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EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis

Published:April 10, 2018DOI:https://doi.org/10.1016/j.jhep.2018.03.024

      Summary

      The natural history of cirrhosis is characterised by an asymptomatic compensated phase followed by a decompensated phase, marked by the development of overt clinical signs, the most frequent of which are ascites, bleeding, encephalopathy, and jaundice. The following Clinical Practice Guidelines (CPGs) represent the first CPGs on the management of decompensated cirrhosis. In this context, the panel of experts, having emphasised the importance of initiating aetiologic treatment for any degree of hepatic disease at the earliest possible stage, extended its work to all the complications of cirrhosis, which had not been covered by the European Association for the Study of the Liver guidelines, namely: ascites, refractory ascites, hyponatremia, gastrointestinal bleeding, bacterial infections, acute kidney injury, hepatorenal syndrome, acute-on-chronic liver failure, relative adrenal failure, cirrhotic cardiomyopathy, hepatopulmonary syndrome, and porto-pulmonary hypertension. The panel of experts, produced these GPGs using evidence from PubMed and Cochrane database searches providing up to date guidance on the management of decompensated cirrhosis with the only purpose of improving clinical practice.

      Introduction

      When the panel of experts nominated by the European Association for the Study of the Liver (EASL) governing board began work to update the Clinical Practice Guidelines (CPGs) on ascites, spontaneous bacterial peritonitis (SBP), and hepatorenal syndrome (HRS),
      EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis.
      it became obvious that all other complications of decompensated cirrhosis had to be covered. Within this framework, a formal definition of decompensated cirrhosis was sought. The natural history of cirrhosis is characterised by a silent, asymptomatic course until increasing portal pressure and worsening liver function produce a clinical phenotype. In the asymptomatic phase of the disease, usually referred to as compensated cirrhosis, patients may have a good quality of life, and the disease may progress undetected for several years. Decompensation is marked by the development of overt clinical signs, the most frequent of which are ascites, bleeding, encephalopathy, and jaundice. Following the first appearance of any of these, the disease usually progresses more rapidly towards death or liver transplantation (LT). This phase of the disease has been designated “decompensated cirrhosis”.
      • D'Amico G.
      The clinical course of cirrhosis. Population based studies and the need of personalized medicine.
      Progression of the decompensated disease may be further accelerated by the development of other complications such as rebleeding, acute kidney injury (AKI), with or without the features of HRS, hepato-pulmonary syndrome (HPS), portopulmonary hypertension (PPHT), cirrhotic cardiomyopathy (CCM), and bacterial infections. Indeed, the development of bacterial infections as well as hepatocellular carcinoma may accelerate the course of the disease at any stage, but especially in decompensated cirrhosis.
      • Moreau R.
      • Jalan R.
      • Gines P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with AD of cirrhosis.
      Having defined the potential field of action, and having emphasised the importance of initiating aetiologic treatment for any degree of hepatic disease at the earliest possible stage, the panel decided to extend the work to all those complications of cirrhosis which have not yet been covered by EASL guidelines, namely: gastrointestinal (GI) bleeding, bacterial infections other than SBP, acute-on-chronic liver failure (ACLF), adrenal failure, HPS, PPHT and CCM. In doing so, we have had to deal with the recommendations regularly proposed by very well recognised international expert groups who have worked in the field of GI bleeding or ascites and ascites-related complications for many years. Given their extreme importance in clinical practice, only specific aspects of their recommendations were further developed in an attempt to give a more integrated view of the pathophysiology and management of patients with decompensated cirrhosis. Thus, this document can no longer be considered an update of earlier guidelines, but rather the first CPG on the management of decompensated cirrhosis with the sole purpose of improving clinical practice.

      Guidelines development process

      A panel of hepatologists with a great interest in decompensated cirrhosis, approved by the EASL Governing Board, wrote and discussed this CPG between March 2017 and February 2018. The guidelines were independently peer reviewed, and all contributors to the CPG disclosed their conflicts of interest by means of a disclosure form provided by the EASL Office prior to work commencing. The EASL Ethics Committee reviewed the composition of the panel to eliminate the potential for real or perceived bias. The CPG panel conflict of interests are declared in this submission. These guidelines have been produced using evidence from PubMed and Cochrane database searches before 27 March 2018. Tables describing the rationale behind the levels of evidence and of recommendations are provided (Table 1).
      Table 1Level of Evidence and Grade of Recommendations.
      Level of evidence
      IRandomised, controlled trials
      II-1Controlled trials without randomisation
      II-2Cohort and case-control analytical studies
      II-3Multiple time series, dramatic uncontrolled experiments
      IIIOpinions of respected authorities, descriptive epidemiology
      Grade of recommendations
      1Strong recommendation: Factors influencing the strength of the recommendation included the quality of the evidence, presumed patient-important outcomes, and cost
      2Weaker recommendation: Variability in preferences and values, or more uncertainty: more likely a weak recommendation is warranted. Recommendation is made with less certainty: higher cost or resource consumption

      Pathophysiology of decompensated cirrhosis

      The transition from compensated asymptomatic cirrhosis to decompensated cirrhosis occurs at a rate of about 5% to 7% per year.
      • D'Amico G.
      • Garcia-Tsao G.
      • Pagliaro L.
      Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies.
      Once decompensation has occurred, cirrhosis becomes a systemic disease, with multi-organ/system dysfunction.
      • Bernardi M.
      • Moreau R.
      • Angeli P.
      • Schnabl B.
      • Arroyo V.
      Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis.
      At this stage, patients become highly susceptible to bacterial infections because of complex cirrhosis-associated immune dysfunction, which involves both innate and acquired immunity.
      • Jalan R.
      • Fernandez J.
      • Wiest R.
      • Schnabl B.
      • Moreau R.
      • Angeli P.
      • et al.
      Bacterial infections in cirrhosis: a position statement based on the EASL Special Conference.
      In turn, patients with bacterial infections are burdened by severe morbidity, up to ACLF, and high mortality.
      • Jalan R.
      • Fernandez J.
      • Wiest R.
      • Schnabl B.
      • Moreau R.
      • Angeli P.
      • et al.
      Bacterial infections in cirrhosis: a position statement based on the EASL Special Conference.
      • Arvaniti V.
      • D'Amico G.
      • Fede G.
      • Manousou P.
      • Tsochatzis E.
      • Pleguezuelo M.
      • et al.
      Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis.
      Because of these events, decompensation represents a prognostic watershed, as the median survival drops from more than 12 years for compensated cirrhosis to about two years for decompensated cirrhosis.
      • D'Amico G.
      • Garcia-Tsao G.
      • Pagliaro L.
      Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies.
      For decades the clinical manifestations of decompensated cirrhosis have been seen as the consequence of a haemodynamic disturbance, the hyperdynamic circulatory syndrome, ascribable to peripheral arterial vasodilation that mainly occurs in the splanchnic circulatory area. The extent of such vasodilation is to endanger effective volaemia, ultimately leading to peripheral organ hypoperfusion, the kidney being most affected.
      • Schrier R.W.
      • Arroyo V.
      • Bernardi M.
      • Epstein M.
      • Henriksen J.H.
      • Rodes J.
      Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis.
      Indeed, reduced effective volaemia brings about the activation of vasoconstrictor and water and sodium retaining mechanisms, such as the renin-angiotensin-aldosterone (RAAS), sympathetic nervous system and arginine-vasopressin secretion. This explains some of the cardinal features of decompensated cirrhosis, such as renal retention of sodium and water leading to ascites formation and HRS. Other manifestations attributable to haemodynamic abnormalities include HPS, increased susceptibility to shock, and a reduced cardiovascular responsiveness to physiological and pharmacological vasoconstrictor stimuli. Subsequent studies have highlighted that a cardiac dysfunction, due to CCM,
      • Wiese S.
      • Hove J.D.
      • Bendtsen F.
      • Moller S.
      Cirrhotic cardiomyopathy: pathogenesis and clinical relevance.
      is also involved in the pathogenesis of effective hypovolaemia.
      • Arroyo V.
      • Terra C.
      • Gines P.
      Advances in the pathogenesis and treatment of type-1 and type-2 hepatorenal syndrome.
      This occurs particularly in the most advanced stages of decompensation, when such an abnormality prevents cardiac output from increasing enough to comply with the needs of systemic circulation. Although the molecular mechanisms responsible for arterial vasodilation, consisting of an enhanced endothelial production of vasodilating substances, such as nitric oxide, carbon monoxide, prostacyclin and endocannabinoids have been convincingly demonstrated,
      • Iwakiri Y.
      • Groszmann R.J.
      The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule.
      the primary causes of such abnormalities remained somewhat obscure until it became clear that patients with advanced cirrhosis present a state of chronic inflammation, as witnessed by increased circulating levels of pro-inflammatory cytokines and chemokines.
      • Claria J.
      • Stauber R.E.
      • Coenraad M.J.
      • Moreau R.
      • Jalan R.
      • Pavesi M.
      • et al.
      Systemic inflammation in decompensated cirrhosis: Characterization and role in acute-on-chronic liver failure.
      This is likely caused by the systemic spread of bacteria and bacterial products, called pathogen associated molecular patterns (PAMPs), as a result of an abnormal bacterial translocation (BT). Changes in the microbiome and increased intestinal permeability account for this phenomenon. A similar role is likely played by other molecules, called danger associated molecular patterns (DAMPs), released by the diseased liver because of local inflammation and cell apoptosis and necrosis. Both PAMPs and DAMPs bind with innate recognition receptors of immune cells that, once activated, produce and release pro-inflammatory molecules, along with reactive oxygen and nitrogen species. This cascade of events contributes to the development of circulatory dysfunction and, along with it, directly favours the development of multi-organ dysfunction and failure (Fig. 1).
      • Bernardi M.
      • Moreau R.
      • Angeli P.
      • Schnabl B.
      • Arroyo V.
      Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis.
      Current strategies for prophylaxis and treatment of decompensation and organ failure in cirrhosis rely on measures aimed to prevent or improve the outcome of each complication, that is renal sodium retention leading to ascites formation, ammonia production in hepatic encephalopathy, effective hypovolaemia after large-volume paracentesis (LVP) or during HRS, renal dysfunction induced by SBP, and intestinal dysbiosis or bacterial overgrowth in patients predisposed to develop infections. All these strategies will be discussed in these CPGs. However, the improved knowledge of the pathophysiological background of decompensated cirrhosis now offers the opportunity for more comprehensive therapeutic and prophylactic approaches to disease management. Indeed, besides treating the underlying aetiologic factor(s), whenever possible, mechanistic approaches to counteract key pathophysiologic mechanisms may prevent or delay disease progression and the incidence of complications and multi-organ dysfunction, thus improving patient survival and quality of life, as well as reducing the economic burden of the disease.
      Figure thumbnail gr1
      Fig. 1The new theory on the development of complications and organ failure/s in patients with cirrhosis (adapted from Ref.
      • Bernardi M.
      • Moreau R.
      • Angeli P.
      • Schnabl B.
      • Arroyo V.
      Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis.
      ). DAMP, damage-associated molecular pattern; HE, hepatic encephalopathy; HPS, hepatopulmonary syndrome; PAMP, pathogen-associated molecular pattern; RNS, reactive nitrogen species; ROS, reactive oxygen species.

      Management of decompensated cirrhosis

      Ideally, the strategy of management of patients with decompensated cirrhosis should be based on preventing cirrhosis progression (i.e. further decompensation) rather than treating complications as they occur. The ultimate treatment for decompensated cirrhosis would be one that targets primarily the pathological alterations within the liver with the aim of restoring the integrity of liver architecture by suppressing inflammation, causing fibrosis regression, regularising the portal and arterial circulation, and normalising cell number and function. Unfortunately, such a treatment does not exist at present. Several antifibrotic or anti-inflammatory drugs have shown promise in experimental models of chronic liver diseases, but no treatment has yet been translated into clinical practice.
      • Trautwein C.
      • Friedman S.L.
      • Schuppan D.
      • Pinzani M.
      Hepatic fibrosis: Concept to treatment.
      Meanwhile, the overall management of decompensated cirrhosis can be addressed using two approaches. The first approach is the suppression of the aetiological factor(s) that has caused liver inflammation and cirrhosis development, whereas the second approach is based on targeting key factors of pathogenesis of cirrhosis decompensation and progression.

      Effects of suppression of aetiological factor on outcome of decompensated cirrhosis

      Removal of the aetiological factor(s) causing liver injury is an important cornerstone in the management of cirrhosis. This approach is clearly effective in preventing decompensation and improving outcome in patients with compensated cirrhosis. However, results in patients with decompensated cirrhosis are less efficacious and probably depend, among other factors, on the actual status of liver disease at the time of removing the aetiological factor of liver injury. For example, although in some patients with decompensated alcoholic cirrhosis suppression of alcohol consumption is associated with progressive “re-compensation” of cirrhosis and excellent long-term outcome, in other patients alcoholic cirrhosis progresses despite stopping alcohol intake.
      • Alvarez M.A.
      • Cirera I.
      • Sola R.
      • Bargallo A.
      • Morillas R.M.
      • Planas R.
      Long-term clinical course of decompensated alcoholic cirrhosis: a prospective study of 165 patients.
      • Powell Jr, W.J.
      • Klatskin G.
      Duration of survival in patients with Laennec's cirrhosis. Influence of alcohol withdrawal, and possible effects of recent changes in general management of the disease.
      Likewise, in patients with cirrhosis due to hepatitis B virus (HBV) infection, treatment with antiviral agents is associated with improved outcome in some, but not all patients.
      • Shim J.H.
      • Lee H.C.
      • Kim K.M.
      • Lim Y.S.
      • Chung Y.H.
      • Lee Y.S.
      • et al.
      Efficacy of entecavir in treatment-naive patients with hepatitis B virus-related decompensated cirrhosis.
      Moreover, treatment of patients with decompensated cirrhosis due to hepatitis C virus infection with direct antiviral agents is associated with beneficial effects in liver function and portal hypertension and likely improves outcome, but these effects are unfortunately not generalisable to all patients treated.
      • Cheung M.C.
      • Walker A.J.
      • Hudson B.E.
      • Verma S.
      • McLauchlan J.
      • Mutimer D.J.
      • et al.
      Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis.
      • Lens S.
      • Alvarado E.
      • Mariño Z.
      • et al.
      Effects of all-oral antiviral therapy on HVPG and systemic hemodynamics in patients with hepatitis C virus-associated cirrhosis.
      The beneficial effects of removing responsible factors in other aetiologies of decompensated cirrhosis are less clear, perhaps with the exception of autoimmune hepatitis.

      Effects of targeting key pathogenic events in prevention of cirrhosis progression

      Several strategies have been evaluated to prevent disease progression in patients with decompensated cirrhosis, including i) targeting microbiome abnormalities and BT, to improve gut-liver axis; ii) improving the disturbed circulatory function; iii) treating the inflammatory state; and iv) targeting portal hypertension.
      Administration of rifaximin has been shown to reduce the risk of development of several complications of cirrhosis besides hepatic encephalopathy in retrospective studies and small case series.
      • Kang S.H.
      • Lee Y.B.
      • Lee J.H.
      • Nam J.Y.
      • Chang Y.
      • Cho H.
      • et al.
      Rifaximin treatment is associated with reduced risk of cirrhotic complications and prolonged overall survival in patients experiencing hepatic encephalopathy.
      Nonetheless, data from prospective randomised double-blind studies are lacking. In patients with decompensated cirrhosis, treatment with norfloxacin reduces the risk of SBP and HRS,
      • Ginès P.
      • Schrier R.W.
      Renal failure in cirrhosis.
      • Moreau R.
      • Elkrief L.
      • Bureau C.
      • Pararnau J.M.
      • Thavenot T.
      • Saliba F.
      • et al.
      A randomized trial of 6-month norfloxacin therapy in patients with Child-Pugh class C cirrhosis.
      but its use is hampered by the possibility of increased risk of infection by resistant bacteria. The potential effectiveness of improving circulatory and kidney function by long-term administration of albumin to patients with decompensated cirrhosis has been explored in two recent randomised controlled trials (RCTs), both published in abstract form, with contradictory findings.
      • Caraceni P.
      • Riggio O.
      • Angeli P.
      • Alessandria C.
      • Neri S.
      • Foschi F.G.
      • et al.
      Long-term albumin administration in decompensated cirrhosis: an open label randomized trial.
      • Sola E.
      • Sola C.
      • Simon-Talero M.
      • Martin-Llahi M.
      • Castellote J.
      • Garcia-Martinez R.
      • et al.
      Midodrine and albumin for prevention of complications of cirrhosis in patients in the waiting list for liver transplantation. A randomized, multicenter, double-blind, placebo-controlled trial.
      The discrepant findings may be related to different doses of albumin used and/or heterogeneity in the study population. Further studies are needed to find out whether long-term albumin administration is efficacious in decompensated cirrhosis. Interestingly, treatment with statins, through their pleotropic effects, has been shown to reduce portal hypertension and improve survival in patients with advanced cirrhosis.
      • Abraldes J.G.
      • Albillos A.
      • Banares R.
      • Turnes J.
      • Gonzalez R.
      • Garcia-Pagan J.C.
      • et al.
      Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial.
      • Abraldes J.G.
      • Villanueva C.
      • Aracil C.
      • Turnes J.
      • Hernandez-Guerra M.
      • Genesca J.
      • et al.
      Addition of simvastatin to standard therapy for the prevention of variceal rebleeding does not reduce rebleeding but increases survival in patients with cirrhosis.
      These remarkable effects require validation in future studies. Another potential terapeutical strategy in the prevention of decompensation may be anticoagulation. Indeed, in a small RCT, a 12-month course of enoxaparin was safe and effective in preventing portal vein thrombosis (PVT) in patients with cirrhosis and a Child-Pugh scores of 7–10. In addition, enoxaparin appeared to delay the occurrence of hepatic decompensation and to improve survival suggesting that both PVT and decompensation may be related to a worsening of portal hypertension and the consequent progressive damage of the intestinal mucosal barrier.
      • Villa E.
      • Cammà C.
      • Marietta M.
      • Luongo M.
      • Critelli R.
      • Colopi S.
      • et al.
      Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis.
      From the same perspective, two other strategies should be considered. In 2010, it was shown that pentoxifylline treatment significantly reduced the risk of liver-related complications compared to placebo in an RCT of patients with advanced cirrhosis. The prevention of these complications, which included bacterial infections, renal failure, and hepatic encephalopathy was probably related to the fact that pentoxifylline prevents intestinal BT and the consequent development of systemic inflammation.
      • Lebrec D.
      • Thabut D.
      • Oberti F.
      • Perarnau J.M.
      • Condat B.
      • Barraud H.
      • et al.
      Pentoxifylline does not decrease short-term mortality but does reduce complications in patients with advanced cirrhosis.
      Finally, some investigations have shown that treatment with propranolol is not only effective in reducing portal hypertension and the consequent the risk of variceal bleeding but also in decreasing the risk of other complications of cirrhosis related to portal hypertension, such as ascites, HRS, SBP, and hepatic encephalopathy.
      • Abraldes J.G.
      • Tarantino I.
      • Turnes J.
      • Garcia-Pagan J.C.
      • Rodes J.
      • Bosch J.
      Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis.
      These effects occur specifically in patients who respond to propranolol treatment by markedly decreasing portal pressure, emphasising the strong relationship between pressure and complications of cirrhosis. Nevertheless, in these studies most of patients had compensated cirrhosis. Therefore, studies should be performed in the group of patients with decompensated cirrhosis with the objective of assessing these beneficial effects in cirrhosis progression.
      • In patients with decompensated cirrhosis, the aetiological factor, should be removed, particularly alcohol consumption and hepatitis B or C virus infection as this strategy is associated with decreased risk of decompensation and increased survival (II-2,1).
      • Strategies based on targeting abnormalities in gut-liver axis by antibiotic administration (i.e. rifaximin), improving the disturbed systemic circulatory function (i.e. long-term albumin administration), decreasing the inflammatory state (i.e. statins), and reducing portal hypertension (i.e. beta-blockers) have shown potential benefit to decrease cirrhosis progression in patients with decompensated cirrhosis. However, further clinical research is needed with these strategies to confirm their safety and potential benefits as therapeutic approaches with the aim of preventing cirrhosis progression in decompensated patients.

      Management of specific complications of decompensated cirrhosis

       Ascites

      Ascites is the most common cause of decompensation in cirrhosis, as 5% to 10% of patients with compensated cirrhosis per year develop this complication.
      • Gines P.
      • Quintero E.
      • Arroyo V.
      • Teres J.
      • Bruguera M.
      • Rimola A.
      • et al.
      Compensated cirrhosis: natural history and prognostic factors.
      The mainstay of ascites formation is renal sodium retention due to the activation of sodium retaining systems, such as the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system. The resulting positive fluid balance ultimately leads to extracellular fluid volume expansion. Reduced effective volaemia secondary to splanchnic arterial vasodilation is a main determinant of these alterations,
      • Schrier R.W.
      • Arroyo V.
      • Bernardi M.
      • Epstein M.
      • Henriksen J.H.
      • Rodes J.
      Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis.
      but renal function abnormalities induced by systemic inflammation also play a role, especially in the most advanced stages of cirrhosis.
      • Bernardi M.
      • Moreau R.
      • Angeli P.
      • Schnabl B.
      • Arroyo V.
      Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis.
      Portal hypertension also contributes
      • Ripoll C.
      • Groszmann R.
      • Garcia-Tsao G.
      • Grace N.
      • Burroughs A.
      • Planas R.
      • et al.
      Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis.
      by acting as a compartmentalising factor of the expanded extracellular fluid volume.
      The occurrence of ascites impairs patient working and social life, often leads to hospitalisation, requires chronic treatment and is a direct cause of further complications, such as SBP, restrictive ventilatory dysfunction, or abdominal hernias. The appearance of ascites heralds a poor prognosis, as the five-year survival drops from about 80% in compensated patients to about 30% in patients with decompensated cirrhosis and ascites.
      • D'Amico G.
      • Garcia-Tsao G.
      • Pagliaro L.
      Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies.

       Uncomplicated ascites

       Evaluation of patients with ascites

      Cirrhosis is the main cause of ascites in the Western world, being responsible for about 80% of cases. Malignancy, heart failure, tuberculosis, pancreatic disease, or other rarer diseases account for the remaining cases. Initial patient evaluation should include history, physical examination, abdominal ultrasound, and laboratory assessment of liver and renal functions, serum and urine electrolytes, as well as an analysis of the ascitic fluid.

       Diagnosis of ascites

      Ascites can be graded from 1 to 3 according to the amount of fluid in the abdominal cavity
      • Moore K.P.
      • Wong F.
      • Gines P.
      • Bernardi M.
      • Ochs A.
      • Salerno F.
      • et al.
      The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club.
      (Table 2). The ascites that recurs at least on three occasions within a 12-month period despite dietary sodium restriction and adequate diuretic dosage is defined as recidivant.
      • Arroyo V.
      • Gines P.
      • Gerbes A.L.
      • Dudley F.J.
      • Gentilini P.
      • Laffi G.
      • et al.
      Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club.
      Table 2Grading of ascites.
      Grade 1.Mild ascites: it is only detectable by ultrasound examination
      Grade 2.Moderate ascites: it is manifest by moderate symmetrical distension of abdomen
      Grade 3.Large or gross ascites: it provokes marked abdominal distension
      Diagnostic paracentesis is indicated in all patients with new onset of grade 2 or 3 ascites and in those admitted to the hospital for any complication of cirrhosis.
      • Moore K.P.
      • Wong F.
      • Gines P.
      • Bernardi M.
      • Ochs A.
      • Salerno F.
      • et al.
      The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club.
      • Arroyo V.
      • Gines P.
      • Gerbes A.L.
      • Dudley F.J.
      • Gentilini P.
      • Laffi G.
      • et al.
      Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club.
      Manual or automated neutrophil count, total protein and albumin concentration, and culture should be always assessed. A neutrophil count above 250 cells/µl denotes SBP.
      • Rimola A.
      • Garcia-Tsao G.
      • Navasa M.
      • Piddock L.J.
      • Planas R.
      • Bernard B.
      • et al.
      Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.
      A total protein concentration <1.5 g/dl is generally considered a risk factor for SBP, although there are conflicting data.
      • Rimola A.
      • Garcia-Tsao G.
      • Navasa M.
      • Piddock L.J.
      • Planas R.
      • Bernard B.
      • et al.
      Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club.
      • Bruns T.
      • Lutz P.
      • Stallmach A.
      Nischalke HD Low ascitic fluid protein does not indicate an increased risk for spontaneous bacterial peritonitis in current cohorts.
      Ascitic fluid culture requires the bedside inoculation of at least 10 ml into blood culture bottles to enhance its sensitivity.
      • Runyon B.A.
      • Canawati H.N.
      • Akriviadis E.A.
      Optimization of ascitic fluid culture technique.
      The calculation of serum-ascites albumin gradient (SAAG) may be useful when the cause of ascites is not immediately evident, as SAAG ≥1.1 g/dl indicates that portal hypertension is involved in ascites formation with an accuracy of about 97%.
      • Runyon B.A.
      • Montano A.A.
      • Akriviadis E.A.
      • Antillon M.R.
      • Irving M.A.
      • McHutchison J.G.
      The serum-ascites albumin gradient is superior to the exudate-transudate concept in the differential diagnosis of ascites.
      Other tests, such as amylase, cytology, or culture for mycobacteria should be guided by clinical presentation. Ascitic cholesterol determination followed by cytology and carcinoembryonic antigen (CEA) determination in samples where cholesterol concentration exceeds 45 mg/dl appears to be a cost-effective method for the differential diagnosis between malignancy-related and non-malignant ascites.
      • Gerbes A.L.
      • Jüngst D.
      • Xie Y.N.
      • Permanetter W.
      • Paumgartner G.
      Ascitic fluid analysis for the differentiation of malignancy-related and nonmalignant ascites. Proposal of a diagnostic sequence.
      • A diagnostic paracentesis is recommended in all patients with new onset grade 2 or 3 ascites, or in those hospitalised for worsening of ascites or any complication of cirrhosis (II-2;1).
      • Neutrophil count and culture of ascitic fluid culture (bedside inoculation blood culture bottles with 10 ml fluid each) should be performed to exclude bacterial peritonitis. A neutrophil count above 250 cells/µl is required to diagnose SBP (II-2;1).
      • Ascitic total protein concentration should be performed to identify patients at higher risk of developing SBP (II-2;1).
      • The SAAG should be calculated when the cause of ascites is not immediately evident, and/or when conditions other than cirrhosis are suspected (II-2;1).
      • Cytology should be performed to differentiate malignancy-related from non-malignant ascites (II-2;1).

       Prognosis of patients with ascites

      The development of ascites in patients with cirrhosis is associated with a poor prognosis, as their one and two-year mortality is about 40 and 50%, respectively.
      EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis.
      Thus, patients with ascites should generally be considered for referral for LT. Hyponatraemia, low arterial pressure, glomerular filtration rate (GFR) and low renal sodium excretion are independent predictors of mortality in cirrhosis with ascites.
      • Llach J.
      • Gines P.
      • Arroyo V.
      • Rimola A.
      • Tito L.
      • Badalamenti S.
      • 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.
      As these parameters are not included in the Child-Pugh score, and only serum creatinine (SCr), which overestimates GFR in cirrhosis,
      • Caregaro L.
      • Menon F.
      • Angeli P.
      • Amodio P.
      • Merkel C.
      • Bortoluzzi A.
      • et al.
      Limitations of serum creatinine level and creatinine clearance as filtration markers in cirrhosis.
      is included in the model for end-stage liver disease (MELD) score, the most commonly used prognostic scores can underestimate the mortality risk in patients with ascites. Modifications of the MELD score, such as the MELD-Na and MELD-Ascites scores have only partially overcome this limitation.
      • Bernardi M.
      • Gitto S.
      • Biselli M.
      The MELD score in patients awaiting liver transplant: strengths and weaknesses.
      Thus, patients with ascites may not receive adequate priority in transplant lists, and improved methods to assess prognosis in these patients are needed. A prognostic score able to identify patients with low MELD score (<18) at high risk of 12-month adverse outcome has recently been proposed, but it still has limited application.
      • Biselli M.
      • Dall'Agata M.
      • Gramenzi A.
      • Gitto S.
      • Liberati C.
      • Brodosi L.
      • et al.
      A new prognostic model to predict dropout from the waiting list in cirrhotic candidates for liver transplantation with MELD score <18.
      • Since the development of grade 2 or 3 ascites in patients with cirrhosis is associated with reduced survival, LT should be considered as a potential treatment option (II-2;1).

       Management of uncomplicated ascites

      Ascites is uncomplicated when it is not infected, refractory or associated with HRS.
      • Moore K.P.
      • Wong F.
      • Gines P.
      • Bernardi M.
      • Ochs A.
      • Salerno F.
      • et al.
      The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club.
      • Arroyo V.
      • Gines P.
      • Gerbes A.L.
      • Dudley F.J.
      • Gentilini P.
      • Laffi G.
      • et al.
      Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club.

       Grade 1 or mild ascites

      No data on the evolution of grade 1 ascites are available, nor it is known whether its treatment modifies its natural history.

       Grade 2 or moderate ascites

      Patients who develop grade 2 ascites do not require hospitalisation, unless other complications are present. They have a positive sodium balance, which can be corrected by reducing the dietary sodium intake and increasing renal sodium excretion with diuretics. Although upright posture favours renal sodium reabsorption
      • Bernardi M.
      • Santini C.
      • Trevisani F.
      • Baraldini M.
      • Ligabue A.
      • Gasbarrini G.
      Renal function impairment induced by change in posture in patients with cirrhosis and ascites.
      and attenuates the response to diuretics,
      • Ring-Larsen H.
      • Henriksen J.H.
      • Wilken C.
      • Clausen J.
      • Pals H.
      • Christensen N.J.
      Diuretic treatment in decompensated cirrhosis and congestive heart failure: effect of posture.
      there is no evidence that a prolonged maintenance of the supine position eases the treatment of ascites.

       Sodium restriction

      The prophylactic use of salt restriction in patients who never had ascites is not supported by evidence. Dietary sodium restriction can lead to the resolution of ascites in about 10% of patients,
      • Bernardi M.
      • Laffi G.
      • Salvagnini M.
      • Azzena G.
      • Bonato S.
      • Marra F.
      • 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.
      especially in those with the first episode of ascites. A clear advantage from the use of low-sodium diets associated with diuretics has not emerged from clinical trials comparing different dietary regimens.
      • Bernardi M.
      • Laffi G.
      • Salvagnini M.
      • Azzena G.
      • Bonato S.
      • Marra F.
      • 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.
      • Michel H.
      • Rueff B.
      • Descos L.
      • et al.
      Salt or no salt in the treatment of cirrhotic ascites: a randomised study.
      Extreme sodium restriction favours the development of diuretic-induced hyponatraemia and renal failure.
      • Reynolds T.B.
      • Lieberman F.L.
      • Goodman A.R.
      Advantages of treatment of ascites without sodium restriction and without complete removal of excess fluid.
      Moreover, even moderate sodium restriction, when not prescribed with an adequate educational programme, is often associated with reduced calorie intake,
      • Morando F.
      • Rosi S.
      • Gola E.
      • Nardi M.
      • Piano S.
      • Fasolato S.
      • et al.
      Adherence to a moderate sodium restriction diet in outpatients with cirrhosis and ascites: a real-life cross-sectional study.
      and may impair nutritional status. The current opinion is that dietary sodium should only be moderately restricted (80–120 mmol/day), mainly to avoid excess salt intake.
      • A moderate restriction of sodium intake (80–120 mmol/day, corresponding to 4.6–6.9 g of salt) is recommended in patients with moderate, uncomplicated ascites (I;1). This is generally equivalent to a no added salt diet with avoidance of pre-prepared meals. Adequate nutritional education of patients on how to manage dietary sodium is also recommended (II-2;1).
      • Diets with a very low sodium content (<40 mmol/day) should be avoided, as they favour diuretic-induced complications and can endanger a patient’s nutritional status (II-2;1).
      • Prolonged bed rest cannot be recommended because there is insufficient evidence that it is beneficial in the treatment of ascites (III;1).

       Diuretics

      Neither diuretics nor LVP are associated with a survival benefit because they act downstream of the pathophysiological cascade, being symptomatic therapies. The negative fluid balance induced by diuretics should not lead to a body weight loss exceeding 0.5 kg/day in patients without peripheral oedema and 1 kg/day in the presence of peripheral oedema to avoid plasma volume contraction, ultimately leading to renal failure and hyponatraemia.
      • Pockros P.J.
      • Reynolds T.B.
      Rapid diuresis in patients with ascites from chronic liver disease: the importance of peripheral edema.
      Since secondary hyperaldosteronism plays a pivotal role in the renal sodium retention in patients with cirrhosis,
      • Bernardi M.
      • Trevisani F.
      • Gasbarrini A.
      • Gasbarrini G.
      Hepatorenal disorders: role of the renin-angiotensin-aldosterone system.
      • Bernardi M.
      • Servadei D.
      • Trevisani F.
      • Rusticali A.G.
      • Gasbarrini G.
      Importance of plasma aldosterone concentration on the natriuretic effect of spironolactone in patients with liver cirrhosis and ascites.
      anti-mineralocorticoid drugs (spironolactone, canrenone or K-canrenoate) represent a mainstay in the medical treatment of ascites.
      • Bernardi M.
      • Servadei D.
      • Trevisani F.
      • Rusticali A.G.
      • Gasbarrini G.
      Importance of plasma aldosterone concentration on the natriuretic effect of spironolactone in patients with liver cirrhosis and ascites.
      Four hundred mg/day represents the maximal dosage usually recommended.
      • Moore K.P.
      • Wong F.
      • Gines P.
      • Bernardi M.
      • Ochs A.
      • Salerno F.
      • et al.
      The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club.
      • Arroyo V.
      • Gines P.
      • Gerbes A.L.
      • Dudley F.J.
      • Gentilini P.
      • Laffi G.
      • et al.
      Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club.
      The mechanism of action of anti-mineralocorticoids explains their slow effect. In fact, the activated aldosterone pathway, which involves interaction with a cytosolic receptor and, then, a nuclear receptor, needs to be exhausted before their natriuretic effect arises. Therefore, the dosage of these drugs should not be increased earlier than 72 h. Amiloride, a diuretic acting in the collecting duct, is less effective than anti-mineralocorticoids, and should only be used in patients who develop severe side effects with aldosterone antagonists.
      • Angeli P.
      • Dalla Pria M.
      • De Bei E.
      • Albino G.
      • Caregaro L.
      • Merkel C.
      • et al.
      Randomized clinical study of the efficacy of amiloride and potassium canrenoate in nonazotemic cirrhotic patients with ascites.
      Proximal tubular sodium reabsorption promotes renal sodium retention through various mechanisms, such as increased angiotensin II production, sympatho-adrenergic hyperactivity and reduced renal perfusion.
      • Bernardi M.
      • Trevisani F.
      • Gasbarrini A.
      • Gasbarrini G.
      Hepatorenal disorders: role of the renin-angiotensin-aldosterone system.
      As proximal tubular sodium reabsorption can become relatively prevalent in patients with long-standing ascites,
      • Angeli P.
      • Gatta A.
      • Caregaro L.
      • Menon F.
      • Sacerdoti D.
      • Merkel C.
      • et al.
      Tubular site of renal sodium retention in ascitic liver cirrhosis evaluated by lithium clearance.
      • 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.
      loop diuretics are indicated in this setting. However, they should be combined with but not substituted for anti-mineralocorticoids. Indeed, despite their potent activity, the natriuretic effect of loop diuretics can be completely blunted by unopposed hyperaldosteronism.
      • Perez-Ayuso R.M.
      • Arroyo V.
      • Planas R.
      • Gaya J.
      • Bory F.
      • Rimola A.
      • et al.
      Randomized comparative study of efficacy of furosemide vs. spironolactone in nonazotemic cirrhosis with ascites. Relationship between the diuretic response and the activity of the renin-aldosterone system.
      Whether diuretic treatment should be initiated with anti-mineralocorticoids alone or should also include a loop diuretic has long been debated. Two studies have addressed this matter providing apparently conflicting results because of differences in patient populations.
      • Angeli P.
      • Fasolato S.
      • Mazza E.
      • Okolicsanyi L.
      • Maresio G.
      • Velo E.
      • et al.
      Combined vs. sequential diuretic treatment of ascites in non-azotaemic patients with cirrhosis: results of an open randomised clinical trial.
      • Santos J.
      • Planas R.
      • Pardo A.
      • Durandez R.
      • Cabre E.
      • Morillas R.M.
      • 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.
      In both studies, the effects of a diuretic regimen initially consisting of spironolactone or K-canrenoate alone at stepwise increasing dosages (from 100/200 to 400 mg/day), with furosemide added in non-responder patients, were compared with those of the combination of anti-mineralocorticoids with furosemide (from 40 to 160 mg/day) from the beginning of treatment. In one study,
      • Santos J.
      • Planas R.
      • Pardo A.
      • Durandez R.
      • Cabre E.
      • Morillas R.M.
      • 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.
      the response rate, the rapidity of ascites mobilisation and the incidence of diuretic-induced complications were similar in both regimens. However, as the sequential treatment required less dose adjustments, it appeared to be more suitable for treating ascites on an outpatient basis. In the other study,
      • Angeli P.
      • Fasolato S.
      • Mazza E.
      • Okolicsanyi L.
      • Maresio G.
      • Velo E.
      • et al.
      Combined vs. sequential diuretic treatment of ascites in non-azotaemic patients with cirrhosis: results of an open randomised clinical trial.
      the combined regimen achieved the resolution of ascites in a shorter time, with a lower incidence of side effects, mainly hyperkalemia. Such divergent results likely arose from differences in the patient populations. In one study,
      • Santos J.
      • Planas R.
      • Pardo A.
      • Durandez R.
      • Cabre E.
      • Morillas R.M.
      • 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.
      patients with ascites at the first appearance and well preserved renal function prevailed, while, in the other,
      • Angeli P.
      • Fasolato S.
      • Mazza E.
      • Okolicsanyi L.
      • Maresio G.
      • Velo E.
      • et al.
      Combined vs. sequential diuretic treatment of ascites in non-azotaemic patients with cirrhosis: results of an open randomised clinical trial.
      most patients had recurrent ascites and many showed a substantial reduction of GFR. Thus, patients with ascites at the first appearance can confidently be treated with anti-mineralocorticoids alone, as they will likely develop a satisfactory response with few side effects. Patients with long-standing, recurrent ascites should receive the combination therapy, which likely shortens the time to achieve natriuresis and lowers the incidence of hyperkalemia.
      EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis.
      In a randomised double-blind cross-over trial torasemide induced greater cumulative 24 h diuresis than furosemide, suggesting that torasemide might be more advantageous in patients exhibiting a weak response to furosemide.
      • Gerbes A.L.
      • Bertheau-Reitha U.
      • Falkner C.
      • Jüngst D.
      • Paumgartner G.
      Advantages of the new loop diuretic torasemide over furosemide in patients with cirrhosis and ascites. A randomized, double blind cross-over trial.
      Following mobilisation of ascites, diuretics should be tapered to the lowest dosages able to maintain patients with minimal or no ascites, to minimise side effects. Whenever possible, an aetiologic treatment of the underlying cirrhosis should be instituted, as this eases the control of ascites in many cases.

       Complications of diuretic therapy

      The haemodynamic status of patients with cirrhosis and ascites
      • Schrier R.W.
      • Arroyo V.
      • Bernardi M.
      • Epstein M.
      • Henriksen J.H.
      • Rodes J.
      Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis.
      makes them highly susceptible to rapid reductions in extracellular fluid volume, which mostly occur with loop diuretics. Thus, renal failure is frequent in this setting,
      • Pockros P.J.
      • Reynolds T.B.
      Rapid diuresis in patients with ascites from chronic liver disease: the importance of peripheral edema.
      as is hepatic encephalopathy, also favoured by increased renal ammonia production. Loop diuretics can also lead to potassium and magnesium depletion. Hyponatraemia is another common diuretic-induced side effect in cirrhosis. It mostly, but not exclusively, occurs with loop diuretics, as they inhibit Na-K-Cl transporter and, therefore, solute-free water generation. Plasma volume contraction can also enhance arginine-vasopressin release. Thus, hyponatraemia can also ensue with anti-mineralocorticoid administration, albeit infrequently. Most experts agree on at least temporarily withdrawing diuretics when serum sodium concentration decreases below 120–125 mmol/L. Hyperkalemia, especially in patients with reduced renal perfusion, and painful gynecomastia are the most common side effects induced by anti-mineralocorticoids.
      Muscle cramps can impair quality of life in patients receiving diuretics. Albumin infusion can relieve cramps,
      • Angeli P.
      • Albino G.
      • Carraro P.
      • Dalla Pria M.
      • Merkel C.
      • Caregaro L.
      • et al.
      Cirrhosis and muscle cramps: evidence of a causal relationship.
      as well as baclofen (10 mg/day, with a weekly increase of 10 mg/day up to 30 mg/day), which was safely used in a recent RCT.
      • Elfert A.A.
      • Abo Ali L.
      • Soliman S.
      • Zakaria S.
      • Shehab El-Din I.
      • Elkhalawany W.
      • et al.
      Randomized placebo-controlled study of baclofen in the treatment of muscle cramps in patients with liver cirrhosis.
      One RCT investigated the use of quinidine at the dose of 400 mg/day for four weeks in patients with cirrhosis with painful muscle cramps. Although more effective than placebo, quinidine was associated with diarrhoea in about one-third of cases requiring treatment withdrawal.
      • Lee F.Y.
      • Lee S.D.
      • Tsai Y.T.
      • et al.
      A randomized controlled trial of quinidine in the treatment of cirrhotic patients with muscle cramps.
      Because of the frequency of diuretic-induced side effects, especially during the first month of treatment,
      • Angeli P.
      • Fasolato S.
      • Mazza E.
      • Okolicsanyi L.
      • Maresio G.
      • Velo E.
      • et al.
      Combined vs. sequential diuretic treatment of ascites in non-azotaemic patients with cirrhosis: results of an open randomised clinical trial.
      serial measurements of SCr, sodium, and potassium are warranted. The assessment of urine sodium excretion can be limited to non-responders, to unveil excessive sodium intake.
      • Patients with the first episode of grade 2 (moderate) ascites should receive an anti-mineralocorticoid drug alone, starting at 100 mg/day with stepwise increases every 72 h (in 100 mg steps) to a maximum of 400 mg/day if there is no response to lower doses (I;1).
      • In patients who do not respond to anti-mineralocorticoids, as defined by a body weight reduction 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) (I;1).
      • Patients with long-standing or recurrent ascites should be treated with a combination of an anti-mineralocorticoid drug and furosemide, the dose of which should be increased sequentially according to the response, as explained (I;1).
      • Torasemide can be given in patients exhibiting a weak response to furosemide (I;2).
      • During diuretic therapy a maximum weight loss of 0.5 kg/day in patients without oedema and 1 kg/day in patients with oedema is recommended (II-2;1).
      • Once ascites has largely resolved, the dose of diuretics should be reduced to the lowest effective dose (III;1).
      • During the first weeks of treatment patients should undergo frequent clinical and biochemical monitoring particularly on first presentation (I;1).
      • In patients presenting with GI haemorrhage, renal impairment, hepatic encephalopathy, hyponatraemia, or alterations in serum potassium concentration, these abnormalities should be corrected before starting diuretic therapy (III;1). In these patients, cautious initiation of diuretic therapy and frequent clinical and biochemical assessments should be performed (III;1). Diuretic therapy is generally not recommended in patients with persistent overt hepatic encephalopathy (III;1).
      • Diuretics should be discontinued if severe hyponatraemia (serum sodium concentration <125 mmol/L), AKI, worsening hepatic encephalopathy, or incapacitating muscle cramps develop (III;1).
      • Furosemide should be stopped if severe hypokalemia occurs (<3 mmol/L). Anti-mineralocorticoids should be stopped if severe hyperkalemia occurs (>6 mmol/L) (III;1).
      • Albumin infusion or baclofen administration (10 mg/day, with a weekly increase of 10 mg/day up to 30 mg/day) are recommended in patients with muscle cramps (I;1).

       Grade 3 or large ascites

      The treatment of choice for the management of patients with grade 3 ascites is represented by LVP. Paracentesis should be performed under strict sterile conditions using disposable sterile materials. The procedure is associated with a very low risk of local complications, particularly bleeding
      • Lin C.H.
      • Shih F.Y.
      • Ma M.H.
      • Chiang W.C.
      • Yang C.W.
      • Ko P.C.
      Should bleeding tendency deter abdominal paracentesis?.
      • Pache I.
      • Bilodeau M.
      Severe haemorrhage following abdominal paracentesis for ascites in patients with liver disease.
      even in patients with international normalized ratio (INR)>1.5 and platelet count <50,000/µl, minor bleeding from puncture site occurred in two out of 142 paracentesis.
      • Lin C.H.
      • Shih F.Y.
      • Ma M.H.
      • Chiang W.C.
      • Yang C.W.
      • Ko P.C.
      Should bleeding tendency deter abdominal paracentesis?.
      Thus, there are no data supporting the prophylactic use of fresh frozen plasma of pooled platelets, even though these are employed in many centres when prothrombin activity is below 40% and platelet count <40,000/µl. LVP should be avoided in the presence of disseminated intravascular coagulation. Other contraindications to LVP are reported (Table 3).
      Table 3Contraindications to paracentesis.
      • Uncooperative patient
      • Abdominal skin infection at the proposed puncture sites
      • Pregnancy
      • Severe coagulopathy (accelerated fibrinolysis or disseminated intravascular coagulation)
      • Severe bowel distension
      The removal of large volumes of ascitic fluid is potentially associated with a further reduction of effective blood volume, a condition known as post-paracentesis circulatory dysfunction (PPCD).
      • Gines P.
      • Tito L.
      • Arroyo V.
      • Planas R.
      • Panes J.
      • Viver J.
      • et al.
      Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis.
      The clinical manifestations of PPCD are renal failure, dilutional hyponatraemia, hepatic encephalopathy and decreased survival.
      • Gines P.
      • Tito L.
      • Arroyo V.
      • Planas R.
      • Panes J.
      • Viver J.
      • et al.
      Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis.
      Plasma volume expansion should be performed at the completion of LVP to prevent this complication. Artificial plasma expanders, such as dextran-70 (8 g/L of ascites removed)
      • Gines A.
      • Fernandez-Esparrach G.
      • Monescillo A.
      • Vila C.
      • Domenech E.
      • Abecasis R.
      • et al.
      Randomized trial comparing albumin, dextran 70, and polygeline in cirrhotic patients with ascites treated by paracentesis.
      or polygeline (150 ml/L),
      • Gines A.
      • Fernandez-Esparrach G.
      • Monescillo A.
      • Vila C.
      • Domenech E.
      • Abecasis R.
      • et al.
      Randomized trial comparing albumin, dextran 70, and polygeline in cirrhotic patients with ascites treated by paracentesis.
      saline solution (170 ml/L),
      • Sola-Vera J.
      • Minana J.
      • Ricart E.
      • Planella M.
      • Gonzalez B.
      • Torras X.
      • et al.
      Randomized trial comparing albumin and saline in the prevention of paracentesis-induced circulatory dysfunction in cirrhotic patients with ascites.
      only show a similar efficacy to 20% albumin (8 g/L)
      • Gines A.
      • Fernandez-Esparrach G.
      • Monescillo A.
      • Vila C.
      • Domenech E.
      • Abecasis R.
      • et al.
      Randomized trial comparing albumin, dextran 70, and polygeline in cirrhotic patients with ascites treated by paracentesis.
      when less than 5 L of ascites are removed. However, polygeline is no longer used in many countries because of the potential risk of transmission of prions and dextran carries the risk of severe allergic reaction and renal failure. A meta-analysis of randomised trials showed that albumin is superior to any other plasma expander or vasoconstrictor not only in preventing PPCD, but also its clinical consequences, such as hyponatraemia and mortality.
      • Bernardi M.
      • Caraceni P.
      • Navickis R.J.
      • Wilkes M.M.
      Albumin infusion in patients undergoing large-volume paracentesis: a meta-analysis of randomized trials.
      Moreover, albumin infusion after LVP appears to be more cost-effective than a cheaper plasma volume expander, such as polygeline, because of the lower number of liver-related complications and hospital costs for a 30-day period.
      • Moreau R.
      • Valla D.C.
      • Durand-Zaleski I.
      • Bronowicki J.P.
      • Durand F.
      • Chaput J.C.
      • et al.
      Comparison of outcome in patients with cirrhosis and ascites following treatment with albumin or a synthetic colloid: a randomised controlled pilot trail.
      LVP combined with infusion of albumin in patients with grade 3 ascites is more effective and safer than diuretics.
      • Gines P.
      • Arroyo V.
      • Quintero E.
      • Planas R.
      • Bory F.
      • Cabrera J.
      • et al.
      Comparison of paracentesis and diuretics in the treatment of cirrhotics with tense ascites. Results of a randomized study.
      • Salerno F.
      • Badalamenti S.
      • Incerti P.
      • Tempini S.
      • Restelli B.
      • Bruno S.
      • et al.
      Repeated paracentesis and i.v. albumin infusion to treat 'tense' ascites in cirrhotic patients. A safe alternative therapy.
      However, LVP does not modify the underlying pathophysiological abnormalities leading to ascites formation. Thus, patients treated with LVP require diuretic therapy to prevent the re-accumulation of ascites.
      • Fernandez-Esparrach G.
      • Guevara M.
      • Sort P.
      • Pardo A.
      • Jimenez W.
      • Gines P.
      • et al.
      Diuretic requirements after therapeutic paracentesis in non-azotemic patients with cirrhosis. A randomized double-blind trial of spironolactone vs. placebo.
      • LVP is the first-line therapy in patients with large ascites (grade 3 ascites), which should be completely removed in a single session (I;1).
      • LVP should be followed with plasma volume expansion to prevent PPCD (I;1).
      • In patients undergoing LVP of greater than 5 L of ascites, plasma volume expansion should be performed by infusing albumin (8 g/L of ascites removed), as it is more effective than other plasma expanders, which are not recommended for this setting (I;1).
      • In patients undergoing LVP of less than 5 L of ascites, the risk of developing PPCD 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 (III;1).
      • After LVP, patients should receive the minimum dose of diuretics necessary to prevent re-accumulation of ascites (I;1).
      • When needed, LVP should also be performed in patients with AKI or SBP (III;1).

       Drugs contraindicated in patients with ascites

      As non-steroidal anti-inflammatory drugs inhibit renal prostaglandin synthesis, they should not be used in patients with cirrhosis and ascites, where an increased vasodilating prostaglandin synthesis counteracts the renal vasoconstrictor effects of angiotensin II. Indeed, their administration can lead to acute renal failure, hyponatraemia, and diuretic resistance.
      • Elia C.
      • Graupera I.
      • Barreto R.
      • Solà E.
      • Moreira R.
      • Huelin P.
      • et al.
      Severe acute kidney injury associated with non-steroidal antiinflammatory drugs in cirrhosis: a case-control study.
      It would appear that selective inhibitors of cyclooxygenase-2 do not impair renal function and response to diuretics in patients with ascites.
      • Claria J.
      • Kent J.D.
      • Lopez-Parra M.
      • Escolar G.
      • Ruiz-Del-Arbol L.
      • Gines P.
      • et al.
      Effects of celecoxib and naproxen on renal function in nonazotemic patients with cirrhosis and ascites.
      However, it is not known whether these drugs can be safely used in clinical practice when analgesia is needed. Patients with ascites are also particularly sensitive to the renal vasoconstrictor effect of endogenous adenosine, and dipyridamole can induce a marked reduction in renal perfusion.
      • Llach J.
      • Gines P.
      • Arroyo V.
      • Salmeron J.M.
      • Gines A.
      • Jimenez W.
      • et al.
      Effect of dipyridamole on kidney function in cirrhosis.
      The maintenance of an adequate arterial pressure in cirrhosis with ascites is assured by the activation of endogenous vasoconstrictor systems. Thus, angiotensin-converting enzyme inhibitors,
      • 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.
      angiotensin II receptor antagonists, and α1-adrenergic blockers
      • Albillos A.
      • Lledo J.L.
      • Rossi I.
      • Perez-Paramo M.
      • Tabuenca M.J.
      • Banares R.
      • et al.
      Continuous prazosin administration in cirrhotic patients: effects on portal hemodynamics and on liver and renal function.
      should be avoided, as they can induce arterial hypotension and renal function impairment. Aminoglycosides should be avoided in the treatment of bacterial infections, except in specific cases (discussed later), because they are associated with high incidence of nephrotoxicity.
      • Cabrera J.
      • Arroyo V.
      • Ballesta A.M.
      • Rimola A.
      • Gual J.
      • Elena M.
      • et al.
      Aminoglycoside nephrotoxicity in cirrhosis. Value of urinary beta 2-microglobulin to discriminate functional renal failure from acute tubular damage.
      Although cirrhosis with ascites and preserved renal function does not appear to be a risk factor for renal failure induced by contrast media,
      • Guevara M.
      • Fernández-Esparrach G.
      • Alessandria C.
      • Torre A.
      • Terra C.
      • Montañà X.
      • et al.
      Effects of contrast media on renal function in patients with cirrhosis: a prospective study.
      this cannot be excluded in patients with impaired renal function. In these cases, preventive measures such as plasma volume expansion with saline may be employed.
      • Solomon R.
      • Werner C.
      • Mann D.
      • D'Elia J.
      • Silva P.
      Comparison of saline, mannitol, and furosemide to prevent acute decreases in renal function induced by radiocontrast agents.
      • Non-steroidal anti-inflammatory drugs should not be used in patients with ascites because of the high risk of developing further sodium retention, hyponatraemia, and AKI (II-2;1).
      • Angiotensin-converting-enyzme inhibitors, angiotensin II antagonists, or α1-adrenergic receptor blockers should not generally be used in patients with ascites because of increased risk of renal impairment (II-2;1).
      • The use of aminoglycosides is discouraged, as they are associated with an increased risk of AKI. Their use should be reserved for patients with severe bacterial infections that cannot be treated with other antibiotics (II-2;1).
      • In patients with ascites and preserved renal function, the use of contrast media does not appear to be associated with an increased risk of renal impairment (II-2). There are insufficient data in patients with renal failure. Nevertheless, a cautious use of contrast media and the use of preventive measures for renal impairment are recommended (III;1).

       Refractory ascites

       Evaluation of patients with refractory ascites

      According to the criteria of the International Ascites Club, refractory ascites is defined as ‘‘ascites that cannot be mobilised or the early recurrence of which (i.e., after LVP) cannot be satisfactorily prevented by medical therapy”.
      • Moore K.P.
      • Wong F.
      • Gines P.
      • Bernardi M.
      • Ochs A.
      • Salerno F.
      • et al.
      The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club.
      • Arroyo V.
      • Gines P.
      • Gerbes A.L.
      • Dudley F.J.
      • Gentilini P.
      • Laffi G.
      • et al.
      Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club.
      The diagnostic criteria of refractory ascites are shown in Table 4. Refractoriness of ascites is associated with a poor prognosis, with a median survival of about six months.
      • 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.
      Therefore, if a patient with refractory ascites has not yet been considered for LT, he/she should be immediately referred to a liver transplant center. The potential underestimation of the mortality risk by commonly used prognostic scores, as discussed earlier also applies to patients with refractory ascites.
      • Guardiola J.
      • Baliellas C.
      • Xiol X.
      • Fernandez Esparrach G.
      • Gines P.
      • Ventura P.
      • et al.
      External validation of a prognostic model for predicting survival of cirrhotic patients with refractory ascites.
      • The diagnosis of refractory ascites relies on the assessment of the response of ascites to diuretic therapy and salt restriction. Such an evaluation should be done in stable patients without associated complications, such as bleeding or infection, after ascertaining patient compliance to treatment (III;1).
      • Patients with refractory ascites should be evaluated for LT (III;1).
      Table 4Definition and diagnostic criteria for refractory ascites in cirrhosis.
      Definition
      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
      Diagnostic criteria
      Treatment durationPatients must be on intensive diuretic therapy (spironolactone 400 mg/day and furosemide 160 mg/day) for at least one week and on a salt-restricted diet of less than 90 mmol/day
      Lack of responseMean weight loss of <0.8 kg over four days and urinary sodium output less than the sodium intake
      Early ascites recurrenceReappearance of grade 2 or 3 ascites within four weeks of initial mobilisation
      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
      Invalidating muscle cramps

       Management of refractory ascites

       Large-volume paracentesis

      There is general agreement that LVP is an effective and safe treatment of refractory ascites,
      • Moore K.P.
      • Wong F.
      • Gines P.
      • Bernardi M.
      • Ochs A.
      • Salerno F.
      • et al.
      The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club.
      • Runyon B.A.
      • Canawati H.N.
      • Akriviadis E.A.
      Optimization of ascitic fluid culture technique.
      which should be associated with albumin administration to prevent PPCD.

       Diuretics in patients with refractory ascites.

      Once refractoriness of ascites has been ascertained, diuretics should be discontinued. Only when renal sodium excretion on diuretics exceeds 30 mmol/day, maintenance of diuretic therapy can be considered, when tolerated.
      • Moore K.P.
      • Wong F.
      • Gines P.
      • Bernardi M.
      • Ochs A.
      • Salerno F.
      • et al.
      The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club.

       Non-selective beta-blockers in patients with refractory ascites

      The controversial issue on the use of non-selective beta-blockers (NSBBs) in patients with ascites and, particularly, in those with refractory ascites will be developed in the section dedicated to GI bleeding.

       Transjugular intrahepatic portosystemic shunts

      Transjugular intrahepatic portosystemic shunts (TIPS) decompresses the portal system by shunting an intrahepatic portal branch into a hepatic vein. Its insertion accentuates perpheral arterial vasodilation in the short term. However, within 4–6 weeks its result is an improvement in effective volaemia and renal function, ultimately leading to an increase in renal sodium excretion.
      • Huonker M.
      • Schumacher Y.O.
      • Ochs A.
      • Sorichter S.
      • Keul J.
      • Rossle M.
      Cardiac function and haemodynamics in alcoholic cirrhosis and effects of the transjugular intrahepatic portosystemic stent shunt.
      • Sanyal A.J.
      • Freedman A.M.
      • Luketic V.A.
      • Purdum 3rd, P.P.
      • Shiffman M.L.
      • DeMeo J.
      • et al.
      The natural history of portal hypertension after transjugular intrahepatic portosystemic shunts.
      • 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.
      • Wong F.
      • Sniderman K.
      • Liu P.
      • Blendis L.
      The mechanism of the initial natriuresis after transjugular intrahepatic portosystemic shunt.
      • Gerbes A.L.
      • Gülberg 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.
      TIPS-induced natriuresis can be delayed by advanced age and reduced pre-TIPS GFR,
      • Wong F.
      • Sniderman K.
      • Liu P.
      • Blendis L.
      The mechanism of the initial natriuresis after transjugular intrahepatic portosystemic shunt.
      and prevented by intrinsic kidney disease.
      • 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.
      TIPS may also exert beneficial effects on nitrogen balance and nutrition
      • Plauth M.
      • Schutz T.
      • Buckendahl D.P.
      • Kreymann G.
      • Pirlich M.
      • Grungreiff S.
      • et al.
      Weight gain after transjugular intrahepatic portosystemic shunt is associated with improvement in body composition in malnourished patients with cirrhosis and hypermetabolism.
      and quality of life.
      • 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.
      A major complication after TIPS insertion using bare stent grafts is the development of hepatic encephalopathy, which can occur in up to 50% of patients.
      • Casado M.
      • Bosch J.
      • Garcia-Pagan J.C.
      • Bru C.
      • Banares R.
      • Bandi J.C.
      • et al.
      Clinical events after transjugular intrahepatic portosystemic shunt: correlation with hemodynamic findings.
      • 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.
      The incidence of this complication can be significantly reduced to about 18% with the use of polytetrafluoroethylene (PTFE)-covered stent grafts of 8 mm,
      • Sauerbruch T.
      • Mengel M.
      • Dollinger M.
      • Zipprich A.
      • Rossle M.
      • Panther E.
      • et al.
      Prevention of rebleeding from esophageal varices in patients with cirrhosis receiving small-diameter stents vs. hemodynamically controlled medical therapy.
      a result confirmed by a recent randomised trial comparing 8 mm and 10 mm stent grafts.
      • Wang Q.
      • Lv Y.
      • Bai M.
      • Wang Z.
      • Liu H.
      • He C.
      • et al.
      Eight millimetre covered TIPS does not compromise shunt function but reduces hepatic encephalopathy in preventing variceal rebleeding.
      Notably, this favourable effect is better than with larger stent grafts underdilated to 8 mm. Indeed, it has been shown that underdilated 10 mm stent grafts passively expand to almost the full diameter within 1–6 weeks.
      • Pieper C.C.
      • Jansen C.
      • Meyer C.
      • Nadal J.
      • Lehmann J.
      • Schild H.H.
      • et al.
      Prospective evaluation of passive expansion of partially dilated transjugular intrahepatic portosystemic shunt stent grafts-a three-dimensional sonography study.
      It must be underlined that the indication for TIPS insertion in these studies was the prevention or treatment of recurrent bleeding, which may restrict the relevance of these results in patients with refractory ascites. Dysfunction of TIPS with bare stent grafts because of stent thrombosis and stenosis can develop in up to 80% of cases.
      • Casado M.
      • Bosch J.
      • Garcia-Pagan J.C.
      • Bru C.
      • Banares R.
      • Bandi J.C.
      • et al.
      Clinical events after transjugular intrahepatic portosystemic shunt: correlation with hemodynamic findings.
      This complication has been significantly reduced with the use of PTFE-covered stents.
      • Bureau C.
      • Garcia-Pagan J.C.
      • Otal P.
      • Pomier-Layrargues G.
      • Chabbert V.
      • Cortez C.
      • et al.
      Improved clinical outcome using polytetrafluoroethylene-coated stents for TIPS: results of a randomized study.

       Controlled studies and meta-analysis

      The clinical effects of TIPS with bare stents in patients with refractory or recurrent ascites have been assessed in six prospective RCTs,
      • Gines P.
      • Uriz J.
      • Calahorra B.
      • Garcia-Tsao G.
      • Kamath P.S.
      • Del Arbol L.R.
      • et al.
      Transjugular intrahepatic portosystemic shunting vs. paracentesis plus albumin for refractory ascites in cirrhosis.
      • Lebrec D.
      • Giuily N.
      • Hadengue A.
      • Vilgrain V.
      • Moreau R.
      • Poynard T.
      • et al.
      Transjugular intrahepatic portosystemic shunts: comparison with paracentesis in patients with cirrhosis and refractory ascites: a randomized trial. French Group of Clinicians and a Group of Biologists.
      • Narahara Y.
      • Kanazawa H.
      • Fukuda T.
      • Matsushita Y.
      • Harimoto H.
      • Kidokoro H.
      • et al.
      Transjugular intrahepatic portosystemic shunt vs. paracentesis plus albumin in patients with refractory ascites who have good hepatic and renal function: a prospective randomized trial.
      • Rossle 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.
      • Salerno F.
      • Merli M.
      • Riggio O.
      • Cazzaniga M.
      • Valeriano V.
      • Pozzi M.
      • et al.
      Randomized controlled study of TIPS vs. paracentesis plus albumin in cirrhosis with severe ascites.
      • Sanyal A.J.
      • Genning C.
      • Reddy K.R.
      • Wong F.
      • Kowdley K.V.
      • Benner K.
      • et al.
      The North American study for the treatment of refractory ascites.
      whose main features are reported (Table 5). Based on these RCTs, seven meta-analyses were performed.
      • Albillos A.
      • Banares R.
      • Gonzalez M.
      • Catalina M.V.
      • Molinero L.M.
      A meta-analysis of transjugular intrahepatic portosystemic shunt vs. paracentesis for refractory ascites.
      • Bai M.
      • Qi X.S.
      • Yang Z.P.
      • Yang M.
      • Fan D.M.
      • Han G.H.
      TIPS improves liver transplantation-free survival in cirrhotic patients with refractory ascites: an updated meta-analysis.
      • Chen R.P.
      • Zhu Ge X.J.
      • Huang Z.M.
      • Ye X.H.
      • Hu C.Y.
      • Lu G.R.
      • et al.
      Prophylactic use of transjugular intrahepatic portosystemic shunt aids in the treatment of refractory ascites: metaregression and trial sequential 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.
      • 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 vs. 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.
      The final messages can be summarised as follow: i) TIPS controlled ascites better than LVP, and ii) TIPS is followed by a greater incidence of hepatic encephalopathy. However, discrepant results were obtained with respect to survival. A better survival with LVP, mainly because of a detrimental effect of TIPS in Child-Pugh class C patients, was reported by one study,
      • Lebrec D.
      • Giuily N.
      • Hadengue A.
      • Vilgrain V.
      • Moreau R.
      • Poynard T.
      • et al.
      Transjugular intrahepatic portosystemic shunts: comparison with paracentesis in patients with cirrhosis and refractory ascites: a randomized trial. French Group of Clinicians and a Group of Biologists.
      while no difference was reported by two.
      • Gines P.
      • Uriz J.
      • Calahorra B.
      • Garcia-Tsao G.
      • Kamath P.S.
      • Del Arbol L.R.
      • et al.
      Transjugular intrahepatic portosystemic shunting vs. paracentesis plus albumin for refractory ascites in cirrhosis.
      • Sanyal A.J.
      • Genning C.
      • Reddy K.R.
      • Wong F.
      • Kowdley K.V.
      • Benner K.
      • et al.
      The North American study for the treatment of refractory ascites.
      A better survival with TIPS was reported in another two studies,
      • Narahara Y.
      • Kanazawa H.
      • Fukuda T.
      • Matsushita Y.
      • Harimoto H.
      • Kidokoro H.
      • et al.
      Transjugular intrahepatic portosystemic shunt vs. paracentesis plus albumin in patients with refractory ascites who have good hepatic and renal function: a prospective randomized trial.
      • Salerno F.
      • Merli M.
      • Riggio O.
      • Cazzaniga M.
      • Valeriano V.
      • Pozzi M.
      • et al.
      Randomized controlled study of TIPS vs. paracentesis plus albumin in cirrhosis with severe ascites.
      while, in the remaining one,
      • Rossle 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.
      although a survival advantage was not found, TIPS was independently associated with transplant-free survival at multivariate analysis. In four meta-analyses including the five studies available at that time no survival advantantage with TIPS emerged. However, a trend towards reduced mortality with TIPS was seen
      • D'Amico G.
      • Luca A.
      • Morabito A.
      • Miraglia R.
      • D'Amico M.
      Uncovered transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis.
      after the exclusion of an outlier trial.
      • Lebrec D.
      • Giuily N.
      • Hadengue A.
      • Vilgrain V.
      • Moreau R.
      • Poynard T.
      • et al.
      Transjugular intrahepatic portosystemic shunts: comparison with paracentesis in patients with cirrhosis and refractory ascites: a randomized trial. French Group of Clinicians and a Group of Biologists.
      The latter was also excluded in the only meta-analysis on individual patient data, and an increased transplant-free survival was found.
      • Salerno F.
      • Camma C.
      • Enea M.
      • Rossle M.
      • Wong F.
      Transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis of individual patient data.
      Finally, the two meta-analyses that included all six trials
      • Bai M.
      • Qi X.S.
      • Yang Z.P.
      • Yang M.
      • Fan D.M.
      • Han G.H.
      TIPS improves liver transplantation-free survival in cirrhotic patients with refractory ascites: an updated meta-analysis.
      • Chen R.P.
      • Zhu Ge X.J.
      • Huang Z.M.
      • Ye X.H.
      • Hu C.Y.
      • Lu G.R.
      • et al.
      Prophylactic use of transjugular intrahepatic portosystemic shunt aids in the treatment of refractory ascites: metaregression and trial sequential meta-analysis.
      provided contrasting results, as an improved transplant-free survival was found in one,
      • Salerno F.
      • Camma C.
      • Enea M.
      • Rossle M.
      • Wong F.
      Transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis of individual patient data.
      while a survival advantage with TIPS was limited to patients with recurrent ascites in the other.
      • Bai M.
      • Qi X.S.
      • Yang Z.P.
      • Yang M.
      • Fan D.M.
      • Han G.H.
      TIPS improves liver transplantation-free survival in cirrhotic patients with refractory ascites: an updated meta-analysis.
      Table 5Characteristics and results of six randomised controlled trials comparing bared TIPS and LVP in patients with cirrhosis and refractory or recidivant ascites.
      Refs.Refractory/recidivant ascites (%)Exclusion criteriaEnrolled patients (N)Ascites improved (%)Encephalopathy (%)Survival (%)
      TIPSLVPTIPSLVPTIPSLVPTIPSLVP
      Lebrec et al. 1995100/0Age >70 yr; severe extra-hepatic diseases; HCC; pulmonary hypertension; HE, bacterial infection; severe alcoholic hepatitis; portal or hepatic vein obstruction or thrombosis; obstruction of biliary tract; obstruction of hepatic artery; serum creatinine >1.7 mg/dl1312380
      Significantly lower than TIPS.
      1562960
      Rössle et al. 200055/45HE ≥grade 2; serum bilirubin >5 mg/dl, serum creatinine >3 mg/dl; portal-vein thrombosis, hepatic hydrothorax; advanced cancer; failure of LVP (ascites persisting after LVP or need for LVP >once per week)29318443
      Significantly lower than TIPS.
      23135832
      Ginés et al. 2002
      • 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.
      100/0Age >18 or >75 yr; serum bilirubin >10 mg/dl; prothrombin time <40% (INR 2.5); platelet count <than 40,000/mm3; serum creatinine >3 mg/dl, HCC, complete portal vein thrombosis; cardiac or respiratory failure; organic renal failure; bacterial infection; chronic HE35355117
      Significantly lower than TIPS.
      60342630
      Sanyal et al. 2003
      • Sanyal A.J.
      • Genning C.
      • Reddy K.R.
      • Wong F.
      • Kowdley K.V.
      • Benner K.
      • et al.
      The North American study for the treatment of refractory ascites.
      100/0Causes of ascites other than cirrhosis; advanced liver failure (serum bilirubin bilirubin >5 mg/dl, PT INR >2); incurable cancers or nonhepatic diseases that were likely to limit life expectancy to 1 yr; congestive heart failure; acute renal failure; parenchymal renal disease; portal vein thrombosis; bacterial infections; HE ≥grade II; florid alcoholic hepatitis, HCC; gastrointestinal hemorrhage within 6 w of randomisation.52575816
      Significantly lower than TIPS.
      38213533
      Salerno et al. 2004
      • Salerno F.
      • Merli M.
      • Riggio O.
      • Cazzaniga M.
      • Valeriano V.
      • Pozzi M.
      • et al.
      Randomized controlled study of TIPS vs. paracentesis plus albumin in cirrhosis with severe ascites.
      68/32Age > 72 yr; recurrent HE ≥grade 2; serum bilirubin >6 mg/dl; serum creatinine >3 mg/dl; Child-Pugh score >11; complete portal vein thrombosis; HCC; gastrointestinal bleeding within 15 d of randomisation; serious cardiac or pulmonary dysfunctions;bacterial infection; SAAG gradient <11 g/L.33337942
      Significantly lower than TIPS.
      61395929
      Significantly lower than TIPS.
      Narahara et al. 2011
      • Narahara Y.
      • Kanazawa H.
      • Fukuda T.
      • Matsushita Y.
      • Harimoto H.
      • Kidokoro H.
      • et al.
      Transjugular intrahepatic portosystemic shunt vs. paracentesis plus albumin in patients with refractory ascites who have good hepatic and renal function: a prospective randomized trial.
      100/0Age >70 yr, chronic HE, HCC and other malignancies, complete portal vein thrombosis with cavernomatous transformation, bacterial infection, severe cardiac or pulmonary disease, organic renal disease.30308730
      Significantly lower than TIPS.
      205205
      Significantly lower than TIPS.
      HCC, hepatocellular carcinoma; HE, hepatic encephalopathy; INR, international normalized ratio; LVP, large volume paracentesis; PT, prothrombin time; SAAG, serum-ascites albumin gradient; TIPS, transjugular intrahepatic portosystemic shunt.
      * Significantly lower than TIPS.
      Fewer studies assessing the effects of TIPS with PTFE-covered stent grafts are available. Two retrospective studies
      • Maleux G.
      • Perez-Gutierrez N.A.
      • Evrard S.
      • Mroue A.
      • Le Moine O.
      • Laleman W.
      • et al.
      Covered stents are better than uncovered stents for transjugular intrahepatic portosystemic shunts in cirrhotic patients with refractory ascites: a retrospective cohort study.
      • Tan H.K.
      • James P.D.
      • Sniderman K.W.
      • Wong F.
      Long-term clinical outcome of patients with cirrhosis and refractory ascites treated with transjugular intrahepatic portosystemic shunt insertion.
      reported better control of ascites and one-year
      • Maleux G.
      • Perez-Gutierrez N.A.
      • Evrard S.
      • Mroue A.
      • Le Moine O.
      • Laleman W.
      • et al.
      Covered stents are better than uncovered stents for transjugular intrahepatic portosystemic shunts in cirrhotic patients with refractory ascites: a retrospective cohort study.
      or two-year
      • Tan H.K.
      • James P.D.
      • Sniderman K.W.
      • Wong F.
      Long-term clinical outcome of patients with cirrhosis and refractory ascites treated with transjugular intrahepatic portosystemic shunt insertion.
      survival with covered stent grafts than bare stent grafts in patients with refractory ascites. A survival benefit of TIPS vs. serial paracentesis in patients with refractory ascites has been reported in a single-centre case-control propensity score analysis.
      • Gaba R.C.
      • Parvinian A.
      • Casadaban L.C.
      • Couture P.M.
      • Zivin S.P.
      • Lakhoo J.
      • et al.
      Survival benefit of TIPS vs. serial paracentesis in patients with refractory ascites: a single institution case-control propensity score analysis.
      In a recent RCT comparing covered TIPS vs. LVP in patients with recurrent ascites, a better one-year transplant-free survival was seen in patients treated with covered stents, without any significant increase in occurrence of hepatic encephalopathy.
      • Bureau C.
      • Thabut D.
      • Oberti F.
      • Dharancy S.
      • Carbonell N.
      • Bouvier A.
      • et al.
      Transjugular intrahepatic portosystemic shunts with covered stents increase transplant-free survival of patients with cirrhosis and recurrent ascites.
      Thus, currently available data suggest that TIPS improves survival compared to LVP in patients with recurrent ascites, but it does not in those with refractory ascites.
      A careful selection of patients is also crucial to maximise the beneficial effects of TIPS, as TIPS can even be detrimental in patients with the most advanced stages of cirrhosis, such as those belonging to Child-Pugh class C.
      • Lebrec D.
      • Giuily N.
      • Hadengue A.
      • Vilgrain V.
      • Moreau R.
      • Poynard T.
      • et al.
      Transjugular intrahepatic portosystemic shunts: comparison with paracentesis in patients with cirrhosis and refractory ascites: a randomized trial. French Group of Clinicians and a Group of Biologists.
      The main exclusion criteria for TIPS insertion in the seven RCTs are reported in Table 5. A score system based on SCr, INR, serum bilirubin and aetiology of cirrhosis has been proposed to predict survival after TIPS insertion for refractory ascites.
      • Malinchoc M.
      • Kamath P.S.
      • Gordon F.D.
      • Peine C.J.
      • Rank J.
      • ter Borg P.C.
      A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts.
      Another simple predictor of survival suggested for patients receiving TIPS for refractory ascites consists of the combination of serum bilirubin concentration and platelet count.
      • Bureau C.
      • Metivier S.
      • D'Amico M.
      • Peron J.M.
      • Otal P.
      • Pagan J.C.
      • et al.
      Serum bilirubin and platelet count: a simple predictive model for survival in patients with refractory ascites treated by TIPS.
      Another factor that seems to influence mortality is the number of TIPS procedures performed in a centre, as the risk of inpatient mortality is lower in hospitals performing ≥20 TIPS per year.
      • Sarwar A.
      • Zhou L.
      • Novack V.
      • Tapper E.B.
      • Curry M.
      • Malik R.
      • et al.
      Hospital volume and mortality after trans-jugular intrahepatic portosystemic shunt creation in the United States.

       Other treatments

      Based on the exclusion criteria reported (Table 5), a substantial portion of patients with refractory ascites are not candidates for TIPS insertion. Thus, the search for alternative treatments is warranted.

       Medical treatments

      Therapies aimed at improving circulatory and renal function have been proposed. The α1-adrenergic agonist midodrine has been shown to improve systemic and renal haemodynamics in patients with cirrhosis and uncomplicated ascites.
      • Angeli P.
      • Volpin R.
      • Piovan D.
      • Bortoluzzi A.
      • Craighero R.
      • Bottaro S.
      • 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.
      In a small RCT comparing the addition of midodrine (7.5 mg t.i.d) to diuretic treatment with diuretic treatment alone in patients with refractory or recurrent ascites for six months, only a transient beneficial effect on the control of ascites was seen at the third month.
      • Singh V.
      • Dhungana S.P.
      • Singh B.
      • Vijayverghia R.
      • Nain C.K.
      • Sharma N.
      • et al.
      Midodrine in patients with cirrhosis and refractory or recurrent ascites: a randomized pilot study.
      The use of terlipressin, an analogue of vasopressin with a predominant vasoconstrictor effect in the splanchnic circulatory area in patients with refractory ascites has only been assessed in acute studies. In one,
      • Gadano A.
      • Moreau R.
      • Vachiery F.
      • Soupison T.
      • Yang S.
      • Cailmail S.
      • et al.
      Natriuretic response to the combination of atrial natriuretic peptide and terlipressin in patients with cirrhosis and refractory ascites.
      terlipressin administration (1 to 2 mg intravenous [i.v.], according to body weight) only increased renal sodium excretion when associated with exogenous atrial natriuretic factor. In another,
      • Krag A.
      • Moller 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.
      2 mg of terlipressin led to an increase in GFR, renal plasma flow and renal sodium excretion. However, in this study only eight patients with refractory ascites were included. Whether a prolonged treatment with terlipressin may lead to a clinically relevant improvement of renal function and sodium excretion in refractory ascites is not known.
      The α2-adrenoceptor agonist clonidine, a sympatholytic drug, which suppresses RAAS activity and improves the response to diuretics in patients with cirrhosis and ascites was tested in a large prospective RCT. It was shown that clonidine administration on top of diuretics for three months led to an overall response to diuretics in 60% of cases, while no response was seen with diuretics alone. This effect was associated with significant reductions of RAAS and sympathetic nervous system activity. Interestingly, the favourable effects of clonidine were predicted by the variant genotype of G protein (GNB3 C825T) and adrenergic receptor (ADRA2C Del 322–325) polymorphisms, and the baseline norepinephrine level.
      • Lenaerts A.
      • Codden T.
      • Meunier J.C.
      • Henry J.P.
      • Ligny G.
      Effects of clonidine on diuretic response in ascitic patients with cirrhosis and activation of sympathetic nervous system.
      Small scale or pilot studies evaluated the effects of various combinations of midodrine with either clonidine,
      • Singh V.
      • Singh A.
      • Singh B.
      • Vijayvergiya R.
      • Sharma N.
      • Ghai A.
      • et al.
      Midodrine and clonidine in patients with cirrhosis and refractory or recurrent ascites: a randomized pilot study.
      the antagonist of vasopressin V2-receptors tolvaptan,
      • Rai N.
      • Singh B.
      • Singh A.
      • Vijayvergiya R.
      • Sharma N.
      • Bhalla A.
      • et al.
      Midodrine and tolvaptan in patients with cirrhosis and refractory or recurrent ascites: a randomised pilot study.
      or octreotide and albumin
      • Tandon P.
      • Tsuyuki R.T.
      • Mitchell L.
      • Hoskinson M.
      • Ma M.M.
      • Wong W.W.
      • et al.
      The effect of 1 month of therapy with midodrine, octreotide-LAR and albumin in refractory ascites: a pilot study.
      in patients with refractory and recurrent ascites. Some promising results were obtained, but they need to be confirmed by sufficiently powered RCTs. A recent RCT
      • Hanafy A.S.
      • Hassaneen A.M.
      Rifaximin and midodrine improve clinical outcome in refractory ascites including renal function, weight loss, and short-term survival.
      compared the effects of the combined administration of midodrine (5 mg t.i.d) and rifaximin (550 mg b.i.d) on top of diuretics for 12 weeks with diuretics alone. After 12 weeks, 80% of patients in the active arm were complete responders with a significant improvement in survival in the midodrine/rifaximin arm. Due to weakness in the study design, these results are not definitive, but they certainly warrant further investigation.

       Alfapump®

      The automated low-flow ascites pump (Alfapump®) system consists of a subcutaneously implanted battery-powered programmable pump. It is connected to catheters that transfer ascites from the peritoneal cavity to the bladder, from which it is eliminated with urine. The device has internal sensors that monitor pump function. In two multicentre safety and efficacy studies,
      • Bellot P.
      • Welker M.W.
      • Soriano G.
      • von Schaewen M.
      • Appenrodt B.
      • Wiest R.
      • et al.
      Automated low flow pump system for the treatment of refractory ascites: a multi-center safety and efficacy study.
      • Stirnimann G.
      • Berg T.
      • Spahr L.
      • Zeuzem S.
      • McPherson S.
      • Lammert F.
      • et al.
      Treatment of refractory ascites with an automated low-flow ascites pump in patients with cirrhosis.
      Alfapump® ensured a significant reduction of the number and volume of paracentesis in patients with advanced cirrhosis and refractory ascites. However, adverse effects directly related to the device occurred in about one-third
      • Bellot P.
      • Welker M.W.
      • Soriano G.
      • von Schaewen M.
      • Appenrodt B.
      • Wiest R.
      • et al.
      Automated low flow pump system for the treatment of refractory ascites: a multi-center safety and efficacy study.
      to half
      • Stirnimann G.
      • Berg T.
      • Spahr L.
      • Zeuzem S.
      • McPherson S.
      • Lammert F.
      • et al.
      Treatment of refractory ascites with an automated low-flow ascites pump in patients with cirrhosis.
      of cases. In a multicentre RCT in patients with refractory ascites, Alfapump® reduced the median number of paracentesis per month by 85% with respect to LVP, and significantly improved quality of life and nutritional parameters, as assessed by hand-grip strength and body mass index. Alfapump® had no effect on survival and was associated with a significantly higher incidence of serious adverse events (85.2 vs. 45.2%), mainly represented by AKI.
      • Bureau C.
      • Adebayo D.
      • Chalret de Rieu M.
      • Elkrief L.
      • Valla D.
      • et al.
      Alfapump® system vs. large volume paracentesis for refractory ascites: A multicenter randomized controlled study.
      Thus, even though Alfapump® is effective in reducing the need for paracentesis in patients with refractory ascites, its frequent side effects require close monitoring of patients. Indeed, in addition to device-related adverse event, it should be noted that the evaluation of kidney and circulatory function in 10 patients with cirrhosis and refractory ascites carrying Alfapump® has shown a significant GFR decline within six months, which was associated with a marked increase in plasma renin activity and norepinephrine concentration.
      • Sola E.
      • Sanchez-Cabus S.
      • Rodriguez E.
      • Elia C.
      • Cela R.
      • Moreira R.
      • et al.
      Effects of alfapump system on kidney and circulatory function in patients with cirrhosis and refractory ascites.
      This likely represented the pathophysiological background of 18 episodes of AKI experienced by seven patients.
      • Repeated LVP plus albumin (8 g/L of ascites removed) are recommended as first line treatment for refractory ascites (I;1).
      • Diuretics should be discontinued in patients with refractory ascites who do not excrete >30 mmol/day of sodium under diuretic treatment (III;1).
      • Although controversial data exist on the use of NSBBs in refractory ascites, caution should be exercised in cases of severe or refractory ascites. High doses of NSBB should be avoided (i.e. propranolol >80 mg/day) (II-2;1). The use of carvedilol can not be recommended at present (I;2).
      • Patients with refractory or recurrent ascites (I;1), or those for whom paracentesis is ineffective (e.g. due to the presence of loculated ascites) should be evaluated for TIPS insertion (III;1).
      • TIPS insertion is recommended in patients with recurrent ascites (I;1) as it improves survival (I;1) and in patients with refractory ascites as it improve the control of ascites (I;1).
      • The use of small-diameter PTFE-covered stents in patients is recommended to reduce the risk of TIPS dysfunction and hepatic encephalopathy with a high risk of hepatic encephalopathy is recommended (I;1).
      • Diuretics and salt restriction should be continued after TIPS insertion up to the resolution of ascites (II-2;1), as well as close clinical follow-up (III,1).
      • Careful selection of patients for elective TIPS insertion is crucial, as is the experience of the centre performing this procedure. TIPS is not recommended in patients with serum bilirubin > 3 mg/dl and a platelet count lower than 75 x 109/L, current hepatic encephalopathy grade ≥2 or chronic hepatic encephalopathy, concomitant active infection, progressive renal failure, severe systolic or diastolic dysfunction, or pulmonary hypertension (III;1).
      • At present the addition of clonidine or midodrine to diuretic treatment cannot be recommended (III;1).
      • Alfapump® implantation in patients with refractory ascites not amenable to TIPS insertion is suggested in experienced centres. However, close patient monitoring is warranted because of the high risk of adverse events including renal dysfunction and technical difficulties (I;2).

       Hepatic hydrotorax

      Hepatic hydrotorax describes the accumulation of transudate in the pleural space of patients with decompensated cirrhosis in the absence of cardiac, pulmonary or pleural disease. Its formation is secondary to small diaphragmatic defects, more often located in the right side, through which ascites moves into the pleural space because of the negative intrathoracic pressure induced by inspiration. Hepatic hydrothorax can lead to respiratory failure and can be complicated by spontaneous bacterial infections (empyema). Its appearance is associated with poor prognosis, as the median survival of patients with hepatic hydrothorax ranges from 8–12 months.
      • Badillo R.
      • Rockey D.C.
      Hepatic hydrothorax. Clinical features, management, and outcomes in 77 patients and review of the literature.
      • Garbuzenko D.V.
      • Arefyev N.O.
      Hepatic hydrothorax: An update and review of the literature.
      Notably, the most common prognostic scores, such as Child-Pugh and MELD, seem to underestimate such an adverse outcome.
      • Badillo R.
      • Rockey D.C.
      Hepatic hydrothorax. Clinical features, management, and outcomes in 77 patients and review of the literature.

       Diagnosis of hepatic hydrothorax

      Once pleural effusion has been ascertained, cardiopulmonary and primary pleural diseases should be excluded by standard clinical approaches. Diagnostic thoracentesis is required to rule out bacterial infection, whose diagnosis relies on the same criteria described for ascites. The protein content of pleural effusion in uncomplicated hepatic hydrothorax is low and the serum to pleural fluid albumin gradient is greater than 1.1 g/dl.
      • Badillo R.
      • Rockey D.C.
      Hepatic hydrothorax. Clinical features, management, and outcomes in 77 patients and review of the literature.
      The presence and extent of diaphragmatic defects can be assessed indirectly, by radioisotope techniques, or directly by magnetic resonance imaging or colour-Doppler ultrasonography.
      • Zenda T.
      • Miyamoto S.
      • Murata S.
      • Mabuchi H.
      Detection of diaphragmatic defect as the cause of severe hepatic hydrothorax with magnetic resonance imaging.
      • Hewett L.J.
      • Bradshaw M.L.
      • Gordon L.L.
      • Rockey D.C.
      Diagnosis of isolated hepatic hydrothorax using peritoneal scintigraphy.

       Treatment of hepatic hydrothorax

      The first-line management relies on the treatment of ascites with diuretics and/or LVP as discussed earlier. However, it is not rare for pleural effusion to persist despite successful treatment of ascites (refractory hydrothorax). Therapeutic thoracentesis is required to relieve dyspnoea. Its efficacy in refractory hepatic hydrothorax is transient and repeated thoracentesis are required, which increase the risk of complications such as pneumothorax, pleural or soft tissue infection, and bleeding.
      • Alonso J.C.
      Pleural effusion in liver disease.
      The frequent occurrence of these complications discourages the use of chronic pleural drainage, which can also be followed by renal dysfunction from fluid loss.
      • Orman E.S.
      • Lok A.S.
      Outcomes of patients with chest tube insertion for hepatic hydrothorax.
      Whenever indicated and possible, LT represents the best option for patients with refractory hepatic hydrothorax, which does not seem to adversely affect the outcome of transplantation.
      • Xiol X.
      • Tremosa G.
      • Castellote J.
      • Gornals J.
      • Lama C.
      • et al.
      Liver transplantation in patients with hepatic hydrothorax.
      • Sersté T.
      • Moreno C.
      • Francoz C.
      • Razek W.A.
      • Paugham C.
      • et al.
      The impact of preoperative hepatic hydrothorax on the outcome of adult liver transplantation.
      TIPS has been effectively employed as definitive treatment or bridge to transplantation in patients with refractory hepatic hydrotorax, whose general outcome seems to be related to the severity of the underlying cirrhosis.
      • Gordon F.D.
      • Anastopoulos H.T.
      • Crenshaw W.
      • Gilchrist B.
      • McEniff N.
      • Falchuk K.R.
      • 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.
      These results have been confirmed by a more recent meta-analysis.
      • Ditah I.C.
      • Al Bawardy B.F.
      • Saberi B.
      • Ditah C.
      • Kamath P.S.
      Transjugular intrahepatic portosystemic stent shunt for medically refractory hepatic hydrothorax: A systematic review and cumulative meta-analysis.
      Pleurodesis induced by various agents, such as talc, tetracycline, doxycycline, bleomycin and povidone-iodine, can be offered to patients who are not candidates for TIPS or LT. A recent meta-analysis showed that the pooled rate of complete response after pleurodesis was 72%. However, the pooled rate of complications related to this procedure was as high as 82%.
      • Hou F.
      • Qi X.
      • Guo X.
      Effectiveness and safety of pleurodesis for hepatic hydrothorax: A systematic review and meta-analysis.
      Finally, thoracoscopic repair with mersilene mesh appears to be effective in patients with well-defined diaphragmatic defects.
      • Huang P.M.
      • Kuo S.W.
      • Chen J.S.
      • Lee J.M.
      Thoracoscopic mesh repair of diaphragmatic defects in hepatic hydrothorax: A 10-year experience.
      Advanced liver disease, as assessed by MELD score, and preoperative renal dysfunction appear to adversely affect three-month survival. Unfortunately, clear cut-off values cannot be retrieved from that study.
      • Patients with hydrothorax should be evaluated for LT (III;1).
      • Cardiopulmonary and primary pleural disease should be ruled out before diagnosing hepatic hydrothorax (III;1). Diagnostic thoracentesis should be performed especially when infection of the pleural effusion is suspected (III;1).
      • Diuretics and thoracentesis are recommended as the first-line management of hepatic hydrothorax (III;1).
      • Therapeutic thoracentesis is indicated in patients with dyspnoea (III;1). Chronic pleural should not be performed because of the frequent occurrence of complications (II-2;1).
      • In selected patients, TIPS insertion for recurrent symptomatic hepatic hydrothorax is recommended (II-2;1).
      • Pleurodesis can be suggested to patients with refractory hepatic hydrothorax not amenable to LT or TIPS insertion. However, the frequent occurrence of side effects related to this technique restricts its use to selected patients (I;2).
      • Mesh repair of diaphragmatic defects is suggested for the management of hepatic hydrothorax in very selected patients. The best results can be achieved in patients with non-advanced cirrhosis without renal dysfunction (II-2;2).

      Hyponatremia

       Definition and pathophysiology

      Hyponatremia is common in patients with advanced cirrhosis, and has been arbitrarily defined as serum sodium concentration lower than 130 mmol/L.
      • Angeli P.
      • Wong F.
      • Watson H.
      Gines P, and the participants to CAPPS. Hyponatremia in cirrhosis: results of a survey.
      • Gines P.
      • Berl T.
      • Bernardi M.
      • Bichet D.G.
      • Hamon G.
      • Jimenez W.
      • et al.
      Hyponatremia in cirrhosis: from pathogenesis to treatment.
      However, according to guidelines on hyponatremia in the general patient population,
      • Spasovski G.
      • Vanholder R.
      • Allolio B.
      • Annane D.
      • Ball S.
      • Bichet D.
      • et al.
      Clinical practice guideline on diagnosis and treatment of hyponatraemia.
      reductions below 135 mmol/L should also be considered. Patients with hyponatremia have a poor prognosis, as it is associated with increased mortality
      • Biggins S.W.
      • Rodriguez H.J.
      • Bacchetti P.
      • Bass N.M.
      • Roberts J.P.
      • Terrault N.A.
      Serum sodium predicts mortality in patients listed for liver transplantation.
      • Porcel A.
      • Diaz F.
      • Rendon P.
      • Macias M.
      • Martin-Herrera L.
      • Giron-Gonzalez J.A.
      Dilutional hyponatremia in patients with cirrhosis and ascites.
      • Cordoba J.
      • Garcia-Martinez R.
      • Simon-Talero M.
      Hyponatremic and hepatic encephalopathies: similarities, differences and coexistence.
      and morbidity, particularly neurological complications,
      • Cordoba J.
      • Garcia-Martinez R.
      • Simon-Talero M.
      Hyponatremic and hepatic encephalopathies: similarities, differences and coexistence.
      • Amodio P.
      • Del Piccolo F.
      • Petteno E.
      • Mapelli D.
      • Angeli P.
      • Iemmolo R.
      • et al.
      Prevalence and prognostic value of quantified electroencephalogram (EEG) alterations in cirrhotic patients.
      and reduced survival after LT.
      • Londono M.C.
      • Guevara M.
      • Rimola A.
      • Navasa M.
      • Taura P.
      • Mas A.
      • et al.
      Hyponatremia impairs early posttransplantation outcome in patients with cirrhosis undergoing liver transplantation.
      Incorporating serum sodium concentration into the MELD score, a new score (MELD-Na) was generated that provides more accurate survival predictions than MELD alone,
      • Biggins S.W.
      • Kim W.R.
      • Terrault N.A.
      • Saab S.
      • Balan V.
      • Schiano T.
      • et al.
      Evidence-based incorporation of serum sodium concentration into MELD.
      especially in patients with ascites and hyponatremia with intermediate MELD score values.
      • Kim W.R.
      • Biggins S.W.
      • Kremers W.K.
      • Wiesner R.H.
      • Kamath P.S.
      • Benson J.T.
      • et al.
      Hyponatremia and mortality among patients on the liver-transplant waiting list.
      Both hypovolaemic and hypervolaemic hyponatremia can occur in patients with cirrhosis. The second, most common, is characterised by an expansion of the extracellular fluid volume, with ascites and oedema. It may occur spontaneously, or because of excessive hypotonic fluids (i.e., 5% dextrose), or secondary to complications of cirrhosis leading to an abrupt worsening of effective volaemia. The main drivers are non-osmotic hypersecretion of vasopressin and enhanced proximal nephron sodium reabsorption, which impair free water generation and are both caused by effective hypovolaemia. As opposed to hypervolaemic hyponatremia, hypovolaemic hyponatremia is characterised by the frequent absence of ascites and oedema. It is caused by a prolonged negative sodium balance with marked loss of extracellular fluid often due to excessive diuretic therapy.

       Management of hyponatremia

      It is generally considered that hyponatremia should be treated when serum sodium is lower than 130 mmol/L, although there is no good evidence regarding the level of serum sodium at which treatment should be initiated. Hypovolaemic hyponatremia requires plasma volume expansion with saline solution and the correction of the causative factor. The management of hypervolemic hyponatremia requires attainment of a negative water balance. Non-osmotic fluid restriction is helpful in preventing a further decrease in serum sodium levels, but it is seldom effective in improving natremia. Hypertonic sodium chloride administration to patients with decompensated cirrhosis may improve natremia but enhances volume overload and worsens the amount of ascites and oedema. Therefore, it should be limited to severely symptomatic hyponatremia, as defined by life-threatening manifestations, cardio-respiratory distress, abnormal and deep somnolence, seizures and coma, which do not frequently occur in patients with cirrhosis. Furthermore, hypertonic sodium chloride administration can be considered in patients with severe hyponatremia who are expected to get a liver transplant within a few days. In these cases, hyponatremia must not be corrected completely and rapidly to avoid the risk of central pontine myelinolysis that is increased in advanced cirrhosis.
      • Spasovski G.
      • Vanholder R.
      • Allolio B.
      • Annane D.
      • Ball S.
      • Bichet D.
      • et al.
      Clinical practice guideline on diagnosis and treatment of hyponatraemia.
      In practice, after an initial rapid correction aimed at attenuating clinical symptoms (5 mmol/L in the first hour), serum sodium concentration should not increase more than 8 mmol/L per day.
      • Spasovski G.
      • Vanholder R.
      • Allolio B.
      • Annane D.
      • Ball S.
      • Bichet D.
      • et al.
      Clinical practice guideline on diagnosis and treatment of hyponatraemia.
      Albumin infusion appears to improve serum sodium concentration, but more information is needed.
      • McCormick P.A.
      • Mistry P.
      • Kaye G.
      • Burroughs A.K.
      • McIntyre N.
      Intravenous albumin infusion is an effective therapy for hyponatraemia in cirrhotic patients with ascites.

       Vaptans

      Vaptans are selective antagonists of the V2-receptors of arginine-vasopressin in the principal cells of the collecting ducts that enhance solute-free water excretion.
      • Quittnat F.
      • Gross P.
      Vaptans and the treatment of water-retaining disorders.
      Indeed, these drugs are effective in improving serum sodium concentration in conditions associated with high vasopressin levels, such as the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and heart failure.
      • Quittnat F.
      • Gross P.
      Vaptans and the treatment of water-retaining disorders.
      The effects of the administration of vaptans to hyponatremic patients with cirrhosis and ascites have been assessed in several studies. Namely, tolvaptan, satavaptan and lixivaptan lead to an increased urine volume, a solute-free water excretion, and an improvement of hyponatremia in 45–82% of cases.
      • Cardenas A.
      • Gines P.
      • Marotta P.
      • Czerwiec F.
      • Oyuang J.
      • Guevara M.
      • et al.
      Tolvaptan, an oral vasopressin antagonist, in the treatment of hyponatremia in cirrhosis.
      • Gerbes A.L.
      • Gulberg V.
      • Gines P.
      • Decaux G.
      • Gross P.
      • Gandjini H.
      • et al.
      Therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist: a randomized double-blind multicenter trial.
      • Gines P.
      • Wong F.
      • Watson H.
      • Milutinovic S.
      • del Arbol L.R.
      • Olteanu D.
      Effects of satavaptan, a selective vasopressin V(2) receptor antagonist, on ascites and serum sodium in cirrhosis with hyponatremia: a randomized trial.
      In another study, a short-term intravenous infusion of conivaptan for one to four days in patients with end stage liver disease awaiting OLT was also effective in increasing serum sodium concentration.
      • O'Leary J.G.
      • Davis G.L.
      Conivaptan increases serum sodium in hyponatremic patients with end-stage liver disease.
      However, the safety of vaptans has only been established for short-term treatments lasting from one week to one month. When satavaptan was used long term, in addition to diuretics, despite improving both serum sodium concentration and control of ascites, a higher all-cause mortality rate, mostly associated with known complications of cirrhosis, was reported compared to standard medical treatment.
      • Wong F.
      • Gines 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.
      • Wong F.
      • Watson H.
      • Gerbes A.
      • Vilstrup H.
      • Badalamenti S.
      • Bernardi M.
      • et al.
      Satavaptan for the management of ascites in cirrhosis: efficacy and safety across the spectrum of ascites severity.
      Moreover, a recent study cast doubt on the efficacy of tolvaptan in patients with cirrhosis and severe hypervolemic hyponatremia (serum sodium ≤125 mEq/L) in a real-life setting.
      • Pose E.
      • Sola E.
      • Piano S.
      • Gola E.
      • Graupera I.
      • Guevara M.
      • et al.
      Limited efficacy of tolvaptan in patients with cirrhosis and severe hyponatremia: real-life experience.
      At present, both conivaptan and tolvaptan have been approved in the US by the FDA, while only tolvaptan in Europe has been approved by the EMA for management of severe hypervolemic hyponatremia (<125 mmol/L). The unique indication given for tolvaptan by the EMA is SIADH, while the FDA also included heart failure and liver cirrhosis. However, the occurrence of serious hepatic injury in three patients with autosomal dominant polycystic kidney disease treated with tolvaptan in a double-blind placebo-controlled trial
      • Torres V.E.
      • Chapman A.B.
      • Devuyst O.
      • Gansevoort R.T.
      • Grantham J.J.
      • Higashihara E.
      • et al.
      Tolvaptan in patients with autosomal dominant polycystic kidney disease.
      led the FDA to conclude that this drug should not be used in patients with underlying liver disease.
      • The development of hyponatremia (serum sodium concentration <130 mmol/L) in patients with cirrhosis carries an ominous prognosis, as it is associated with increased mortality and morbidity. These patients should be evaluated for LT (II-2,1).
      • The removal of the cause and administration of normal saline are recommended in the management of hypovolemic hyponatremia (III;1).
      • Fluid restriction to 1,000 ml/day is recommended in the management of hypervolemic hyponatremia since it may prevent a further reduction in serum sodium levels (III;1).
      • The use of hypertonic saline in the management of hypervolemic hyponatremia should be limited to the rare cases presenting with life threatening complications. It could also be considered in patients with severe hyponatremia who are expected to get LT within a few days. The correction of serum sodium concentration, once an attenuation of symptoms has been obtained, should be slow (≤8 mmol/L per day) to avoid irreversible neurological sequelae, such as osmotic demyelination (II-3;1).
      • Albumin administration can be suggested in hypervolemic hyponatremia, but data are very limited to support its use (II-3;2).
      • At present, the use of vaptans should be limited to controlled clinical studies (III;1).

      Gastrointestinal bleeding

       Pathophysiology

      Variceal haemorrhage (VH) occurs because of the rupture of the variceal wall due to excessive wall tension. Variceal wall tension is an intrinsic property of the vessel wall that opposes the expansive force determined by variceal transmural pressure, which depends on portal pressure and vessel size. Tissue support surrounding the varix may counteract the increase in variceal pressure and size, protecting the wall from rupture.
      • Bosch J.
      • Groszmann R.J.
      • Shah V.H.
      Evolution in the understanding of the pathophysiological basis of portal hypertension: How changes in paradigm are leading to successful new treatments.
      Once variceal wall rupture occurs, the amount of bleeding is related to transmural pressure (which mainly depends on portal pressure), to the area of rupture in the vessel wall and to blood viscosity and/or alterations of haemostasis.
      • Bosch J.
      • Groszmann R.J.
      • Shah V.H.
      Evolution in the understanding of the pathophysiological basis of portal hypertension: How changes in paradigm are leading to successful new treatments.
      All these factors can be influenced by therapy. Drug therapy and portal-systemic derivative procedures, reduce portal (and variceal) pressure. Endoscopic therapies and other physical methods, such as balloon tamponade or expandable prosthesis, act merely by both interrupting the blood flow into the varix and sealing the vascular wall. Portal pressure is a key factor determining both variceal rupture and the severity of the bleeding episode.
      • Bosch J.
      • Groszmann R.J.
      • Shah V.H.
      Evolution in the understanding of the pathophysiological basis of portal hypertension: How changes in paradigm are leading to successful new treatments.
      During acute bleeding, portal pressure may increase because of different factors such as over-transfusion or absorption of blood from the gut, which may have a role in failure to control bleeding and/or precipitating rebleeding. Portal pressure is usually assessed by the hepatic venous pressure gradient (HVPG).

       Natural history of gastro-oesophageal varices and variceal haemorrhage

      Variceal haemorrhage, causative of 70% of all upper GI bleeding events in patients with portal hypertension, remains one of the most severe and immediate life-threatening complications in patients with cirrhosis and constitutes the second most frequent decompensating event after ascites.
      • D'Amico G.
      • De Franchis R.
      Upper digestive bleeding in cirrhosis. Post-therapeutic outcome and prognostic indicators.
      • Jepsen P.
      • Ott P.
      • Andersen P.K.
      • Sorensen H.T.
      • Vilstrup H.
      Clinical course of alcoholic liver cirrhosis: a Danish population-based cohort study.