doi:10.1111/j.1440-1746.2011.06925.

A D VA N C E S I N C L I N I C A L P R A C T I C E

jgh_6925

11..20

Management of ascites in cirrhosis

Florence Wong
Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada

Key words
ascites, diuretics, large volume paracentesis,
portal hypertension, renal sodium retention,
TIPS.
Accepted for publication 24 August 2011.
Correspondence
Dr Florence Wong, 9th floor, North Wing,
Room 983, Toronto General Hospital, 200
Elizabeth Street, Toronto, ON M5G2C4,
Canada. Email: florence.wong@utoronto.ca

Abstract
Ascites is a common complication of liver cirrhosis associated with a poor prognosis. The
treatment of ascites requires dietary sodium restriction and the judicious use of distal and
loop diuretics, sequential at an earlier stage of ascites, and a combination at a later stage of
ascites. The diagnosis of refractory ascites requires the demonstration of diuretic nonresponsiveness, despite dietary sodium restriction, or the presence of diuretic-related complications. Patients with refractory ascites require second-line treatments of repeat largevolume paracentesis (LVP) or the insertion of a transjugular intrahepatic portosystemic
shunt (TIPS), and assessment for liver transplantation. Careful patient selection is paramount for TIPS to be successful as a treatment for ascites. Patients not suitable for TIPS
insertion should receive LVP. The use of albumin as a volume expander is recommended for
LVP of >56 L to prevent the development of circulatory dysfunction, although the clinical
significance of post-paracentesis circulatory dysfunction is still debated. Significant mortality is still being observed in cirrhotic patients with ascites and relatively preserved liver
and renal function, as indicated by a lower Model for End-Stage Liver Disease (MELD)
score. It is proposed that patients with lower MELD scores and ascites should receive
additional points in calculating their priority for liver transplantation. Potential new treatment options for ascites include the use of various vasoconstrictors, vasopressin V2 receptor
antagonists, or the insertion of a peritoneo-vesical shunt, all of which could possibly
improve the management of ascites.

Introduction
The risk for developing ascites is approximately 60% at 10 years
after cirrhosis diagnosis if the underlying cause of the cirrhosis is
left untreated.1 The appearance of ascites heralds the onset of
decompensation, and the survival of these patients changes from
80% at 5 years1 to 50% at 5 years2 without liver transplantation.
This is because the hemodynamic changes and circulatory dysfunction that accompany the progression of cirrhosis predispose
these patients to other complications (Fig. 1) associated with worsening prognosis (Table 1).3 In a study assessing the natural history
of patients with cirrhosis, hospitalized for the management of
ascites, during a mean follow-up period of 41 3 months, 28% of
263 patients developed dilutional hyponatremia, 11% developed
refractory ascites, and 7.6% developed hepatorenal syndrome
(HRS). The occurrence of any of these complications further
reduced survival2 (Fig. 2).
The effective treatment of ascites in cirrhosis involves correcting one or more of the pathophysiological processes that lead to
ascites formation (Fig. 3). In short, the presence of cirrhosis and
portal hypertension leads to vasodilatation in the systemic and
splanchnic circulations, but vasoconstriction in the renal circulation. Together with alterations in renal auto-regulation, a reduction
in functional liver cell mass, and the development of cirrhotic

cardiomyopathy, these processes result in a gradual increase in

renal sodium and water retention. The presence of portal hypertension then preferentially localizes the excess fluid in the peritoneal cavity as ascites.
The management of ascites requires a stepwise approach, beginning with dietary sodium restriction and diuretic therapy, followed
by second-line treatments once refractory ascites sets in.

Dietary sodium restriction

The underlying pathophysiology that leads to ascites formation in
cirrhosis is renal sodium retention; therefore, the mainstay of
treatment of ascites is to induce a negative sodium balance. This
can be achieved by reducing the dietary sodium intake, as well as
increasing the renal sodium output using a combination of diuretics.4 It is not uncommon for patients with ascites who are not on
diuretics to have renal sodium excretion of < 20 mmol/day. Such a
patient on a no-added-salt diet containing 130150 mmol of
sodium will retain at least 100 mmol of sodium/day, equivalent to
the accumulation of 10 L of ascitic fluid in 2 weeks (100 mmol/
day 14 days 140 mmol/L = 10 L) (Table 2). The International
Ascites Club has recommended a sodium intake of 88 mmol/day.5
This will require the use of special, low-sodium food items, and
consultation with a dietician is usually required. Patients are more

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Management of ascites in cirrhosis

F Wong

Figure 1 Stages of ascites in cirrhosis. HRS,

hepatorenal syndrome. = spontaneous bacterial peritonitis.

Table 1

Prognosis factors in cirrhotic patients with ascites

Parameter
Mean arterial pressure (mmHg)
> 80
< 80
Serum creatinine (mg/dL)
< 1.2
1.21.5
1.5
Hyponatremia (serum [Na] < 130 mmEq/L)
No
Yes
Urinary Na excretion (mmEq/day)
10
< 10
Plasma renin activity
Normal
Increased
Plasma norepinephrine (epinephrine)
Normal
Increased

Median survival (months)

46
11
25
11
4
27
7
46
17
57
6
23
13

Na, sodium. Adapted from Cardenas and Arroyo,3 with permission.

likely to adhere to a low-sodium diet if there is family support. In

patients who normally consume a high-salt diet, the use of sodium
restriction alone can lead to the reduction of ascites, especially if
the urinary sodium excretion is > 78 mmol/day.6 If a patient who
admits to adhering to a low-sodium diet and is still gaining weight
rapidly, calculating the sodium balance (see Table 2) can often
bring the message home. Salt substitutes usually contain high
potassium contents, and can lead to hyperkalemia if patients are
also on potassium-sparing diuretics. In the majority of cirrhotic
patients with ascites, diuretics are usually required to induce a
natriuresis.

Diuretic therapy
Diuretics block sodium reabsorption along the various nephron
sites, thereby increasing renal sodium excretion. Water excretion
then follows passively. It is customary to start diuretic therapy with
an aldosterone antagonist, such as spironolactone, otherwise all
12

Figure 2 Survival of hospitalized patients with ascites with or without

, No
complications. (Adapted from Planas et al.,2 with permission.)
complications;
, Spontaneous bacterial peritonitis;
, Refractory
, Dilutional hyponatremia;
, Hepatorenal syndrome.
ascites;

the renal sodium that is not absorbed at the loop of Henle with the
use of a loop diuretic alone will be reabsorbed at the distal tubule
under the unopposed action of the high aldosterone levels.
Spironolactone is usually administered at a start-up dose of
100 mg/day, and gradually increased up to 400 mg/day. The
diuretic effect can be seen within 48 h, but the peak onset of action
is 2 weeks, due to impaired metabolism in cirrhotics and a very
long half-life of up to 5 days.5 Amiloride can be used instead of
spironolactone, starting at 5 mg/day, and gradually increased to
20 mg/day. It has a shorter half-life, and therefore, a quicker onset
of action, but is less effective than spironolactone, as shown in a
randomized, controlled trial.7 Potassium canrenoate, another
aldosterone antagonist, is popular in Europe, and has been shown
to reduce the 1-year cumulative occurrence of ascites in cirrhosis.8
The starting dose is usually 200 mg/day, and gradually increased
to 400 mg/day.
If the use of a distal diuretic is not producing the desired
response, a loop diuretic, such as furosemide, can be added, starting at a dose of 40 mg/day, and gradually increased to 160 mg/day.
The dose response curve of furosemide is sigmoidal. Therefore,
once a maximum diuretic response is reached, further increases in
furosemide dose will not increase the diuretic response. The most
successful therapeutic regimen is the combination of a distal

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F Wong

Management of ascites in cirrhosis

Figure 3 Pathogenesis of ascites formation.

EABV, effective arterial blood volume; GFR,
glomerular filtration rate; Na, sodium; RAAS,
renninangiotensinaldosterone system; RBF,
renal blood flow; SNS, sympathetic nervous
system.

diuretic, such as spironolactone, and a loop diuretic, such as furosemide, beginning with 100 mg and 40 mg respectively, and
increased in a step-wise fashion, preferably maintaining the same
ratio of dosages, in order to maintain normal potassium levels.6
There have been discussions as to whether the simultaneous or
sequential use of an aldosterone antagonist and a loop diuretic is
more efficacious in the treatment of ascites. Santos et al.9 reported
that both the sequential or combined use of diuretics was similar
in terms of the diuretic response and diuretic-induced complications. However, Angeli et al. demonstrated in a randomized, controlled trial that treatment with combined diuretics could mobilize
moderate ascites more rapidly than sequential diuretics, and was

associated with less side-effects, including renal failure.10 The

explanation for the difference in the findings could be that the
patients in the study of Santos et al. were at a much earlier stage
of ascites, with 60% of the patients enrolled at their first presentation of ascites, and at least 40% of them had normal supine
levels of aldosterone.9 In the study of Angeli et al.,10 at least 70%
of patients had recurrent ascites that required repeat paracenteses.
Most had hyperaldosteronism, and many had reduced renal function. Therefore, it is reasonable to use sequential diuretics in
patients with ascites at first appearance, and they will likely
respond with a satisfactory natriuresis with ascites reduction.
However, patients with recurrent ascites will be better served with

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Management of ascites in cirrhosis

Table 2
Scenario
I

Scenario
II

F Wong

Calculating the sodium balance

Urinary sodium excretion is 90 mmol/day
Insensible sodium loss is 10 mmol/day
Na intake = 88 mmol/day
Na output = 100 mmol/day
Na balance = (88100) mmol/day = -12 mmol or
-84 mmol/week
Ascitic [Na] = 140 mmol/L (Same as serum [Na])
Therefore fluid loss = -84 mmol / 140 mmol/L = -0.6 L
Weight loss/week = 0.6 kg
Urinary sodium excretion is 0 mmol/day
Insensible sodium loss is 10 mmol/day
Na intake = 88 mmol/day
Na output = 10 mmol/day
Na balance = (8810) mmol/day = +78 mmol
Ascitic [Na] = 140 mmol/L (Same as serum [Na])
Therefore fluid gain = +78 mmol / 140 mmol/L = 0.56 L
Weight gain/day = 0.56 kg or Weight gain/week = 3.92 kg

Na, sodium.

Refractory ascites

combination diuretic therapy in order to reduce the time required

to achieve a satisfactory diuretic response and to reduce the risk of
hyperkalemia.
Patients on diuretic therapy need to be monitored regularly for
electrolyte abnormalities, over-diuresis, and renal failure. As the
volume of ascites that can be resorbed into the systemic circulation
is approximately 400 mL/day,11 weight loss in excess of 0.5 kg/day
means that there is reduction of the intravascular volume, thereby
placing these patients at risk of the development of renal failure
from over-diuresis. Patients with peripheral edema can tolerate
more rapid fluid loss until the edema has resolved. Compliance
with and response to sodium restriction and diuretics can be evaluated regularly by 24-h urine collection for sodium excretion. In
situations where this is not feasible, a random urine sodium to a
potassium ratio of > 1 predicts a > 78 mmol/day sodium excretion
in 90% of patients.12 Non-compliance with a low-sodium diet is
reflected by an adequate renal sodium excretion, but without any
weight loss. A low renal sodium excretion necessitates increasing
the diuretics doses as tolerated, up to the maximum recommended
levels. When the combination of sodium restriction and diuretics is
given to carefully-monitored patients, 90% of them can reduce or
even eliminate their ascites with significant improvement in their
quality of life.

Albumin
Albumin is a plasma protein that is most responsible for plasma
colloid oncotic pressure. It is a negatively-charged molecule that
attracts sodium and water, and therefore, it is a very good volume
expander.13 In addition, it has many other functions, such as ligand
binding, and antioxidant and endothelial stabilizing properties.
Therefore, albumin seems the ideal solution to manage conditions
where there is intravascular volume reduction, inflammation, or
circulatory dysfunction. Albumin has been advocated as a treatment for many complications of cirrhosis and ascites, such as
spontaneous bacterial peritonitis14 and HRS.15 As the basic pathophysiological process that leads to the development of ascites is a
14

reduction of the effective arterial blood volume,16 it makes physiological sense to use albumin in the management of ascites,
although this has been controversial.
In one randomized, controlled trial in cirrhotic patients with
ascites, weekly infusions of 25 g of albumin added to standard
diuretics was shown to produce a significantly better diuretic
response compared to diuretics alone, including shorter hospital
stay, lower probability of ascites reaccumulation, and a lower
likelihood of readmission to hospital, but no effect on survival.17 In
a later study by the same investigators, the use of 25 g/week
albumin for 1 year, and thereafter, 25 g every 2 weeks for up to
120 months in patients with first-onset ascites, resulted in a significant increase in survival of 16 months and a significantly lower
probability of ascites recurrence.18 The major drawback of chronic
albumin use is its cost. For this reason, there is currently no
standard recommendation to use albumin as an adjunct therapy to
diuretics in the treatment of uncomplicated ascites.

Refractory ascites is defined as ascites that cannot be easily mobilized (< 1.5 kg weight loss/week), despite daily doses of 400 mg
spironolactone or 30 mg amiloride plus 160 mg furosemide; and
the patient must have been compliant with dietary sodium restriction of 90 mmol/day for 1 week.19 Patients who cannot tolerate diuretics because of the development of complications are
defined as having diuretic-intractable ascites (Table 3).19 Because
these patients are either unresponsive to or are intolerant of diuretics, second-line treatments, such as regular large-volume paracentesis (LVP) or the insertion of a transjugular intrahepatic
portosystemic shunt (TIPS), are needed for the management of
their ascites. All of these patients should also be considered for
liver transplantation, unless there is a contraindication.

LVP
Several large randomized, controlled trials have shown that LVP of
46 L is safer and more effective for the treatment of tense ascites
than the use of high doses of diuretics.2022 The incidence of systemic and hemodynamic disturbance, electrolyte abnormalities,
renal impairment, and encephalopathy was lower in those treated
with repeated LVP compared to diuretic therapy. Shorter duration
of hospitalization was observed with LVP, but the rates of hospital
readmission and survival were similar to those of diuretic
therapy.20 Because LVP does not alter the pathogenetic mechanisms that lead to ascites formation, ascites will recur following a
paracentesis.
The frequency and the volume of LVP can be determined from
the patients sodium intake. For a patient who is adherent to
sodium restriction of 88 mmol/day, the weekly weight gain, and
therefore ascites accumulation, should be < 4 L/week (Table 2),
and this should be correspondingly less for patients whose
sodium intake is less than 88 mmol/day. Therefore, a patient who
is requesting a LVP of 1012 L every week is obviously not
adhering to a low-sodium diet. Counseling with a dietician is
often helpful to reduce the sodium intake in order to make LVP
more manageable for both the physician and the patient.
The next question is whether intravascular volume replacement
is necessary following LVP. Reaccumulation of ascites following

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Table 3

Management of ascites in cirrhosis

Diagnostic criteria for refractory ascites

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 or 5.2 g of salt/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
a. Diuretic-induced hepatic encephalopathy: development of
encephalopathy in the absence of any other precipitating factor.
b. Diuretic-induced renal impairment: increase of serum creatinine
by > 100% to a value > 2 mg/dL in patients with ascites
responding to treatment.
c. Diuretic-induced hyponatremia: decrease of serum sodium by
> 10 mmol/L to a serum sodium of < 125 mmol/L.
d. Diuretic induced hypo- or hyperkalemia: change in serum
potassium to < 3 mmol/L or > 6 mmol/L, despite appropriate
measures.

Grading of ascites; Grade 1 = mild ascites only detectable by ultrasound

examination; Grade 2 = moderate ascites that is manifest by moderate
symmetrical distension of the abdomen; Grade 3 = large or gross
ascites with marked abdominal distension.
Adapted from Salerno et al.19

LVP can lead to a reduction in central circulatory volume, with

potential for compromising systemic hemodynamics, a condition
known as paracentesis-induced circulatory dysfunction (PICD),
defined as an increase in plasma renin activity by > 50% of the
preparacentesis level to a final value of > 4 ng/mL/h.23 This could
lead to further activation of the already activated vasoconstrictor
systems and place the patient at risk of the development of renal
dysfunction. There are data to suggest that paracentesis of < 6 L
can be safely performed without the use of volume expanders,24,25
thus the incidence of circulatory dysfunction is only 7% in paracenteses of < 6 L, and there is little, if any, clinical consequence.25
This is especially true in patients with peripheral edema, since the
edema fluid can be reabsorbed to replenish the central circulation.
In contrast, the use of total paracentesis was associated with the
development of PICD in 37% of patients.23
There has been much debate about the use of volume expanders
following every paracentesis, because PICD does not occur after
every episode of LVP,26 nor does every case of PICD lead to the
development of renal impairment.27 In one study, only 40% of
patients who experienced PICD developed significant renal
impairment, while 11% developed renal impairment, even without
any evidence of circulatory dysfunction.23 Gines et al. not only
advocated the use of plasma expanders following every paracentesis, they also demonstrated that the use of albumin was the most
effective of all volume expanders to reduce the incidence of
PICD.28 However, other studies have shown that synthetic plasma
expanders are as effective as albumin in preventing hyponatremia
and renal impairment following LVP.29,30 To support the use of
albumin, a recent double-blind, randomized pilot study showed
that the number of liver-related complications was significantly
lower in patients who were infused with albumin compared with

those infused with polygeline.31 Given the fact that albumin has
not been shown to cause any harm in cirrhosis, the International
Ascites Club recommends that, until further results are available,
the infusion of albumin of 68 g is to be given per liter of ascitic
fluid removed for LVP of > 56 L.19 A recent study from Toronto
demonstrated that as long as the ascitic volume removed is less
than 8 L, and the standard dose of albumin of 68 g/L of ascitic
fluid removed is given, the development of PICD is not associated
with any renal dysfunction.32
Although cirrhotic patients might have coagulopathy and
thrombocytopenia, the incidence of clinically-significant intraabdominal bleeding during an LVP is estimated to be 0.5%.
Therefore, the routine use of freshfrozen plasma or platelet concentrates is not recommended. Leakage of ascitic fluid through the
puncture site is a relatively frequent complication. The Z-tract
technique should reduce its occurrence. Ascites leakage post-LVP
should be managed by placing a purse-string suture around the
puncture site or by applying skin adhesive, and instructing the
patient to lie with the puncture site uppermost.33 The use of a
colostomy bag to contain the ascites leak should be discouraged
because of the increased risk of infection.

TIPS
A TIPS functions like a side-to-side portocaval shunt, and is very
effective in reducing portal pressure. As sinusoidal portal hypertension is one of the pathogenetic mechanisms of ascites formation in cirrhosis, it stands to reason that a successful TIPS
insertion should be able to eliminate ascites. In addition, the successful insertion of TIPS returns a significant volume from the
splanchnic circulation to the systemic circulation, thereby reducing the extent of underfilling of the effective arterial blood
volume.34 Even in the absence of diuretics, increased sodium
excretion begins after the first month following TIPS insertion.
Thereafter, it increases further to culminate in a renal sodium
excretion of approximately 100 mmol/day at 12 months.35
Patients will need to stay on a low-sodium diet in the post-TIPS
period, or must take diuretics in order to facilitate ascites clearance. Within 6 months, complete resolution of ascites occurs in
approximately two-thirds of patients, and a partial response in
the other one-third. Further resolution can occur up to 12 months
post-TIPS, with ultimately approximately 80% of patients completely clearing their ascites.
Recent results have shown that the presence of diastolic dysfunction, part of the cirrhotic cardiomyopathy syndrome,36 is associated with poor ascites clearance after TIPS.37 Successful TIPS
placement with elimination of ascites improves renal function
and35 nutritional status, and causes positive nitrogen balance,38 all
leading to improved quality of life.
Five randomized, controlled trials have compared LVP versus
TIPS as a treatment for ascites.3943 All have showed that TIPS is
much more effective than LVP in terms of the control of ascites,
but at the expense of more episodes of hepatic encephalopathy.44
Other TIPS-related complications include those related to the
procedure itself, and those related the presence of a shunt
(Table 4).45,46 The recent advent of polytetrafluoroethylene
(PTFE)-covered stents has significantly reduced the incidence of
TIPS stenosis; this was seen in up to 70% of cases with bare stents

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Management of ascites in cirrhosis

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Table 4 Complications related to transjugular intrahepatic portosystemic shunts (TIP)

Procedure related

Prosthesis related

TIPS dysfunction
Hepatic encephalopathy
Progressive liver failure
Hepatocellular carcinoma
Cardiovascular

Hemoperitoneum
Laceration of capsule
Laceration of vessels
Arteriovenous fistula
Hemobilia
Arrhythmia
Migration of stent
Kinking
Hemolytic anemia
Infection of stent (endotipsitis)
Thrombosis
Stenosis
New onset
Worsening
ChildPugh score 12
Arrhythmia
Cardiac failure

in the first year after TIPS insertion,47 but with PTFE-covered

stents, hepatic encephalopathy occurs in approximately 50% of
patients in the first 2 years.48 This can easily be controlled with
medical therapy, although occasionally, reducing the diameter of
the stent is required for the management of the hepatic encephalopathy. The covered stents have the advantage of avoiding bile
leakage into the stent lumen due to decreased abluminal porosity,
and also a smoother internal lining, thereby permitting a more
uniform endothelial growth.47,49,50
Until recently, TIPS has not been shown to provide a survival
benefit in patients who receive it for the management of ascites.44
However, a recent meta-analysis using individual patient data from
the four larger TIPS versus LVP randomized, controlled trials
showed that TIPS does provide a survival advantage in the
carefully-selected patients (Fig. 4).51 Therefore, patient selection is
crucial to maximize the benefits of TIPS. In general, patients who
are elderly, with a history of recurrent hepatic encephalopathy, or
those with known cardiac dysfunction or pulmonary hypertension,
as well as those with renal failure should be carefully assessed
before being accepted for TIPS. In addition, TIPS insertion
requires a patent portal vein for TIPS insertion to be technically
feasible, and there should no structural abnormalities, such as
multiple hepatic cysts. Finally, patients should be free of infections
prior to TIPS insertion. If the presence of infection at another site
colonizes the TIPS, which is not removable once inserted, the
patient will become intermittently bacteremic, making it difficult
to eradicate the infection.
The absolute and relative contraindications for TIPS insertion
are shown in Table 5. Currently, a randomized, controlled trial is
being conducted to assess the effect of TIPS versus LVP on the
survival of patients at an earlier stage of the natural history of
ascites, especially those with better liver function. If improved
survival can be confirmed in certain subgroups of patients using
TIPS, then the selection of patients for TIPS placement will have
to take into consideration the patients age, severity of liver dysfunction, and extent of circulatory dysfunction.
16

Liver transplantation
All patients with refractory ascites should be assessed for liver
transplantation, the only procedure which corrects both the
impaired liver function and portal hypertension. Splanchnic and
systemic hemodynamic abnormalities, which are pivotal in the
pathogenesis of ascites formation, slowly return to normal after
liver transplantation. Therefore, liver transplantation is the ideal
treatment for advanced cirrhosis and ascites. However, with the
introduction of the Model for End-Stage Liver Disease (MELD)
score for the allocation of donor organs for liver transplantation,52
the presence of ascites no longer has any weighting in prioritizing
patients for liver transplantation. It follows that patients with
refractory ascites and low MELD scores, such as abstinent alcoholics or patients with inactive viral hepatitis, can remain on the
liver transplant waiting list for an extended period of time without
ever receiving a donor organ.
Various investigators have confirmed that mortality for patients
on the liver transplant waiting list remains high (> 20% at
180 days), despite a lower MELD score of < 21, if the patient also
has moderate ascites and hyponatremia.5355 The more severe the
ascites, the higher the waiting-list mortality.55 In fact, low-serum
sodium and the presence of moderate ascites have been shown to
be independent predictors of early pretransplant mortality in
patients with a MELD score of < 21.53 As well, the ChildPugh
score, which includes ascites, seems to be a better index of prognosis than the MELD score in patients who have a MELD score of
> 14.4.56 Efforts are now being made to modify the criteria for the
allocation of donor organs, such as assigning points for persistent
ascites and low-serum sodium in calculating the final score for
organ allocation. This would improve the likelihood of patients
with ascites receiving liver transplantation in a timely fashion.

Potential new treatments for ascites

Many investigators have been exploring other treatments for
refractory ascites, because not all cases of refractory ascites are
suitable for TIPS insertion, nor can every patient who receives a
TIPS eliminate their ascites, and liver transplant is not available for
all patients with advanced liver disease. The following is a
summary of potentially-available agents.

Vasoconstrictors
Various vasoconstrictors have been assessed to determine whether
improved splanchnic and systemic hemodynamics could lead to
improved renal hemodynamics and increased renal sodium excretion, thereby reducing the ascites.
Midodrine is an alpha adrenergic receptor agonist that is
approved for the treatment of postural hypotension. It is also
popular in North America for the treatment of HRS. Its alpha
agonist action results in an increase in mean arterial pressure in
cirrhosis.57 In two small studies totaling 56 patients, the use of
midodrine, either as a single oral dose,58 or given three times per
day orally for 7 days,59 significantly improved renal hemodynamics, together with a significant increase in renal sodium excretion.
In one of the studies,59 there was a significant correlation between
the increase in systemic vascular resistance and an increase in
glomerular filtration rate and enhanced renal sodium excretion.

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Management of ascites in cirrhosis

Figure 4 Survival of different subgroups of

patients following transjugular intrahepatic
portosystemic shunt insertion. (Adapted from
Salerno et al.,51 with permission.)

Table 5 Contraindications for transjugular intrahepatic portosystemic

shunt insertion for the management of refractory ascites
Absolute

Relative

Uncontrolled encephalopathy
Congestive heart failure

> 70 years of age

Any infection, including dental
sepsis
Non-compliance with sodium
restriction
Hepatoma (especially if central)
Portal vein thrombosis

Severe pulmonary
hypertension
ChildPugh score 12
Multiple hepatic cysts
Unrelieved biliary obstruction

However, in patients who have normal systemic hemodynamics,

the use of midodrine has not been shown to improve renal sodium
excretion.60 With longer-term administration of midodrine (for
1 month in 8 patients with cirrhosis and refractory ascites),
together with weekly albumin infusion and long-acting, slowrelease octreotide, there was a significant reduction in plasma
renin and aldosterone concentrations, but only a trend towards a
reduction in the volume of ascites removed by paracentesis,
without any effects on renal function.61
Terlipressin is a vasopressin analog that acts on the V1 receptor
in the splanchnic vasculature to cause splanchnic vasoconstriction,
thereby decreasing splanchnic inflow and lowering the portal pressure. The improvement in systemic hemodynamics has been successfully used in the treatment of HRS in cirrhosis. The role of
terlipressin in the management of ascites has also been assessed in
several studies. A single dose of 2 mg terlipressin given intravenously was effective in improving renal blood flow, the glomerular
filtration rate, and renal sodium excretion in cirrhotics without
renal dysfunction with (n = 8) or without (n = 11) ascites.62 The
improvement in renal function correlated with decreased plasma
norepinephrine and renin levels, and increased atrial natriuretic
peptide concentrations. These results were confirmed in another
study, which included 12 patients with cirrhosis and ascites, but
without azotemia or hyponatremia.63 Systemic hemodynamics
improved, associated with increases in creatinine clearance, diuresis and natriuresis.63

The positive results in these preliminary studies suggest that

vasoconstrictors should be explored further as potential treatments
for ascites. However, until the results of randomized, controlled
trials are available, these agents cannot be regarded as standard of
care in the management of refractory ascites.

Vasopressin V2 receptor antagonists

Vasopressin V2 receptor antagonists, or vaptans, are agents that
compete with vasopressin for attachment onto the V2 receptors at
the renal collecting duct to inhibit water reabsorption at that site,
thereby inducing an aquaresis and reduced serum water content.
The vaptans were first developed for the management of
hyponatremia in patients with edematous states.6466 It was
observed in some of the above studies that the vaptans were also
able to reduce the extent of ascites in cirrhotic patients.66 It is
feasible that by maintaining serum sodium, the use of vaptans had
permitted diuretics to be continued, thereby improving the control
of ascites.
In a recent publication that reports on three large randomized,
controlled trials involving 1200 patients with cirrhosis and ascites,
the use of satavaptan either alone or in combination with diuretics
was not shown to be clinically beneficial in the management of
ascites. Further, in one of the three studies, it was associated with
an increased mortality.67 Short-term studies involving other
vaptans, such as M000268 or tolvaptan,69 have shown efficacy of
these two vaptans in improving ascites. However, the study with
M0002 only involved 15 patients for a total administration course
of 2 weeks, while that using tolvaptan included 18 patients for a
total of nine study days. Therefore, while the results are encouraging, it is not clear whether longer-term studies involving a larger
cohort of patients with either M0002 or tolvaptan will confirm
their efficacy in reducing ascites in cirrhosis. Currently there is no
recommendation to use vaptans in the management of ascites.

ALFApump system
The ALFApump system (Sequana Medical AG, Zurich, Switzerland) is the latest investigational tool that is being developed for
the management of ascites. It is a subcutaneously-implanted,

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Management of ascites in cirrhosis

F Wong

confirm the results of these recent studies to ultimately provide

better treatments for ascites in patients with cirrhosis.

References

Figure 5

Schematic picture of a peritoneo-vesical shunt in situ.

battery-powered peritoneo-vesical shunt that pumps excess peritoneal fluid into the bladder where the patient can eliminate it
through normal urination (Fig. 5). To date, 40 patients have
received the device in a phase-3 clinical trial, which successfully
removed 90% of the ascites (Dr Noel Johnson, pers. comm., 2011).
With meticulous attention to aseptic techniques and the use of
prophylactic antibiotics, the rate of infection has been no higher
than what is expected in the cirrhotic population, despite the presence of the foreign body. With the device recently being approved
in Europe, it is expected that this will significantly transform the
management of ascites in the future, ultimately reducing the
number of patients who require LVP as the mainstay of treatment
for their ascites.

Conclusion
The medical management of ascites, including dietary sodium
restriction and diuretic therapy, has not changed significantly for
several decades. The development of TIPS two decades ago as a
treatment for refractory ascites was regarded as the new kid on
the block, but the emergence of many TIPS-associated complications quickly dampened the enthusiasm of clinicians caring for
patients with refractory ascites, until the randomized, controlled
trials and subsequent meta-analyses further refined the patient
selection criteria for TIPS insertion. Currently, patients who are
not suitable for TIPS insertion depend on regular LVP to control
their ascites, while they await their turn for liver transplantation.
With the recognition that the presence of ascites in patients with
low MELD scores can negatively impact their prognosis, efforts
are now being made to reassign points for the presence of ascites
in calculating the priority for liver transplantation, so that patients
with low MELD scores and ascites are not being disadvantaged.
Improved understanding of the pathophysiology of ascites formation provides possible novel options for the future, such as
vasoconstrictor therapy that aims at correcting the abnormal physiology of cirrhosis. Technological advances mean that even in those
patients whose only option is repeat LVP, it is possible in the future
to have a device implanted so as to discharge the ascites through
the urinary system. Preliminary data have suggested that survival
might be improved with these newer treatments. The future will
need to include randomized, controlled trials to evaluate and
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