Professor Gleeson and Dr Min provide a guide on how to handle refractory ascites.
About 50% of patients with cirrhosis develop ascites within 10 years of diagnosis [1,2]. The main drivers are sodium retention due to splanchnic arterial vasodilatation and perceived hypovolaemia (acting via the renin–angiotensin–aldosterone and sympathetic nervous systems) and portal hypertension [1–3]. Refractory ascites is classified either as resistant (ie, no response to diuretic treatment with spironolactone 400mg/day, furosemide 160mg/day and sodium restriction for >7 days) or intractable (ie, the patient does not tolerate diuretics). Lack of response is also characterised by weight loss of less than 0.8 kg over 4 days and urinary sodium concentrations being lower than sodium intake. Early recurrence is indicated by the reappearance of ascites with a moderate to large volume within 4 weeks of fluid mobilisation. Patients might experience diuretic-induced complications, such as encephalopathy, renal impairment, hyponatraemia and hypo- or hyperkalaemia. About half of patients with refractory ascites die within 1 year of onset [5,6] and, therefore, liver transplantation should be considered if feasible (Figure).
In about 20% of patients with cirrhosis, ascites has an alternative cause . These include thrombosis in the portal or hepatic vein, pancreatitis, cardiac disease (constrictive pericarditis might be present in patients with recurrent ascites) and abdominal tuberculosis or malignancy. Initial or repeat investigations to consider are full fluid analysis and imaging of the heart, liver and other abdominal and pelvic organs. Testing blood for tumour markers might be misleading when ascites is present .
Repeated large-volume paracentesis (LVP) with albumin replacement is a safe and effective first-line treatment for refractory ascites [1–5,7,8]. Albumin infusion prevents post-paracentesis circulatory dysfunction. This complication is caused by fluid shift, hypovolaemia and further activation of the renin–angiotensin system , and can lead to renal-failure hyponatraemia, rapid re-accumulation of ascites, and shortened survival.
In a study of 171 LVP procedures, two patients (1.2%) had significant haemorrhages and one (0.6%) had a bowel perforation . In another study of 4729 patients, significant haemorrhage occurred in nine patients (0.2%), among whom eight had renal impairment .
Severity of coagulopathy does not predict bleeding in patients with cirrhosis [2–4, 12, 13] and no data support routine use of fresh-frozen plasma or platelets before LVP. Guidelines acknowledge the absence of evidence-based cut-off values for coagulation parameters contraindicating paracentesis [2–4]. Nevertheless, platelet count might be a useful predictor of bleeding [4,12,13]. Contraindications to LVP include disseminated intravascular coagulation, bowel distension, pregnancy, infection at the proposed puncture site and an uncooperative patient . Specialist vascular guidelines suggest continuing aspirin, but, if feasible, stopping clopidogrel or ticagrelor 5 days before the procedure, which is graded as having a low risk of bleeding , and seeking cardiological advice when needed [14,15].
Diuretics and non-selective beta-blockers
Diuretics are usually ineffective, but, if tolerated, they might be tried in patients who have urinary sodium excretion greater than 30 mmol per day .
Use of non-selective beta-blockers to treat advanced liver disease remains controversial [16,18]. These drugs may be continued if the patients demonstrates cardiovascular stability , but should be stopped or the dose reduced if systolic blood pressure falls below 90 mmHg or if renal impairment or hyponatraemia (serum sodium <130 mEq/L) develop [3,18].
Non-steroidal anti-inflammatory drugs, angiotensin-converting-enzyme inhibitors, and angiotensin-II-receptor or alpha-1 adrenergic-receptor blockers should be avoided due to the risk of renal impairment [3,4].
Transjugular intrahepatic portosystemic shunts
Transjugular intrahepatic portosystemic shunts (TIPS) dramatically reduce portal pressure in patients with cirrhosis [2–4]. Meta-analyses of randomised controlled trials of TIPS versus continued LVP have indicated that use of TIPS effectively controls ascites and reduces the need for LVP [19,20]. TIPS also improve renal function and possibly (although not conclusively) transplant-free survival [19,20]. The main complication is hepatic encephalopathy, for which incidence is about 25% over 6 months and is higher than that in patients managed by LVP .
The Model for End-Stage Liver disease (MELD) score (based on international normalised ratio of prothrombin time and serum bilirubin and creatinine concentrations) predicts 3-month survival following TIPS [1,2]. The risk of encephalopathy is also predicted by higher MELD scores and low mean arterial pressure.
Contraindications to TIPS include hepatic encephalopathy and a high MELD and/or Child-Pugh score (although agreement on optimum cut-off values is lacking), heart failure, pulmonary hypertension, multiple hepatic cysts, portal or hepatic vein thrombosis, large central hepatic tumours and severe thrombocytopenia .
Small-diameter polytetrafluroethylene-covered stents are now favoured over uncovered stents [3,23] as they reduce the risk of TIPS dysfunction (including stenosis, thrombosis or migration) and ascites re-accumulation. Use of these stents was associated with better survival than repeated LVP in one randomised controlled trial . Furthermore, encephalopathy risk is not increased and might be reduced if smaller (8 mm) covered stents are used .
In a pilot randomised controlled trial in 40 patients with cirrhosis and refractory ascites, midodrine added to diuretics achieved better control of ascites and possibly survival than diuretics alone [4,26]. This and other vasoactive drugs, such as vasopressin, alpha-2 agonists and vaptans, require further evaluation before they can be recommended for routine use [26–29].
Regular infusions of albumin in patients with decompensated cirrhosis reduced the need for LVP and improved survival in one randomised controlled trial  but not in another in which lower doses were used and combined with midodrine . In a non-randomised study involving patients with refractory ascites, albumin administration improved ascites control and reduced the 2-year hospitalisation and mortality rates .
The Alfapump (Sequana, Ghent, Belgium) is an automated low-flow pump system that is implanted subcutaneously and pumps ascitic fluid into the bladder at an adjustable rate . It might be considered for patients unsuitable for TIPS or liver transplant . A multicentre randomised controlled trial involving 58 patients showed improved ascites control but a serious complication rate of 85% compared with 45% in those who underwent LVP .
The PleurX drainage system (BD, Eysins, Switzerland) is a tunnelled indwelling peritoneal catheter that represents a potential community-based palliative treatment for refractory cirrhotic ascites to improve quality of life . Typically, 2 L of ascitic fluid is drained three times per week under district nurse supervision. In a retrospective study, drains remained patent in 30 of the 33 patients over a median of 117 days . Micro-organisms from the catheter were isolated in 11 (38%) of patients after a median of 105 days. All patients were treated successfully. In another study of 25 patients with cirrhotic refractory ascites, mortality did not differ between patients treated with PleurX and those treated with LVP . Prophylactic use of antibiotics has been suggested in recipients of PleurX, but evidence of a benefit is lacking .
Figure 1: Management protocol for refractory ascites in patients with decompensated cirrhosis
LVP: large volume paracentesis; TIPS: transjugular intrahepatic portosystemic shunts.
Refractory ascites remains difficult to manage with detrimental impact on patient’s quality of life and significant increase in mortality. Early consideration for liver transplantation and feasibility of TIPS is important in the selected group of patients. Novel therapies are promising but require further validation. Palliative approach in end stage liver disease has an important role in symptom control.
About the Authors
Dr Thazin Min is a Gastroenterology Specialist Registrar at Sheffield Teaching Hospitals. She received her medical degree from the University of Leeds, 2011.
Professor Dermot Gleeson is a Consultant Hepatologist at Sheffield Teaching Hospitals and Honorary Professor of Hepatology at the University of Sheffield . His interests include Alcohol related and Immune mediated liver disease.
- Moore KP, Wong F, Gines P et al. The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club. Hepatology 2003;38:258–266.
- European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol 2010;53:397–417.
- European Association for the Study of the Liver. EASL clinical practice guidelines for the management of patients with decompensated cirrhosis. J Hepatol 2018;69:406–460.
- Runyon BY, AASLD. Introduction to the revised American Association for the Study of Liver Diseases practice guideline management of adult patients with ascites due to cirrhosis 2012. Hepatology 2013;57:1651–1653.
- Moore KP, Aithal GP. Guidelines on the management of ascites in cirrhosis. Gut 2006;55(suppl 6):vi1–12.
- Moreau R, Delègue P, Pessione F et al. Clinical characteristics and outcome of patients with cirrhosis and refractory ascites. Liver Int 2004;24:457–464.
- Ginès P, Titó L, Arroyo V, Planas R et al. Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis. Gastroenterology 1988;94:1493–1502.
- Salerno F, Badalamenti S, Incerti P et al. Repeated paracentesis and i.v. albumin infusion to treat ‘tense’ ascites in cirrhotic patients. A safe alternative therapy. J Hepatol 1987;5:102–108.
- Kim JH. What we know about paracentesis induced circulatory dysfunction? Clin Mol Hepatol 2015;21:349–351.
- De Gottardi A, Thévenot T, Spahr L et al. Risk of complications after abdominal paracentesis in cirrhotic patients: a prospective study. Clin Gastroenterol Hepatol 2009;7:906–909.
- Pache I, Bilodeau M. Severe haemorrhage following abdominal paracentesis for ascites in patients with liver disease. Aliment Pharmacol Ther 2005;21:525–529.
- Kujovich JL. Coagulopathy in liver disease: a balancing act. Hematology Am Soc Hematol Educ Program 2015;2015:243–249.
- Giannini EG, Greco A, Marenco S, Andorno E, Valente U, Savarino V. Incidence of bleeding following invasive procedures in patients with thrombocytopenia and advanced liver disease. Clin Gastroenterol Hepatol 2010;8:899–902; quiz e109.
- Patel IJ, Davidson JC, Nikolic B et al; Standards of Practice Committee, with Cardiovascular and Interventional Radiological Society of Europe (CIRSE). Consensus guidelines for periprocedural management of coagulation status and hemostasis risk in percutaneous image-guided interventions. J Vasc Interv Radiol 2012;23:727–736.
- Kristensen SD, Knuuti J, Saraste A et al. 2014 ESC/ESA Guidelines on non-cardiac surgery: cardiovascular assessment and management: the Joint Task Force on non-cardiac surgery: cardiovascular assessment and management of the European Society of Cardiology (ESC) and the European Society of Anaesthesiology (ESA). Eur J Anaesthesiol 2014;31:517–573.
- Sersté T, Melot C, Francoz C et al. Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites. Hepatology 2010;52:1017–1022.
- Mookerjee RP, Pavesi M, Thomsen KL et al. Treatment with non-selective beta blockers is associated with reduced severity of systemic inflammation and improved survival of patients with acute-on-chronic liver failure. J Hepatol 2016;64:574–582.
- de Franchis R, Baveno VI Faculty. Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension. J Hepatol 2015;63:743–752.
- Bai M, Qi XS, Yang ZP, Yang M, Fan DM, Han GH. TIPS improves liver transplantation-free survival in cirrhotic patients with refractory ascites: an updated meta-analysis. World J Gastroenterol 2014;20:2704–2714.
- D’Amico G, Luca A, Morabito A, Miraglia R, D’Amico M. Uncovered transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis. Gastroenterology 2005;129:1282–1293.
- Salerno F, Cammà C, Enea M, Rössle M, Wong F. Transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis of individual patient data. Gastroenterology 2007; 133:825–834.
- Boyer TD, Haskal ZJ, American Association for the Study of Liver Diseases. The role of transjugular intrahepatic portosystemic shunt (TIPS) in the management of portal hypertension: update 2009. Hepatology 2010;51:306.
- Triantafyllou T, Aggarwal P, Gupta E, Svetanoff WJ, Bhirud DP, Singhal S. Polytetrafluoroethylene-covered stent graft versus bare stent in transjugular intrahepatic portosystemic shunt: systematic review and meta-analysis. J Laparoendosc Adv Surg Tech A 2018;28:867–879.
- Bureau C, Thabut D, Oberti F et al. Transjugular intrahepatic portosystemic shunts with covered stents increase transplant-free survival of patients with cirrhosis and recurrent ascites. Gastroenterology 2017;152:157–163.
- Wang Q, Lv Y, Bai M et al. Eight millimetre covered TIPS does not compromise shunt function but reduces hepatic encephalopathy in preventing variceal rebleeding. J Hepatol 2017;67:508–516.
- Singh V, Dhungana SP, Singh B et al. Midodrine in patients with cirrhosis and refractory or recurrent ascites: a randomized pilot study. J Hepatol 2012;56:348–54.
- Singh V, Singh A, Singh B et al. Midodrine and clonidine in patients with cirrhosis and refractory or recurrent ascites: a randomized pilot study. Am J Gastroenterol 2013;108:560–567.
- Rai N, Singh B, Singh A et al. Midodrine and tolvaptan in patients with cirrhosis and refractory or recurrent ascites: a randomised pilot study. Liver Int 2017;37:406–414 (2017).
- Yosry A, Soliman ZA, Eletreby R, Hamza I, Ismail A, Elkady MA. Oral midodrine is comparable to albumin infusion in cirrhotic patients with refractory ascites undergoing large-volume paracentesis: results of a pilot study. Eur J Gastroenterol Hepatol 2019;31:345–351.
- Caraceni P, Riggio O, Angeli P et al. Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial. Lancet 2018;391:2417–2429.
- Solà E, Solé C, Simón-Talero M et al. Midodrine and albumin for prevention of complications in patients with cirrhosis awaiting liver transplantation. A randomized placebo-controlled trial. J Hepatol 2018;69:1250–1259.
- Di Pascoli M, Fasolato S, Piano S, Bolognesi M, Angeli P. Long-term administration of human albumin improves survival in patients with cirrhosis and refractory ascites. Liver Int 2019;39:98–105.
- lbach P, Höner Zu Siederdissen C, Wellhöner F et al. Automated low-flow ascites pump in a real-world setting: complications and outcomes. Eur J Gastroenterol Hepatol 2018;30:1082–1089.
- Bureau C, Adebayo D, Chalret de Rieu M et al., Alfapump® system vs. large volume paracentesis for refractory ascites: a multicenter randomized controlled study. J Hepatol 2017;67:940–949.
- Reinglas J, Amjadi K, Petrcich B, Momoli F, Shaw-Stiffel T. The palliative management of refractory cirrhotic ascites using the PleurX© Catheter. Can J Gastroenterol Hepatol 2016;2016:4680543.
- Riedel AN, Kimer N, Hobolth L, Gluud LL. Prognosis of patients with ascites after PleurX insertion: an observational study. Scand J Gastroenterol 2018;53:340–344.
- Rashid S, Hussain S, Mojibian H, Quencer K. Utility of prophylactic antibiotics in tunneled peritoneal and pleural drainage catheters. J Vasc Interv Radiol 2016;27(suppl):S175[abstr 389].