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Ascites: Pathogenesis and therapeutic principles

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DOI: 10.1080/00365520902912555 Source: PubMed

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Scandinavian Journal of Gastroenterology, 2009; 44: 902
911

REVIEW ARTICLE

Ascites: Pathogenesis and therapeutic principles

SREN MLLER1, JENS H. HENRIKSEN1 & FLEMMING BENDTSEN2

Department of Clinical Physiology 239, and 2Department of Medical Gastroenterology 439, Hvidovre Hospital, Faculty of
Health Sciences, University of Copenhagen, Hvidovre, Denmark

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Abstract
Ascites is a classic complication of advanced cirrhosis and it often marks the first sign of hepatic decompensation. Ascites
occurs in more than 50% of patients with cirrhosis, worsens the course of the disease, and reduces survival substantially.
Portal hypertension, splanchnic vasodilatation, liver insufficiency, and cardiovascular dysfunction are major pathophysiological hallmarks. Modern treatment of ascites is based on this recognition and includes modest salt restriction and stepwise
diuretic therapy with spironolactone and loop-diuretics. Tense and refractory ascites should be treated with large volume
paracentesis followed by plasma volume expansion or transjugular intrahepatic portosystemic shunt. Ascites complicated by
spontaneous bacterial peritonitis requires adequate treatment with antibiotics. New potential treatment strategies include
the use of vasopressin V2-receptor antagonists and vasoconstrictors. Since formation of ascites is associated with a poor
prognosis, and treatment of fluid retention does not substantially improve survival, such patients should always be
considered for liver transplantation.

Key Words: Ascites, hepatobiliary-clinical, portal-hypertension

Introduction
The genesis and perpetuation of ascites is a common
complication, occurring in more than 50% of patients
within 10 years of the diagnosis of cirrhosis [1]. Ascites
is defined as more than 25 ml fluid in the peritoneal
cavity and can be seen in various diseases, but is most
frequently caused by cirrhosis with portal hypertension and by peritoneal carcinomatosis. Less common
aetiologies of ascites are hepatocellular carcinoma,
Budd-Chiari syndrome, congestive heart failure,
pancreatitis, and tuberculosis. The normal hepatosplanchnic lymph formation is about 1 ml/min. In
patients with cirrhosis, this rate can increase up to 10
ml/min [2,3]. When the production of lymphatic fluid
exceeds the lymphatic transport capacity, ascites
develops. According to the amount of ascites, this
can be divided into grades 0
3 [4]. Grade 3 represents
the gross and tense ascites with vast discomfort to the
patient (Table I). However, the presence of even lower

grades of ascites is not just a cosmetic problem since it

is associated with poor survival with a 50% mortality
rate within 3 years [5,6]. In these patients, survival
depends mainly on the degree of portal hypertension,
liver insufficiency, and circulatory dysfunction. In
about 25% of patients, bacterial translocation leads to
the development of spontaneous bacterial peritonitis
(SBP), which further worsens the prognosis [7]. A
substantial number of patients with ascites caused by
advanced cirrhosis also develop hepatic nephropathy,
which carries a very poor prognosis despite new
treatment modalities [1,8
10]. Contemporary treatments range from diuretics, the use of new therapeutic
principles such as aquaretics and vasoconstrictors,
large volume paracentesis, transjugular intrahepatic
portosystemic shunts (TIPS), liver-supporting devices, antibiotics, and, at the end stage, liver transplantation. In this paper we summarize the most
recent advances in our understanding of the formation of ascites and modern aspects of treatment.

Correspondence: Sren Mller, MD, DMSc, Associate Professor, Department of Clinical Physiology 239, Hvidovre Hospital, DK-2650 Hvidovre, Denmark.
Tel: 45 3632 3568. Fax: 45 3632 3750. E-mail: soeren.moeller@hvh.regionh.dk

(Received 28 January 2009; accepted 18 March 2009)

ISSN 0036-5521 print/ISSN 1502-7708 online # 2009 Informa UK Ltd.
DOI: 10.1080/00365520902912555

Treatment of ascites
Table I. Grades of ascites according to the International Club of
Ascites [4].
Grade of ascites
Grade 0
Grade 1

Explanation
No detectable ascites
Mild ascites that is only detectable by
ultrasound examination
Moderate ascites with moderate distension of
the abdomen
Large or tense ascites with marked distension
of the abdomen

Grade 2
Grade 3

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Pathogenesis and perpetuation of the ascites

syndrome
Major factors involved in the complex pathogenesis
of ascites are portal and sinusoidal hypertension,
arterial vasodilatation, and neurohumoral activation,
all leading to sodium and water retention [10,11].
According to the peripheral arterial vasodilatation
theory, development of systemic and splanchnic
vasodilatation results in a decrease in the effective
arterial blood volume and a hyperdynamic circulation [12]. This theory has lately been modified into
what has been termed the forward theory of ascites
formation (Figure 1) which combines arterial
underfilling with a forward increase in splanchnic
capillary pressure and filtration with increased
lymph formation [3].

Cirrhosis and liver

dysfunction
Portal
hypertension

Increased splanchnic
capillary pressure

TIPS
-adrenergic
blockers

Increased production
of vasodilators

Splanchnicarteriolar

Increased lymph
formation

Ascites

vasodilatation

Paracentesis
plasma
Volume
expansion

V1 receptor
agonists

-1agonist

Central hypovolaemia
Arterial hypotension
Deloadingof arterial
baroreceptors

Plasma volume
expansion

-adrenergic
blockers
Loopdiuretics

Sodium and water

retention

Activation of
SNS
Activation of
RAAS

Aldosterone
antagonists

Activation of
vasopressin

V2 receptor
antagonists

Figure 1. Pathophysiology of the development of ascites in

cirrhosis and potential targets for treatment. SNS  sympathetic
nervous system; RAAS  renin-angiotensin-aldosterone system;
AVP  arginine vasopressin.

903

Portal hypertension
In cirrhosis, portal and sinusoidal hypertension is a
prerequisite for the development of ascites. The
hydrostatic pressure within the hepatic sinusoids
favours transudation of fluid into hepatic lymphatics
and the peritoneal cavity [2,13]. The topographic
site of the lesion is therefore important. Patients with
post-hepatic portal hypertension with hepatic vein
thrombosis, as in Budd-Chiari syndrome, often
develop ascites which is difficult to treat [14]. On
the other hand, development of ascites is considered
a late-phase manifestation in patients with portal
hypertension due to portal vein thrombosis, and
ascites in these patients is usually easy to control
[15]. The hepatic vascular resistance and portal
venous inflow together with the development of
portosystemic collaterals determine the height of
the portal pressure. Factors that determine hepatic
vascular resistance include both structural and
dynamic components [16]. Among the structural
components are fibrosis and regeneration nodules.
Dynamic structures include hepatic stellate cells,
myofibroblasts, and other cells with contractile
properties. A preferential sinusoidal constriction in
the liver seems to be attributed to a defective nitric
oxide (NO) production but also to endogenous
vasoconstrictors like endothelin-1 (ET-1), angiotensin II, catecholamines, and leukotrienes may all
increase the hepatic sinusoidal resistance [16
18].
The haemodynamic imbalance with a predominant
sinusoidal constriction contributes significantly to
the development of portal hypertension and thereby
is an important target for treatment.
Moreover, the formation of ascites depends on the
balance between the increased local transvascular
filtration and augmented lymph drainage [2]. Thus,
the amount of ascitic fluid produced is governed by
increased transsinusoidal filtration of protein and
fluid and by accelerated transperitoneal hydrostatic
and oncotic dynamics. However, in contrast to
earlier assumptions, the decreased plasma oncotic
pressure may be of minor importance for the
generation of ascites and low plasma concentrations
of albumin have little influence on the rate of ascites
formation (Figure 2) [2,19,20]. In this context, the
increased hydrostatic pressure in the sinusoids and
intestinal capillaries is critical, and ascites rarely
develops in patients with a hepatic venous pressure
gradient below 12 mmHg [21].
Pathophysiology of arterial vasodilatation and
neurohumoral activation
The pathophysiological coupling between early portal
hypertension and the development of the systemic
and splanchnic vasodilatation and the hyperdynamic

904

S. Mller et al.
FHVP = 2 mmHg

WHVP = 20 mmHg

HVPG = WHVP FHVP = 18 mmHg

Hepatocytes
Space of Disse
with stellate cells

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Sinusoid lined by
endothelial cells

Total splanchnic
lymph flow:
10-25 l/24h

Peritoneal
spill-over:
0.5 l/24h

Figure 2. Hydrostatic pressures and transperitoneal fluid dynamics in cirrhosis: An increased hepatic venous pressure gradient (HVPG)
generates increased transsinusoidal fluid filtration with an overall increased hepatosplanchnic lymph flow of 10
25 l/24 h. As long as the
transsinusoidal filtration keeps pace with lymphatic drainage, no surplus protein-rich fluid will spill over into the peritoneal cavity. When
filtration exceeds the lymphatic drainage, protein-rich fluid will accumulate in the peritoneal cavity as ascites. However, this spillover
fraction (0.5 l/24 h) is relatively small compared to the overall transsinusoidal filtration and lymphatic drainage. WHVPwedged hepatic
venous pressure; FHVPfree hepatic venous pressure.

syndrome is still obscure. It may be brought about

either by overproduction of circulating vasodilators
induced by shear stress in the splanchnic circulation or
by direct neurohumoral signals from the liver to the
brain [18,22]. Several findings indicate that the
splanchnic vasodilatation precedes renal sodium and
water retention [23]. In experimental as well as in
human portal hypertension, splanchnic vasodilatation leads to reduced systemic vascular resistance,
decreased effective blood volume, and a reduction in
arterial blood pressure with activation of potent
vasoconstricting systems such as the sympathetic
nervous system (SNS), the renin-angiotensin-aldosterone system (RAAS), and non-osmotic release of
vasopressin [3,11,18]. The haemodynamic consequences of the development of a hyperdynamic
circulation with an increased heart rate and cardiac
output have previously been described as a mediator
of the effective blood volume, and underfilling of the
arterial circulation occurs in these patients as a result
of diminished systemic vascular resistance [12].
However, at a much later stage of the disease, underfilling of the arterial circulation may also occur
secondary to a reduction of the increased cardiac
output, as described in patients with renal failure and
SBP [24].
NO is among the vasodilators that have been
implicated in the systemic vasodilatation, and is

primarily synthesized in the systemic vascular

endothelium by NO synthase [25,26]. In portal
hypertension, there seems to be a diminished release
of NO from sinusoidal endothelial cells in the
cirrhotic liver, whereas in the systemic circulation
there is evidence of an up-regulation of the NO
synthesis [27]. Calcitonin gene-related peptide
(CGRP) and adrenomedulin are potent vasodilatating neuropeptides, which have been found increased
especially in patients with ascites and the hepatorenal syndrome (HRS) [18,23]. The increase in
circulating vasoactive substances is mainly due to
increased production and, to a lesser extent, to a
decrease in hepatic clearance [28]. It is likely that
these peptides play a role as neurotransmitters, both
in the initiation of the haemodynamic changes and in
the perpetuation of the hyperdynamic circulation
and the formation of ascites. Systemic vasodilatation
has also been related to resistance to pressor
substances, such as noradrenaline, angiotensin II,
and vasopressin. An impaired response to these
vasoconstrictors is most likely related to changes in
receptor affinity, down-regulation of receptors, and
to post-receptor defects related to increased NO
expression [18,29,30]. Recently, alterations in arterial and total vascular compliance have also been
considered [31,32].

Treatment of ascites
Although the pathophysiology and the role of
arterial vasodilatation are complex, there is definite
experimental and clinical evidence to show that it
precedes the counter-regulatory neurohumoral activation and the renal sodium and water retention in
cirrhosis.

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Renal dysfunction
In the early phases of cirrhotic portal hypertension,
the renal sodium excretion capacity is impaired, with
reduced natriuretic response to acute administration
of sodium chloride or to changes in posture [33,34].
These early events are seen before the development
of ascites, but in most of the patients they represent
the initiation of a more pronounced renal dysfunction. This includes progressively increased sodium
and water reabsorption and decreases in renal
perfusion and the glomerular filtration rate (GFR)
often in parallel with reduced liver function [35]. In
healthy individuals on a normal intake of sodium
chloride, the free water clearance approximates
10 ml/min [36]. In particular decompensated cirrhotic patients, the free water clearance is often less
than 1 ml/min, equivalent to an intake of 1.5 l/day
before accumulation of fluid begins. The consequences are the development of dilutional hyponatraemia (serum sodium concentration of less than
130 mmol/l) [37]. At later stages, there is a
progressive fall in GFR and renal blood flow
(RBF) [8]. According to the sequence of the development of the functional renal abnormalities, genesis of ascites has been divided into successive
pathophysiological phases (Table II). The early
phase 1 is also called the pre-ascitic phase, because
ascites is not present, but the renal metabolism of
sodium is impaired, despite normal RBF, GFR, and
free water clearance [38,39]. From a haemodynamic
point of view, these patients often exhibit an
increased plasma volume, supporting the presence
of a period with increased sodium and water retention and adaptation between the vascular capacitance and the circulating medium [38]. The second
phase denotes a negative sodium balance despite

905

decreased urinary sodium excretion, and the absence

of ascites in this phase can be achieved by reducing
the dietary intake of sodium. At this stage there is
only activation of the RAAS and SNS in some
patients, and the GFR and RBF may be normal
[40]. In phase 3, sodium excretion is often below
10 mmol/day and there is immense activation of the
RAAS and SNS, but the RBF and GFR are still
normal or low normal [41,42]. The arterial blood
pressure is often low or low normal, despite activation of RAAS and SNS, and therefore these patients
are highly susceptible to the hypotensive effects of
angiotensin-converting enzyme (ACE) inhibitors,
angiotensin II receptor inhibitors, and V1-vasopressin antagonist [8]. Phases 4 and 5 ascites denote the
development of the HRS type 2 and type 1,
respectively. Type-2 HRS is characterized by moderate renal failure with a slow progressive course and
it is typically associated with refractory ascites. Type1 HRS is characterized by a rapid decrease in renal
function which is often precipitated by SBP [43].
The new diagnostic criteria for HRS according to
The International Club of Ascites are presented in
Table III [43].

Principles of ascites therapy

Diagnostic investigations
The presence of ascites should be confirmed by
abdominal ultrasonography. In the case of identification of ascitic fluid, diagnostic paracentesis should,
as a minimum, include measurement of albumin or
protein concentrations, a neutrophil count, and
aerobic and anaerobic cultures of the ascitic fluid.
Presence of SBP, defined as a neutrophil count

250 cells/ml, is seen in about 15% of patients
with ascites [20,44]. Determination of the serumascites albumin gradient may be helpful in distinguishing between ascites caused by cirrhosis, cardiac
failure, and primary renal diseases from ascites
caused by pancreatic and malignant diseases. Thus,
a serum-ascites albumin gradient
11 g/l favours a
hepatic, cardiac, or renal aetiology [20]. Ascitic fluid

Table II. Pathophysiological phases in the development of ascites and the hepatorenal syndrome.
Term
Pre-ascitic cirrhosis
Mild
moderate ascites
Moderate
tense ascites
HRS type 2
HRS type 1

Phase
Phase
Phase
Phase
Phase
Phase

1
2
3
4
5

Sodium and water retention

Activated RAAS and SNS

Impaired RBF and GFR

No/Yes
Yes
Yes
Yes
Yes

No
No/Yes
Yes
Yes
Yes

No
No
No/Yes
Yes
Yes

Abbreviations: RAASrenin-angiotensin-aldosterone system; SNSsympathetic nervous system; RBFrenal blood flow; GFR
glomerular filtration rate; HRShepatorenal syndrome.
Modified from Arroyo et al. [3].

906

S. Mller et al.

Table III. New diagnostic criteria of the hepatorenal syndrome

(HRS) according to The International Club of Ascites [43].

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Cirrhosis with ascites.

Serum creatinine
133 mmol/l (1.5 mg/dl)
No improvement of serum creatinine (decrease to a level of
5133 mmol/l) after at least 2 days with diuretic withdrawal and
volume expansion with albumin. The recommended dose of
albumin is 1 g/kg body weight per day up to a maximum of
100 g/day
Absence of shock
No current or recent treatment with nephrotoxic drugs
Absence of parenchymal kidney disease as indicated by
proteinuria
500 mg/day, microhaematuria (
50 red
blood cells per high-power field) and/or abnormal renal
ultrasonography

amylase should be measured on clinical suspicion of

pancreatic disease. Analyses of cytology should be
carried if malignancy is suspected [45].
Treatment of non-complicated ascites
Para-medical treatment. Previous studies have shown
that the supine position ameliorates the RBF and
GFR and improves sodium and water excretion [46].
A less activated RAAS and SNS and a more
favourable diuretic response in the supine patient
have led to the assumption that bedrest would
benefit the treatment of ascites. However, severe
side effects of prolonged bedrest, for example an
increased risk of thromboembolic complications,
decalcification of the bones, and muscular atrophy,
imply that bedrest in general cannot be recommended for the treatment of ascites [20].
Reduced salt intake will counteract the sodium
imbalance in patients with fluid retention and may
create a negative sodium balance in some of the
patients; therefore a low salt diet should be part of
the basic treatment of ascites. However, a rigorous
low salt diet is usually unacceptable to the patient
and thus a no-salt-added diet of 80
120 mmol NaCl
per day is recommended. In patients with dilutional
hyponatraemia in particular, water restriction (1.0

1.5 l/day) has been used, but the effectiveness of this
treatment to increase the serum sodium concentration more than 5 mmol/l is limited and ranges from
0% to 26% [47]. Moreover, water restriction has a
limited effect on improving serum sodium, because
the daily fluid intake cannot be reduced to less than
one litre per day, which is insufficient to ensure a
negative fluid balance [48]. Water restriction should
be reserved only for patients who are clinically
hypervolaemic with severe hyponatraemia and decreased free water clearance. Thus, for practical
purposes, water can only be restricted in very few
(if any) patients.

Medical treatment. A strategy for the treatment of

ascites is presented in Table IV. Diuretics have been
used for the treatment of fluid retention for more than
60 years. The diuretic treatment of ascites should be
initiated with an aldosterone antagonist that acts
mainly on the distal tubules in order to increase
natriuresis, since, if furosemide is administered alone,
its natriuretic effects on the loop of Henle will be
counteracted by sodium reabsorbed in the distal
tubules, because of activation of aldosterone. The
initial prescription in mild to moderate ascites should
be 100 mg/day, a dose that can be gradually increased
up to 400 mg/day [3,4]. But, to avoid hyperkalaemia,
it is often necessary to give a loop diuretic supplement
before the full aldosterone antagonist dose. The full
effect of diuretic treatment is normally seen after 3
5
days. Body-weight should be checked daily and serum
sodium, potassium, and creatinine concentrations
monitored. A daily weight loss of no more than 500

800 g is recommended to prevent intravascular volume depletion [1]. In the case of massive peripheral
oedema, higher weight losses can be accepted. When
this is insufficient, a loop diuretic should be added,
usually furosemide, as it may induce marked diuresis
and natriuresis. The initial recommended dose is 40
mg/day and can be increased to 160 mg/day with a
stepwise increase every 2
3 days [4]. Additional
diuresis can sometimes be achieved with the supplementation of other diuretics such as amiloride or a
thiazide, but side effects are common. The main
purpose of the treatment is to keep the patient free
of ascites. When the ascites has been resolved,
Table IV. Suggestions for a progressive strategy in the treatment
of sodium and fluid retention and renal complications in cirrhosis.
Clinical
condition

Treatment

Pre-ascitic
cirrhosis

No treatment
Modest salt restriction (80
120 mmol/day)

Mild ascites

Salt restriction
Stepwise spironolactone (100
400 mg/day)
Salt restriction
Spironolactone
Stepwise furosemide (40
160 mg/day)
Large volume paracentesis and plasma volume
substitution and diuretics
TIPS
Serum sodiumB125 mmol/l: diuretics
discontinued
Serum sodiumB120 mmol/l: plasma volume
expansion
Hyper/euvolaemia: modest water restriction
Experimental vasopressin V2 receptor
antagonists

Moderate
tense
ascites
Refractory
ascites
Hyponatraemia

Abbreviation: TIPStransjugular intrahepatic portosystemic

shunt.

Treatment of ascites
Table V. Definition of and diagnostic criteria for refractory ascites
in cirrhosis according to a consensus report from the International
Club of Ascites [4].

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

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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 dose
Conditions
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 a salt-restricted diet of less than
90 mmol/day or 5.2 g salt per day
2. Lack of response: Mean weight loss B0.8 kg over 4 days and
urinary sodium output less than the sodium intake
3. Early ascites recurrence: Reappearance of grades 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 factors. Diuretic-induced
renal impairment is an increase of serum creatinine by

100% to a value
2 mg/dl (177 mmol/l) in patients
with ascites responding to treatment. Diuretic-induced
hyponatraemia is defined as a decrease in serum sodium by

10 mol/l to B125 mmol/l. Diuretic-induced hypo- or
hyperkalaemia is defined as a change in serum potassium to
B3 mol/l or
6 mmol/l, despite appropriate measures
Adopted from Moore et al. The management of ascites in
cirrhosis: Report on the consensus conference of the International
Club of Ascites [4].

the diuretic dose should be reduced to the minimum

and, if possible, discontinued. Non-steroidal antiinflammatory drugs (NSAIDs) enhance sodium retention and formation of ascites, and are associated
with the development of renal failure, hyponatraemia
and resistance to diuretics and, for these reasons,
should be avoided [20]. Drugs that can induce arterial
hypotension and interfere with renal function, such as
ACE inhibitors, angiotensin II antagonists, and a1adrenergic blockers, should be used cautiously and
only when weight loss, blood pressure, serum creatinine, and clinical status are monitored.
Treatment of refractory ascites
Ten percent of patients with ascites become refractory
to medical treatment and paracentesis, and so other
treatment modalities are necessary [20]. Refractory
ascites is defined as diuretic-resistant ascites which
cannot be mobilized by intensive diuretic therapy and
a low salt diet (weight loss less than 200 g/day over 4
days) (Table V). Diuretic-intractable ascites is characterized by the presence of diuretic-induced compl

907

ications, such as encephalopathy and hyponatraemia

[4]. The response to diuretics and the salt diet should
be validated only in stable patients without bleeding or
infection, since such conditions affect the ability to
excrete salt and water.
Ascites recurs in as much as 90% of patients
particularly in those with post-sinusoidal alcoholic
cirrhosis after therapeutic paracentesis, and supplementation with a minimum dose of diuretics is
therefore essential [49]. Therapeutic paracentesis
should be done in a single session and should always
be combined with plasma volume expansion. The
intra-abdominal, right atrial, and pulmonary capillary wedge pressures decrease after large volume
paracentesis [31]. Cardiac output increases after 2
3
h and the mean arterial blood pressure decreases by
an average of 8
10 mmHg [50,51]. Large volume
paracentesis without adequate volume substitution
may result in the development of post-paracentesisinduced circulatory dysfunction (PICD) in up to
75% of patients [52]. This condition is characterized
by pronounced activation of the RAAS and SNS,
which reflects central hypovolaemia. PICD is mainly
caused by paracentesis-induced splanchnic arteriolar
vasodilatation and brings about a further reduction
in systemic vascular resistance and an increase in
portal pressure [53]. Several randomized, controlled
trials of albumin versus synthetic plasma expanders,
such as dextran, collagen-based colloids, and starch,
have shown equal effectiveness as synthetic plasma
expanders and albumin in the prevention of postparacentesis-induced complications after small volume paracentesis [54
57]. After paracentesis of
large volume ascites (
5 l), albumin (8 g/l) seems
to be more effective than polygeline in preventing the
paracentesis-induced increase in RAAS and liverrelated complications [58,59]. Intravenous albumin
may therefore prevent the development of complications caused by circulatory dysfunction, such as
HRS and rapid recurrence of ascites, and may also
improve survival [52,53]. For these reasons alternative plasma expanders should be avoided for the
prevention of PICD after large volume paracentesis.
In the case of tense ascites, which may cause the
patient abdominal discomfort and haemodynamic or
respiratory dysfunction, therapeutic paracentesis
should be preferred because of fewer complications
and a shorter hospital stay compared to intensive
diuretic treatment [3]. Recent studies have shown
that administration of vasoconstrictors such as
terlipressin, midodrine, or noradrenaline may also
be effective, either alone or in combination with
albumin [60
62]. In a recent study, the vasoconstrictor midodrine was as effective as albumin in
preventing PICD, and at a lower cost [63]. This has,
however, been questioned in a newer pilot study of

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908

S. Mller et al.

24 patients [64]. PICD is an example of a complication attributable to further vasodilatation and reduction in effective blood volume, which can be
prevented by specific volume support and vasoconstriction. The use of specific vasoconstrictors such as
midodrine or terlipressin may potentially play a role
in the future strategy of treatment.
In the case of recurrent ascites, insertion of a TIPS
should be considered. In experienced centres the
technical success rate is usually high, at about 95%
[65]. Control of ascites is achieved in 80
90%, with
complete resolution in 75%. TIPS is now considered
more effective than large volume paracentesis for the
control of ascites [66
68]. A major problem with
insertion of TIPS is the relatively high frequency of
hepatic encephalopathy, and, although patients often
report a better quality of life, no significant effect on
survival has been demonstrated after TIPS insertion
[69]. However, improved survival after TIPS for
refractory ascites has been demonstrated in a metaanalysis based on individual patient data from three
large randomized trials [68]. The use of polytetrafluoroethylene-covered stents improves shunt patency and may contribute to enhance the overall
efficacy of this procedure [70]. Risk factors and
relative contraindications for TIPS insertion include
serum bilirubin
85 mmol/l, INR
2, episodic or
chronic encephalopathy greater than grade 2, and
bacterial infections and renal, cardiac, and respiratory failure [71]. Although TIPS is more effective in
removing ascites compared with large volume paracentesis, it is at the cost of a higher frequency of
hepatic encephalopathy and it may not significantly
affect transplant-free survival. Large volume paracentesis with plasma expander infusion should therefore continue to be the first-line treatment for
refractory ascites. TIPS should be regarded as a
second-choice treatment in patients with preserved
liver function and recurrence of ascites [48].
Hyponatraemia
Hyponatraemia in cirrhosis is defined as a reduction
in serum sodium below 130 mmol/l [48]. Hyponatraemia often develops in cirrhosis, preferentially
because of immense release of vasopressin. In the
presence of plasma volume expansion, this is hypervolaemic or dilutional hyponatraemia [48]. Vasopressin acts on V2 receptors (G protein coupled with
cyclic AMP as second messenger) in the collecting
ducts and is responsible for the vasopressin-induced
reabsorption of water [48]. This effect is mediated
through aquaporins (AQPs), which are selective
water channels, AQP2 being the most important
[72]. Activation of AQPs increases water permeability and in patients with ascites there is evidence

of reduced excretion of AQP2 [72,73]. Clinical use

of V2-receptor antagonists, known as the vaptans,
may prove to be effective in the treatment of
dilutional hyponatraemia. Up to the present time,
data on the long-term effects are needed but
randomized trials are currently in progress [47,74].
Diuretics should be discontinued if serum sodium is
lower than 120 mmol/l.
Spontaneous bacterial peritonitis (SBP)
As mentioned above, SBP is defined as
250
neutrophil cells/ml. Culture from ascitic fluid often
discloses bacterial species, such as Escherichia coli and
Streptococcus [44]. Antibiotic treatment of SBP significantly improves survival and third-generation
cephalosporins should be considered, such as
cefotaxime 2 g twice a day for up to two weeks.
Alternatively, amoxicillin/clavolanic acid can be considered. Fluoroquinolones are also effective. Other
recommended antibiotics are ceftizoxime, cefonicid,
ceftriaxone, and ceftazidime. In patients with ascites
and a history of SBP, prophylactic treatment with, for
example, ciprofloxacin 250 mg/day orally is recommended, especially in the case of low ascites protein
[4,20,48,75]. Prophylactic treatment of patients with
SBP with antibiotics alone or in combination with
albumin has significantly reduced the risk of development of type-1 HRS [76,77]. Aminoglycosides
should not be used, because of their nephrotoxic side
effects.
Summary and conclusions
Ascites and its complications, including HRS, are
still conditions associated with a poor prognosis
despite treatment. However, our knowledge of the
pathophysiology underlying these severe complications has improved considerably and novel medical
treatments combined with different pharmacological
approaches may improve prognosis. The future
approach will probably be to attack various aspects
in the pathophysiological process. A multitarget
strategy should seek efficiently to counteract the
splanchnic vasodilatation, central hypovolaemia, and
arterial hypotension by administration of potent
vasoconstrictors, such as midodrine or terlipressin,
combined with plasma expanders such as albumin.
Development of long-acting systemic vasoconstrictors should be encouraged. Aquaporins may have a
future, especially in the treatment of dilutional
hyponatraemia. TIPS or beta-blockers should be
applied to reduce portal pressure, whereas nitrates,
COX-inhibitors and nephrotoxic antibiotics should
be used with caution. Cardiac function should be

909

Treatment of ascites
supported, especially in the presence of simultaneous infections.

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