EASL Clinical Practice Guidelines

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 mobilized or the early recurrence of which (i.e., after LVP) cannot be satisfactorily prevented by medical therapy" [[11], [56]]. The diagnostic criteria of refractory ascites are shown in Table 3.

Table 3
Definition and diagnostic criteria for refractory ascites in cirrhosis.

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
Requisites
 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 less than 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
 4. Diuretic-induced complications Diuretic-induced hepatic encephalopathy is the development of encephalopathy in the absence of any other precipitating factor
Diuretic-induced renal impairment is an increase of serum creatinine by >100% to a value >2 mg/dl (177 μmol/L) in patients with ascites responding to treatment
Diuretic-induced hyponatremia is defined as a decrease of serum sodium by >10 mmol/L to a serum sodium of <125 mmol/L
Diuretic-induced hypo- or hyperkalemia is defined as a change in serum potassium to <3 mmol/L or >6 mmol/L despite appropriate measures
Modified with permission from Moore KP, Wong F, Ginès P, et al. The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club. Hepatology 2003;38:258–266.

Once ascites becomes refractory to medical treatment, the median survival of patients is approximately 6 months [[7], [56], [57], [58], [59]]. As a consequence, patients with refractory ascites should be considered for liver transplantation. The MELD score system predicts survival in patients with cirrhosis [[60], [61]]. However, other factors in patients with cirrhosis and ascites are also associated with poor prognosis, including low arterial pressure, low serum sodium, low urine sodium, and high Child-Pugh score [[7], [57], [58], [59], [60], [61]]. Patients with refractory ascites may have a poor prognosis despite a relatively low MELD score (e.g. <18) and this may be of importance with respect to prioritisation for liver transplantation [14]. For these reasons, inclusion of additional parameters in the MELD score, such as serum sodium has been suggested [[14], [61], [62], [63], [64], [65]].

Recommendations The assessment of the response of ascites to diuretic therapy and salt restriction should only be performed in stable patients without associated complications, such as bleeding or infection. (Level B1).

The prognosis of patients with refractory ascites is poor and therefore they should be considered for liver transplantation (Level B1).

Management of refractory ascites

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

Large-volume paracentesis

A large body of evidence indicates that repeated LVP is an effective and safe therapy of refractory ascites [[8], [11], [56], [66]]. The administration of albumin prevents circulatory dysfunction associated with LVP (see discussion in a previous section of these guidelines).

Diuretics in patients with refractory ascites

In most patients (>90%), diuretics are not effective in preventing or delaying the recurrence of ascites after LVP since by definition patients have ascites which is refractory to diuretic therapy [56]. Diuretics should be discontinued permanently in patients with diuretic-induced complications (hepatic encephalopathy, renal impairment, or electrolyte abnormalities). In the remaining patients, treatment should be continued only when urinary sodium excretion under diuretic therapy is greater than 30 mmol/day [11].

Transjugular intrahepatic portosystemic shunts (TIPS)
Uncontrolled studies

TIPS decompresses the portal system like a side-to-side portocaval shunt inserted between the high pressure portal venous area and the low pressure hepatic venous area [67]. Because of the reduction in portal pressure TIPS has proved to be effective in the control of recurrent ascites. In the short-term, TIPS induces an increase in cardiac output, right atrial pressure, and pulmonary artery pressure leading to a secondary reduction in systemic vascular resistance and effective arterial blood volume [[68], [69], [70], [71], [72], [73], [74], [75], [76], [77], [78], [79]]. With time, the increase in cardiac output that follows a TIPS insertion tends to return to pre-TIPS levels [[72], [74], [75]]. Beneficial effects on renal function include increase in urinary sodium excretion and glomerular filtration rate [[72], [76], [77], [78]]. In addition, TIPS may have beneficial effects on nitrogen balance and body weight [[79], [80], [81]]. TIPS also improves quality of life, but in randomized studies the degree of improvement is similar to that observed in patients treated with repeated LVP and albumin [82]. TIPS has been successfully used in patients with recurrent hydrothorax but the outcome seems to be highly related to liver function and age [[83], [84], [85], [86]].

A major complication after TIPS insertion is the development of hepatic encephalopathy which occurs in 30–50% of the patients [[67], [87]]. Other complications include shunt thrombosis and stenosis. Uncovered stents are complicated by stenosis in up to approximately 80% of the cases [[67], [88]].

Controlled studies

The effects of TIPS on the control of ascites, frequency of encephatlopahty, and survival in the 5 randomised controlled trials so far published is shown in Table 4 [[79], [89], [90], [91], [92]]. TIPS was superior to LVP in the control of ascites but was associated with a greater frequency of encephalopathy. Studies showed discrepancies with respect to survival.

Table 4
Characteristics and results of five multicenter randomised controlled trials comparing transjugular intrahepatic portosystemic shunt (TIPS) and large-volume paracentesis (LVP) in patients with cirrhosis and refractory or recidivant ascites.

Reference Refractory/recidivant Ascites (%) Number of patients Ascites improved (%) Encephalopathy (%) Survival (%)
TIPS LVP TIPS LVP TIPS LVP TIPS LVP
Lebrec et al., 1996 [ 89] 100/0 13 12 38 0 15 6 29 60
Rössle et al., 2000 [ 79] 55/45 29 31 84 43 23 13 58 32
Ginès et al., 2002 [ 90] 100/0 35 35 51 17 60 34 26 30
Sanyal et al., 2003 [ 91] 100/0 52 57 58 16 38 21 35 33
Salerno et al., 2004 [ 92] 68/32 33 33 79 42 61 39 59 29

The majority of the trials, excluded patients with very advanced disease as indicated by serum bilirubin >5 mg/dl [[79], [91]], INR >2 [91], episodic hepatic encephalopathy >grade 2, or persistent encephalopathy [90], bacterial infections [[89], [91], [92]], renal failure [[79], [89], [90], [91], [92]], and cardiac and respiratory failure [[79], [91], [92]]. Because of insufficient data on efficacy and safety, TIPS cannot be recommended in patients with very advanced liver disease or associated severe extrahepatic diseases.

Meta-analyses

Patients in the five above-mentioned randomised controlled clinical trials have variably been included in five meta-analyses yielding almost similar conclusions (Table 5) [[93], [94], [95], [96], [97]]. All meta-analyses agree that recurrence of ascites after 3 and 12 months is lower in patients treated with TIPS compared to that in patients treated with LVP. The frequency of hepatic encephalopathy is higher in the TIPS treated patients in all meta-analyses. Three meta-analyses showed no difference in survival between the TIPS and LVP groups [[93], [94], [96]]. One meta-analysis found a trend towards reduced mortality in patients treated with TIPS after having excluded an outlier trial [95] and another meta-analysis found an increased transplant-free survival in the TIPS group [97].

Table 5
Main results of 5 meta-analyses on multicenter randomised controlled trials of the effects of transjugular intrahepatic portosystemic shunt (TIPS) and large-volume paracentesis (LVP) on refractory ascites.

Reference Number of trials included Number of patients included Significant heterogeneity among trials Recurrence of ascites Encephalopathy Survival
Albillos et al., 2005 [93] 5 330 Yes Lower in TIPS group. RR 0.56 Higher in TIPS group. RR 1.72 No difference between groups. RR 0.93
Deltenre et al., 2005 [94] 5 330 No Lower in TIPS group. DifE4M: 0.41, p <0.001 DifE12M: 0.35, p <0.001 Higher in TIPS group. DifE: 0.17, p <0.001 No difference between groups DifE1y: 0.03, p = 0.7 DifE2y: 0.07, p = 0.4
D'Amico et al., 2005 [95] 5 330 Yes Lower in TIPS group. OR 0.14 (0.7–0.27) Higher in TIPS group. OR 2.26 (1.35–3.76) No difference between groups A trend towards better survival in TIPS group OR 0.74 (0.40–1.37)
Saab et al., 2006 [96] 5 330 ? Lower after 3 months in TIPS group. OR 0.07 (0.03–0.18, p <0.01) 12 months OR 0.14 (0.06–0.28, p <0.01) Higher in TIPS group. OR 2.24 (1.39–3.6) p <0.01 30-days OR 1.0 (0.10–0.06, p = 1) 24 months OR 1.29 (0.65–2.56, p = 0.5)
Salerno et al., 2007 [97] 4 305 No Lower in TIPS group. 42 versus 89% in LVP group (p <0.0001) Higher in TIPS group. (1.13 versus 0.63 (p = 0.006)). Transplant-free survival better in TIPS group (p = 0.035)
Peritoneovenous shunt

Due to frequent complications related to surgical insertion, shunt dysfunction, and infections, this treatment has currently very little role in the management of patients with refractory ascites [11].

Other treatments

Since circulatory dysfunction and activation of neuro-humoral systems with sodium and water retention play a major role in the pathogenesis of refractory ascites, there has been an increasing interest in research on drugs that may improve circulatory and renal function, particularly vasoconstrictors and selective antagonists of the V2-receptors of vasopressin, known as vaptans. Vasoconstrictors such as the α1-adrenergic agonist midodrine or terlipressin improve circulatory and renal function in patients with and without refractory ascites [[98], [99], [100]]. However, large randomized controlled studies have not been reported yet. Terlipressin has the inconvenience of requiring intravenous administration.

In two phase-2 studies the administration of a vaptan, satavaptan, in combination with fixed doses of diuretics, in addition to improving serum sodium levels was associated with weight loss, suggesting an effect of the drug on ascites and/or edema [[101], [102]]. In another phase-2 study, the administration of satavaptan was associated with a reduction of ascites recurrence after LVP [103]. Unfortunately, however, phase-3 randomized, placebo-controlled studies failed to demonstrate a significant beneficial effect of satavaptan in combination with diuretics in the control of ascites and treatment was associated with an increased morbidity and mortality, the causes of which are unclear [104].

Recommendations Repeated large-volume paracentesis plus albumin (8 g/L of ascites removed) is the first line of treatment for refractory ascites (Level A1). Diuretics should be discontinued in patients with refractory ascites who do not excrete >30 mmol/day of sodium under diuretic treatment.

TIPS is effective in the management of refractory ascites but is associated with a high risk of hepatic encephalopathy and studies have not been shown to convincingly improve survival compared to repeated large-volume paracentesis (Level A1). TIPS should be considered in patients with very frequent requirement of large-volume paracentesis, or in those in whom paracentesis is ineffective (e.g. due to the presence of loculated ascites) (Level B1).

Resolution of ascites after TIPS is slow and most patients require continued administration of diuretics and salt restriction (Level B1).

TIPS cannot be recommended in patients with severe liver failure (serum bilirubin >5 mg/dl, INR >2 or Child-Pugh score >11, current hepatic encephalopathy ⩾grade 2 or chronic hepatic encephalopathy), concomitant active infection, progressive renal failure, or severe cardiopulmonary diseases (Level B1).

In selected patients TIPS may be helpful for recurrent symptomatic hepatic hydrothorax (Level B2).