efit of albumin on survival. Although there are no studies on how
fast and when albumin should be given to patients treated with
LVP, it seems advisable to administer it slowly to avoid a possible
cardiac overload due to the existence of a latent cirrhotic cardio-
myopathy and at the end of LVP when the volume of ascites
removed is known and the increasing cardiac output begins to
return to baseline [42].
As far as alternative plasma volume expanders are concerned,
it should be noted that polygeline is no longer used in many
countries because of the potential risk of transmission of prions.
Despite some evidence of the fact that the use of saline is not
associated with an increased risk to develop PPCD after small vol-
ume paracentesis [40], there are no randomized controlled stud-
ies comparing saline versus albumin in patients who require LVP
of less than 5 L. Few data exist on the use of starch as a plasma
expander in patients with cirrhosis and grade 3 ascites treated
with LVP, while there are some concerns about the possibility
for starch to induce renal failure [43] and hepatic accumulation
of starch [44].
Furthermore, a recent health economic analysis suggested
that it is more cost-effective to use albumin after LVP compared
with alternative but cheaper plasma volume expanders since the
administration of albumin post-paracentesis is associated with a
lower number of liver-related complications within the first
30 days [41].
Although LVP is the treatment of choice for large ascites in
patients with cirrhosis, it is important to realise that LVP does
not address the underlying cause of the condition, namely renal
sodium and water retention. Therefore, patients treated with
LVP require diuretic treatment after the removal of ascitic fluid
to prevent the re-accumulation of ascites [45].
LVP should be performed under strict sterile conditions using
disposable sterile materials. It is generally agreed that there are
no contraindications to LVP other than loculated ascites, although
studies have excluded several subsets of patients. Hemorrhagic
complications after LVP are infrequent. In one study, which also
included patients with INR >1.5 and platelet count <50,000/
l
l,
only two patients experienced minor cutaneous bleedings out
of 142 paracenteses [46]. The frequency of bleeding complica-
tions in patients with coagulopathy after LVP are also reported
to be low in other studies and do not support a relation between
risk of bleeding and the degree of coagulopathy [37]. Thus, there
are no data to support the use of fresh frozen plasma or pooled
platelets before LVP, yet in many centers these products are given
if there is severe coagulopathy (prothrombin activity less than
40%) and/or thrombocytopenia (less than 40,000/
l
l). Neverthe-
less, caution should be exercised in patients with severe coagu-
lopathy and LVP should be avoided in the presence of
disseminated intravascular coagulation.
Recommendations Large-volume paracentesis (LVP) is the
first-line therapy in patients with large ascites (grade 3 asci-
tes) (Level A1). LVP should be completed in a single session
(Level A1).
LVP should be performed together with the administration
of albumin (8 g/L of ascitic fluid removed) to prevent circula-
tory dysfunction after LVP (Level A1).
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397–417
In patients undergoing LVP of greater than 5 L of ascites, the
use of plasma expanders other than albumin is not recom-
mended because they are less effective in the prevention of
post-paracentesis circulatory dysfunction (Level A1). In
patients undergoing LVP of less than 5 L of ascites, the risk of
developing post-paracentesis circulatory dysfunction is low.
However, it is generally agreed that these patients should still
be treated with albumin because of concerns about use of alter-
native plasma expanders (Level B1).
After LVP, patients should receive the minimum dose of
diuretics necessary to prevent the re-accumulation of ascites
(Level A1).
1.5. Drugs contraindicated in patients with ascites
The administration of non-steroidal anti-inflammatory drugs
(NSAIDs), such as indomethacin, ibuprofen, aspirin, and sulindac
to patients with cirrhosis and ascites is associated with a high
risk of development of acute renal failure, hyponatremia, and
diuretic resistance [47]. The impairment in glomerular filtration
rate is due to a reduced renal perfusion secondary to inhibition
of renal prostaglandin synthesis. Thus, NSAIDs should not be
used in patients with cirrhosis and ascites. This represents an
important therapeutic limitation for these patients when anal-
gesis are needed. Preliminary data show that short-term admin-
istration of selective inhibitors of cyclooxygenase-2 does not
impair renal function and the response to diuretics. However,
further studies are needed to confirm the safety of these drugs
[48].
Angiotensin-converting enzyme inhibitors, even in low doses,
should be avoided in patients with cirrhosis and ascites since
they can induce arterial hypotension [49] and renal failure [50].
Likewise,
a
1
-adrenergic blockers, such as prazosin, should be
used with great caution because despite a reduction in portal
pressure, they can further impair renal sodium and water reten-
tion and cause an increase in ascites and/or edema [51]. Among
cardiovascular drugs, dipyridamole should be used with caution
since it can induce renal impairment [52]. Aminoglycosides alone
or in combination with ampicillin, cephalothin, or mezlocillin
should be avoided in the treatment of bacterial infections,
because they are associated with high incidence of nephrotoxi-
city [53,54].
Nephrotoxicity induced by the administration of contrast
media is a frequent cause of renal failure in the general popula-
tion of hospitalized patients. However, it has been shown that
cirrhosis with ascites and substantially normal renal function
does not appear to be a risk factor for the development of con-
trast media-induced renal failure [55]. Nevertheless, the possibil-
ity that contrast media administration can cause a further
impairment of renal function in patients with pre-existing renal
failure cannot be excluded.
Recommendations Non-steroidal anti-inflammatory drugs
(NSAIDs) are contraindicated in patients with ascites because
of the high risk of developing further sodium retention, hypo-
natremia, and renal failure (Level A1).
Drugs that decrease arterial pressure or renal blood flow
such as ACE-inhibitors, angiotensin II antagonists, or
a
1-
adrenergic receptor blockers should generally not be used in
patients with ascites because of increased risk of renal impair-
ment (Level A1).
The use of aminoglycosides is associated with an increased
risk of renal failure. Thus, their use should be reserved for
patients with bacterial infections that cannot be treated with
other antibiotics (Level A1).
In patients with ascites without renal failure, the use of
contrast media does not appear to be associated with an
increased risk of renal impairment (Level B1). In patients with
renal failure there are insufficient data. Nevertheless, contrast
media should be used with caution and the use of general pre-
ventive measures of renal impairment is recommended (Level
C1).
2. Refractory ascites
2.1. Evaluation of patients with refractory ascites
According to the criteria of the International Ascites Club, refrac-
tory 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
l
mol/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.
JOURNAL OF HEPATOLOGY
Journal of Hepatology 2010 vol. 53
j
397–417
401
Once ascites becomes refractory to medical treatment, the
median survival of patients is approximately 6 months [7,56–
59]. As a consequence, patients with refractory ascites should be
considered for liver transplantation. The MELD score system pre-
dicts 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 [7,57–61].
Patients with refractory ascites may have a poor prognosis despite
a relatively low MELD score (e.g. <18) and this may be of impor-
tance 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 [14,61–65].
Recommendations The assessment of the response of asci-
tes to diuretic therapy and salt restriction should only be per-
formed 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 transplanta-
tion (Level B1).
2.2. 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.
2.2.1. Large-volume paracentesis
A large body of evidence indicates that repeated LVP is an effec-
tive and safe therapy of refractory ascites [8,11,56,66]. The
administration of albumin prevents circulatory dysfunction asso-
ciated with LVP (see discussion in a previous section of these
guidelines).
2.2.2. 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].
2.2.3. Transjugular intrahepatic portosystemic shunts (TIPS)
2.2.3.1. 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 [68–79]. 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
[72,76–78]. In addition, TIPS may have beneficial effects on nitro-
gen balance and body weight [79–81]. 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 [83–86].
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].
2.2.3.2. Controlled studies. The effects of TIPS on the control of
ascites, frequency of encephatlopahty, and survival in the 5 ran-
domised controlled trials so far published is shown in Table 4
[79,89–92]. 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.
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 [79,89–92], 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.
2.2.3.3. Meta-analyses. Patients in the five above-mentioned ran-
domised controlled clinical trials have variably been included in
five meta-analyses yielding almost similar conclusions (Table 5)
[93–97]. 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 sur-
vival 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 sur-
vival in the TIPS group [97].
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
Clinical Practice Guidelines
402
Journal of Hepatology 2010 vol. 53
j
397–417
2.2.4. Peritoneovenous shunt
Due to frequent complications related to surgical insertion, shunt
dysfunction, and infections, this treatment has currently very lit-
tle role in the management of patients with refractory ascites [11].
2.2.5. 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 increas-
ing 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
a
1
-adrenergic agonist midodrine or
terlipressin improve circulatory and renal function in patients
with and without refractory ascites [98–100]. However, large ran-
domized controlled studies have not been reported yet. Terlipres-
sin has the inconvenience of requiring intravenous administration.
In two phase-2 studies the administration of a vaptan, satav-
aptan, 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 sat-
avaptan 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 treat-
ment for refractory ascites (Level A1). Diuretics should be dis-
continued 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 fre-
quent 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 restric-
tion (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 Pgrade 2 or chronic
hepatic encephalopathy), concomitant active infection, pro-
gressive renal failure, or severe cardiopulmonary diseases
(Level B1).
In selected patients TIPS may be helpful for recurrent
symptomatic hepatic hydrothorax (Level B2).
3. Spontaneous bacterial peritonitis
SBP is a very common bacterial infection in patients with cirrho-
sis and ascites [10,105–107]. When first described, its mortality
exceeded 90% but it has been reduced to approximately 20% with
early diagnosis and treatment [6,108].
3.1. Diagnosis of spontaneous bacterial peritonitis
3.1.1. Diagnostic paracentesis: in whom and when
The diagnosis of SBP is based on diagnostic paracentesis [10]. All
patients with cirrhosis and ascites are at risk of SBP and the prev-
alence of SBP in outpatients is 1.5–3.5% [109,110] and $10% in
hospitalized patients [109]. Half the episodes of SBP are present
at the time of hospital admission while the rest are acquired dur-
ing hospitalization [10].
Patients with SBP may have one of the following [10,109,111]:
(1) local symptoms and/or signs of peritonitis: abdominal pain,
abdominal tenderness, vomiting, diarrhea, ileus; (2) signs of sys-
temic inflammation: hyper or hypothermia, chills, altered white
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. DifE
4M
: 0.41,
p <0.001 DifE
12M
: 0.35, p <0.001
Higher in TIPS
group. DifE: 0.17,
p <0.001
No difference between groups
DifE
1y
: 0.03, p = 0.7 DifE 3>125> Dostları ilə paylaş: |