin administration in cirrhotic patients: effects on portal hemodynamics and on liver and renal function.
      ]. Among cardiovascular drugs, dipyridamole should be used with caution since it can induce renal impairment [
      • Llach J.
      • Ginès P.
      • Arroyo V.
      • et al.
      Effect of dipyridamole on kidney function in cirrhosis.
      ]. Aminoglycosides alone or in combination with ampicillin, cephalothin, or mezlocillin should be avoided in the treatment of bacterial infections, because they are associated with a high incidence of nephrotoxicity [
      • Cabrera J.
      • Arroyo V.
      • Ballesta A.M.
      • et al.
      Aminoglycoside nephrotoxicity in cirrhosis. Value of urinary beta 2-microglobulin to discriminate functional renal failure from acute tubular damage.
      ,
      • Haupel H.
      • Bynum G.D.
      • Zamora E.
      • El-Serag H.B.
      Risk factors for the development of renal dysfunction in hospitalized patients with cirrhosis.
      ].
      Nephrotoxicity induced by the administration of contrast media is a frequent cause of renal failure in the general population of hospitalized patients. However, it has been shown that cirrhosis with ascites and substantially normal renal function does not appear to be a risk factor for the development of contrast media-induced renal failure [
      • Guevara M.
      • Fernández-Esparrach G.
      • Alessandria C.
      • et al.
      Effects of contrast media on renal function in patients with cirrhosis: a prospective study.
      ]. Nevertheless, the possibility that contrast media administration can cause a further impairment of renal function in patients with pre-existing renal failure cannot be excluded.
      Recommendations Non-steroidal anti-inflammatory drugs (NSAIDs) are contraindicated in patients with ascites because of the high risk of developing further sodium retention, hyponatremia, and renal failure (Level A1).
      Drugs that decrease arterial pressure or renal blood flow such as ACE-inhibitors, angiotensin II antagonists, or α1-adrenergic receptor blockers should generally not be used in patients with ascites because of increased risk of renal impairment (Level A1).
      The use of aminoglycosides is associated with an increased risk of renal failure. Thus, their use should be reserved for patients with bacterial infections that cannot be treated with other antibiotics (Level A1).
      In patients with ascites without renal failure, the use of contrast media does not appear to be associated with an increased risk of renal impairment (Level B1). In patients with renal failure there are insufficient data. Nevertheless, contrast media should be used with caution and the use of general preventive measures of renal impairment is recommended (Level C1).

      2. Refractory ascites

       2.1. Evaluation of patients with refractory ascites

      According to the criteria of the International Ascites Club, refractory ascites is defined as “ascites that cannot be mobilized or the early recurrence of which (i.e., after LVP) cannot be satisfactorily prevented by medical therapy” [
      • Moore K.P.
      • Wong F.
      • Ginès P.
      • et al.
      The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club.
      ,
      • Arroyo V.
      • Ginès P.
      • Gerbes A.L.
      • Dudley F.J.
      • et al.
      Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis.
      ]. The diagnostic criteria of refractory ascites are shown in Table 3.
      Table 3Definition and diagnostic criteria for refractory ascites in cirrhosis.
      Diuretic-resistant ascitesAscites that cannot be mobilized or the early recurrence of which cannot be prevented because of a lack of response to sodium restriction and diuretic treatment
      Diuretic-intractable ascitesAscites that cannot be mobilized or the early recurrence of which cannot be prevented because of the development of diuretic-induced complications that preclude the use of an effective diuretic dosage
      Requisites
       1. Treatment durationPatients must be on intensive diuretic therapy (spironolactone 400 mg/day and furosemide 160 mg/day) for at least 1 week and on a salt-restricted diet of less than 90 mmol/day
       2. Lack of responseMean weight loss of <0.8 kg over 4 days and urinary sodium output less than the sodium intake
       3. Early ascites recurrenceReappearance of grade 2 or 3 ascites within 4 weeks of initial mobilization
       4. Diuretic-induced complicationsDiuretic-induced hepatic encephalopathy is the development of encephalopathy in the absence of any other precipitating factor
      Diuretic-induced renal impairment is an increase of serum creatinine by >100% to a value >2 mg/dl (177 μmol/L) in patients with ascites responding to treatment
      Diuretic-induced hyponatremia is defined as a decrease of serum sodium by >10 mmol/L to a serum sodium of <125 mmol/L
      Diuretic-induced hypo- or hyperkalemia is defined as a change in serum potassium to <3 mmol/L or >6 mmol/L despite appropriate measures
      Modified with permission from Moore KP, Wong F, Ginès P, et al. The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club. Hepatology 2003;38:258–266.
      Once ascites becomes refractory to medical treatment, the median survival of patients is approximately 6 months [
      • Guevara M.
      • Cárdenas A.
      • Uriz J.
      • Ginès P.
      Prognosis in patients with cirrhosis and ascites.
      ,
      • Arroyo V.
      • Ginès P.
      • Gerbes A.L.
      • Dudley F.J.
      • et al.
      Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis.
      ,
      • Salerno F.
      • Borroni G.
      • Moser P.
      • Badalamenti S.
      • Cassara L.
      • Maggi A.
      • et al.
      Survival and prognostic factors of cirrhotic patients with ascites: a study of 134 outpatients.
      ,
      • Guardiola J.
      • Baliellas C.
      • Xiol X.
      • Fernandez E.G.
      • Ginès P.
      • Ventura P.
      • et al.
      External validation of a prognostic model for predicting survival of cirrhotic patients with refractory ascites.
      ,
      • Moreau R.
      • Delegue P.
      • Pessione F.
      • Hillaire S.
      • Durand F.
      • Lebrec D.
      • et al.
      Clinical characteristics and outcome of patients with cirrhosis and refractory ascites.
      ]. As a consequence, patients with refractory ascites should be considered for liver transplantation. The MELD score system predicts survival in patients with cirrhosis [
      • Kamath P.S.
      • Wiesner R.H.
      • Malinchoc M.
      • et al.
      A model to predict survival in patients with end-stage liver disease.
      ,
      • Durand F.
      • Valla D.
      Assessment of prognosis in cirrhosis.
      ]. However, other factors in patients with cirrhosis and ascites are also associated with poor prognosis, including low arterial pressure, low serum sodium, low urine sodium, and high Child-Pugh score [
      • Guevara M.
      • Cárdenas A.
      • Uriz J.
      • Ginès P.
      Prognosis in patients with cirrhosis and ascites.
      ,
      • Salerno F.
      • Borroni G.
      • Moser P.
      • Badalamenti S.
      • Cassara L.
      • Maggi A.
      • et al.
      Survival and prognostic factors of cirrhotic patients with ascites: a study of 134 outpatients.
      ,
      • Guardiola J.
      • Baliellas C.
      • Xiol X.
      • Fernandez E.G.
      • Ginès P.
      • Ventura P.
      • et al.
      External validation of a prognostic model for predicting survival of cirrhotic patients with refractory ascites.
      ,
      • Moreau R.
      • Delegue P.
      • Pessione F.
      • Hillaire S.
      • Durand F.
      • Lebrec D.
      • et al.
      Clinical characteristics and outcome of patients with cirrhosis and refractory ascites.
      ,
      • Kamath P.S.
      • Wiesner R.H.
      • Malinchoc M.
      • et al.
      A model to predict survival in patients with end-stage liver disease.
      ,
      • Durand F.
      • Valla D.
      Assessment of prognosis in cirrhosis.
      ]. Patients with refractory ascites may have a poor prognosis despite a relatively low MELD score (e.g. <18) and this may be of importance with respect to prioritisation for liver transplantation [
      • Heuman D.M.
      • Abou-assi S.G.
      • Habib A.
      • et al.
      Persistent ascites and low sodium identify patients with cirrhosis and low MELD score who are at high risk for early death.
      ]. For these reasons, inclusion of additional parameters in the MELD score, such as serum sodium has been suggested [
      • Heuman D.M.
      • Abou-assi S.G.
      • Habib A.
      • et al.
      Persistent ascites and low sodium identify patients with cirrhosis and low MELD score who are at high risk for early death.
      ,
      • Durand F.
      • Valla D.
      Assessment of prognosis in cirrhosis.
      ,
      • Silberhumer G.R.
      • Hetz H.
      • Rasoul-Rockenschaub S.
      • et al.
      Is MELD score sufficient to predict not only death on waiting list, but also post-transplant survival?.
      ,
      • O’Leary J.G.
      • Lepe R.
      • Davis G.L.
      Indications for liver transplantation.
      ,
      • Kim W.R.
      • Biggins S.W.
      • Krmers W.K.
      • et al.
      Hyponatremia and mortality among patients on the liver transplant waiting list.
      ,
      • Luca A.
      • Angermayr B.
      • Bertolini G.
      • et al.
      An integrated MELD model including serum sodium and age improves the prediction of early mortality in patients with cirrhosis.
      ].
      Recommendations The assessment of the response of ascites to diuretic therapy and salt restriction should only be performed in stable patients without associated complications, such as bleeding or infection. (Level B1).
      The prognosis of patients with refractory ascites is poor and therefore they should be considered for liver transplantation (Level B1).

       2.2. Management of refractory ascites

      Methods for treatment of refractory ascites include LVP with albumin administration, continuing diuretic therapy (if effective in inducing natriuresis), insertion of transjugular intrahepatic portosystemic shunt (TIPS), and liver transplantation. The use of therapies under investigation will also be discussed briefly.

       2.2.1. Large-volume paracentesis

      A large body of evidence indicates that repeated LVP is an effective and safe therapy of refractory ascites [
      • Runyon B.A.
      Practice Guidelines Committee, American Association for the Study of Liver Diseases (AASLD)
      Management of adult patients with ascites due to cirrhosis.
      ,
      • Moore K.P.
      • Wong F.
      • Ginès P.
      • et al.
      The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club.
      ,
      • Arroyo V.
      • Ginès P.
      • Gerbes A.L.
      • Dudley F.J.
      • et al.
      Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis.
      ,
      • Moore K.P.
      • Aithal G.P.
      Guidelines on the management of ascites in cirrhosis.
      ]. The administration of albumin prevents circulatory dysfunction associated with LVP (see discussion in a previous section of these guidelines).

       2.2.2. Diuretics in patients with refractory ascites

      In most patients (>90%), diuretics are not effective in preventing or delaying the recurrence of ascites after LVP since by definition patients have ascites which is refractory to diuretic therapy [
      • Arroyo V.
      • Ginès P.
      • Gerbes A.L.
      • Dudley F.J.
      • et al.
      Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis.
      ]. Diuretics should be discontinued permanently in patients with diuretic-induced complications (hepatic encephalopathy, renal impairment, or electrolyte abnormalities). In the remaining patients, treatment should be continued only when urinary sodium excretion under diuretic therapy is greater than 30 mmol/day [
      • Moore K.P.
      • Wong F.
      • Ginès P.
      • et al.
      The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club.
      ].

       2.2.3. Transjugular intrahepatic portosystemic shunts (TIPS)

       2.2.3.1. Uncontrolled studies

      TIPS decompresses the portal system like a side-to-side portocaval shunt inserted between the high pressure portal venous area and the low pressure hepatic venous area [
      • Boyer T.D.
      • Haskal Z.J.
      The role of transjugular intrahepatic portosystemic shunt in the management of portal hypertension.
      ]. Because of the reduction in portal pressure TIPS has proved to be effective in the control of recurrent ascites. In the short-term, TIPS induces an increase in cardiac output, right atrial pressure, and pulmonary artery pressure leading to a secondary reduction in systemic vascular resistance and effective arterial blood volume [
      • Ochs A.
      • Rossle M.
      • Haag K.
      • Hauenstein K.H.
      • Deibert P.
      • Siegerstetter V.
      • et al.
      The transjugular intrahepatic portosystemic stent-shunt procedure for refractory ascites.
      ,
      • Wong F.
      • Sniderman K.
      • Liu P.
      • Allidina Y.
      • Sherman M.
      • Blendis L.
      Transjugular intrahepatic portosystemic stent shunt: effects on hemodynamics and sodium homeostasis in cirrhosis and refractory ascites.
      ,
      • Sanyal A.J.
      • Freedman A.M.
      • Luketic V.A.
      • Purdum P.P.
      • Shiffman M.L.
      • Demeo J.
      • et al.
      The natural history of portal hypertension after transjugular intrahepatic portosystemic shunts.
      ,
      • Quiroga J.
      • Sangro B.
      • Nunez M.
      • Bilbao I.
      • Longo J.
      • Garcia-Villarreal L.
      • et al.
      Transjugular intrahepatic portal-systemic shunt in the treatment of refractory ascites: effect on clinical, renal, humoral, and hemodynamic parameters.
      ,
      • Colombato L.A.
      • Spahr L.
      • Martinet J.P.
      • Dufresne M.P.
      • Lafortune M.
      • Fenyves D.
      • et al.
      Haemodynamic adaptation two months after transjugular intrahepatic portosystemic shunt (TIPS) in cirrhotic patients.
      ,
      • Huonker M.
      • Schumacher Y.O.
      • Ochs A.
      • Sorichter S.
      • Keul J.
      • Rössle M.
      Cardiac function and haemodynamics in alcoholic cirrhosis and effects of the transjugular intrahepatic portosystemic stent shunt.
      ,
      • Merli M.
      • Valeriano V.
      • Funaro S.
      • Attili A.F.
      • Masini A.
      • Efrati C.
      • et al.
      Modifications of cardiac function in cirrhotic patients treated with transjugular intrahepatic portosystemic shunt (TIPS).
      ,
      • Lotterer E.
      • Wengert A.
      • Fleig W.E.
      Transjugular intrahepatic portosystemic shunt: short-term and long-term effects on hepatic and systemic hemodynamics in patients with cirrhosis.
      ,
      • Wong F.
      • Sniderman K.
      • Liu P.
      • Blendis L.
      The mechanism of the initial natriuresis after transjugular intrahepatic portosystemic shunt.
      ,
      • Guevara M.
      • Ginès P.
      • Bandi J.C.
      • Gilabert R.
      • Sort P.
      • Jimenez W.
      • et al.
      Transjugular intrahepatic portosystemic shunt in hepatorenal syndrome: effects on renal function and vasoactive systems.
      ,
      • Gerbes A.L.
      • Gulberg V.
      • Waggershauser T.
      • Holl J.
      • Reiser M.
      Renal effects of transjugular intrahepatic portosystemic shunt in cirrhosis: comparison of patients with ascites, with refractory ascites, or without ascites.
      ,
      • Rössle M.
      • Ochs A.
      • Gulberg V.
      • Siegerstetter V.
      • Holl J.
      • Deibert P.
      • et al.
      A comparison of paracentesis and transjugular intrahepatic portosystemic shunting in patients with ascites.
      ]. With time, the increase in cardiac output that follows a TIPS insertion tends to return to pre-TIPS levels [
      • Colombato L.A.
      • Spahr L.
      • Martinet J.P.
      • Dufresne M.P.
      • Lafortune M.
      • Fenyves D.
      • et al.
      Haemodynamic adaptation two months after transjugular intrahepatic portosystemic shunt (TIPS) in cirrhotic patients.
      ,
      • Merli M.
      • Valeriano V.
      • Funaro S.
      • Attili A.F.
      • Masini A.
      • Efrati C.
      • et al.
      Modifications of cardiac function in cirrhotic patients treated with transjugular intrahepatic portosystemic shunt (TIPS).
      ,
      • Lotterer E.
      • Wengert A.
      • Fleig W.E.
      Transjugular intrahepatic portosystemic shunt: short-term and long-term effects on hepatic and systemic hemodynamics in patients with cirrhosis.
      ]. Beneficial effects on renal function include increase in urinary sodium excretion and glomerular filtration rate [
      • Colombato L.A.
      • Spahr L.
      • Martinet J.P.
      • Dufresne M.P.
      • Lafortune M.
      • Fenyves D.
      • et al.
      Haemodynamic adaptation two months after transjugular intrahepatic portosystemic shunt (TIPS) in cirrhotic patients.
      ,
      • Wong F.
      • Sniderman K.
      • Liu P.
      • Blendis L.
      The mechanism of the initial natriuresis after transjugular intrahepatic portosystemic shunt.
      ,
      • Guevara M.
      • Ginès P.
      • Bandi J.C.
      • Gilabert R.
      • Sort P.
      • Jimenez W.
      • et al.
      Transjugular intrahepatic portosystemic shunt in hepatorenal syndrome: effects on renal function and vasoactive systems.
      ,
      • Gerbes A.L.
      • Gulberg V.
      • Waggershauser T.
      • Holl J.
      • Reiser M.
      Renal effects of transjugular intrahepatic portosystemic shunt in cirrhosis: comparison of patients with ascites, with refractory ascites, or without ascites.
      ]. In addition, TIPS may have beneficial effects on nitrogen balance and body weight [
      • Rössle M.
      • Ochs A.
      • Gulberg V.
      • Siegerstetter V.
      • Holl J.
      • Deibert P.
      • et al.
      A comparison of paracentesis and transjugular intrahepatic portosystemic shunting in patients with ascites.
      ,
      • Gülberg V.
      • Liss I.
      • Bilzer M.
      • Waggershauser T.
      • Reiser M.
      • Gerbes A.L.
      Improved quality of life in patients with refractory or recidivant ascites after insertion of transjugular intrahepatic portosystemic shunts.
      ,
      • Plauth M.
      • Schutz T.
      • Buckendahl D.P.
      • et al.
      Weight gain after transjugular intrahepatic portosystemic shunt is associated with improvement in body composition in malnourished patients with cirrhosis and hypermetabolism.
      ]. TIPS also improves quality of life, but in randomized studies the degree of improvement is similar to that observed in patients treated with repeated LVP and albumin [
      • Campbell M.S.
      • Brensinger C.M.
      • Sanyal A.J.
      • et al.
      Quality of life in refractory ascites: transjugular intrahepatic portal-systemic shunting versus medical therapy.
      ]. TIPS has been successfully used in patients with recurrent hydrothorax but the outcome seems to be highly related to liver function and age [
      • Gur C.
      • Ilan Y.
      • Shibolet O.
      Hepatic hydrothorax: pathophysiology, diagnosis and treatment – review of the literature.
      ,
      • Gordon F.D.
      • Anastopoulos H.T.
      • Crenshaw W.
      • et al.
      The successful treatment of symptomatic, refractory hepatic hydrothorax with transjugular intrahepatic portosystemic shunt.
      ,
      • Siegerstetter V.
      • Deibert P.
      • Ochs A.
      • Olschewski M.
      • Blum H.E.
      • Rossle M.
      Treatment of refractory hepatic hydrothorax with transjugular intrahepatic portosystemic shunt: long-term results in 40 patients.
      ,
      • Wilputte J.Y.
      • Goffette P.
      • Zech F.
      • Godoy-Gepert A.
      • Geubel A.
      The outcome after transjugular intrahepatic portosystemic shunt (TIPS) for hepatic hydrothorax is closely related to liver dysfunction: a long-term study in 28 patients.
      ].
      A major complication after TIPS insertion is the development of hepatic encephalopathy which occurs in 30–50% of the patients [
      • Boyer T.D.
      • Haskal Z.J.
      The role of transjugular intrahepatic portosystemic shunt in the management of portal hypertension.
      ,
      • Riggio O.
      • Angeloni S.
      • Salvatori F.M.
      • De Santis A.
      • Cerini F.
      • Farcomeni A.
      • et al.
      Incidence, natural history, and risk factors of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt with polytetrafluoroethylene-covered stent grafts.
      ]. Other complications include shunt thrombosis and stenosis. Uncovered stents are complicated by stenosis in up to approximately 80% of the cases [
      • Boyer T.D.
      • Haskal Z.J.
      The role of transjugular intrahepatic portosystemic shunt in the management of portal hypertension.
      ,
      • Casado M.
      • Bosch J.
      • Garcia-Pagan J.C.
      • Bru C.
      • Bañares R.
      • Bandi J.C.
      • et al.
      Clinical events after transjugular intrahepatic portosystemic shunt: correlation with hemodynamic findings.
      ].

       2.2.3.2. Controlled studies

      The effects of TIPS on the control of ascites, frequency of encephatlopahty, and survival in the 5 randomised controlled trials so far published is shown in Table 4 [
      • Rössle M.
      • Ochs A.
      • Gulberg V.
      • Siegerstetter V.
      • Holl J.
      • Deibert P.
      • et al.
      A comparison of paracentesis and transjugular intrahepatic portosystemic shunting in patients with ascites.
      ,
      • Lebrec D.
      • Giuily N.
      • Hadengue A.
      • et al.
      Transjugular intrahepatic portosystemic shunts: comparison with paracentesis in patients with cirrhosis and refractory ascites: a randomized trial.
      ,
      • Ginès P.
      • Uriz J.
      • Calahorra B.
      • Garcia-Tsao G.
      • AL E.T.
      Transjugular intrahepatic portosystemic shunting versus paracentesis plus albumin for refractory ascites in cirrhosis.
      ,
      • Sanyal A.J.
      • Genning C.
      • Reddy K.R.
      • et al.
      The North American study for the treatment of refractory ascites.
      ,
      • Salerno F.
      • Merli M.
      • Riggio O.
      • et al.
      Randomized controlled study of TIPS versus paracentesis plus albumin in cirrhosis with severe ascites.
      ]. TIPS was superior to LVP in the control of ascites but was associated with a greater frequency of encephalopathy. Studies showed discrepancies with respect to survival.
      Table 4Characteristics and results of five multicenter randomised controlled trials comparing transjugular intrahepatic portosystemic shunt (TIPS) and large-volume paracentesis (LVP) in patients with cirrhosis and refractory or recidivant ascites.
      ReferenceRefractory/recidivant Ascites (%)Number of patientsAscites improved (%)Encephalopathy (%)Survival (%)
      TIPSLVPTIPSLVPTIPSLVPTIPSLVP
      Lebrec et al., 1996
      • Lebrec D.
      • Giuily N.
      • Hadengue A.
      • et al.
      Transjugular intrahepatic portosystemic shunts: comparison with paracentesis in patients with cirrhosis and refractory ascites: a randomized trial.
      100/013123801562960
      Rössle et al., 2000
      • Rössle M.
      • Ochs A.
      • Gulberg V.
      • Siegerstetter V.
      • Holl J.
      • Deibert P.
      • et al.
      A comparison of paracentesis and transjugular intrahepatic portosystemic shunting in patients with ascites.
      55/452931844323135832
      Ginès et al., 2002
      • Ginès P.
      • Uriz J.
      • Calahorra B.
      • Garcia-Tsao G.
      • AL E.T.
      Transjugular intrahepatic portosystemic shunting versus paracentesis plus albumin for refractory ascites in cirrhosis.
      100/03535511760342630
      Sanyal et al., 2003
      • Sanyal A.J.
      • Genning C.
      • Reddy K.R.
      • et al.
      The North American study for the treatment of refractory ascites.
      100/05257581638213533
      Salerno et al., 2004
      • Salerno F.
      • Merli M.
      • Riggio O.
      • et al.
      Randomized controlled study of TIPS versus paracentesis plus albumin in cirrhosis with severe ascites.
      68/323333794261395929
      The majority of the trials, excluded patients with very advanced disease as indicated by serum bilirubin >5 mg/dl [
      • Rössle M.
      • Ochs A.
      • Gulberg V.
      • Siegerstetter V.
      • Holl J.
      • Deibert P.
      • et al.
      A comparison of paracentesis and transjugular intrahepatic portosystemic shunting in patients with ascites.
      ,
      • Sanyal A.J.
      • Genning C.
      • Reddy K.R.
      • et al.
      The North American study for the treatment of refractory ascites.
      ], INR >2 [
      • Sanyal A.J.
      • Genning C.
      • Reddy K.R.
      • et al.
      The North American study for the treatment of refractory ascites.
      ], episodic hepatic encephalopathy >grade 2, or persistent encephalopathy [
      • Ginès P.
      • Uriz J.
      • Calahorra B.
      • Garcia-Tsao G.
      • AL E.T.
      Transjugular intrahepatic portosystemic shunting versus paracentesis plus albumin for refractory ascites in cirrhosis.
      ], bacterial infections [
      • Lebrec D.
      • Giuily N.
      • Hadengue A.
      • et al.
      Transjugular intrahepatic portosystemic shunts: comparison with paracentesis in patients with cirrhosis and refractory ascites: a randomized trial.
      ,
      • Sanyal A.J.
      • Genning C.
      • Reddy K.R.
      • et al.
      The North American study for the treatment of refractory ascites.
      ,
      • Salerno F.
      • Merli M.
      • Riggio O.
      • et al.
      Randomized controlled study of TIPS versus paracentesis plus albumin in cirrhosis with severe ascites.
      ], renal failure [
      • Rössle M.
      • Ochs A.
      • Gulberg V.
      • Siegerstetter V.
      • Holl J.
      • Deibert P.
      • et al.
      A comparison of paracentesis and transjugular intrahepatic portosystemic shunting in patients with ascites.
      ,
      • Lebrec D.
      • Giuily N.
      • Hadengue A.
      • et al.
      Transjugular intrahepatic portosystemic shunts: comparison with paracentesis in patients with cirrhosis and refractory ascites: a randomized trial.
      ,
      • Ginès P.
      • Uriz J.
      • Calahorra B.
      • Garcia-Tsao G.
      • AL E.T.
      Transjugular intrahepatic portosystemic shunting versus paracentesis plus albumin for refractory ascites in cirrhosis.
      ,
      • Sanyal A.J.
      • Genning C.
      • Reddy K.R.
      • et al.
      The North American study for the treatment of refractory ascites.
      ,
      • Salerno F.
      • Merli M.
      • Riggio O.
      • et al.
      Randomized controlled study of TIPS versus paracentesis plus albumin in cirrhosis with severe ascites.
      ], and cardiac and respiratory failure [
      • Rössle M.
      • Ochs A.
      • Gulberg V.
      • Siegerstetter V.
      • Holl J.
      • Deibert P.
      • et al.
      A comparison of paracentesis and transjugular intrahepatic portosystemic shunting in patients with ascites.
      ,
      • Sanyal A.J.
      • Genning C.
      • Reddy K.R.
      • et al.
      The North American study for the treatment of refractory ascites.
      ,
      • Salerno F.
      • Merli M.
      • Riggio O.
      • et al.
      Randomized controlled study of TIPS versus paracentesis plus albumin in cirrhosis with severe ascites.
      ]. Because of insufficient data on efficacy and safety, TIPS cannot be recommended in patients with very advanced liver disease or associated severe extrahepatic diseases.

       2.2.3.3. Meta-analyses

      Patients in the five above-mentioned randomised controlled clinical trials have variably been included in five meta-analyses yielding almost similar conclusions (Table 5) [
      • Albillos A.
      • Bañares R.
      • Gonzalez M.
      • Catalina M.V.
      • Molinero L.M.
      A meta-analysis of transjugular intrahepatic portosystemic shunt versus paracentesis for refractory ascites.
      ,
      • Deltenre P.
      • Mathurin P.
      • Dharancy S.
      • Moreau R.
      • Bulois P.
      • Henrion J.
      • et al.
      Transjugular intrahepatic portosystemic shunt in refractory ascites: a meta-analysis.
      ,
      • D’Amico G.
      • Luca A.
      • Morabito A.
      • Miraglia R.
      • D’Amico M.
      Uncovered transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis.
      ,
      • Saab S.
      • Nieto J.M.
      • Lewis S.K.
      • Runyon B.A.
      TIPS versus paracentesis for cirrhotic patients with refractory ascites.
      ,
      • Salerno F.
      • Camma C.
      • Enea M.
      • Rossle M.
      • Wong F.
      Transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis of individual patient data.
      ]. All meta-analyses agree that recurrence of ascites after 3 and 12 months is lower in patients treated with TIPS compared to that in patients treated with LVP. The frequency of hepatic encephalopathy is higher in the TIPS treated patients in all meta-analyses. Three meta-analyses showed no difference in survival between the TIPS and LVP groups [
      • Albillos A.
      • Bañares R.
      • Gonzalez M.
      • Catalina M.V.
      • Molinero L.M.
      A meta-analysis of transjugular intrahepatic portosystemic shunt versus paracentesis for refractory ascites.
      ,
      • Deltenre P.
      • Mathurin P.
      • Dharancy S.
      • Moreau R.
      • Bulois P.
      • Henrion J.
      • et al.
      Transjugular intrahepatic portosystemic shunt in refractory ascites: a meta-analysis.
      ,
      • Saab S.
      • Nieto J.M.
      • Lewis S.K.
      • Runyon B.A.
      TIPS versus paracentesis for cirrhotic patients with refractory ascites.
      ]. One meta-analysis found a trend towards reduced mortality in patients treated with TIPS after having excluded an outlier trial [
      • D’Amico G.
      • Luca A.
      • Morabito A.
      • Miraglia R.
      • D’Amico M.
      Uncovered transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis.
      ] and another meta-analysis found an increased transplant-free survival in the TIPS group [
      • Salerno F.
      • Camma C.
      • Enea M.
      • Rossle M.
      • Wong F.
      Transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis of individual patient data.
      ].
      Table 5Main results of 5 meta-analyses on multicenter randomised controlled trials of the effects of transjugular intrahepatic portosystemic shunt (TIPS) and large-volume paracentesis (LVP) on refractory ascites.
      ReferenceNumber of trials includedNumber of patients includedSignificant heterogeneity among trialsRecurrence of ascitesEncephalopathySurvival
      Albillos et al., 2005
      • Albillos A.
      • Bañares R.
      • Gonzalez M.
      • Catalina M.V.
      • Molinero L.M.
      A meta-analysis of transjugular intrahepatic portosystemic shunt versus paracentesis for refractory ascites.
      5330YesLower in TIPS group. RR 0.56Higher in TIPS group. RR 1.72No difference between groups. RR 0.93
      Deltenre et al., 2005
      • Deltenre P.
      • Mathurin P.
      • Dharancy S.
      • Moreau R.
      • Bulois P.
      • Henrion J.
      • et al.
      Transjugular intrahepatic portosystemic shunt in refractory ascites: a meta-analysis.
      5330NoLower in TIPS group. DifE4M: 0.41, p <0.001 DifE12M: 0.35, p <0.001Higher in TIPS group. DifE: 0.17, p <0.001No difference between groups DifE1y: 0.03, p = 0.7 DifE2y: 0.07, p = 0.4
      D’Amico et al., 2005
      • D’Amico G.
      • Luca A.
      • Morabito A.
      • Miraglia R.
      • D’Amico M.
      Uncovered transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis.
      5330YesLower in TIPS group. OR 0.14 (0.7–0.27)Higher in TIPS group. OR 2.26 (1.35–3.76)No difference between groups A trend towards better survival in TIPS group OR 0.74 (0.40–1.37)
      Saab et al., 2006
      • Saab S.
      • Nieto J.M.
      • Lewis S.K.
      • Runyon B.A.
      TIPS versus paracentesis for cirrhotic patients with refractory ascites.
      5330?Lower after 3 months in TIPS group. OR 0.07 (0.03–0.18, p <0.01) 12 months OR 0.14 (0.06–0.28, p <0.01)Higher in TIPS group. OR 2.24 (1.39–3.6) p <0.0130-days OR 1.0 (0.10–0.06, p = 1) 24 months OR 1.29 (0.65–2.56, p = 0.5)
      Salerno et al., 2007
      • Salerno F.
      • Camma C.
      • Enea M.
      • Rossle M.
      • Wong F.
      Transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis of individual patient data.
      4305NoLower in TIPS group. 42 versus 89% in LVP group (p <0.0001)Higher in TIPS group. (1.13 versus 0.63 (p = 0.006)).Transplant-free survival better in TIPS group (p = 0.035)
      DifE4M and DifE12M: Difference in effects at 4 and 12 months. DifE1y and DifE2y OR, odds ratio. RR, relative risk.

       2.2.4. Peritoneovenous shunt

      Due to frequent complications related to surgical insertion, shunt dysfunction, and infections, this treatment has currently very little role in the management of patients with refractory ascites [
      • Moore K.P.
      • Wong F.
      • Ginès P.
      • et al.
      The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club.
      ].

       2.2.5. Other treatments

      Since circulatory dysfunction and activation of neuro-humoral systems with sodium and water retention play a major role in the pathogenesis of refractory ascites, there has been an increasing interest in research on drugs that may improve circulatory and renal function, particularly vasoconstrictors and selective antagonists of the V2-receptors of vasopressin, known as vaptans. Vasoconstrictors such as the α1-adrenergic agonist midodrine or terlipressin improve circulatory and renal function in patients with and without refractory ascites [
      • Singh V.
      • Dheerendra P.C.
      • Singh B.
      • et al.
      Midodrine versus albumin in the prevention of paracentesis-induced circulatory dysfunction in cirrhotics: a randomized pilot study.
      ,
      • Angeli P.
      • Volpin R.
      • Piovan D.
      • et al.
      Acute effects of the oral administration of midodrine, an alpha-adrenergic agonist, on renal hemodynamics and renal function in cirrhotic patients with ascites.
      ,
      • Krag A.
      • Møller S.
      • Henriksen J.H.
      • Holstein-Rathlou N.H.
      • Larsen F.S.
      • Bendtsen F.
      Terlipressin improves renal function in patients with cirrhosis and ascites without hepatorenal syndrome.
      ]. However, large randomized controlled studies have not been reported yet. Terlipressin has the inconvenience of requiring intravenous administration.
      In two phase-2 studies the administration of a vaptan, satavaptan, in combination with fixed doses of diuretics, in addition to improving serum sodium levels was associated with weight loss, suggesting an effect of the drug on ascites and/or edema [
      • Ginès P.
      • Wong F.
      • Watson M.
      • Ruiz-Del-Arbol L.
      • Bilic A.
      • Dobru D.
      Effects of satavaptan, a selective vasopressin V2 receptor antagonist, on ascites and serum sodium in cirrhosis with hyponatremia.
      ,
      • Ginès P.
      • Wong F.
      • Watson H.
      • Terg R.
      • Bruha R.
      • Zarski P.
      • et al.
      Clinical trial: short term effects of combination of satavaptan, a selective vasopressin V receptor antagonist, and diuretics on ascites in patients with cirrhosis without hyponatremia – a randomized, double blind, placebo controlled study.
      ]. In another phase-2 study, the administration of satavaptan was associated with a reduction of ascites recurrence after LVP [
      • Wong F.
      • Ginès P.
      • Watson H.
      • Horsmans Y.
      • Angeli P.
      • Gow P.
      • et al.
      Effects of a selective vasopressin V2 receptor antagonist, satavaptan, on ascites recurrence after paracentesis in patients with cirrhosis.
      ]. Unfortunately, however, phase-3 randomized, placebo-controlled studies failed to demonstrate a significant beneficial effect of satavaptan in combination with diuretics in the control of ascites and treatment was associated with an increased morbidity and mortality, the causes of which are unclear [
      • Wong F.
      • Bernardi M.
      • Horsmans Y.
      • Cabrijan Z.
      • Watson H.
      • Ginès P.
      Effects of satavaptan, an oral vasopressin V2 receptor antagonist, on management of ascites and morbidity in liver cirrhosis in a long-term, placebo-controlled study.
      ].
      Recommendations Repeated large-volume paracentesis plus albumin (8 g/L of ascites removed) is the first line of treatment for refractory ascites (Level A1). Diuretics should be discontinued in patients with refractory ascites who do not excrete >30 mmol/day of sodium under diuretic treatment.
      TIPS is effective in the management of refractory ascites but is associated with a high risk of hepatic encephalopathy and studies have not been shown to convincingly improve survival compared to repeated large-volume paracentesis (Level A1). TIPS should be considered in patients with very frequent requirement of large-volume paracentesis, or in those in whom paracentesis is ineffective (e.g. due to the presence of loculated ascites) (Level B1).
      Resolution of ascites after TIPS is slow and most patients require continued administration of diuretics and salt restriction (Level B1).
      TIPS cannot be recommended in patients with severe liver failure (serum bilirubin >5 mg/dl, INR >2 or Child-Pugh score >11, current hepatic encephalopathy ⩾grade 2 or chronic hepatic encephalopathy), concomitant active infection, progressive renal failure, or severe cardiopulmonary diseases (Level B1).
      In selected patients TIPS may be helpful for recurrent symptomatic hepatic hydrothorax (Level B2).

      3. Spontaneous bacterial peritonitis

      SBP is a very common bacterial infection in patients with cirrhosis and ascites [
      • Rimola A.
      • Gracia-Tsao G.
      • Navasa M.
      • et al.
      Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.
      ,
      • Caly W.R.
      • Strauss E.
      A prospective study of bacterial infections in patients with cirrhosis.
      ,
      • Fernández J.
      • Navasa M.
      • Gómez J.
      • Colmenero J.
      • Vila J.
      • Arroyo V.
      • et al.
      Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis.
      ,
      • Wong F.
      • Bernardi M.
      • Balk R.
      • Christman B.
      • Moreau R.
      • Garcia-Tsao G.
      • et al.
      Sepsis in cirrhosis: report on the 7th meeting of the International Ascites Club.
      ]. When first described, its mortality exceeded 90% but it has been reduced to approximately 20% with early diagnosis and treatment [
      • Tandon P.
      • Garcia-Tsao G.
      Bacterial infections, sepsis, and multiorgan failure in cirrhosis.
      ,
      • Garcia-Tsao G.
      Current management of the complications of cirrhosis and portal hypertension: variceal hemorrhage, ascites, and spontaneous bacterial peritonitis.
      ].

       3.1. Diagnosis of spontaneous bacterial peritonitis

       3.1.1. Diagnostic paracentesis: in whom and when

      The diagnosis of SBP is based on diagnostic paracentesis [
      • Rimola A.
      • Gracia-Tsao G.
      • Navasa M.
      • et al.
      Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.
      ]. All patients with cirrhosis and ascites are at risk of SBP and the prevalence of SBP in outpatients is 1.5–3.5% [
      • Nousbaum J.B.
      • Cadranel J.F.
      • Nahon P.
      • Nguyen Khac E.
      • Moreau R.
      • Thévenot T.
      • et al.
      Diagnostic accuracy of the Multistix 8 SG® reagent strip in diagnosis of spontaneous bacterial peritonitis.
      ,
      • Evans L.T.
      • Kim W.R.
      • Poterucha J.J.
      • Kamath P.S.
      Spontaneous bacterial peritonitis in asymptomatic outpatients with cirrhotic ascites.
      ] and ∼10% in hospitalized patients [
      • Nousbaum J.B.
      • Cadranel J.F.
      • Nahon P.
      • Nguyen Khac E.
      • Moreau R.
      • Thévenot T.
      • et al.
      Diagnostic accuracy of the Multistix 8 SG® reagent strip in diagnosis of spontaneous bacterial peritonitis.
      ]. Half the episodes of SBP are present at the time of hospital admission while the rest are acquired during hospitalization [
      • Rimola A.
      • Gracia-Tsao G.
      • Navasa M.
      • et al.
      Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.
      ].
      Patients with SBP may have one of the following [
      • Rimola A.
      • Gracia-Tsao G.
      • Navasa M.
      • et al.
      Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.
      ,
      • Nousbaum J.B.
      • Cadranel J.F.
      • Nahon P.
      • Nguyen Khac E.
      • Moreau R.
      • Thévenot T.
      • et al.
      Diagnostic accuracy of the Multistix 8 SG® reagent strip in diagnosis of spontaneous bacterial peritonitis.
      ,
      • Plessier A.
      • Denninger M.A.
      • Consigny Y.
      • Pessione F.
      • Francoz C.
      • Durand F.
      • et al.
      Coagulation disorders in patients with cirrhosis and severe sepsis.
      ]: (1) local symptoms and/or signs of peritonitis: abdominal pain, abdominal tenderness, vomiting, diarrhea, ileus; (2) signs of systemic inflammation: hyper or hypothermia, chills, altered white blood cell count, tachycardia, and/or tachypnea; (3) worsening of liver function; (4) hepatic encephalopathy; (5) shock; (6) renal failure; and (7) gastrointestinal bleeding. However, it is important to point out that SBP may be asymptomatic, particularly in outpatients [
      • Nousbaum J.B.
      • Cadranel J.F.
      • Nahon P.
      • Nguyen Khac E.
      • Moreau R.
      • Thévenot T.
      • et al.
      Diagnostic accuracy of the Multistix 8 SG® reagent strip in diagnosis of spontaneous bacterial peritonitis.
      ,
      • Evans L.T.
      • Kim W.R.
      • Poterucha J.J.
      • Kamath P.S.
      Spontaneous bacterial peritonitis in asymptomatic outpatients with cirrhotic ascites.
      ].

       3.1.2. Ascitic fluid cell analysis

      Peritoneal infection causes an inflammatory reaction resulting in an increased number of neutrophils in ascitic fluid. Despite the use of sensitive methods, ascites culture is negative in as many as 60% of patients with clinical manifestations suggestive of SBP and increased ascites neutrophil count [
      • Rimola A.
      • Gracia-Tsao G.
      • Navasa M.
      • et al.
      Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.
      ,
      • Fernández J.
      • Navasa M.
      • Gómez J.
      • Colmenero J.
      • Vila J.
      • Arroyo V.
      • et al.
      Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis.
      ,
      • Wong F.
      • Bernardi M.
      • Balk R.
      • Christman B.
      • Moreau R.
      • Garcia-Tsao G.
      • et al.
      Sepsis in cirrhosis: report on the 7th meeting of the International Ascites Club.
      ,
      • Garcia-Tsao G.
      Current management of the complications of cirrhosis and portal hypertension: variceal hemorrhage, ascites, and spontaneous bacterial peritonitis.
      ]. Ascitic fluid neutrophil count is obtained as follows: ascitic fluid is centrifuged, then a smear is stained with Giemsa and total and differential cell counts are made with an optical microscope. This can be done in less than 4 h [
      • Rimola A.
      • Gracia-Tsao G.
      • Navasa M.
      • et al.
      Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.
      ,
      • Wong F.
      • Bernardi M.
      • Balk R.
      • Christman B.
      • Moreau R.
      • Garcia-Tsao G.
      • et al.
      Sepsis in cirrhosis: report on the 7th meeting of the International Ascites Club.
      ,
      • Garcia-Tsao G.
      Current management of the complications of cirrhosis and portal hypertension: variceal hemorrhage, ascites, and spontaneous bacterial peritonitis.
      ,
      • Guarner C.
      • Soriano G.
      Spontaneous bacterial peritonitis.
      ]. Historically, manual counts were recommended, as coulter counter determinations of neutrophil counts were inaccurate at the relatively low levels of neutrophils in ascitic fluid [
      • Rimola A.
      • Gracia-Tsao G.
      • Navasa M.
      • et al.
      Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.
      ]. However, a recent study found excellent correlation between these two techniques, even at low counts, suggesting that automated counting may replace manual counts [
      • Angeloni S.
      • Nicolini G.
      • Merli M.
      • Nicolao F.
      • Pinto G.
      • Aronne T.
      • et al.
      Validation of automated blood cell counter for the determination of polymorphonuclear cell count in the ascitic fluid of cirrhotic patients with or without spontaneous bacterial peritonitis.
      ]. The greatest sensitivity for the diagnosis of SBP is reached with a cutoff neutrophil count of 250/mm3, although the greatest specificity is reached with a cutoff of 500 neutrophils/mm3 [
      • Rimola A.
      • Gracia-Tsao G.
      • Navasa M.
      • et al.
      Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.
      ,
      • Moore K.P.
      • Aithal G.P.
      Guidelines on the management of ascites in cirrhosis.
      ,
      • Wong F.
      • Bernardi M.
      • Balk R.
      • Christman B.
      • Moreau R.
      • Garcia-Tsao G.
      • et al.
      Sepsis in cirrhosis: report on the 7th meeting of the International Ascites Club.
      ]. Since there may be some delay in obtaining an ascitic fluid cell count, the use of reagent strips (RSs) has been proposed for a rapid diagnosis of SBP (reviewed in [
      • Nguyen Khac E.
      • Cadranel J.F.
      • Thévenot T.
      • Nousbaum J.B.
      Review article: utility of reagent strips in diagnosis of infected ascites in cirrhotic patients.
      ]). These reagent strips, designed for use in urine, identify leukocytes by detecting their esterase activity via a colorimetric reaction [
      • Nguyen Khac E.
      • Cadranel J.F.
      • Thévenot T.
      • Nousbaum J.B.
      Review article: utility of reagent strips in diagnosis of infected ascites in cirrhotic patients.
      ]. However, a large, multicenter prospective study has shown that the Multistix 8 SG® RS has a low diagnostic accuracy for the diagnosis of SBP [
      • Nousbaum J.B.
      • Cadranel J.F.
      • Nahon P.
      • Nguyen Khac E.
      • Moreau R.
      • Thévenot T.
      • et al.
      Diagnostic accuracy of the Multistix 8 SG® reagent strip in diagnosis of spontaneous bacterial peritonitis.
      ]. A critical review of 19 studies comparing RSs (i.e., either Multistix 8 SG®, Nephur®, Combur®, UriScan®, or Aution®) to cytobacteriological methods has shown that RSs have low sensitivity and a high risk of false negative results, in particular in patients with SBP and low neutrophil count [
      • Nguyen Khac E.
      • Cadranel J.F.
      • Thévenot T.
      • Nousbaum J.B.
      Review article: utility of reagent strips in diagnosis of infected ascites in cirrhotic patients.
      ]. Thus, the use of reagent strips cannot be recommended for the rapid diagnosis of SBP.

       3.1.3. Ascitic fluid culture

      When culture is positive (∼40% of cases), the most common pathogens include Gram-negative bacteria (GNB), usually Escherichia coli and Gram-positive cocci (mainly streptococcus species and enterococci) [
      • Rimola A.
      • Gracia-Tsao G.
      • Navasa M.
      • et al.
      Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.
      ,
      • Caly W.R.
      • Strauss E.
      A prospective study of bacterial infections in patients with cirrhosis.
      ,
      • Fernández J.
      • Navasa M.
      • Gómez J.
      • Colmenero J.
      • Vila J.
      • Arroyo V.
      • et al.
      Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis.
      ,
      • Wong F.
      • Bernardi M.
      • Balk R.
      • Christman B.
      • Moreau R.
      • Garcia-Tsao G.
      • et al.
      Sepsis in cirrhosis: report on the 7th meeting of the International Ascites Club.
      ,
      • Garcia-Tsao G.
      Current management of the complications of cirrhosis and portal hypertension: variceal hemorrhage, ascites, and spontaneous bacterial peritonitis.
      ]. A recent study has shown that 30% of isolated GNB are resistant to quinolones and 30% are resistant to trimethoprim–sulfamethoxazole [
      • Fernández J.
      • Navasa M.
      • Gómez J.
      • Colmenero J.
      • Vila J.
      • Arroyo V.
      • et al.
      Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis.
      ]. Seventy percent of quinolone-resistant GNB are also resistant to trimethoprim–sulfamethoxazole [
      • Fernández J.
      • Navasa M.
      • Gómez J.
      • Colmenero J.
      • Vila J.
      • Arroyo V.
      • et al.
      Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis.
      ]. The incidence of SBP due to quinolone-resistant GNB is higher in patients on norfloxacin therapy than in patients ‘naïve’ for this treatment [
      • Fernández J.
      • Navasa M.
      • Gómez J.
      • Colmenero J.
      • Vila J.
      • Arroyo V.
      • et al.
      Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis.
      ]. The rate of cephalosporin-resistant GNB is low in patients with SBP regardless of norfloxacin prophylaxis [
      • Fernández J.
      • Navasa M.
      • Gómez J.
      • Colmenero J.
      • Vila J.
      • Arroyo V.
      • et al.
      Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis.
      ]. Patients on norfloxacin prophylaxis may develop SBP caused by Gram-positive cocci [
      • Rimola A.
      • Gracia-Tsao G.
      • Navasa M.
      • et al.
      Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.
      ,
      • Fernández J.
      • Navasa M.
      • Gómez J.
      • Colmenero J.
      • Vila J.
      • Arroyo V.
      • et al.
      Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis.
      ,
      • Wong F.
      • Bernardi M.
      • Balk R.
      • Christman B.
      • Moreau R.
      • Garcia-Tsao G.
      • et al.
      Sepsis in cirrhosis: report on the 7th meeting of the International Ascites Club.
      ,
      • Garcia-Tsao G.
      Current management of the complications of cirrhosis and portal hypertension: variceal hemorrhage, ascites, and spontaneous bacterial peritonitis.
      ]. Finally, the epidemiology of bacterial infections differs between community-acquired (in which GNB infections predominate) and nosocomial infections (in which Gram-positive infections predominate) [
      • Fernández J.
      • Navasa M.
      • Gómez J.
      • Colmenero J.
      • Vila J.
      • Arroyo V.
      • et al.
      Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis.
      ].
      Patients with an ascitic fluid neutrophil count ⩾250 cells/mm3 and negative culture have culture-negative SBP [
      • Rimola A.
      • Gracia-Tsao G.
      • Navasa M.
      • et al.
      Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.
      ,
      • Runyon B.A.
      • Hoefs J.C.
      Culture-negative neutrocytic ascites: a variant of spontaneous bacterial peritonitis.
      ]. Their clinical presentation is similar to that of patients with culture-positive SBP [
      • Rimola A.
      • Gracia-Tsao G.
      • Navasa M.
      • et al.
      Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.
      ,
      • Terg R.
      • Levi D.
      • Lopez P.
      • Rafaelli C.
      • Rojter S.
      • Abecasis R.
      • et al.
      Analysis of clinical course and prognosis of culture-positive spontaneous bacterial peritonitis and neutrocytic ascites. Evidence of the same disease.
      ] and should be treated in a similar manner.
      Some patients have ‘bacterascites’ in which cultures are positive but there is normal ascitic neutrophil count (<250/mm3) [
      • Rimola A.
      • Gracia-Tsao G.
      • Navasa M.
      • et al.
      Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.
      ]. In some patients bacterascites is the result of secondary bacterial colonization of ascites from an extraperitoneal infection. These patients usually have general symptoms and signs of infection. In other patients, ‘bacterascites’ is due to the spontaneous colonization of ascites, and they can either be clinically asymptomatic or have abdominal pain or fever. While in some patients, particularly in those who are asymptomatic, bacterascites represents a transient and spontaneously reversible colonization of ascites, in other patients, mainly those who are symptomatic, bacterascites may represent the first step in the development of SBP [
      • Rimola A.
      • Gracia-Tsao G.
      • Navasa M.
      • et al.
      Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.
      ].

       3.1.4. Spontaneous bacterial pleural empyema

      Infection of a pre-existing hydrothorax, known as spontaneous bacterial pleural empyema, is uncommon although the exact prevalence is unknown [
      • Guarner C.
      • Soriano G.
      Spontaneous bacterial peritonitis.
      ]. The diagnosis is based on pleural fluid analysis obtained by diagnostic thoracocentesis. In the largest observational study reported so far, the diagnosis of spontaneous bacterial empyema was established when the pleural fluid analysis showed a positive culture and more than 250 neutrophils/mm3 or a negative culture and more than 500 neutrophils/mm3, in the absence of lung infection [
      • Xiol X.
      • Castellví J.M.
      • Guardiola J.
      • Sesé E.
      • Castellote J.
      • Perelló A.
      • et al.
      Spontaneous bacterial empyema in cirrhotic patients: a prospective study.
      ]. Pleural fluid culture in blood culture bottles was positive in 75% of cases [
      • Xiol X.
      • Castellví J.M.
      • Guardiola J.
      • Sesé E.
      • Castellote J.
      • Perelló A.
      • et al.
      Spontaneous bacterial empyema in cirrhotic patients: a prospective study.
      ]. Spontaneous bacterial pleural empyema was associated with SBP in ∼50% of cases [
      • Xiol X.
      • Castellví J.M.
      • Guardiola J.
      • Sesé E.
      • Castellote J.
      • Perelló A.
      • et al.
      Spontaneous bacterial empyema in cirrhotic patients: a prospective study.
      ].

       3.1.5. Secondary bacterial peritonitis

      A small proportion of patients with cirrhosis may develop peritonitis due to perforation or inflammation of an intra-abdominal organ, a condition known as secondary bacterial peritonitis. The differentiation of this condition from SBP is important. Secondary bacterial peritonitis should be suspected in patients who have localized abdominal symptoms or signs, presence of multiple organisms on ascitic culture, very high ascitic neutrophil count and/or high ascitic protein concentration, or in those patients with an inadequate response to therapy [
      • Guarner C.
      • Soriano G.
      Spontaneous bacterial peritonitis.
      ]. Patients with suspected secondary bacterial peritonitis should undergo appropriate radiological investigation such as CT scanning [
      • Guarner C.
      • Soriano G.
      Spontaneous bacterial peritonitis.
      ]. The use of other tests such as measurement of glucose or lactate dehydrogenase in ascitic fluid has been suggested to help with the diagnosis of secondary bacterial peritonitis [
      • Guarner C.
      • Soriano G.
      Spontaneous bacterial peritonitis.
      ]. However, there are very limited data on the specificity and sensitivity of these tests in this setting.
      Recommendations A diagnostic paracentesis should be carried out in all patients with cirrhosis and ascites at hospital admission to rule out SBP. A diagnostic paracentesis should also be performed in patients with gastrointestinal bleeding, shock, fever, or other signs of systemic inflammation, gastrointestinal symptoms, as well as in patients with worsening liver and/or renal function, and hepatic encephalopathy (Level A1).
      The diagnosis of SBP is based on neutrophil count in ascitic fluid of >250/mm3 as determined by microscopy (Level A1). At present there are insufficient data to recommend the use of automated cell counters or reagent strips for the rapid diagnosis of SBP.
      Ascitic fluid culture is frequently negative even if performed in blood culture bottles and is not necessary for the diagnosis of SBP, but it is important to guide antibiotic therapy (Level A1). Blood cultures should be performed in all patients with suspected SBP before starting antibiotic treatment (Level A1).
      Some patients may have an ascitic neutrophil count less than 250/mm3 but with a positive ascitic fluid culture. This condition is known as bacterascites. If the patient exhibits signs of systemic inflammation or infection, the patient should be treated with antibiotics (Level A1). Otherwise, the patient should undergo a second paracentesis when culture results come back positive. Patients in whom the repeat ascitic neutrophil count is >250/mm3 should be treated for SBP, and the remaining patients (i.e., neutrophils <250/mm3) should be followed up (Level B1).
      Spontaneous bacterial pleural empyema may complicate hepatic hydrothorax. Diagnostic thoracocentesis should be performed in patients with pleural effusion and suspected infection with inoculation of fluid into blood culture bottles (Level A1). The diagnosis is based on positive pleural fluid culture and increased neutrophil count of >250/mm3 or negative pleural fluid culture and >500 neutrophils/mm3 in the absence of pneumonia (Level B1).
      Patients with suspected secondary bacterial peritonitis should undergo appropriate radiological investigation such as CT scanning (Level A1). The use of other tests such as measurement of glucose or lactate dehydrogenase in ascitic fluid cannot be recommended for the diagnosis of secondary bacterial peritonitis (Level B1).

       3.2. Management of spontaneous bacterial peritonitis

       3.2.1. Empirical antibiotic therapy

      Empirical antibiotic therapy must be initiated immediately after the diagnosis of SBP, without the results of ascitic fluid culture [
      • Rimola A.
      • Gracia-Tsao G.
      • Navasa M.
      • et al.
      Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.
      ,
      • Wong F.
      • Bernardi M.
      • Balk R.
      • Christman B.
      • Moreau R.
      • Garcia-Tsao G.
      • et al.
      Sepsis in cirrhosis: report on the 7th meeting of the International Ascites Club.
      ]. Potentially nephrotoxic antibiotics (i.e., aminoglycosides) should not be used as empirical therapy [
      • Rimola A.
      • Gracia-Tsao G.
      • Navasa M.
      • et al.
      Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.
      ]. Cefotaxime, a third-generation cephalosporin, has been extensively investigated in patients with SBP because it covers most causative organisms and because of its high ascitic fluid concentrations during therapy [
      • Felisart J.
      • Rimola A.
      • Arroyo V.
      • Pérez-Ayuso R.M.
      • Quintero E.
      • Ginès P.
      • et al.
      Cefotaxime is more effective than is ampicillin–tobramycin in cirrhotics with severe infections.
      ,
      • Rimola A.
      • Salmerón J.M.
      • Clemente G.
      • Rodrigo L.
      • Obrador A.
      • Miranda M.L.
      • et al.
      Two different dosages of cefotaxime in the treatment of spontaneous bacterial peritonitis in cirrhosis: results of a prospective, randomized, multicenter study.
      ,
      • Navasa M.
      • Follo A.
      • Llovet J.M.
      • Clemente G.
      • Vargas V.
      • Rimola A.
      • et al.
      Randomized, comparative study of oral ofloxacin versus intravenous cefotaxime in spontaneous bacterial peritonitis.
      ,
      • 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.
      ,
      • Ricart E.
      • Soriano G.
      • Novella M.T.
      • Ortiz J.
      • Sàbat M.
      • Kolle L.
      • et al.
      Amoxicillin–clavulanic acid versus cefotaxime in the therapy of bacterial infections in cirrhotic patients.
      ]. Infection resolution is obtained in 77–98% of patients. A dose of 4 g/day is as effective as a dose of 8 g/day [
      • Rimola A.
      • Salmerón J.M.
      • Clemente G.
      • Rodrigo L.
      • Obrador A.
      • Miranda M.L.
      • et al.
      Two different dosages of cefotaxime in the treatment of spontaneous bacterial peritonitis in cirrhosis: results of a prospective, randomized, multicenter study.
      ]. A 5-day therapy is as effective as a 10-day treatment [
      • Runyon B.A.
      • McHutchison J.G.
      • Antillon M.R.
      • Akriviadis E.A.
      • Montano A.A.
      Short-course versus long-course antibiotic treatment of spontaneous bacterial peritonitis. A randomized controlled study of 100 patients.
      ] (Table 6).
      Table 6Antibiotic therapy for spontaneous bacterial peritonitis in patients with cirrhosis.
      ReferenceTreatmentsNumber of patientsInfection resolution (%)In-hospital survival (%)
      Felisart, 1985
      • Felisart J.
      • Rimola A.
      • Arroyo V.
      • Pérez-Ayuso R.M.
      • Quintero E.
      • Ginès P.
      • et al.
      Cefotaxime is more effective than is ampicillin–tobramycin in cirrhotics with severe infections.
      Tobramycin (1.75 mg/kg/8h IV)

      plus ampicillin (2 g/4h IV)

      versus cefotaxime (2 g/4h IV)
      365661
      3785
      p<0.02 versus tobramycin plus ampicillin.
      73
      Rimola, 1995
      • Rimola A.
      • Salmerón J.M.
      • Clemente G.
      • Rodrigo L.
      • Obrador A.
      • Miranda M.L.
      • et al.
      Two different dosages of cefotaxime in the treatment of spontaneous bacterial peritonitis in cirrhosis: results of a prospective, randomized, multicenter study.
      Cefotaxime (2 g/6h IV)

      versus cefotaxime (2 g/12h IV)
      717769
      727979
      Navasa, 1996
      • Navasa M.
      • Follo A.
      • Llovet J.M.
      • Clemente G.
      • Vargas V.
      • Rimola A.
      • et al.
      Randomized, comparative study of oral ofloxacin versus intravenous cefotaxime in spontaneous bacterial peritonitis.
      Ofloxacin (400 mg/12h PO)

      versus cefotaxime (2 g/6h IV)
      648481
      598581
      Sort, 1999
      • 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.
      Cefotaxime (2 g/6h IV)

      versus cefotaxime (2 g/6h IV) plus IV albumin
      639471
      639890
      p=0.01 versus cefotaxime alone.
      Ricart, 2000
      • Ricart E.
      • Soriano G.
      • Novella M.T.
      • Ortiz J.
      • Sàbat M.
      • Kolle L.
      • et al.
      Amoxicillin–clavulanic acid versus cefotaxime in the therapy of bacterial infections in cirrhotic patients.
      Amoxicillin/clavulanic acid (1/0.2 g/8h)

      IV followed by 0.5/0.125 g/8h PO

      versus cefotaxime (1 g/6h IV)
      248787
      248379
      Terg, 2000
      • Terg R.
      • Cobas S.
      • Fassio E.
      • Landeira G.
      • Ríos B.
      • Vasen W.
      • et al.
      Oral ciprofloxacin after a short course of intravenous ciprofloxacin in the treatment of spontaneous bacterial peritonitis: results of a multicenter, randomized study.
      Ciprofloxacin (200 mg/12h IV for 7 days) versus ciprofloxacin (200 mg/12h for 2 days, followed by 500 mg/12h PO for 5 days)407677
      407877
      low asterisk p <0.02 versus tobramycin plus ampicillin.
      low asterisklow asterisk p = 0.01 versus cefotaxime alone.
      Alternatively, amoxicillin/clavulanic acid, first given intravenously then orally, has similar results with respect to SBP resolution and mortality, compared with cefotaxime [
      • Ricart E.
      • Soriano G.
      • Novella M.T.
      • Ortiz J.
      • Sàbat M.
      • Kolle L.
      • et al.
      Amoxicillin–clavulanic acid versus cefotaxime in the therapy of bacterial infections in cirrhotic patients.
      ] and with a much lower cost. However, there is only one comparative study with a small sample size and results should be confirmed in larger trials. Ciprofloxacin, given either for 7 days intravenously or for 2 days intravenously followed by 5 days orally, results in a similar SBP resolution rate and hospital survival compared with cefotaxime, but with a significantly higher cost [
      • Terg R.
      • Cobas S.
      • Fassio E.
      • Landeira G.
      • Ríos B.
      • Vasen W.
      • et al.
      Oral ciprofloxacin after a short course of intravenous ciprofloxacin in the treatment of spontaneous bacterial peritonitis: results of a multicenter, randomized study.
      ]. However, switch therapy (i.e., use of intravenous antibiotic initially, followed by oral step-down administration) with ciprofloxacin is more cost-effective than intravenous cefotaxime [
      • Angeli P.
      • Guarda S.
      • Fasolato S.
      • Miola E.
      • Craighero R.
      • Piccolo F.
      • et al.
      Switch therapy with ciprofloxacin vs. intravenous ceftazidime in the treatment of spontaneous bacterial peritonitis in patients with cirrhosis: similar efficacy at lower cost.
      ]. Oral ofloxacin has given similar results as intravenous cefotaxime in uncomplicated SBP, without renal failure, hepatic encephalopathy, gastrointestinal bleeding, ileus, or shock [
      • Navasa M.
      • Follo A.
      • Llovet J.M.
      • Clemente G.
      • Vargas V.
      • Rimola A.
      • et al.
      Randomized, comparative study of oral ofloxacin versus intravenous cefotaxime in spontaneous bacterial peritonitis.
      ]. Cefotaxime or amoxicillin/clavulanic acid are effective in patients who develop SBP while on norfloxacin prophylaxis [
      • Rimola A.
      • Gracia-Tsao G.
      • Navasa M.
      • et al.
      Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.
      ].
      If ascitic fluid neutrophil count fails to decrease to less than 25% of the pre-treatment value after 2 days of antibiotic treatment, there is a high likelihood of failure to respond to therapy [
      • Rimola A.
      • Gracia-Tsao G.
      • Navasa M.
      • et al.
      Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.
      ,
      • Guarner C.
      • Soriano G.
      Spontaneous bacterial peritonitis.
      ]. This should raise the suspicion of an infection caused by bacteria resistant to antibiotic therapy, indicating the need for modification of antibiotic treatment according to in vitro sensitivity or on empiric basis or the presence of ‘secondary peritonitis’.
      Recommendations. Empirical antibiotics should be started immediately following the diagnosis of SBP (Level A1).
      Since the most common causative organisms of SBP are Gram-negative aerobic bacteria, such as E. coli, the first line antibiotic treatment are third-generation cephalosporins (Level A1). Alternative options include amoxycillin/clavulanic acid and quinolones such as ciprofloxacin or ofloxacin. However, the use of quinolones should not be considered in patients who are taking these drugs for prophylaxis against SBP, in areas where there is a high prevalence of quinolone-resistant bacteria or in nosocomial SBP (Level B1).
      SBP resolves with antibiotic therapy in approximately 90% of patients. Resolution of SBP should be proven by demonstrating a decrease of ascitic neutrophil count to <250/mm3 and sterile cultures of ascitic fluid, if positive at diagnosis (Level A1). A second paracentesis after 48 h of start of treatment may help guide the effect of antibiotic therapy.
      Failure of antibiotic therapy should be suspected if there is worsening of clinical signs and symptoms and/or no marked reduction or increase in ascitic fluid neutrophil count compared to levels at diagnosis. Failure of antibiotic therapy is usually due to resistant bacteria or secondary bacterial peritonitis. Once secondary bacterial peritonitis has been excluded, antibiotics should be changed according to in vitro susceptibility of isolated organisms, or modified to alternative empiric broad spectrum agents (Level A1).
      Spontaneous bacterial empyema should be managed similarly as SBP

       3.2.2. Intravenous albumin in patients with spontaneous bacterial peritonitis without septic shock

      SBP without septic shock may precipitate deterioration of circulatory function with severe hepatic insufficiency, hepatic encephalopathy, and type 1 hepatorenal syndrome (HRS) [
      • 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.
      ,
      • Follo A.
      • Llovet J.M.
      • 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.
      ,
      • Fasolato S.
      • Angeli P.
      • Dallagnese L.
      • Maresio G.
      • Zola E.
      • Mazza E.
      • et al.
      Renal failure and bacterial infections in patients with cirrhosis: epidemiology and clinical features.
      ] and has approximately a 20% hospital mortality rate despite infection resolution [
      • 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.
      ,
      • Follo A.
      • Llovet J.M.
      • 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.
      ].
      A randomized, controlled study in patients with SBP treated with cefotaxime showed that albumin (1.5 g/kg body weight at diagnosis, followed by 1 g/kg on day 3) significantly decreased the incidence of type 1 HRS (from 30% to 10%) and reduced mortality from 29% to 10% compared with cefotaxime alone. Treatment with albumin was particularly effective in patients with baseline serum bilirubin ⩾68 μmol/L (4 mg/dl) or serum creatinine ⩾88 μmol/L (1 mg/dl). It is unclear whether intravenous albumin is useful in patients with baseline bilirubin <68 μmol/L and creatinine <88 μmol/L, as the incidence of type 1 HRS was very low in the two treatment groups (7% without albumin and 0% with albumin) [
      • 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.
      ]. Non-randomized studies in patients with SBP also show that the incidence of renal failure and death are very low in patients with moderate liver failure and without renal dysfunction at diagnosis of SBP [
      • Navasa M.
      • Follo A.
      • Filella X.
      • Jiménez W.
      • Francitorra A.
      • Planas R.
      • et al.
      Tumor necrosis factor and interleukin-6 in spontaneous bacterial peritonitis in cirrhosis: relationship with the development of renal impairment and mortality.
      ,
      • Sigal S.H.
      • Stanca C.M.
      • Fernandez J.
      • Arroyo V.
      • Navasa M.
      Restricted use of albumin for spontaneous bacterial peritonitis.
      ,
      • Terg R.
      • Gadano A.
      • Cartier M.
      • Casciato P.
      • Lucero R.
      • Muñoz A.
      • et al.
      Serum creatinine and bilirubin predict renal failure and mortality in patients with spontaneous bacterial peritonitis: a retrospective study.
      ]. It is not known whether crystalloids or artificial colloids could replace albumin in the prevention of HRS in patients with SBP. Albumin improves circulatory function in patients with SBP while equivalent doses of hydroxyethyl starch have no such beneficial effect [
      • Fernández J.
      • Monteagudo J.
      • Bargallo X.
      • Jiménez W.
      • Bosch J.
      • Arroyo V.
      • et al.
      A randomized unblinded pilot study comparing albumin versus hydroxyethyl starch in spontaneous bacterial peritonitis.
      ]. Clearly, further studies are needed to assess the efficacy of albumin as well as other expanders in the management of SBP. Until further trials are completed, albumin infusion appears a valuable adjunction to the treatment of SBP.
      Recommendations HRS occurs in approximately 30% of patients with SBP treated with antibiotics alone, and is associated with a poor survival. The administration of albumin (1.5 g/kg at diagnosis and 1g/kg on day 3) decreases the frequency of HRS and improves survival (Level A1). It is unclear whether albumin is useful in the subgroup of patients with baseline serum bilirubin <68 μmol/L and creatinine <88 μmol/L (Level B2). Until more information is available, we recommend that all patients who develop SBP should be treated with broad spectrum antibiotics and intravenous albumin (Level A2).

       3.3. Prophylaxis of spontaneous bacterial peritonitis

      Since most episodes of SBP are thought to result from the translocation of enteric GNB, the ideal prophylactic agent should be safe, affordable, and effective at decreasing the amounts of these organisms from the gut while preserving the protective anaerobic flora (selective intestinal decontamination) [
      • Garcia-Tsao G.
      Current management of the complications of cirrhosis and portal hypertension: variceal hemorrhage, ascites, and spontaneous bacterial peritonitis.
      ]. Given the high cost and inevitable risk of developing resistant organisms, the use of prophylactic antibiotics must be strictly restricted to patients at high risk of SBP. Three high-risk patient populations have been identified: (1) patients with acute gastrointestinal hemorrhage; (2) patients with low total protein content in ascitic fluid and no prior history of SBP (primary prophylaxis); and (3) patients with a previous history of SBP (secondary prophylaxis).

       3.3.1. Patients with acute gastrointestinal hemorrhage

      Bacterial infection, including SBP, is a major problem in patients with cirrhosis and acute gastrointestinal hemorrhage, occurring in between 25% and 65% of patients with gastrointestinal bleeding [
      • Rimola A.
      • Bory F.
      • Teres J.
      • Pérez-Ayuso R.M.
      • Arroyo V.
      • Rodés J.
      Oral, nonabsorbable antibiotics prevent infection in cirrhotics with gastrointestinal hemorrhage.
      ,
      • Bleichner G.
      • Boulanger R.
      • Squara P.
      • Sollet J.P.
      • Parent A.
      Frequency of infections in cirrhotic patients presenting with acute gastrointestinal haemorrhage.
      ,
      • Soriano G.
      • Guarner C.
      • Tomas A.
      • Villanueva C.
      • Torras X.
      • González D.
      • et al.
      Norfloxacin prevents bacterial infection in cirrhotics with gastrointestinal hemorrhage.
      ,
      • Blaise M.
      • Pateron D.
      • Trinchet J.C.
      • Levacher S.
      • Beaugrand M.
      • Porriat J.L.
      Systemic antibiotic therapy prevents bacterial infection in cirrhotic patients with gastrointestinal hemorrhage.
      ,
      • Bernard B.
      • Cadranel J.F.
      • Valla D.
      • Escolano S.
      • Jarlier V.
      • Opolon P.
      Prognostic significance of bacterial infection in bleeding cirrhotic patients: a prospective study.
      ,
      • Pauwels A.
      • Mostefa-Kara N.
      • Debenes B.
      • Degoutte E.
      • Levy V.G.
      Systemic antibiotic prophylaxis after gastrointestinal hemorrhage in cirrhotic patients with a high risk of infection.
      ,
      • Deschenes M.
      • Villeneuve J.P.
      Risk factors for the development of bacterial infections in hospitalized patients with cirrhosis.
      ,
      • Bernard B.
      • Grange J.D.
      • Khac E.N.
      • Amiot X.
      • Opolon P.
      • Poynard T.
      Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: a meta-analysis.
      ,
      • Hsieh W.J.
      • Lin H.C.
      • Hwang S.J.
      • Hou M.C.
      • Lee F.Y.
      • Chang F.Y.
      • et al.
      The effect of ciprofloxacin in the prevention of bacterial infection in patients with cirrhosis after upper gastrointestinal bleeding.
      ,
      • Hou M.C.
      • Lin H.C.
      • Liu T.T.
      • Kuo B.I.
      • Lee F.Y.
      • Chang F.Y.
      • et al.
      Antibiotic prophylaxis after endoscopic therapy prevents rebleeding in acute variceal hemorrhage: a randomized trial.
      ]. The incidence of bacterial infection is particularly high in patients with advanced cirrhosis and/or severe hemorrhage [
      • Deschenes M.
      • Villeneuve J.P.
      Risk factors for the development of bacterial infections in hospitalized patients with cirrhosis.
      ,
      • Bernard B.
      • Grange J.D.
      • Khac E.N.
      • Amiot X.
      • Opolon P.
      • Poynard T.
      Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: a meta-analysis.
      ]. In addition, the presence of bacterial infection in patients with variceal hemorrhage is associated with an increased rate of failure to control bleeding [
      • Goulis J.
      • Armonis A.
      • Patch D.
      • Sabin C.
      • Greenslade L.
      • Burroughs A.K.
      Bacterial infection is independently associated with failure to control bleeding in cirrhotic patients with gastrointestinal hemorrhage.
      ,
      • Vivas S.
      • Rodríguez M.
      • Palacio M.A.
      • Linares A.
      • Alonso J.L.
      • Rodrigo L.
      Presence of bacterial infection in bleeding cirrhotic patients is independently associated with early mortality and failure to control bleeding.
      ], rebleeding [
      • Bernard B.
      • Cadranel J.F.
      • Valla D.
      • Escolano S.
      • Jarlier V.
      • Opolon P.
      Prognostic significance of bacterial infection in bleeding cirrhotic patients: a prospective study.
      ,
      • Deschenes M.
      • Villeneuve J.P.
      Risk factors for the development of bacterial infections in hospitalized patients with cirrhosis.
      ], and hospital mortality [
      • Bernard B.
      • Grange J.D.
      • Khac E.N.
      • Amiot X.
      • Opolon P.
      • Poynard T.
      Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: a meta-analysis.
      ,
      • Vivas S.
      • Rodríguez M.
      • Palacio M.A.
      • Linares A.
      • Alonso J.L.
      • Rodrigo L.
      Presence of bacterial infection in bleeding cirrhotic patients is independently associated with early mortality and failure to control bleeding.
      ,
      • Soares-Weiser K.
      • Brezis M.
      • Tur-Kaspa R.
      • Leibovici L.
      Antibiotic prophylaxis for cirrhotic patients with gastrointestinal bleeding.
      ,
      • Carbonell N.
      • Pauwels A.
      • Serfaty L.
      • Fourdan O.
      • Lévy V.G.
      • Poupon R.
      Improved survival after variceal bleeding in patients with cirrhosis over the past two decades.
      ]. Antibiotic prophylaxis has been shown to prevent infection in patients with gastrointestinal bleeding [
      • Rimola A.
      • Gracia-Tsao G.
      • Navasa M.
      • et al.
      Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.
      ,
      • Wong F.
      • Bernardi M.
      • Balk R.
      • Christman B.
      • Moreau R.
      • Garcia-Tsao G.
      • et al.
      Sepsis in cirrhosis: report on the 7th meeting of the International Ascites Club.
      ,
      • Garcia-Tsao G.
      Current management of the complications of cirrhosis and portal hypertension: variceal hemorrhage, ascites, and spontaneous bacterial peritonitis.
      ] and decrease the rate of rebleeding [
      • Soares-Weiser K.
      • Brezis M.
      • Tur-Kaspa R.
      • Leibovici L.
      Antibiotic prophylaxis for cirrhotic patients with gastrointestinal bleeding.
      ]. A meta-analysis [
      • Bernard B.
      • Grange J.D.
      • Khac E.N.
      • Amiot X.
      • Opolon P.
      • Poynard T.
      Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: a meta-analysis.
      ] of five studies performed in patients with gastrointestinal bleeding [
      • Rimola A.
      • Bory F.
      • Teres J.
      • Pérez-Ayuso R.M.
      • Arroyo V.
      • Rodés J.
      Oral, nonabsorbable antibiotics prevent infection in cirrhotics with gastrointestinal hemorrhage.
      ,
      • Soriano G.
      • Guarner C.
      • Tomas A.
      • Villanueva C.
      • Torras X.
      • González D.
      • et al.
      Norfloxacin prevents bacterial infection in cirrhotics with gastrointestinal hemorrhage.
      ,
      • Blaise M.
      • Pateron D.
      • Trinchet J.C.
      • Levacher S.
      • Beaugrand M.
      • Porriat J.L.
      Systemic antibiotic therapy prevents bacterial infection in cirrhotic patients with gastrointestinal hemorrhage.
      ,
      • Pauwels A.
      • Mostefa-Kara N.
      • Debenes B.
      • Degoutte E.
      • Levy V.G.
      Systemic antibiotic prophylaxis after gastrointestinal hemorrhage in cirrhotic patients with a high risk of infection.
      ,
      • Hsieh W.J.
      • Lin H.C.
      • Hwang S.J.
      • Hou M.C.
      • Lee F.Y.
      • Chang F.Y.
      • et al.
      The effect of ciprofloxacin in the prevention of bacterial infection in patients with cirrhosis after upper gastrointestinal bleeding.
      ] has shown that antibiotic prophylaxis significantly decreased both the incidence of severe infections (SBP and/or septicemia) and mortality.
      Selective intestinal decontamination with norfloxacin (400 mg/12 h orally for 7 days), a quinolone with relatively poor gastrointestinal absorption, and which has antibacterial activity against GNB but not against Gram-positive cocci or anaerobic bacteria, is the most commonly used approach for the prophylaxis of bacterial infections in patients with gastrointestinal hemorrhage [
      • Rimola A.
      • Gracia-Tsao G.
      • Navasa M.
      • et al.
      Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.
      ,
      • Wong F.
      • Bernardi M.
      • Balk R.
      • Christman B.
      • Moreau R.
      • Garcia-Tsao G.
      • et al.
      Sepsis in cirrhosis: report on the 7th meeting of the International Ascites Club.
      ,
      • Soriano G.
      • Guarner C.
      • Tomas A.
      • Villanueva C.
      • Torras X.
      • González D.
      • et al.
      Norfloxacin prevents bacterial infection in cirrhotics with gastrointestinal hemorrhage.
      ]. In recent years, the epidemiology of bacterial infections in cirrhosis has changed, with an increasing incidence of SBP and other infections caused by quinolone-resistant bacteria (see above) [
      • Fernández J.
      • Navasa M.
      • Gómez J.
      • Colmenero J.
      • Vila J.
      • Arroyo V.
      • et al.
      Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis.
      ,
      • 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.
      ,
      • Aparicio J.R.
      • Such J.
      • Pascual S.
      • Arroyo A.
      • Plazas J.
      • Girona E.
      • et al.
      Development of quinolone-resistant strains of Escherichia coli in stools of patients with cirrhosis undergoing norfloxacin prophylaxis: clinical consequences.
      ]. In addition, a substantial number of infections in patients with gastrointestinal hemorrhage are caused by Gram-positive bacteria likely related to invasive procedures used in these patients [
      • Fernández J.
      • Navasa M.
      • Gómez J.
      • Colmenero J.
      • Vila J.
      • Arroyo V.
      • et al.
      Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis.
      ].
      A recent study comparing oral norfloxacin to intravenous ceftriaxone for the prophylaxis of bacterial infection in patients with gastrointestinal bleeding and advanced cirrhosis (at least 2 of the following: ascites, severe malnutrition, encephalopathy, or bilirubin >3 mg/dl) showed that ceftriaxone was more effective than norfloxacin in the prevention of infections [
      • Fernández J.
      • Ruiz del Arbol L.
      • Gómez C.
      • Durandez R.
      • Serradilla R.
      • Guarner C.
      • et al.
      Norfloxacin vs ceftriaxone in the prophylaxis of infections in patients with advanced cirrhosis and hemorrhage.
      ].
      Recommendations In patients with gastrointestinal bleeding and severe liver disease (see text) ceftriaxone is the prophylactic antibiotic of choice, whilst patients with less severe liver disease may be given oral norfloxacin or an alternative oral quinolone to prevent the development of SBP (Level A1).

       3.3.2. Patients with low total protein content in ascitic fluid without prior history of spontaneous bacterial peritonitis

      Cirrhotic patients with low ascitic fluid protein concentration (<10 g/L) and/or high serum bilirubin levels are at high risk of developing a first episode of SBP [
      • Rimola A.
      • Gracia-Tsao G.
      • Navasa M.
      • et al.
      Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.
      ,
      • Runyon B.A.
      Low-protein-concentration ascitic fluid is predisposed to spontaneous bacterial peritonitis.
      ,
      • Andreu M.
      • Solá R.
      • Sitges-Serra A.
      • Alia C.
      • Gallen M.
      • Vila M.C.
      • et al.
      Risk factors for spontaneous bacterial peritonitis.
      ,
      • Llach J.
      • Rimola A.
      • Navasa M.
      • Ginès P.
      • Salmerón J.M.
      • Ginès A.
      • et al.
      Incidence and predictive factors of first episode of spontaneous bacterial peritonitis in cirrhosis with ascites: relevance of ascitic fluid protein concentration.
      ,
      • Guarner C.
      • Solà R.
      • Soriano G.
      • Andreu M.
      • Novella M.T.
      • Vila C.
      • et al.
      Risk of a first community-acquired spontaneous bacterial peritonitis in cirrhotics with low ascitic fluid protein levels.
      ]. Several studies have evaluated prophylaxis with norfloxacin in patients without prior history of SBP (Table 7) [
      • Soriano G.
      • Guarner C.
      • Teixidó M.
      • Such J.
      • Barrios J.
      • Enríquez J.
      • et al.
      Selective intestinal decontamination prevents spontaneous bacterial peritonitis.
      ,
      • Novella M.
      • Solà R.
      • Soriano G.
      • Andreu M.
      • Gana J.
      • Ortiz J.
      • et al.
      Continuous versus inpatient prophylaxis of the first episode of spontaneous bacterial peritonitis with norfloxacin.
      ,
      • Grange J.D.
      • Roulot D.
      • Pelletier G.
      • Pariente E.A.
      • Denis J.
      • Ink O.
      • et al.
      Norfloxacin primary prophylaxis of bacterial infections in cirrhotic patients with ascites: a double-blind randomized trial.
      ,
      • 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.
      ,
      • Terg R.
      • Fassio E.
      • Guevara M.
      • Cartier M.
      • Longo C.
      • Lucero R.
      • et al.
      Ciprofloxacin in primary prophylaxis of spontaneous bacterial peritonitis: a randomized, placebo-controlled study.
      ]. One pilot, randomized, open-label trial was performed comparing primary continuous prophylaxis with norfloxacin to inpatient-only prophylaxis in 109 patients with cirrhosis and ascitic fluid total protein level ⩽15 g/L or serum bilirubin level >2.5 mg/dl [
      • Novella M.
      • Solà R.
      • Soriano G.
      • Andreu M.
      • Gana J.
      • Ortiz J.
      • et al.
      Continuous versus inpatient prophylaxis of the first episode of spontaneous bacterial peritonitis with norfloxacin.
      ]. SBP was reduced in the continuous treatment group at the expense of more resistance of gut flora to norfloxacin in that group. In another study, 107 patients with ascitic fluid total protein level <15 g/L were randomized in a double-blind manner to receive norfloxacin (400 mg/day for 6 months) or placebo [
      • Grange J.D.
      • Roulot D.
      • Pelletier G.
      • Pariente E.A.
      • Denis J.
      • Ink O.
      • et al.
      Norfloxacin primary prophylaxis of bacterial infections in cirrhotic patients with ascites: a double-blind randomized trial.
      ]. Of note, the existence of severe liver failure was not an inclusion criterion. The primary endpoint was the occurrence of GNB infections. Norfloxacin significantly decreased the probability of developing GNB infections, but had no significant effect on the probability of developing SBP or survival. However, in this trial, the sample size was not calculated to detect differences in survival. In a third investigation, 68 patients with cirrhosis and low ascites protein levels (<15 g/L) with advanced liver failure [Child-Pugh score ⩾9 points with serum bilirubin level ⩾3 mg/dl or impaired renal function (serum creatinine level ⩾1.2 mg/dl, blood urea nitrogen level ⩾25 mg/dl, or serum sodium level ⩽130 mEq/L)] were randomized in a double-blind, placebo-controlled trial, to receive norfloxacin (400 mg/day for 12 months) or placebo [
      • 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.
      ]. The primary endpoints of the trial were 3-month and 1-year survival. Norfloxacin significantly improved the 3-month probability of survival (94% versus 62%; p = 0.03) but at 1 year the difference in survival was not significant (60% versus 48%; p = 0.05). Norfloxacin administration significantly reduced the 1-year probability of developing SBP (7% versus 61%) and HRS (28% versus 41%). In a fourth study, 100 patients with ascitic fluid total protein level <15 g/L were randomized in double-blind, placebo-controlled trial to ciprofloxacin (500 mg/day for 12 months) or placebo [
      • Terg R.
      • Fassio E.
      • Guevara M.
      • Cartier M.
      • Longo C.
      • Lucero R.
      • et al.
      Ciprofloxacin in primary prophylaxis of spontaneous bacterial peritonitis: a randomized, placebo-controlled study.
      ]. Enrolled patients had moderate liver failure (the Child-Pugh scores were 8.3 ± 1.3 and 8.5 ± 1.5, in the placebo and ciprofloxacin group, respectively). The primary endpoint was the occurrence of SBP. Although SBP occurred in 2 (4%) patients of the ciprofloxacin group and in 7 (14%) patients of the placebo group, this difference was not significant. Moreover, the probability of being free of SBP was not significant (p = 0.076). The probability of remaining free of bacterial infections was higher in patients receiving ciprofloxacin (80% versus 55%; p= 0.05). The probability of survival at 1 year was higher in patients receiving ciprofloxacin (86% versus 66%; p < 0.04). Nevertheless, a type II error cannot be ruled out as the sample size was not calculated to detect differences in survival. The duration of primary antibiotic prophylaxis has not been established.
      Table 7Antibiotic therapy for prophylaxis of spontaneous bacterial peritonitis (SBP) in patients with cirrhosis.
      Studies appear in chronological order.
      ReferenceType of prophylaxisTreatmentsNumber of patientsNumber of GNB
      GNB means Gram-negative bacteria.
      infections
      p-valueIncidence of SBP n (%)p-value
      Ginès, 1990
      • Ginès P.
      • Rimola A.
      • Planas R.
      • Vargas V.
      • Marco F.
      • Almela M.
      • et al.
      Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial.
      Enrolled only patients

      with prior SBP
      Randomized, double-blind, placebo-controlled trial.
      Norfloxacin

      versus placebo
      4015 (12)0.02
      401014 (35)
      Soriano, 1991
      • Soriano G.
      • Guarner C.
      • Teixidó M.
      • Such J.
      • Barrios J.
      • Enríquez J.
      • et al.
      Selective intestinal decontamination prevents spontaneous bacterial peritonitis.
      Enrolled patients without prior SBP and patients

      with prior SBP
      Randomized, unblinded trial.
      Norfloxacin

      versus no treatment
      320<0.0010 (0)<0.02
      3197 (22.5)
      Singh, 1995
      • Singh N.
      • Gayowski T.
      • Yu V.L.
      • Wagener M.M.
      Trimethoprim–sulfamethoxazole for the prevention of spontaneous bacterial peritonitis in cirrhosis: a randomized trial.
      Enrolled patients without prior SBP and patients

      with prior SBP
      Randomized, unblinded trial.
      Trimethoprim–sulfamethoxazole versus no treatment3091 (3)0.03
      3008 (27)
      Including one patient with spontaneous bacteremia due to Klebsiella pneumonia.
      Rolachon, 1995
      • Rolachon A.
      • Cordier L.
      • Bacq Y.
      • Nousbaum J.B.
      • Franza A.
      • Paris J.C.
      • et al.
      Ciprofloxacin and long-term prevention of spontaneous bacterial peritonitis: results of a prospective controlled trial.
      Enrolled patients without prior SBP and patients

      with prior SBP
      Randomized, double-blind, placebo-controlled trial.
      Ciprofloxacin

      versus placebo
      2811 (4)<0.05
      3207 (22)
      Novella, 1997
      • Novella M.