Management of refractory cirrhotic ascites: challenges and solutions

Figures & data

Table 1 Definition of refractory ascites in international guidelines (A) and criteria of refractory ascites used by authors from China and Japan (B)

A
EASL clinical practice guideline^Citation4	Ascites that cannot be mobilized or the early recurrence of which (i.e., after therapeutic paracentesis) cannot be satisfactorily prevented by medical therapy
International Ascites Club^Citation2	Diuretic-resistant ascites: Ascites 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 ascites: Ascites 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
	1. Treatment duration: Patients must be on intensive diuretic therapy (spironolactone 400 mg/day and furosemide 160 mg/day) for at least 1 week and on a salt-restricted diet of <90 mmol/day
	2. Lack of response: Mean weight loss of <0.8 kg over 4 days and urinary sodium output less than the sodium intake
	3. Early ascites recurrence: Reappearance of grade 2 or 3 ascites within 4 weeks of initial mobilization
AASLD clinical practice guideline^Citation5	Refractory ascites is defined as fluid overload that 1) is unresponsive to sodium-restricted diet and high-dose diuretic treatment (400 mg/day of spironolactone and 160 mg/day of furosemide), or 2) recurs rapidly after therapeutic paracentesis
B
Zhang et al^Citation36	Ascites that cannot be satisfactorily controlled after a patient had either 1) 1 week of sodium intake restrictions (<6 g/day), intermittent albumin infusion (10–20 g per treatment), and high doses of diuretics (>160 mg/day of furosemide and 200 mg/day of spironolactone), or 2) 2 weeks of therapeutic paracentesis (3000–5000 mL per treatment)
Taki et al^Citation125	Defined either as a <1.5 kg/week weight loss while being treated with furosemide (100 mg/day) and spironolactone (150 mg/day) or as a <1.5 kg/week weight loss due to the inability to use an effective dose of diuretics because of development of diuretic-induced hyponatremia (sodium level <125 mEq/L), hyperkalemia (potassium level >5.5 mEq/L), azotemia (doubling of serum creatinine or values >1.5 mg/dL), or hepatic encephalopathy (greater than grade 2 as defined by Parsons-Smith criteria) while on a dietary restriction of sodium 5 g/day as a minor modification
Ohki et al^Citation6	Ascites detected by ultrasound under the treatment of a loop diuretic at a daily dose equivalent to ≥40 mg/day furosemide and ≥25 mg/day spironolactone, a loop diuretic at a daily dose equivalent to ≥20 mg/day furosemide and ≥50 mg/day spironolactone, or a loop diuretic alone at a daily dose equivalent to ≥60 mg/day furosemide
Tahara et al^Citation7	Ascites that had not been controlled by standard diuretics (≥20 mg/day furosemide and/or 25 mg/day spironolactone)

Abbreviations: AASLD, American Association for the Study of Liver Diseases; EASL, European Association for the Study of the Liver.

Table 2 Comparisons of various treatments for refractory ascites: review of available information

	Indications	Contraindications	Pros	Cons
Repeated LVP	• First-line treatment for tense ascites • Respiratory compromise and abdominal pain or pressure secondary to tense ascites • Refractory ascites unresponsive to routine medical therapy (after discontinuing β-blockers and adding midodrine^Citation5)	• Acute abdomen that requires surgery • Severe thrombocytopenia (platelet count <20×10^9/L) • Coagulopathy (INR >2.0) • Multiple abdominal scars • Infection of peritoneal cavity or abdominal wall • Intra-abdominal adhesions • Uncontrollable HE	• Fast, effective, and safe • Achieves a marked reduction of intra-abdominal, intrathoracic, and pulmonary pressures • A rapid fall of portal pressure without any renal and hepatic dysfunction	• Carries a risk of post-paracentesis circulatory dysfunction that causes reduced long-term survival
Indwelling peritoneal catheter (PleurX™ catheter)	• Refractory ascites unresponsive to routine medical therapy • Still symptomatic despite bimonthly LVP and were not candidates for TIPS or PVS	• Acute abdomen that requires surgery • Multi-loculated peritoneal cavity • Severe thrombocytopenia (platelet count <20×10^9/L) • Coagulopathy (INR >2.0) • Infection of peritoneal cavity or abdominal wall • Intra-abdominal adhesions • Uncontrollable HE	• Reduce the incidence of post-paracentesis circulatory dysfunction by enabling more frequent but less extensive drainages	• High incidence of infection for a long-term drainage
CART	• Refractory ascites unresponsive to routine medical therapy	• Ascites infection such as SBP • High level of endotoxin in ascites • Bloody ascites • Serum total bilirubin >85.5 μmol/L (>5 mg/dL) • Uncontrollable portal hypertension-related gastrointestinal bleeding • Uncontrollable HE	• Safe and effective just like LVP with albumin infusion • Prevents prerenal failure and hypoalbuminemia caused by frequent LVP • Improves abdominal distension and anorexia • Reduces albumin transfusion	• High costs of the instruments • Frequent fever and chill • Occasional allergic reactions
Peritoneal- urinary drainage (alfapump^® system)	• Refractory ascites unresponsive to routine medical therapy • Unable to tolerate frequent LVP (patients requiring more than two LVP per month)	• Active systemic or local infections, such as SBP and urinary tract infection • Extensive ascites loculation • Obstructive uropathy • Contraindications for general anesthesia • Uncontrollable portal hypertension-related gastrointestinal bleeding • Uncontrollable HE	• Effective for reducing the need for paracentesis (>50% over 6 months) and improving QOL • Improves nutritional status compared with LVP	• Frequent device and procedure-related adverse events • Associated with activation of endogenous vasoconstrictor systems and impairment of kidney function
PVS	• Diuretic-resistant patients who are not candidates for LT or TIPS, and who are not candidates for serial paracenteses (multiple abdominal scars, etc.) • Symptomatic ascites following a TIPS revision	• Patients with HRS • Serum total bilirubin level >119.7 μmol/L (>7 mg/dL) • Uncorrectable coagulopathy (INR >2.2) • Liver cirrhosis with HCC and those with prolonged PT • End-stage renal failure • Severe heart failure • Sepsis • SBP or uncontrollable infection • Septation of the peritoneal cavity • Uncontrollable portal hypertension-related gastrointestinal bleeding • Uncontrollable HE	• Improves GFR and provides palliation in 83% of patients with intractable ascites waiting LT without severe side effects • Controls ascites sooner than TIPS • Prolongs the time to the recurrence of ascites compared with diuretic treatment and LVP with albumin infusion • Reduces postoperative acute renal failure compared with LVP and albumin infusion	• Poor long-term patency • Excessive complications (DIC, cardiac failure, sepsis, etc.) • No survival advantage compared with medical therapy
TIPS	• Selected cirrhotic patients with refractory ascites who require more than two to three LVP per month • A bridge to liver transplantation, especially in patients with refractory ascites and HRS	Absolute contraindications • CHF (particularly right-sided heart failure) • Tricuspid regurgitation • Severe pulmonary hypertension (mean pulmonary pressure >45 mmHg) • Advanced liver failure (serum total bilirubin >85.5 μmol/L) • Multiple hepatic cysts • Uncontrolled systemic infection or biliary obstruction Relative contraindications • Obstruction of all hepatic veins • Complete portal vein thrombosis • Hepatocellular carcinoma (especially centrally located) • Severe coagulopathy (INR >5) • Thrombocytopenia (<20×10^9/L) • Moderate pulmonary hypertension • Recurrent or persistent severe spontaneous HE • Liver failure (serum total bilirubin >51.3 μmol/L, Child–Pugh score >12) • Cardiac dysfunction (ejection fraction <60%) • Cardiac diastolic dysfunction • Advanced age (e.g., >69 years)	• Reduces recurrence of tense ascites compared with LVP • Improves renal function especially in participants with baseline estimated GFRs <60 mL/min/1.73 m^2 • Improves renal perfusion and sodium excretion, controls ascites, and reverses HRS* • Improves the LT-free survival of patients, compared with LVP* • Corrects vascular dysfunction and enhances the benefits of NSBB • Decreases the risk of HRS • Economically advantageous due to less requirement for paracentesis • Improves body composition (fat-free mass, fluid-free body weight)	• Induces HE • Frequent shunt dysfunction • Associated with increased mortality in patients with severe liver dysfunction • Possible induction of early liver failure in cirrhotics with MELD score of 11 or 12 and low hemoglobin and platelet count • Induces long-term cardiovascular changes, including cardiac volume overload • Increases pulmonary hypertension

Note:

* Results by covered TIPS stent.

Abbreviations: CART, cell-free and concentrated ascites reinfusion therapy; CHF, congestive heart failure; DIC, disseminated intravascular coagulation; GFR, glomerular filtration rate; HCC, hepatocellular carcinoma; HE, hepatic encephalopathy, HRS, hepatorenal syndrome; INR, international normalized ratio; LT, liver transplantation; LVP, large-volume paracentesis; MELD, Model for End-stage Liver Disease; NSBB, nonselective β-blocker; PT, prothrombin time; PVS, peritoneovenous shunt; QOL, quality of life; SBP, spontaneous bacterial peritonitis; TIPS, transjugular intrahepatic portosystemic shunt.

Table 3 The evidence-based grading about the usefulness of various therapeutic approaches to refractory ascites applying the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system

Therapeutic approaches	Quality of evidence	Strength of a recommendation
Repeated LVP	A	1
Indwelling peritoneal catheter	B	2
Peritoneal-urinary drainage	B	2
CART	B	2
PVS	A	2
TIPS	A	1

Notes: The quality of evidence was graded as A (high), B (moderate), C (low), or D (very low). The strength of a recommendation was indicated as either 1 (strong recommendation) or 2 (weak recommendation), for which benefit versus risk and cost were adequately evaluated.

Abbreviations: CART, cell-free and concentrated ascites reinfusion therapy; LVP, large-volume paracentesis; PVS, peritoneovenous shunt; TIPS, transjugular intrahepatic portosystemic shunt.

Figure 1 Therapeutic algorithm for refractory ascites.

Notes: Diuretic-resistant or diuretic-intractable ascites are treated by serial therapeutic paracentesis. Meanwhile, all these patients necessitate the consideration of liver transplantation. If transplantation is difficult or takes long time, the patients should be treated by paracentesis for a time being. If indicated, TIPS and PVS can be selected as bridge therapies to liver transplantation. Indwelling peritoneal catheter and peritoneal-urinary drainage are rarely selected for improving QOL of patients who are not candidates for liver transplantation or TIPS. In Japan, CART is sometimes selected to save the requirement of albumin solution after therapeutic paracentesis. Causal treatment of liver disease itself with direct-acting antivirals may dramatically improve the prognosis of patients with hepatitis C virus infection.
Abbreviations: alb. inf., albumin infusion; CART, cell-free and concentrated ascites reinfusion therapy; PVS, peritoneovenous shunt; QOL, quality of life; TIPS, transjugular intrahepatic portosystemic shunt.

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