Review article

The clinical management of abdominal ascites,

spontaneous bacterial peritonitis and hepatorenal
syndrome: a review of current guidelines and
recommendations
Marinos Pericleousa,*, Alexander Sarnowskib,*, Alice Moorea,*, Rik Fijtenc,* and Murtaza Zamana,*

Several pathogenic processes have been implicated in the development of abdominal ascites. Portal hypertension, most usually
in the context of liver cirrhosis, can explain about 75% of the cases, whereas infective, inammatory and inltrative aetiologies can
account for the rest. In this article, we discuss the consensus best practice as published by three professional bodies for the
management of ascites, spontaneous bacterial peritonitis (SBP) and hepatorenal syndrome (HRS). The aim of this study was to
compare available clinical guidelines and identify areas of agreement and conict. We carried out a review of the guidance
documentation published by three expert bodies including the British Society of Gastroenterology, the European Association for
the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD), as well as a wider literature
search for ascites, SBP and HRS. Abdominal ultrasonography, diagnostic paracentesis and ascitic uid cultures are
recommended by all three guidelines, especially when there is strong clinical suspicion for infection. EASL and AASLD advocate
the use of ascitic amylase and mycobacterial cultures/PCR when there is strong suspicion for tuberculosis and pancreatitis,
respectively. Ascitic cytology can be useful when cancer is suspected and has a good diagnostic yield if performed correctly.
EASL supports the use of urinary electrolytes for all patients; however, the British Society of Gastroenterology and AASLD only
recommend their use for therapy monitoring. All three societies recommend cefotaxime as the antibiotic of choice for SBP and
large-volume paracentesis for the management of ascites greater than 5 l in volume. For HRS, cautious diuresis, volume
expansion with albumin and the use of vasoactive drugs are recommended. There appears to be good concordance between
recommendations by the European, American and British guidelines for the management of ascites and the possible
complications arising from it. Eur J Gastroenterol Hepatol 28:e10e18
Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.

Introduction promote the formation of ascites in cirrhotic patients [3,4].

Ascites is dened as an accumulation of uid within the
peritoneal cavity with a volume greater than 25 ml. In
75% of the cases, it is caused by cirrhosis and portal
hypertension of various aetiologies. The remaining cases
can be explained by infective, inammatory and inltrative
pathologies such as pancreatitis, malignancy and tuber-
culosis [1]. In patients with portal hypertension and cir-
rhosis, the development of ascites is a poor prognostic
marker, with 50% mortality at 3 years [2].
Neurohumoral activation, portal hypertension, poor
protein synthetic function and arterial vasodilatation
European Journal of Gastroenterology & Hepatology 2016, 28:e10e18
Keywords: ascites, bleeding, diuretics, hepatorenal, paracentesis,
peritonitis, spontaneous bacterial peritonitis, transjugular intrahepatic
portosystemic shunting
Departments of aGastroenterology, bInternal Medicine, Frimley Park Hospital,
Frimley, Surrey and cDepartment of Surgery, Warrington General Hospital,
Warrington, UK
Correspondence to Marinos Pericleous, BSc, MBBS, MRCP (UK), Department of
Gastroenterology, Frimley Park Hospital, Frimley, Surrey, GU16 7UJ, UK
Tel: + 44 (0)1276 604604; fax: + 44 (0)2082 867886;
e-mail: pericleousmarinos@gmail.com
*All ve authors are joint rst authors.
Received 21 September 2015 Accepted 6 November 2015
Fibrotic changes lead to high portal pressures and increased
hydrostatic pressure, resulting in transudation of uid into
the peritoneal cavity and other third spaces. The reduced
hepatic protein synthesis and the subsequent hypoalbumi-
naemia lead to reduced intravascular oncotic pressure and
promote the formation of ascites [5,6]. Shear stress in the
splanchnic system, altered properties of smooth muscle cells
and neurohumoral signalling between the brain and liver
result in arterial vasodilatation [79], which activates the
reninangiotensinaldosterone and sympathetic nervous
systems. This results in sodium and water retention, as well
as renal vasoconstriction, which worsens ascites and impairs
renal function. Hyperaldosteronism drives sodium retention
in the distal convoluted tubule, whereas absorption at the
proximal convoluted tubule is less well understood [2].
The management of ascites is determined by the cause
and extent of ascites and includes uid restriction, diuresis,
large-volume paracentesis (LVP) and transjugular intra-
hepatic portosystemic shunting (TIPSS). Complications of
ascites are common and include spontaneous bacterial
peritonitis (SBP), circulatory dysfunction, hyponatraemia
and hepatorenal syndrome (HRS) [1,2]. In this review
article, we set out to explore the evidence-based manage-
ment of ascites and compare the different guidelines as
published by three expert professional bodies.

0954-691X Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MEG.0000000000000548 e10

Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.

Ascites, SBP and HRS; comparing three guidelines Pericleous et al.
Methods
We carried out a review of the guidance documentation
published by the British Society of Gastroenterology (BSG),
the European Association for the Study of the Liver (EASL)
and the American Association for the Study of Liver Diseases
(AASLD). The literature was also searched for the terms
ascites, abdominal paracentesis, exudates ascites, transu-
date ascites, peritonitis, bacterial peritonitis, spontaneous
bacterial peritonitis, vaptans and hepatorenal syndrome.
Results
Investigation of ascites
Ascites may be classied into three grades: grade 1 is only
detectable with ultrasound imaging, grade 2 presents as
moderate, symmetrical distension of the abdomen and
grade 3 comprises large-volume ascites with gross
abdominal distension [1]. The management approaches
differ according to the extent and cause of ascites.
Ultrasound is recognized as a rst-line investigation in
all patients with ascites by EASL and BSG. The AASLD
guidelines state that ultrasound may be required to
determine with certainty whether uid is present; how-
ever, it is not explicitly required for all patients [1,5,10].
The BSG recommends measurement of urea and elec-
trolytes (U&Es), prothrombin time and full blood count, as
well as liver function tests (LFTs). The EASL recommends
conducting liver function tests and measuring U&Es. The
AASLD does not specify a standard battery of blood tests,
but does mention measurement of U&Es [1,5,10].
The EASL recommends that a diagnostic paracentesis
be performed before therapy in patients with new-onset
ascites of grades 2 and 3 and in patients who present with
worsening ascites or complications of cirrhosis. The
AASLD supports the use of diagnostic ascitic taps in
patients with new-onset ascites. BSG guidelines recom-
mend an ascitic tap in all patients.
All guidelines suggest that analysis of the ascitic uid
should include neutrophil counts for the diagnosis of SBP
and estimation of total protein, as levels less than 15 g/l
increase the risk for SBP [11]. Calculation of the serum
albumin ascites gradient (SAAG) from same-day samples
should then be performed [1,5,10]. A SAAG value greater
than 1.1 or 11 g/l implies the presence of ascites due to
portal hypertension, with an accuracy of 97% [12]. The
accuracy of this test is unaffected by the administration of
diuretics or intravenous uid therapy [13]. The total pro-
tein content of the ascitic uid is now considered less useful
in determining aetiology, but it does allow the uid to be
classied as transudate and exudate (< 2.5 or > 2.5 g/dl,
respectively). Exudative ascites tends to be seen in inl-
trative, inammatory and infective aetiologies, whereas
portal hypertension and hypoalbuminaemia generally
result in transudative ascites.
Inoculation of ascitic uid into blood culture bottles at
the bedside before administration of antibiotics has been
shown to increase the chance of culturing an infecting
organism from 50 to 80% in SBP [12,14]. EASL and BSG
guidelines sanction culturing ascitic uid in all patients,
but AASLD only promotes cultures if infection is clinically
suspected [1,5,10]. There are some other discrepancies
between the guidelines with regard to the usefulness of
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www.eurojgh.com e11
different tests. Gram staining is recommended by AASLD
when there is a suspicion of infection; BSG nds staining
unhelpful and EASL guidance does not mention it. These
recommendations are summarized in Table 1.
Akriviadis and Runyon [17] developed an algorithm for the
differentiation of primary from secondary bacterial peritonitis,
involving measurement of ascitic uid total protein, glucose
and lactate dehydrogenase. Protein levels greater than 1 g/dl, in
association with lactate dehydrogenase greater than the upper
limit of normal for serum and glucose less than 50 mg/dl,
predicted gut perforation with 100% sensitivity and 45%
specicity. Repeating the ascitic tap after 48 h of antibiotic
administration allows further differentiation between primary
and secondary bacterial peritonitis, as the polymorphonuclear
count improves after antibiotic treatment in SBP and continues
to rise in secondary bacterial peritonitis [17]. The presence of
carcinoembryonic antigen and alkaline phosphatase at quan-
tities greater than 5 ng/ml and 240 U/l, respectively, in ascitic
uid also indicates visceral perforation [18].
The guideline recommendations on ascitic lactate
dehydrogenase, glucose, carcinoembryonic antigen and
alkaline phosphatase testing are summarized in Table 1.
Other tests for ascitic uid include amylase, cancer antigen
125 (CA-125), mycobacterial cultures/PCR levels and
cytology. Ascitic amylase can be raised in pancreatic
aetiologies of ascites. Measuring CA-125 has low sensi-
tivity, as levels can be raised in ascites of all causes and it is
nonspecic, with levels falling when the ascites is better
controlled [1,5,10,19,20]. Mycobacterial cultures and
PCR for tuberculous ascites are only useful when there is
doubt about the aetiology or when there is a clinical sus-
picion of tuberculosis [21]. Sensitivities are as low as 50%
[22]. Ascitic uid cytology is expensive and will only yield
a positive result in the presence of peritoneal carcinoma-
tosis; as such, its use should be limited to those in whom
malignant ascites is considered to be a possibility. It has a
sensitivity of up to 96.7% for peritoneal carcinomatosis if
three samples from separate paracentesis are analysed [23].
Management of ascites
The successful management of ascites secondary to cir-
rhosis and portal hypertension concentrates on reducing
sodium intake and increasing renal sodium excretion,
leading to net reabsorption of uid from the ascites into
the circulating volume [1]. This is commonly achieved
through restricting dietary salt intake and promoting
sodium and water excretion with diuretics.
Dietary sodium restriction
Most guidelines advise restriction of sodium by eliminating
added salt and avoiding preprepared foods. Severe
restriction of salt intake is no longer recommended because
of the risk for protein malnutrition [24]. It is important to
factor in the high sodium content of some effervescent
drugs and intravenous antibiotics [5]. All guidelines sug-
gest a degree of salt restriction as the mainstay of rst-line
treatment, with specic targets varying slightly. Table 2
describes those targets in more detail.
e12 European Journal of Gastroenterology & Hepatology March 2016 Volume 28 Number 3

Table 1. Initial investigations for patients presenting with ascites

British Society of European Association for the Study of the American Association for the Study of Liver
Gastroenterology [5] Liver [1] Diseases [10,15,16]

Abdominal ultrasonography Required for all patients
Diagnostic paracentesis Required for all patients
(tap)
Ascitic uid cultures Required for all patients
Ascitic uid Grams stain Described as unhelpful
Suspicion of secondary Erect chest radiograph and
bacterial peritonitis abdominal CT recommended
Ascitic uid amylase Required for all patients
CA-125 Not mentioned
Mycobacterial cultures and Not mentioned
PCR for TB
Ascitic uid cytology Liaise with local cytology
department before performing
Urinary electrolytes Useful for measuring
compliance with dietary
sodium restrictions
Required for all patients
Required for patients with new-onset grade
2/3 ascites, worsening abdominal
distension or complications of cirrhosis
Required for all patients
Not mentioned
Immediate cross-sectional imaging (CT)
recommended
Useful when pancreatic disease suspected
Not mentioned
Only in high-risk patients or when there is
strong clinical suspicion of TB
Only if suspicion of malignant aetiology
Required for all patients
May be required to determine whether ascitic uid is
present (not explicitly required for all patients)
Required for all patients
Only where there is a strong suspicion of infection
Recommended when there is a suspicion of infection
Ascitic uid LDH, glucose, protein, ALP and CEA
recommended with CT to follow whether the
aforementioned biochemical markers suggest
secondary bacterial peritonitis or whether this is
clinically suspected
Useful when pancreatic disease suspected
The use of this test is discouraged
Only in high-risk patients or when there is a strong clinical
suspicion of TB
Only if suspicion of malignant aetiology
Urinary sodium may be of use when weight loss is
occurring at a suboptimal rate

ALP, alkaline phosphatase; CA-125, cancer antigen-125; CEA, carcinoembryonic antigen; CT, computed tomography; LDH, lactate dehydrogenase; TB, tuberculosis.

Dietary water restriction and management of
hyponatraemia
There is controversy about the role of water restriction in
patients with ascites secondary to cirrhosis and portal
hypertension. In an uncomplicated patient with normal
serum sodium levels, expert opinion dictates that there is
no role for water restriction [1]. However, in patients with
ascites and hypervolaemic hyponatraemia, water restric-
tion has become a standard management strategy. EASL
guidelines emphasize the importance of differentiating
between hypervolaemic hyponatraemia, characterized by
low serum sodium levels with ascites and oedema, and
hypovolaemic hyponatraemia, characterized by low serum
sodium levels with no ascites or oedema, as the treatment
will differ. BSG guidelines highlight the uncertainty and
lack of clinical studies in this area, questioning the rea-
soning behind uid restriction in hyponatraemic patients.
The authors state that uid restriction is illogical, as the
cause of hyponatraemia is reduced renal blood ow acti-
vating the reninangiotensinaldosterone system to retain
sodium and water. They also comment that some hepa-
tolgists in this instance would prescribe volume expansion
instead [5]. The EASL suggests that uid restriction pre-
vents further reductions in serum sodium levels but rarely
yields an improvement in levels. This is probably because
of the difculties in restricting uid to less than 1 l/day [1].
The AASLD guidelines discuss a paper by Sterns [25], who
showed that correcting hyponatraemia with hypertonic
saline can lead to more complications than the hypona-
traemia itself.
Fogel et al. [26] conducted a randomized control trial
that showed that spironolactone was superior to fur-
osemide when administered as a sole agent. It is often
necessary to start furosemide in addition to spironolactone
to prevent hyperkalaemia caused by the potassium-sparing
effects of aldosterone antagonists. Side effects of spir-
onolactone may necessitate the use of amiloride as an
alternative. The AASLD guidelines explore other diuretics
including metolazone, hydrochlorthiazide and triamterene,
all of which have been shown to be inferior to spir-
onolactone and furosemide. These recommendations are
summarized in Table 2.
Monitoring weight loss during diuresis is imperative.
In patients with peripheral oedema, the BSG and
AASLD guidelines agree that there should be no limit to
the rate of weight loss, with the EASL guidelines limiting
weight loss to 1 kg/day. All the guidelines agree that, in
patients without peripheral oedema, weight loss should be
limited to a maximum of 0.5 kg/day to prevent renal
impairment, hepatic encephalopathy and hypona-
traemia [27].
Measurement of urinary electrolytes can help with the
management of ascites. EASL recommends measuring
urine electrolytes, including sodium, for all patients. Low
urine sodium has been shown to be a poor prognostic
indicator in cirrhotic patients with ascites [28]. BSG
guidelines only mention the use of urinary electrolytes in
measuring compliance with dietary sodium restriction.
AASLD guidelines recognize that urinary sodium may be
of use during treatment when weight loss occurs at a
suboptimal rate [1,5,10].

Diuretics and speed of weight loss Large-volume paracentesis

All the guidelines recognize that diuretics have a central
role in the management of ascites and recommend starting
diuretics in a stepwise approach. Spironolactone is an
aldosterone antagonist that acts on the sodium/potassium
pumps in the distal tubule and collecting ducts to promote
diuresis.
LVP is the treatment of choice for the management of
patients with large-volume ascites (>5 l) [5]. Although it
does not correct the underlying cause, it provides symp-
tomatic relief and is more effective and safer than diuretics
alone [29]. It also shortens the duration of hospital stay
and has been reported to decrease the incidence of

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Ascites, SBP and HRS; comparing three guidelines Pericleous et al. www.eurojgh.com e13

Table 2. Recommendations for the management of abdominal ascites

European Association for the Study of the American Association for the Study of Liver
British Society of Gastroenterology [5] Liver [1] Diseases [10,15,16]

Dietary salt restriction
Fluid restriction in patients
with normal serum
sodium level
Fluid restriction in patients
with hypervolaemic
hyponatraemia
Diuretics
Speed of weight loss
Diuretics in patients with
hyponatraemia
Vasopressin receptor
antagonists (vaptans)
Transjugular intrahepatic
portosystemic stent
(TIPSS)
Large-volume paracentesis
Postparacentesis albumin
infusion
90 mmol salt/day (5.2 g salt/day)
Not recommended
More clinical studies required
100 mg spironolactone, increasing to a
maximum of 400 mg/day, as rst-line
treatment
Addition of furosemide at a dose up to
160 mg/day as second-line treatment
No limit in patients with severe oedema
< 0.5 kg/day weight loss when oedema
resolved
Na 126 mmol/l: continue diuretics with no
water restriction
Na 121125 mmol/l with a normal
creatinine level: consider stopping
diuretics or continue with caution
Na 121125 mmol/l with an increasing in
creatinine: stop diuretics and give volume
expansion
Na 120 mmol/l: stop diuretics and give
volume expansion. Avoid increasing
serum Na > 12 mmol/l per 24 h
No recommendation
Used for the treatment of refractory ascites
requiring frequent therapeutic
paracentesis with appropriate
assessment of the risk benet ratio
Required for all patients with large or
refractory ascites
Required if > 5 l drained. Synthetic Plasma
expander if < 5 l drained
80120 mmol salt/day (4.66.9 g salt/day)
Not recommended
Fluid restriction to 1000 ml/day may prevent a
further reduction in serum sodium
An aldosterone antagonist e.g. spironolactone
started at 100 mg/day and increasing
stepwise every 7 days by 100 mg to a
maximum of 400 mg/day
In non-responders, Furosemide added at a
dose of 40 mg/day increasing stepwise to a
maximum dose of 160 mg/day
1 kg/day in patients with peripheral oedema
< 0.5 kg/day in patients with no peripheral
oedema
Stop diuretics if:
Na < 120 mmol/l
Progressive renal failure
Worsening hepatic encephalopathy
Incapacitating muscle cramps
In hypervolaemic hyponatraemia with
Na < 125 mmol/day, vaptans may be
considered
Effective in the management of refractory
ascites but is associated with a high risk for
hepatic encephalopathy with no
improvement in survival compared with
LVPs. Considered in patients with very
frequent requirement for LVPs
Not recommended in patients were severe
liver failure, concomitant active infection,
progressive renal failure or severe
cardiopulmonary disease.
Required for all patients with large or
refractory ascites
Required if > 5 l drained. Synthetic plasma
expander or albumin if < 5 l drained
88 mmol salt/day
Not recommended
Fluid restriction if Na < 125 mmol/day
100 mg/day spironolactone and 40 mg/day
furosemide (single-agent use of
spironolactone only in patients with
minimal uid overload)
The doses of both drugs can be increased
simultaneously every 35 days
No limit in patients with signicant oedema
Maximum weight loss should be 0.5 kg/day
when oedema has resolved
Stop diuretics if:
Na < 120 mmol/l despite uid restriction
Serum creatinine > 2.0 mg/dl
recurrent or uncontrolled encephalopathy
Avoid in patients with cirrhosis
Considered in appropriately selected
patients who meet criteria similar to those
of published randomized trials
Required for all patients with large or
refractory ascites
Required if > 5 l drained
Postparacentesis colloid infusion after < 5 l
drainage may not be necessary

LVP, large-volume paracentesis; Na, sodium.

complications such as hyponatraemia, renal failure and
hepatic encephalopathy [29,30]. It is relatively safe to
perform, with a low risk of complications [31].
Although both EASL and BSG advise using a strict
sterile technique while performing the procedure, the BSG
guidelines are more robust and advise inserting the needle
in the left lower abdominal quadrant using a Z track. The
BSG and AASLD advise a single LVP as rapidly as possi-
ble, ideally within 14 h.
Haemodynamic changes after LVP lead to circulatory
dysfunction, a condition called postparacentesis circula-
tory dysfunction [29,32]. All three guidelines recommend
albumin (8 g albumin/litre of ascitic uid) if greater than 5 l
is drained (Table 2). In the case of paracentesis less
than 5 l, the BSG and EASL advise plasma expansion
with synthetic plasma expanders such as dextran-70 or
polygeline, whereas the AASLD suggests that a
postparacentesis colloid infusion may not be necessary
[1,5,10,15].
AASLD guidelines recognize the use of indwelling
catheters for malignant ascites but specify that their safety
and efcacy in the setting of cirrhosis must be proved
before advocating their use. EASL and BSG guidelines do
not address the management of malignant ascites, and
none of the major bodies comment on the use of albumin
when draining malignant ascites [1,5,15].
Vaptans
Anti-diuretic hormone/vasopressin is released from the pos-
terior pituitary gland in response to changes in blood pres-
sure and plasma osmolality. Levels are increased in patients
with cirrhosis because of a decrease in the effective blood
volume [33]. Anti-diuretic hormone/vasopressin acts antag-
onistically on V2 receptors in the collecting ducts, leading to
increased water reabsorption, exacerbating the dilutional
hyponatraemia [34]. The BSG guideline does not consider or
discuss the use of vaptans. The EASL and AASLD guidelines
both consider the use of vaptans in the management of a

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e14 European Journal of Gastroenterology & Hepatology
patient with hypervolaemic hyponatraemia. Clinical studies
have demonstrated that short courses of vaptans are asso-
ciated with an improvement in hyponatraemia [34].
However, the potential side effects of hypernatraemia, such
as dehydration, renal impairment and osmotic demyelina-
tion syndrome, are still of concern. The EASL guidelines
state that olvaptan and onivaptan are approved for use in
the USA for the management of severe hypervolaemic
hyponatraemia (sodium levels < 125 mmol/l) associated with
cirrhosis. Strict sodium monitoring must be undertaken to
avoid complications. EASL guidance recommends that
vaptans be started in hospital and should not be given in
patients who have an altered mental state, as they will be
unable to drink appropriate amounts of uids and will be at
risk of hypernatraemia and dehydration.
The updated 2013 AASLD guidelines reference a recent
large, randomized-controlled trial showing that the use of
vaptans for patients with ascites secondary to cirrhosis has
no clinical benet in the long-term and may be associated
with an increased mortality and, therefore, should be
avoided [35,36]. This is a large area of development, and
more studies are required to consider the use of vaptans in
the correction of hyponatraemia, especially in the short
term before a liver transplantation [36,37].
Transjugular intrahepatic portosystemic shunt
TIPSS is a side-to-side portocaval shunt inserted between
the high-pressure portal venous area and the lower-
pressure hepatic venous area. This subsequent reduction
in portal pressure has been proven to be effective in con-
trolling refractory ascites. Ochs et al. [38] showed that,
after insertion of TIPSS, 75% of patients had complete
resolution of ascites at 3 months. All three guidelines
compare at least four different large-scale, multicentre,
randomized-controlled trials that compared TIPSS with
repeated LVP in patients with cirrhosis and ascites. TIPSS
appears to be more effective; however, transplant-free
survival varied between studies [3942].
One of the biggest complications of TIPSS is hepatic
encephalopathy, as shown in multiple meta-analyses [43,
44]. Sanyal et al. [45] showed that hepatic encephalopathy
occurs in 25% of patients, with an increased incidence in
those older than 60 years. Stent thrombosis is also of
concern. For these reasons, TIPSS is not routinely recom-
mended in encephalopathic patients or in those with
advanced liver disease (ChildPugh score > 11).
Spontaneous bacterial peritonitis
SBP is the most frequently seen bacterial infection in hos-
pitalized patients with cirrhosis [46]. SBP carries a poor
prognosis, and hospital mortality ranges from 10 to 50%
[33]. Thus, timely diagnosis and initiation of treatment are
key to improving survival. Diagnosis requires ascitic uid
sampling and a polymorphonuclear leucocyte count
greater than 250 cells/mm3 (Table 1) [10]. However, some
clinicians may accept a lower threshold for treatment if
there is high clinical suspicion. Treatment should be initi-
ated with a broad-spectrum antibiotic, such as third-
generation cephalosporins.
The mechanisms leading to SBP include bacterial
translocation, reduced gut motility leading to intestinal
bacterial overgrowth, altered structure and function of the
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
March 2016 Volume 28 Number 3
intestinal mucosal defence barrier and deciencies in local
immune response systems. This leads to the development
of bacteraemia and ascitic uid contamination [47].
A polymorphonuclear cell count greater than 250 cells/
mm3 without evidence of an intra-abdominal surgically
treatable source of infection is diagnostic [1,5,15]. Timely
diagnosis is key; however, it can take hours to obtain
results of ascitic uid cell count. Thus, novel diagnostic
methods, such as leukocyte esterase reagent strips, which
offer rapid diagnosis, are being looked at. However, this
method carries a high false-positive rate [48].
The importance of inoculation of the blood culture
bottle with ascitic uid to increase the diagnostic yield of
SBP has already been discussed (Table 1). The most com-
mon SBP isolates are Escherichia coli, Klebsiella pneu-
moniae and Streptococcus pneumoniae [15]. Cefotaxime
confers effective cover against 95% of the ascitic/gut ora,
including the three most common organisms [49,50].
Alternatively, cephalosporins, such as ceftriaxone and
ceftazidime, have been shown to be as effective [11].
Posology and treatment length vary across the board
and tend to be guided by local policy. One study assessed
the therapeutic efcacy of two different doses of cefotax-
ime 2 g every 6 h versus 2 g every 12 h and reported
similar rates of infection resolution and survival [51].
Similar outcomes have been reported for duration of
treatment with antibiotics that is, 5 versus 10 days [52].
Hence, duration of therapy should be a minimum of
5 days. In patients who develop renal impairment, the BSG
recommends the use of intravenous albumin along with
ceftriaxone [5].
Secondary prevention of SBP should always be con-
sidered especially in high-risk patients, including those with
acute gastrointestinal haemorrhage and low ascitic uid
protein, and survivors of a previous episode of SBP [1]. In
patients who have had one episode of SBP, the recurrence
rate within 1 year is 70%; thus, antibiotic prophylaxis is
important [53]. Evidence from the study by Soriano et al.
[53] suggested that administration of 400 mg noroxacin
twice daily for 7 days reduced the probability of recurrence
of SBP from 68 to 20%. However, it must be noted that
prolonged antibiotic therapy can lead to antibiotic-resistant
SBP and increases the likelihood of other bacterial infections.
Hence, clinical judgement must guide the use of antibiotic
prophylaxis [53]. Table 3 summarizes the guideline recom-
mendations for SBP.
There is very little guidance on the use of LVP in
patients with conrmed SBP. LVP is rarely used in clinical
practice because of fear of precipitating haemodynamic
instability. However, Choi et al. [54] compared the use of
LVP with conventional treatment of SBP and found that
there was no difference in the efcacy or safety of both
treatment options.
Bleeding prophylaxis in patients with ascites
Routine tests of coagulation do not appear to accurately
reect bleeding risk during and after LVP [55]. Patients
with liver disease form thrombin in similar amounts as
healthy individuals [56] and have a ne balance between
reduced levels of both brinolytic and antibrinolytic
agents, resulting in normal levels of brinolysis [57]. To
effectively assess coagulation, more sophisticated tests are
Ascites, SBP and HRS; comparing three guidelines Pericleous et al.
Table 3. Recommendations for the management of spontaneous bacterial peritonitis and hepatorenal syndrome
British Society of Gastroenterology [5]
Spontaneous bacterial peritonitis
Diagnosis of SBP PMN count greater than 250 cells/mm3 without
evidence of an intra-abdominal surgically
treatable source of infection
Treatment of SBP Cefotaxime
Prophylaxis for SBP Intravenous ceftriaxone for 7 days or twice daily
noroxacin for 7 days should be given to
prevent bacterial infections in patients with
cirrhosis and gastrointestinal haemorrhage
Hepatorenal syndrome
Additional
diagnostic tests
for SBP
Albumin and No rm recommendation but mention the
vasoactive drugs advice by the International Ascites Club to
give normal saline to patients developing
HRS. Vasoactive drugs not mentioned
Diuretics
HSR, hepatorenal syndrome; PMN, polymorphonuclear; SBP, spontaneous bacterial peritonitis.
required, which look at the coagulation process as a whole.
These include thrombin generation time, sonorheometry
and thromboelastography. Thromboelastography was
found to reduce transfusion requirements in liver trans-
plants by effectively identifying the need for platelets or
clotting factors [58]. Studies have shown that draining
ascites in patients with an international normalized ratio as
high as 8.7 and a low platelet count was not associated
with a signicant risk for bleeding [32,59,60]. Thus pro-
phylaxis with platelets and other blood products is not
routinely recommended by any guideline.
Hepatorenal syndrome
Cirrhotic patients can develop renal impairment from a
number of causes, but most importantly from renal vaso-
constriction secondary to complex circulatory changes in
cirrhosis. Other important causes include infections,
hypovolemia, paracentesis, bleeding and nephrotoxic
medication [61,62]. HRS refers to the occurrence of renal
impairment in a patient with advanced liver disease in the
absence of an identiable cause [63].
It may be rapidly progressive (type I HRS) or may
develop gradually (type II HRS), which is usually associated
with refractory ascites [62]. Renal dysfunction is common,
occurring in 20% of hospitalized patients, and is a strong
predictor of mortality in patients with cirrhosis [64,65].
EASL guidelines emphasize the early recognition of
HRS, along with investigations to rule out other possible
causes of renal impairment. Urine output, uid balance
and arterial pressure, as well as standard vital signs and,
ideally, central venous pressure to prevent volume over-
load, should be monitored in an intensive care or semi-
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
www.eurojgh.com e15
European Association for the Study American Association for the Study of Liver
of the Liver [1] Diseases [10,15,16]
PMN count greater than 250 cells/mm3 PMN count greater than 250 cells/mm3
without evidence of an intra-abdominal without evidence of an intra-abdominal
surgically treatable source of infection surgically treatable source of infection
Cefotaxime Cefotaxime
In patients with gastrointestinal bleeding and Patients recovering from one episode of
severe liver disease, ceftriaxone is the SBP should receive prophylaxis with
prophylactic antibiotic of choice, whereas continuous oral noroxacin 400 mg/day
patients with less severe liver disease may (or ciprooxacin at 500 mg once daily)
be given oral noroxacin or an alternative
oral quinolone to prevent the development of
SPB
Patients who recover from an episode of SPB
have a high risk of developing recurrent
SPB. In these patients, the administration of
prophylactic antibiotics reduces the risk for
recurrent SPB. Noroxacin (400 mg/day) is
the treatment of choice
Neutrophil gelatinase-associated lipocalin
can be used
Terlipressin 1 mg/46 h plus albumin should be Albumin infusion plus octreotide, midodrine
considered for HRS 1 and 2 as rst-line or norepinephrine can be used for HSR 1
treatment unless contraindicated.
Octreotide, midodrine or norepinephrine can
also be used
All diuretics should be stopped but furosemide
can be considered if urine output needs to
be maintained
intensive care unit. All diuretics should be stopped in
patients on diagnosis, but furosemide may be used for
maintaining urine output and treating volume overload.
Terlipressin (1 mg/46 h intravenous bolus) with albumin
should be considered as the rst-line treatment. TIPSS and
renal replacement therapy may be considered as second-
line therapy. The BSG recommends that when starting
diuretics, the renal function should be carefully monitored.
Furthermore, patients with SBP and signs of deteriorating
renal function should be given 1.5 g/kg albumin over the
rst 6 h, followed by 1 g/kg albumin on day 3.
The criteria for HRS in AASLD include (i) cirrhosis
with ascites, (ii) serum creatinine greater than 1.5 mg/dl
(132 mmol/l), (iii) no improvement in serum creatinine
after at least 2 days of diuretic withdrawal and volume
expansion with albumin, (iv) absence of shock, (v) no
current or recent treatment with nephrotoxic drugs and
(vi) absence of parenchymal kidney disease. It recommends
the use of new urinary biomarkers such as neutrophil
gelatinase-associated lipocalin to make it less of a diag-
nosis of exclusion. Like EASL, albumin and vasoactive
drugs are considered in the treatment of type I HRS. Both
EASL and AASLD advise consideration of all patients with
HRS for expedited liver transplantation.
Discussion
There appears to be good concordance between recommen-
dations of the European, American and British guidelines both
for the diagnosis and for the management of ascites SBP and
HRS. The recommendations on the investigation of ascites
differ slightly; however, all three generally promote the use of
e16 European Journal of Gastroenterology & Hepatology
ultrasound, diagnostic paracentesis, calculation of SAAG and
ascitic uid cultures (especially when SBP is considered to be a
possibility). The routine endorsement of such investigations is
likely because of their high diagnostic yield, high sensitivities
and specicities and, in the case of ascitic uid cultures, the need
to exclude SBP due to the severity of clinical sequelae associated
with this condition. The advent of the serum albumin ascites
gradient as a tool has advanced the diagnostic approach to
patients with ascites and offers a more useful device in terms of
determining the aetiology when compared with measuring
ascitic uid protein levels in isolation.
The statistics prove that cirrhosis is by far the most com-
mon cause of ascites [1] and, therefore, investigations for
other rarer causes, which may incur considerable nancial
costs on the healthcare providers, should only be used at the
discretion of the attending physician. The risks for over-
investigation do not only have nancial implications in terms
of costs of the different tests but may also lead to stretching of
resources in other ways for example, increasing the work-
load of the relevant staff involved such as lab technicians,
microbiologists, radiology staff, histopathologists, etc. As
such, a rational and realistic approach is required.
The evidence base for the various tests is taken into
consideration when developing the guidelines, reinforcing
the mantra that advocates only those investigations that
are cost-effective, those that will add value and those that
are absolutely necessary on clinical grounds. This means
that tests with low specicity such as ascitic uid CA-125
are either not mentioned or are actively discouraged. In
some cases, practical considerations will dictate recom-
mended actions; for instance, the BSG mentions the use of
ascitic uid analysis algorithms, which can help with the
detection of secondary bacterial peritonitis, but it states
that erect chest radiographs and computed tomography
scanning are more helpful in practice.
Siddiqui et al. [66] suggested that the presence of bro-
nectin in ascitic uid at a concentration of at least 110 mg/ml
can diagnose ascites as being of a malignant aetiology with
100% accuracy. Despite this, it has yet to be incorporated
into the guidelines discussed. Cost and availability of the
assay could be factors that preclude its use. It is, however,
likely that we will see some evolution in the guidelines as
new biomarkers emerge as useful clinical indices.
SBP can be complex and life threatening. There appears to
be a consistent approach to the management of the condition,
with timely administration of antibiotics being key to improving
prognosis. Diagnosis is dependent on ascitic uid sampling; a
neutrophil count greater than 250 cells/mm3 is deemed diag-
nostic. The most common causative pathogens include E. coli,
K. pneumoniae and S. pneumoniae. However, recent research
has suggested that extended-spectrum -lactamase (ESBL)-pro-
ducing bacteria and multiresistant organisms such as
Enterococcus faecium are becoming more common causes of
hospital-acquired SBP. One study demonstrated that the inci-
dence of hospital-acquired ESBL-positive E. coli in intra-
abdominal infections increased from 4.3% in 2002 to 11.8% in
2008 [67]. Interestingly, this has not been addressed in any of
the guidelines reviewed. As our knowledge of therapeutics
improves, it would be prudent to incorporate recommendations
on appropriate antibiotic use in cases of ESBL-positive SBP.
The use of appropriate antibiotics is key to the effective
management of SBP, and this is reected in all of the
guidelines that we have reviewed. There also appears to be
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
March 2016 Volume 28 Number 3
agreement with regard to the use of an intravenous albu-
min solution in patients with a diagnosis of SBP. These
patients are at high risk of developing HRS, which is one of
the strongest predictors of mortality. Research by Singh
and colleagues demonstrated that patients who were
administered high-dose adjuvant intravenous albumin
solution had improved inhospital and 3-month survival.
These patients, however, had end-stage liver disease, and
thus it has been argued that low-risk patients may not
benet from the use of intravenous albumin. Our knowl-
edge of this subgroup is limited; hence, EASL recommends
that all patients with SBP be treated with intravenous
antibiotics and albumin. Interestingly, both the AASL and
BSG guidelines recommend the use of albumin only in
patients with signs of development of renal function [68].
Possibly the biggest difference between the three guidelines
is the detailed analysis of the management of hypona-
traemia in BSG but not in EASL and AASLD. However, the
BSG guidelines do not appear to provide guidance on the
management of secondary bacterial peritonitis, the diag-
nosis of tuberculosis, the use of V2-receptor antagonists
and the diagnosis and management of HRS. The AASLD
appears to dictate most guideline parameters on the basis of
clinical suspicion rather than concrete and prescriptive
advice. It should be highlighted that guidelines should not
remove clinical judgment, and high-risk patients should be
individually assessed on their own merit, especially patients
with complications such as sepsis, disseminated intravas-
cular coagulation and haemodynamic instability.
Acknowledgements
Conicts of interest
There are no conicts of interest.
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