2y
: 0.07,
p = 0.4
D’Amico et al., 2005 [95]
5
330
Yes
Lower in TIPS group. OR 0.14 (0.7–
0.27)
Higher in TIPS
group. OR 2.26
(1.35–3.76)
No difference between groups A
trend towards better survival in
TIPS group OR 0.74 (0.40–1.37)
Saab et al., 2006 [96]
5
330
?
Lower after 3 months in TIPS group.
OR 0.07 (0.03–0.18, p <0.01)
12 months OR 0.14 (0.06–0.28,
p <0.01)
Higher in TIPS
group. OR 2.24
(1.39–3.6) p <0.01
30-days OR 1.0 (0.10–0.06, p = 1)
24 months OR 1.29 (0.65–2.56,
p = 0.5)
Salerno et al., 2007 [97]
4
305
No
Lower in TIPS group. 42 versus 89% in
LVP group (p <0.0001)
Higher in TIPS
group. (1.13
versus 0.63
(p = 0.006)).
Transplant-free survival better in
TIPS group (p = 0.035)
DifE
4M
and DifE
12M
: Difference in effects at 4 and 12 months. DifE
1y
and DifE
2y
OR, odds ratio. RR, relative risk.
JOURNAL OF HEPATOLOGY
Journal of Hepatology 2010 vol. 53
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397–417
403
blood cell count, tachycardia, and/or tachypnea; (3) worsening of
liver function; (4) hepatic encephalopathy; (5) shock; (6) renal
failure; and (7) gastrointestinal bleeding. However, it is impor-
tant to point out that SBP may be asymptomatic, particularly in
outpatients [109,110].
3.1.2. Ascitic fluid cell analysis
Peritoneal infection causes an inflammatory reaction resulting in
an increased number of neutrophils in ascitic fluid. Despite the
use of sensitive methods, ascites culture is negative in as many as
60% of patients with clinical manifestations suggestive of SBP
and increased ascites neutrophil count [10,106–108]. Ascitic fluid
neutrophil count is obtained as follows: ascitic fluid is centrifuged,
then a smear is stained with Giemsa and total and differential cell
counts are made with an optical microscope. This can be done in
less than 4 h [10,107,108,112]. Historically, manual counts were
recommended, as coulter counter determinations of neutrophil
counts were inaccurate at the relatively low levels of neutrophils
in ascitic fluid [10]. However, a recent study found excellent corre-
lation between these two techniques, even at low counts, suggest-
ing that automated counting may replace manual counts [113]. The
greatest sensitivity for the diagnosis of SBP is reached with a cutoff
neutrophil count of 250/mm
3
, although the greatest specificity is
reached with a cutoff of 500 neutrophils/mm
3
[10,66,107]. Since
there may be some delay in obtaining an ascitic fluid cell count,
the use of reagent strips (RSs) has been proposed for a rapid diag-
nosis of SBP (reviewed in [114]). These reagent strips, designed
for use in urine, identify leukocytes by detecting their esterase
activity via a colorimetric reaction [114]. However, a large, multi-
center prospective study has shown that the Multistix 8 SG
Ò
RS
has a low diagnostic accuracy for the diagnosis of SBP [109]. A crit-
ical review of 19 studies comparing RSs (i.e., either Multistix 8 SG
Ò
,
Nephur
Ò
, Combur
Ò
, UriScan
Ò
, or Aution
Ò
) to cytobacteriological
methods has shown that RSs have low sensitivity and a high risk
of false negative results, in particular in patients with SBP and
low neutrophil count [114]. Thus, the use of reagent strips cannot
be recommended for the rapid diagnosis of SBP.
3.1.3. Ascitic fluid culture
When culture is positive ($40% of cases), the most common
pathogens include Gram-negative bacteria (GNB), usually Esche-
richia coli and Gram-positive cocci (mainly streptococcus species
and enterococci) [10,105–108]. A recent study has shown that
30% of isolated GNB are resistant to quinolones and 30% are resis-
tant to trimethoprim–sulfamethoxazole [106]. Seventy percent of
quinolone-resistant GNB are also resistant to trimethoprim–sul-
famethoxazole [106]. The incidence of SBP due to quinolone-
resistant GNB is higher in patients on norfloxacin therapy than
in patients ‘naïve’ for this treatment [106]. The rate of cephalo-
sporin-resistant GNB is low in patients with SBP regardless of
norfloxacin prophylaxis [106]. Patients on norfloxacin prophy-
laxis may develop SBP caused by Gram-positive cocci [10,106–
108]. Finally, the epidemiology of bacterial infections differs
between community-acquired (in which GNB infections predom-
inate) and nosocomial infections (in which Gram-positive infec-
tions predominate) [106].
Patients with an ascitic fluid neutrophil count P250 cells/
mm
3
and negative culture have culture-negative SBP [10,115].
Their clinical presentation is similar to that of patients with cul-
ture-positive SBP [10,116] and should be treated in a similar
manner.
Some patients have ‘bacterascites’ in which cultures are posi-
tive but there is normal ascitic neutrophil count (<250/mm
3
)
[10]. In some patients bacterascites is the result of secondary bac-
terial colonization of ascites from an extraperitoneal infection.
These patients usually have general symptoms and signs of infec-
tion. In other patients, ‘bacterascites’ is due to the spontaneous col-
onization of ascites, and they can either be clinically asymptomatic
or have abdominal pain or fever. While in some patients, particu-
larly in those who are asymptomatic, bacterascites represents a
transient and spontaneously reversible colonization of ascites, in
other patients, mainly those who are symptomatic, bacterascites
may represent the first step in the development of SBP [10].
3.1.4. Spontaneous bacterial pleural empyema
Infection of a pre-existing hydrothorax, known as spontaneous
bacterial pleural empyema, is uncommon although the exact
prevalence is unknown [112]. The diagnosis is based on pleural
fluid analysis obtained by diagnostic thoracocentesis. In the larg-
est observational study reported so far, the diagnosis of sponta-
neous bacterial empyema was established when the pleural
fluid analysis showed a positive culture and more than 250 neu-
trophils/mm
3
or a negative culture and more than 500 neutro-
phils/mm
3
, in the absence of lung infection [117]. Pleural fluid
culture in blood culture bottles was positive in 75% of cases
[117]. Spontaneous bacterial pleural empyema was associated
with SBP in $50% of cases [117].
3.1.5. Secondary bacterial peritonitis
A small proportion of patients with cirrhosis may develop perito-
nitis due to perforation or inflammation of an intra-abdominal
organ, a condition known as secondary bacterial peritonitis. The
differentiation of this condition from SBP is important. Secondary
bacterial peritonitis should be suspected in patients who have
localized abdominal symptoms or signs, presence of multiple
organisms on ascitic culture, very high ascitic neutrophil count
and/or high ascitic protein concentration, or in those patients
with an inadequate response to therapy [112]. Patients with sus-
pected secondary bacterial peritonitis should undergo appropri-
ate radiological investigation such as CT scanning [112]. The
use of other tests such as measurement of glucose or lactate
dehydrogenase in ascitic fluid has been suggested to help with
the diagnosis of secondary bacterial peritonitis [112]. However,
there are very limited data on the specificity and sensitivity of
these tests in this setting.
Recommendations A diagnostic paracentesis should be
carried out in all patients with cirrhosis and ascites at hospital
admission to rule out SBP. A diagnostic paracentesis should
also be performed in patients with gastrointestinal bleeding,
shock, fever, or other signs of systemic inflammation, gastroin-
testinal symptoms, as well as in patients with worsening liver
and/or renal function, and hepatic encephalopathy (Level A1).
The diagnosis of SBP is based on neutrophil count in ascitic
fluid of >250/mm
3
as determined by microscopy (Level A1). At
present there are insufficient data to recommend the use of
automated cell counters or reagent strips for the rapid diagno-
sis of SBP.
Ascitic fluid culture is frequently negative even if per-
formed in blood culture bottles and is not necessary for the
Clinical Practice Guidelines
404
Journal of Hepatology 2010 vol. 53
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397–417
diagnosis of SBP, but it is important to guide antibiotic ther-
apy (Level A1). Blood cultures should be performed in all
patients with suspected SBP before starting antibiotic treat-
ment (Level A1).
Some patients may have an ascitic neutrophil count less
than 250/mm
3
but with a positive ascitic fluid culture. This
condition is known as bacterascites. If the patient exhibits
signs of systemic inflammation or infection, the patient
should be treated with antibiotics (Level A1). Otherwise, the
patient should undergo a second paracentesis when culture
results come back positive. Patients in whom the repeat ascit-
ic neutrophil count is >250/mm
3
should be treated for SBP,
and the remaining patients (i.e., neutrophils <250/mm
3
)
should be followed up (Level B1).
Spontaneous bacterial pleural empyema may complicate
hepatic hydrothorax. Diagnostic thoracocentesis should be
performed in patients with pleural effusion and suspected
infection with inoculation of fluid into blood culture bottles
(Level A1). The diagnosis is based on positive pleural fluid cul-
ture and increased neutrophil count of >250/mm
3
or negative
pleural fluid culture and >500 neutrophils/mm
3
in the absence
of pneumonia (Level B1).
Patients with suspected secondary bacterial peritonitis
should undergo appropriate radiological investigation such
as CT scanning (Level A1). The use of other tests such as mea-
surement of glucose or lactate dehydrogenase in ascitic fluid
cannot be recommended for the diagnosis of secondary bacte-
rial peritonitis (Level B1).
3.2. Management of spontaneous bacterial peritonitis
3.2.1. Empirical antibiotic therapy
Empirical antibiotic therapy must be initiated immediately after
the diagnosis of SBP, without the results of ascitic fluid culture
[10,107]. Potentially nephrotoxic antibiotics (i.e., aminoglyco-
sides) should not be used as empirical therapy [10]. Cefotaxime,
a third-generation cephalosporin, has been extensively investi-
gated in patients with SBP because it covers most causative
organisms and because of its high ascitic fluid concentrations
during therapy [118–122]. Infection resolution is obtained in
77–98% of patients. A dose of 4 g/day is as effective as a dose of
8 g/day [119]. A 5-day therapy is as effective as a 10-day treat-
ment [123] (Table 6).
Alternatively, amoxicillin/clavulanic acid, first given intrave-
nously then orally, has similar results with respect to SBP res-
olution and mortality, compared with cefotaxime [122] and
with a much lower cost. However, there is only one compara-
tive study with a small sample size and results should be
confirmed in larger trials. Ciprofloxacin, given either for 7 days
intravenously or for 2 days intravenously followed by 5 days
orally, results in a similar SBP resolution rate and hospital sur-
vival compared with cefotaxime, but with a significantly higher
cost [124]. However, switch therapy (i.e., use of intravenous
antibiotic initially, followed by oral step-down administration)
with ciprofloxacin is more cost-effective than intravenous
cefotaxime [125]. Oral ofloxacin has given similar results as
intravenous cefotaxime in uncomplicated SBP, without renal
failure, hepatic encephalopathy, gastrointestinal bleeding, ileus,
or shock [120]. Cefotaxime or amoxicillin/clavulanic acid are
effective in patients who develop SBP while on norfloxacin
prophylaxis [10].
If ascitic fluid neutrophil count fails to decrease to less than
25% of the pre-treatment value after 2 days of antibiotic treat-
ment, there is a high likelihood of failure to respond to therapy
[10,112]. This should raise the suspicion of an infection caused
by bacteria resistant to antibiotic therapy, indicating the need
for modification of antibiotic treatment according to in vitro sensi-
tivity or on empiric basis or the presence of ‘secondary peritonitis’.
Recommendations. Empirical antibiotics should be started
immediately following the diagnosis of SBP (Level A1).
Since the most common causative organisms of SBP are
Gram-negative aerobic bacteria, such as E. coli, the first line
antibiotic treatment are third-generation cephalosporins
(Level A1). Alternative options include amoxycillin/clavulanic
acid and quinolones such as ciprofloxacin or ofloxacin. How-
ever, the use of quinolones should not be considered in
patients who are taking these drugs for prophylaxis against
SBP, in areas where there is a high prevalence of quinolone-
resistant bacteria or in nosocomial SBP (Level B1).
Table 6. Antibiotic therapy for spontaneous bacterial peritonitis in patients with cirrhosis.
Reference
Treatments
Number of
patients
Infection resolution
(%)
In-hospital survival
(%)
Felisart, 1985 [118]
Tobramycin (1.75 mg/kg/8h IV)
plus ampicillin (2 g/4h IV)
versus cefotaxime (2 g/4h IV)
36
56
61
37
85
*
73
Rimola, 1995 [119]
Cefotaxime (2 g/6h IV)
versus cefotaxime (2 g/12h IV)
71
77
69
72
79
79
Navasa, 1996 [120]
Ofloxacin (400 mg/12h PO)
versus cefotaxime (2 g/6h IV)
64
84
81
59
85
81
Sort, 1999 [121]
Cefotaxime (2 g/6h IV)
versus cefotaxime (2 g/6h IV) plus IV albumin
63
94
71
63
98
90
**
Ricart, 2000 [122]
Amoxicillin/clavulanic acid (1/0.2 g/8h)
IV followed by 0.5/0.125 g/8h PO
versus cefotaxime (1 g/6h IV)
24
87
87
24
83
79
Terg, 2000 [124]
Ciprofloxacin (200 mg/12h IV for 7 days)
versus ciprofloxacin (200 mg/12h for 2 days,
followed by 500 mg/12h PO for 5 days)
40
76
77
40
78
77
*
p <0.02 versus tobramycin plus ampicillin.
**
p = 0.01 versus cefotaxime alone.
JOURNAL OF HEPATOLOGY
Journal of Hepatology 2010 vol. 53
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405
SBP resolves with antibiotic therapy in approximately 90%
of patients. Resolution of SBP should be proven by demon-
strating a decrease of ascitic neutrophil count to <250/mm
3
and sterile cultures of ascitic fluid, if positive at diagnosis
(Level A1). A second paracentesis after 48 h of start of treat-
ment may help guide the effect of antibiotic therapy.
Failure of antibiotic therapy should be suspected if there is
worsening of clinical signs and symptoms and/or no marked
reduction or increase in ascitic fluid neutrophil count com-
pared to levels at diagnosis. Failure of antibiotic therapy is
usually due to resistant bacteria or secondary bacterial perito-
nitis. Once secondary bacterial peritonitis has been excluded,
antibiotics should be changed according to in vitro suscepti-
bility of isolated organisms, or modified to alternative empiric
broad spectrum agents (Level A1).
Spontaneous bacterial empyema should be managed similarly
as SBP
3.2.2. Intravenous albumin in patients with spontaneous bacterial
peritonitis without septic shock
SBP without septic shock may precipitate deterioration of circu-
latory function with severe hepatic insufficiency, hepatic enceph-
alopathy, and type 1 hepatorenal syndrome (HRS) [121,126,127]
and has approximately a 20% hospital mortality rate despite
infection resolution [121,126].
A randomized, controlled study in patients with SBP treated
with cefotaxime showed that albumin (1.5 g/kg body weight at
diagnosis, followed by 1 g/kg on day 3) significantly decreased
the incidence of type 1 HRS (from 30% to 10%) and reduced
mortality from 29% to 10% compared with cefotaxime alone.
Treatment with albumin was particularly effective in patients
with baseline serum bilirubin P68
l
mol/L (4 mg/dl) or serum
creatinine P88
l
mol/L (1 mg/dl). It is unclear whether intrave-
nous albumin is useful in patients with baseline bilirubin
<68
l
mol/L and creatinine <88
l
mol/L, as the incidence of type
1 HRS was very low in the two treatment groups (7% without
albumin and 0% with albumin) [121]. Non-randomized studies
in patients with SBP also show that the incidence of renal
failure and death are very low in patients with moderate liver
failure and without renal dysfunction at diagnosis of SBP
[128–130]. It is not known whether crystalloids or artificial col-
loids could replace albumin in the prevention of HRS in patients
with SBP. Albumin improves circulatory function in patients
with SBP while equivalent doses of hydroxyethyl starch have
no such beneficial effect [131]. Clearly, further studies are needed
to assess the efficacy of albumin as well as other expanders in
the management of SBP. Until further trials are completed,
albumin infusion appears a valuable adjunction to the treatment
of SBP.
Recommendations HRS occurs in approximately 30% of
patients with SBP treated with antibiotics alone, and is associ-
ated with a poor survival. The administration of albumin (1.5 g/
kg at diagnosis and 1g/kg on day 3) decreases the frequency of
HRS and improves survival (Level A1). It is unclear whether
albumin is useful in the subgroup of patients with baseline
serum bilirubin <68
l
mol/L and creatinine <88
l
mol/L (Level
B2). Until more information is available, we recommend that
all patients who develop SBP should be treated with broad
spectrum antibiotics and intravenous albumin (Level A2).
3.3. Prophylaxis of spontaneous bacterial peritonitis
Since most episodes of SBP are thought to result from the trans-
location of enteric GNB, the ideal prophylactic agent should be
safe, affordable, and effective at decreasing the amounts of these
organisms from the gut while preserving the protective anaerobic
flora (selective intestinal decontamination) [108]. Given the high
cost and inevitable risk of developing resistant organisms, the use
of prophylactic antibiotics must be strictly restricted to patients
at high risk of SBP. Three high-risk patient populations have been
identified: (1) patients with acute gastrointestinal hemorrhage;
(2) patients with low total protein content in ascitic fluid and
no prior history of SBP (primary prophylaxis); and (3) patients
with a previous history of SBP (secondary prophylaxis).
3.3.1. Patients with acute gastrointestinal hemorrhage
Bacterial infection, including SBP, is a major problem in patients
with cirrhosis and acute gastrointestinal hemorrhage, occurring
in between 25% and 65% of patients with gastrointestinal bleed-
ing [132–141]. The incidence of bacterial infection is particularly
high in patients with advanced cirrhosis and/or severe hemor-
rhage [138,139]. In addition, the presence of bacterial infection
in patients with variceal hemorrhage is associated with an
increased rate of failure to control bleeding [142,143], rebleeding
[136,138], and hospital mortality [139,143–145]. Antibiotic pro-
phylaxis has been shown to prevent infection in patients with
gastrointestinal bleeding [10,107,108] and decrease the rate of
rebleeding [144]. A meta-analysis [139] of five studies performed
in patients with gastrointestinal bleeding [132,134,135,137,140]
has shown that antibiotic prophylaxis significantly decreased
both the incidence of severe infections (SBP and/or septicemia)
and mortality.
Selective
intestinal
decontamination
with
norfloxacin
(400 mg/12 h orally for 7 days), a quinolone with relatively poor
gastrointestinal absorption, and which has antibacterial activity
against GNB but not against Gram-positive cocci or anaerobic
bacteria, is the most commonly used approach for the prophy-
laxis of bacterial infections in patients with gastrointestinal hem-
orrhage [10,107,134]. In recent years, the epidemiology of
bacterial infections in cirrhosis has changed, with an increasing
incidence of SBP and other infections caused by quinolone-resis-
tant bacteria (see above) [106,146,147]. In addition, a substantial
number of infections in patients with gastrointestinal hemor-
rhage are caused by Gram-positive bacteria likely related to inva-
sive procedures used in these patients [106].
A recent study comparing oral norfloxacin to intravenous cef-
triaxone for the prophylaxis of bacterial infection in patients with
gastrointestinal bleeding and advanced cirrhosis (at least 2 of the
following: ascites, severe malnutrition, encephalopathy, or biliru-
bin >3 mg/dl) showed that ceftriaxone was more effective than
norfloxacin in the prevention of infections [148].
Recommendations In patients with gastrointestinal bleed-
ing and severe liver disease (see text) ceftriaxone is the prophy-
lactic antibiotic of choice, whilst patients with less severe liver
disease may be given oral norfloxacin or an alternative oral 68>68> Dostları ilə paylaş: |