Gastroenterology 2014;146:16801690

Nonselective b Blockers Increase Risk for Hepatorenal

Syndrome and Death in Patients With Cirrhosis
and Spontaneous Bacterial Peritonitis
Mattias Mandorfer,1,2 Simona Bota,1,2 Philipp Schwabl,1,2 Theresa Bucsics,1,2
Nikolaus Psterer,1,2 Matthias Kruzik,1,2 Michael Hagmann,3 Alexander Blacky,4
Arnulf Ferlitsch,1,2 Wolfgang Sieghart,1,2 Michael Trauner,1,2 Markus Peck-Radosavljevic,1,2
and Thomas Reiberger1,2
CLINICAL LIVER

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna,
Austria; 2Vienna Hepatic Hemodynamic Lab, Vienna, Austria; 3Section for Medical Statistics, Center for Medical Statistics,
Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria; and 4Clinical Institute of Hospital Hygiene,
Vienna General Hospital, Vienna, Austria
This article has an accompanying continuing medical education activity on page e14. Learning Objective: Upon completion of this
exam, successful learners will be able to identify patients with cirrhosis and ascites that no longer benet from non-selective
b blocker treatment since the development of spontaneous bacterial peritonitis indicates an event when non-selective betablockers can compromise the circulatory reserve.

See Covering the Cover synopsis on page 1583;

see editorial on page 1597.
BACKGROUND & AIMS: Nonselective b blockers (NSBBs)
reduce portal pressure and the risk for variceal hemorrhage in
patients with cirrhosis. However, development of spontaneous
bacterial peritonitis (SBP) in these patients could preclude
treatment with NSBBs because of their effects on the circulatory reserve. We investigated the effects of NSBBs in patients with cirrhosis and ascites with and without SBP.
METHODS: We performed a retrospective analysis of data
from 607 consecutive patients with cirrhosis who had their
rst paracentesis at the Medical University of Vienna from
2006 through 2011. Cox models were calculated to investigate the effect of NSBBs on transplant-free survival time
and adjusted for Child-Pugh stage and presence of varices.
RESULTS: NSBBs increased transplant-free survival in
patients without SBP (hazard ratio 0.75; 95% condence
interval: 0.5810.968; P .027) and reduced days of nonelective hospitalization (19.4 days/year for patients on NSBBs
vs 23.9 days/year for patients not taking NSBBs). NSBBs had
only moderate effects on systemic hemodynamics at patients
rst paracentesis. However, at the rst diagnosis of SBP, the
proportion of hemodynamically compromised patients with
systolic arterial pressure <100 mm Hg was higher among
those who received NSBBs (38% vs 18% of those not taking
NSBBs; P .002), as was the proportion of patients with
arterial pressure <82 mm Hg (64% of those taking NSBBs vs
44% of those not taking NSBBs; P .006). Among patients
with SBP, NSBBs reduced transplant-free survival (hazard
ratio 1.58; 95% condence interval: 1.0982.274; P .014)
and increased days of nonelective hospitalization (29.6 days/
person-year in patients on NSBBs vs 23.7 days/person-year
in those not taking NSBBs). A higher proportion of patients

on NSBBs had hepatorenal syndrome (24% vs 11% in those

not taking NSBBs; P .027) and grade C acute kidney injury
(20% vs 8% for those not taking NSBBs; P .021). CONCLUSIONS: Among patients with cirrhosis and SBP, NSBBs
increase the proportion who are hemodynamically compromised, time of hospitalization, and risks for hepatorenal
syndrome and acute kidney injury. They also reduce
transplant-free survival. Patients with cirrhosis and SBP
should not receive NSBBs.

Keywords: Liver Fibrosis; Bacterial Infection; Mortality;

b Blocker; Adrenergic Receptor.

irrhosis accounts for 1.8% of all deaths in Europe1

and is the 12th leading cause of death in the
United States, and a recent report suggests that even this
might be an underestimation.2
According to a prognostic model proposed by DAmico
et al,3 the occurrence of varices initiates the second stage of
cirrhosis, and the third stage is dened by the development
of ascites. Variceal hemorrhage, the most common lethal
complication of cirrhosis, results directly from portal hypertension and triggers the fourth stage of cirrhosis.

Abbreviations used in this paper: AKI, acute kidney injury; CI, condence
interval; CPS, Child-Pugh score; DAP, diastolic arterial pressure; HR,
hazard ratio; HRS, hepatorenal syndrome; IQR, interquartile range; MAP,
mean arterial pressure; NSBB, nonselective b blocker; PMN, polymorphonuclear neutrophil; SAP, systemic arterial pressure; SBP, spontaneous bacterial peritonitis.
2014 by the AGA Institute
0016-5085/$36.00
http://dx.doi.org/10.1053/j.gastro.2014.03.005

Nonselective b blockers (NSBBs) have been shown to

reduce the hepatic venous portal pressure gradient by
lowering cardiac output and splanchnic vasoconstriction
through the inhibition of the binding of catecholamines to b1
and b2 adrenoreceptors.4
Based on a broad body of evidence, current guidelines57
recommend NSBB treatment for the prevention of the rst
variceal hemorrhage and rebleeding. NSBBs are among the
most widely used drugs in patients with cirrhosis and have
even been referred to as the aspirin of hepatologists.4
However, the role of b blockers appears to have changed
over the years.4 Although the efcacy of NSBB treatment in
prevention of variceal hemorrhage was established as early
as 1981,8 recent studies suggest additional benecial effects
of NSBB treatment. In patients with compensated cirrhosis,
hemodynamic response to NSBBs has been shown to reduce
the risk of developing ascites, refractory ascites, and hepatorenal syndrome (HRS).9 In addition, NSBB treatment has
been shown to decrease intestinal permeability independently of hemodynamic response10 and to prevent the
development of spontaneous bacterial peritonitis (SBP).11 In
contrast, a recent study by Serste et al12 has demonstrated a
detrimental effect of NSBB treatment in patients with
cirrhosis and refractory ascites and has initiated an intense
debate on whether the use of NSBBs should be contraindicated in this group of patients.
The window hypothesis,13 proposed by Krag et al, is
consistent with these results and implies the existence of a
therapeutic window for NSBB treatment, which closes late
in the natural course of cirrhosis. As meta-analysis has shown
that the reduction of the risk of variceal hemorrhage by NSBB
treatment is signicantly lower among patients with
ascites,14 the end of this therapeutic window might be expected at some point after the rst development of ascites.
The occurrence of bacterial infections, even with recovery, can establish an additional fth stage of cirrhosis, termed
the critically ill patient with cirrhosis.15 These bacterial infections predominately occur in advanced cirrhosis, which is
associated with profound changes in systemic hemodynamics, most importantly peripheral vasodilation with an
impaired responsiveness to vasoconstrictors16 and a simultaneous increase in cardiac output to maintain adequate
organ perfusion.13 However, parallel to the progression of
hyperdynamic circulation, the cardiac compensatory reserve
gradually decreases, resulting in an impaired adaptive
response to acute circulatory stress, such as SBP. Development of SBP has been shown to be associated with pronounced portal and systemic hemodynamic derangements,
as bacteremia has been found to decrease systemic vascular
resistance17 and patients with low cardiac output have been
shown to be at high risk for development of HRS,18 a major
complication of SBP that further reduces survival. In patients
with ascites, impaired cardiac output has been found to be
associated with substantially increased mortality.19
We therefore hypothesized that the development of SBP
closes the window of opportunity for NSBB treatment, as
maintaining the circulatory reserve is crucial in critically ill
patients with cirrhosis. The main adaptive mechanism to
circulatory stress is the increase in heart rate mediated by

b Blockers in Spontaneous Bacterial Peritonitis 1681

b1 adrenoreceptors that are down-regulated and desensitized in patients with advanced cirrhosis.20 Additional
pharmaceutical blockade induces chronotropic incompetence,20 decreases cardiac output,21 and blood pressure and
can increase the rate of HRS development after an SBP
episode, resulting in worse survival.
The aim of this study was to assess the inuence of NSBB
treatment on SBP incidence and the impact of SBP development on the effect of NSBB treatment on hospitalization
and transplant-free survival. In addition, rates of HRS and
acute kidney injury (AKI) development after the rst SBP
diagnosis were assessed in patients with NSBB treatment
and without.

Patients and Methods

Study Design
A total of 607 consecutive patients with cirrhosis who underwent their rst paracentesis at the Medical University of
Vienna between 2006 and 2011, had bacterial cultures from
ascites, and did not display any exclusion criteria, were
included in this retrospective study. Patients with other causes
of ascites, such as severe cardiovascular disease, renal insufciency, extrahepatic malignancies, and noncirrhotic portal
hypertension, were excluded from the study.

Assessed Parameters
Epidemiological characteristics, etiology of cirrhosis, presence of varices, and information on previous variceal bleeding,
as well as follow-up variceal bleeding and liver transplantation,
were assessed from patient medical history. In addition, information on NSBB and rifaximin treatment, as well as systemic
hemodynamics, was obtained from patient medical history. The
following laboratory parameters were assessed at the time
of the rst paracenteses and the rst diagnosis of SBP: platelet
count, albumin, bilirubin, international normalized ratio,
creatinine, and ascitic uid neutrophil count. Hepatic venous
portal pressure gradient measurements were performed as
described previously.22 The model for end-stage liver disease23
and Child-Pugh score (CPS)24 were calculated based on laboratory parameters and patients medical history.

Paracenteses and Diagnosis of Spontaneous

Bacterial Peritonitis
Paracenteses were performed either in a diagnostic or
therapeutic setting. In accordance with national guidelines,5,25
albumin was administered in all large-volume paracenteses.
SBP was diagnosed if the ascitic uid neutrophil count was
>250 mL without an evident intra-abdominal source of infection or another explanation for an elevated ascitic uid
neutrophil count.5,26,27 Patients with SBP were receiving albumin in addition to antibiotic treatment, as recommended by
national guidelines during the full study period.5,25

Diagnosis of Hepatorenal Syndrome and Acute

Kidney Injury
The diagnosis of HRS was established if creatinine levels
increased to >1.5 mg/dL or doubled to a level of >2.5 mg/dL in
the absence of evidence for shock or hypovolemia5,26,27 within

CLINICAL LIVER

June 2014

1682 Mandorfer et al
90 days after the rst SBP diagnosis. Patients with a history of
chronic kidney disease other than HRS or evidence for parenchymal kidney disease, such as proteinuria, microhematuria, or
abnormal renal ultrasonography were excluded from this
analysis.
AKI was diagnosed if a patient fullled the criteria of group
C of the modied AKI classication proposed by Fagundes
et al,28 comprising both stages 2 and 3 of the Acute Kidney
Injury Network criteria.29 AKI was dened as an increase of
serum creatinine >2-fold from baseline or a serum creatinine
4.0 mg/dL with an acute increase >0.5 mg/dL. In addition,
urine output <0.5 mL/kg per hour for >12 hours was
considered as AKI.

Statistics
CLINICAL LIVER

Statistical analyses were conducted using IBM SPSS Statistics 21 (SPSS Inc., Armonk, NY) and R.3.0.1 (R Development
Core Team 2008, The R Foundation for Statistical Computing,
Vienna, Austria). Continuous variables were reported as mean
 standard deviation (SD) or median (interquartile range
[IQR]), and categorical variables were reported as number (n)
of patients with the certain characteristic (proportion of patients with the certain characteristic [%]). Student t test was
used for group comparisons of continuous variables when
applicable. Otherwise, Mann-Whitney U test was applied. Group
comparisons of categorical variables were performed using
either Pearsons c2 or Fishers exact test. The impact of NSBB
treatment on SBP incidence and transplant-free survival was
analyzed using semi-parametric proportional hazard Cox
models. The proportional hazard assumption was veried by
inspecting the cumulative hazard plot for parallel curves.
Patients entered the SBP incidence model (Model 1) with
their rst paracentesis and were followed until their last paracentesis. In liver transplant recipients and in case of death, the
last paracentesis before the liver transplantation or death was
the end of follow-up. Patients who had only one paracentesis,
as well as patients with SBP at their rst paracentesis, were
excluded from this analysis. NSBB treatment and CPS stage
were considered as covariates. In addition, SBP incidence rates
among patients with NSBB treatment, and without, as well as
the SBP incidence rate ratio were calculated.
The rates of follow-up paracentesis and variceal bleeding
after the rst paracentesis were calculated for NSBB and noNSBB patients. Similarly, follow-up paracentesis and bleeding
rates after the rst development of SBP were calculated.
Patients entered the rst transplant-free survival model
(Model 2) with their rst paracentesis and were followed until
2013. Transplant-free survival time was dened as the time to
liver transplantation, death, or end of follow-up. Patients who
received a liver transplantation were censored at the day of
surgery. Besides NSBB treatment, the model included presence
of varices, CPS stage, and SBP status as covariates. The latter
variable was treated as a time-dependent covariate in the
following fashion: The rst development of SBP in patients
without SBP at the rst paracentesis separated the follow-up
into 2 adjoining time intervals. In the rst (right censored)
interval the SBP status is negative, and it is positive in the
second (left or interval censored) time period. To assess the
modulating effect of SBP development on the impact of NSBB
treatment on transplant-free survival, the interaction term
NSBB  SBP was incorporated into the model.

Gastroenterology Vol. 146, No. 7

A second transplant-free survival model (Model 3)
restricted to SBP patients was calculated with patients entering
the model with the rst development of SBP and NSBB treatment, presence of varices and CPS stage at the time of SBP
diagnosis as covariates. Kaplan-Meier curves are shown for all
models.
P values <.05 were considered as statistically signicant.
No adjustment for multiplicity was performed.

Ethics
This study was conducted in accordance with the Declaration of Helsinki and approved by the local ethics committee of
the Medical University of Vienna (EK Nr. 1008/2011).

Results
Patient Characteristics and Systemic
Hemodynamics at the First Paracentesis
Except for a higher proportion of female subjects (NSBB:
34% vs no-NSSB: 27%; P .048) and patients with varices
(NSBB: 90% vs no-NSBB: 62%; P < .001) in the NSBB group,
no statistically signicant differences in patient characteristics between patients with NSBB treatment, and without,
were observed (Table 1).
Although the mean heart rate (NSBB: 77.5  16.5 beats/
min vs no-NSBB: 83.9  15.5 beats/min; P < .001) and systolic arterial pressure (SAP) (NSBB: 114  18 vs no-NSBB:
117  18 mm Hg; P .05) (Figure 1) were lower among
patients with NSBB treatment than in patients without, no
differences in diastolic arterial pressure (DAP) and mean
arterial pressure (MAP) (Figure 1B) were observed. The
proportion of hemodynamically compromised patients, as
dened by a SAP <100 mm Hg (NSBB: 18% vs no-NSBB: 15%;
P .391) (Figure 1C) or an MAP <82 mm Hg (NSBB: 39% vs
no-NSBB: 38%; P .757) (Figure 1D), was comparable between the NSBB treatment groups at the rst paracentesis.
In the NSBB group, daily propranolol doses ranged between 20 mg and 120 mg (20 mg: 10%, 30 mg: 4%, 40 mg:
25%, 50 mg: 1%; 60 mg: 12%; 80 mg: 17%, 100 mg: 1%,
120 mg: 4%), and the administered carvedilol doses ranged
between 6.25 mg and 25 mg (6.25 mg: 7%, 12.5 mg: 18%,
25 mg: 3%).

Inuence of Nonselective b Blocker Treatment on

Spontaneous Bacterial Peritonitis Incidence
NSBB treatment (hazard ratio [HR] 0.699; 95% condence interval [CI]: 0.4271.146; P .156) and CPS stage
(stage B: HR 1.211; 95% CI: 0.2835.192; P .796 and
stage C: HR 2.033; 95% CI: 0.4858.519; P .332) were
not associated with SBP incidence in univariate analysis
(Model 1, Supplementary Figure 1).
In multivariate analysis, neither NSBB treatment (HR
0.728; 95% CI: 0.4221.198; P .211), nor CPS stage (stage
B: HR 1.082; 95% CI: 0.254.686; P .916 and stage C:
HR 1.792; 95% CI: 0.4227.611; P .429) were associated
with SBP development (Model 1, Supplementary Figure 1).
SBP incidence rates were comparable between patients
with (0.107 per person-year; 95% CI: 0.0710.15) and

At the rst paracentesis

All (n 607)

Age, y, mean  SD
Sex, n (%)
Male
Female
Etiology, n (%)
ALD
Viral
ALD and viral
Other
HCC, n (%)
Previous variceal bleeding, n (%)
Varices, n (%)
HVPG, mm Hg, mean  SD
MELD, median (IQR)/mean  SD
CPS stage, n (%)
A
B
C
Platelet count, 109/L, median (IQR)
Albumin, g/L, mean  SD
Bilirubin, mg/dL, median (IQR)
INR, median (IQR)
Creatinine, mg/dL, median (IQR)
Rifaximin treatment, n (%)
Any
Before rst paracentesis
After the rst paracentesis
Heart rate, beats/min, mean  SD
SAP, mm Hg, mean  SD
SAP <100 mm Hg, n (%)
DAP, mm Hg, mean  SD
MAP, mm Hg, mean  SD
MAP <82 mm Hg, n (%)

57.5  11.8
426 (70)
181 (30)

No NSBB (n 362)
57.2  12.1

NSBB (n 245)
58  11.2

265 (73)
97 (27)

161 (66)
84 (34)

336 (55)
113 (19)
49 (8)
109 (18)
129 (21)
98 (16)
443 (73)
18.7  6.5a
17.5 (10.6)

192 (53)
70 (19)
27 (7)
73 (20)
74 (20)
54 (15)
223 (62)
18.3  7.1
17.8 (11)

144 (59)
43 (18)
22 (9)
36 (15)
55 (22)
44 (18)
220 (90)
19  5.8
17.2 (9.9)

22
281
304
117
27.2
3.2
1.38
1.14

13 (4)
166 (46)
183 (51)
117 (108)
27  5.4
3.05 (6.98)
1.41 (1.19)
1.14 (0.83)

9
115
121
120
27.6
3.05
1.41
1.14

36 (10)
8 (2)
34 (9)
83.9  15.5
117  18
55 (15)
71  12.5
86.2  13.2
135 (38)

33 (14)
6 (2)
29 (12)
77.5  16.5
114  18
43 (18)
69.8  12.4
84.4  13.2
93 (39)

P value
.438
.048

All (n 182)

No NSBB (n 96)

NSBB (n 86)

57.7  11.1

58.1  10.5

57.3  11.8

76 (79)
20 (21)

58 (67)
28 (33)

134 (74)
48 (26)
.264

(4)
(46)
(50)
(107)
 5.7
(6.02)
(0.58)
(0.78)

69 (11)
14 (2)
63 (10)
81.2  16.2c
115  18e
98 (16)e
70.5  12.5
85.4  13.3
228 (38)

(4)
(47)
(49)
(107)
 6.1
(5.98)
(0.58)
(0.83)

.553
.318
<.001
.398
.422
.961

.912
.231
.623
.262
.288
.18
.847
.333
<.001
.05
.391
.263
.112
.757

P value
.655
.073

.07
94 (52)
43 (24)
14 (8)
31 (17)
46 (25)
37 (20)
139 (76)
19.3  6.6b
20.8  9

42 (44)
25 (26)
11 (11)
18 (19)
25 (26)
17 (18)
58 (60)
19.1  7.3
20  8.7

52
18
3
13
21
20
81
19.5
21.6

(60)
(21)
(4)
(15)
(24)
(23)
(94)
 5.8
 9.3

6 (3)
67 (37)
109 (60)
118 (97)
27.1  5.9
3.61 (5.8)
1.41 (0.71)
1.39 (1.26)

3
42
51
119
27.5
3
1.41
1.4

3
25
58
118
26.6
5.11
1.39
1.34

(4)
(29)
(67)
(111)
 6.3
(9.32)
(0.69)
(1.31)

23 (13)
9 (5)
21 (12)
79.4  15.7d
109  18
50 (27)
65.7  12.5
80.1  13
97 (53%)

14 (15)
4 (4)
13 (14)
82.9  15.7
113  18
17 (18)
67.3  12.5
82.6  12.5
42 (44)

(3)
(44)
(53)
(86)
 5.6
(5)
(0.74)
(1.2)

9 (11)
5 (6)
8 (9)
76.2  15.2
104  17
33 (38)
63.8  12.3
77.2  13.1
55 (64)

.801
.353
<.001
.806
.241
.107

.36
.315
.024
.534
.876
.404
.609
.371
.027
<.001
.002
.06
.005
.006

ALD, alcoholic liver disease; CPS, Child-Pugh score; DAP, diastolic arterial pressure; HCC, hepatocellular carcinoma; HVPG, hepatic venous pressure gradient; INR,
international normalized ratio; MAP, mean arterial pressure; MELD model for end-stage liver disease; SAP, systolic arterial pressure.
a
Available in 220 patients.
b
Available in 82 patients.
c
Available in 395 patients.
d
Available in 109 patients.
e
Available in 595 patients.

CLINICAL LIVER

b Blockers in Spontaneous Bacterial Peritonitis 1683

Patient characteristics

At the rst development of SBP

June 2014

Table 1.Patient Characteristics at the First Paracentesis and at the First Development of Spontaneous Bacterial Peritonitis and Comparison of Patients With and Without
Nonselective b Blocker Treatment

1684 Mandorfer et al

Gastroenterology Vol. 146, No. 7

CLINICAL LIVER

Figure 1. Effect of NSBB

treatment on (A) systolic
arterial pressure (SAP), (B)
mean arterial pressure
(MAP) and the proportion
of hemodynamically comprised patients with (C)
SAP <100 mmHg and (D)
MAP <82 mmHg at the
time of the rst paracentesis and the rst SBP
development.

without NSBB treatment (0.117 per person-year; 95% CI:

0.0840.156), with an incidence rate ratio of 0.915 (95% CI:
0.5651.483).

Inuence of Nonselective b Blocker Treatment on

Spontaneous Bacterial Peritonitis Development,
Paracentesis and Variceal Bleeding Rates,
Hospitalization as Well as Transplant-Free
Survival
A total of 607 patients were followed for 660 personyears after their rst paracentesis. There was a trend toward a lower paracentesis rate among patients with (2.45
per person-year; 95% CI: 2.272.63), when compared with
patients without NSBB treatment (2.76 per person-year;
95% CI: 2.62.94).
Thirty-three episodes of variceal bleeding were observed
during follow-up. Bleeding rates were comparable between
patients with (0.059 per person-year; 95% CI: 0.0340.068)
and without NSBB treatment (0.043 per person-year; 95%
CI: 0.0250.067). The proportions of patients receiving a
liver transplant were 12% and 10% in the NSBB and noNSBB group, respectively (P .46).
After their rst paracentesis, patients with NSBB treatment were hospitalized for 26.7 days per person-year (95%
CI: 26.127.3), and patients without NSBB treatment were
hospitalized for 30.9 days per person-year (95% CI:
30.431.5). Although the duration of elective hospitalizations was similar (NSBB: 7.37 days per person-year; 95% CI:
7.077.69 vs no-NSBB: 6.98 days per person-year; 95% CI:

6.727.26), the duration of nonelective hospitalization was

lower among patients with (19.4 days per person-year; 95%
CI: 18.919.9) when compared with patients without NSBB
treatment (23.9 days per person-year; 95% CI: 23.424.4).
NSBB treatment was associated with higher transplantfree survival (HR 0.771; 95% CI: 0.5980.993; P .044)
in multivariate analysis, when adjusting for the presence of
varices (HR 0.983; 95% CI: 0.7831.235; P .886), CPS
stage (stage B: HR 1.134; 95% CI: 0.6152.09; P .687 and
stage C: HR 2.24; 95% CI: 1.2224.107; P .009), and
SBP development (HR 1.401; 95% CI: 1.0561.857;
P .019) (Model 2, Table 2). In addition, the interaction term
NSBB  SBP (HR 1.917; 95% CI: 1.2562.924; P .003)
was statistically signicantly associated with transplant-free
survival. This suggests that the development of SBP modulates the effect of NSBB treatment on transplant-free survival
warranting additional subgroup analysis.

Impact of Spontaneous Bacterial Peritonitis

Development on the Effect of Nonselective b
Blocker Treatment on Transplant-Free Survival
Up to the development of SBP, NSBB treatment had a
benecial effect on transplant-free survival (HR 0.75;
95% CI: 0.5810.968; P .027) when adjusting for the
presence of varices and CPS stage (Model 2, Table 2,
Figure 2A) and was associated with a reduction in mortality
risk of 25%. In contrast, once a patient developed SBP, NSBB
treatment was associated with lower transplant-free survival (HR 1.58; 95% CI: 1.0982.274; P .014) when

b Blockers in Spontaneous Bacterial Peritonitis 1685

June 2014

Table 2.Impact of Spontaneous Bacterial Peritonitis Development on the Effect of Nonselective b Blocker Treatment on
Transplant-Free Survival (Model 2): Univariate and Multivariate Analyses Including All patients and Multivariate
Analysis According to Spontaneous Bacterial Peritonitis Status

Patient characteristics

HR

Varices, yes
CPS stage B
CPS stage C
SBP, yes
NSBB, yes
NSBB  SBP

1.047
1.076
2.203
1.893
0.945

Varices, yes
CPS stage B
CPS stage C
NSBB, yes

1.112
0.934
1.778
0.75

Lower

Upper

Univariate (n 607)
0.841
1.303
0.584
1.983
1.203
4.035
1.538
2.328
0.775
1.152
Multivariate, no-SBP (n 493)
0.846
1.46
0.455
1.916
0.872
3.625
0.581
0.968

adjusting for the same variables (Model 2, Table 2,

Figure 2B). NSBB treatment was associated with an increase
of 58% in mortality risk once a patient developed SBP.

Patient Characteristics and Systemic

Hemodynamics at First Development of
Spontaneous Bacterial Peritonitis
A total of 182 patients developed at least one SBP
episode. Comparing NSBB and no-NSBB patient characteristics revealed no statistically signicant differences except
for a higher prevalence of varices (NSBB, 94% vs no-NSBB,
60%; P < .001) and higher median bilirubin levels (NSBB:
5.11 mg/dL [IQR, 9.32 mg/dL] vs no-NSBB: 3 mg/dL [IQR, 5
mg/dL]; P .024) in the NSBB group. In addition, there was
a trend toward a higher proportion of female patients
(NSBB: 33% vs no-NSBB: 21%; P .073), as well as patients
with alcoholic etiology (NSBB: 60% vs no-NSBB: 44%;
P .07) and CPS stage C (NSBB: 67% vs no-NSBB: 53%;
P .107) among patients with NSBB treatment.
Patients with NSBB treatment had a lower mean heart
rate (NSBB: 76.2  15.2 beats/min vs no-NSBB: 82.9  15.7

Figure 2. Impact of NSBB

treatment on transplantfree survival according to
SBP
status.
Patients
without SBP at rst diagnosis started in (A) (noSBP), while Patients with
SBP at the rst paracentesis started in (B)
(SBP). At the rst SBP
diagnosis, patients were
censored in (A) (no-SBP),
entered (B) (SBP), and
remained in this group.

95% CI
P value

HR

.682
.814
.011
<.001
.578

0.983
1.134
2.24
1.401
0.771
1.917

.447
.852
.113
.027

0.703
1.71
3.717
1.58

Lower

Upper

Multivariate (n 607)
0.783
1.235
0.615
2.09
1.222
4.107
1.056
1.857
0.598
0.993
1.256
2.924
Multivariate, SBP (n 182)
0.462
1.068
0.527
5.552
1.157
11.946
1.098
2.274

P value
.886
.687
.009
.019
.044
.003
.098
.372
.028
.014

beats/min; P .027), SAP (NSBB: 104  17 mm Hg vs

no-NSBB: 113  18 mm Hg; P < .001) (Figure 1A), and MAP
(NSBB: 77.2  13.1 mm Hg vs no-NSBB: 82.6  12.5 mm Hg;
P .005) (Figure 1B). In addition, DAP tended to be lower
among patients with NSBB treatment (NSBB: 63.8  12.3 mm
Hg vs no-NSBB: 67.3  12.5 mm Hg; P .06). Similarly, the
proportion of patients with SAP <100 mm Hg (NSBB: 38% vs
no-NSBB:18%; P .002) (Figure 1C) or MAP <82 mm Hg
(NSBB: 64% vs no-NSBB:44%; P .006) (Figure 1D) was
substantially higher among patients with NSBB treatment.

Impact of Nonselective b Blocker Treatment on

Paracentesis and Variceal Bleeding Rates,
Hospitalization as Well as Transplant-Free
Survival After the First Spontaneous Bacterial
Peritonitis Diagnosis
After SBP development, 182 patients were followed for a
total of 147 person-years. The paracentesis rate was comparable between no-NSBB (3.67 per person-year; 95% CI:
3.294.08) and NSBB patients (3.36 per person-year; 95%
CI: 2.93.84).

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95% CI

1686 Mandorfer et al

Gastroenterology Vol. 146, No. 7

CLINICAL LIVER

Thirteen episodes of variceal bleeding were observed

after the rst SBP diagnosis. Bleeding rates were similar
among patients with (0.086 per person-year; 95% CI:
0.0280.175) and without NSBB treatment (0.09 per personyear; 95% CI: 0.0390.162). In addition, the proportion of
patients receiving a liver transplantation did not vary statistically signicantly throughout the NSBB treatment groups
(no-NSBB: 9% vs NSBB: 13%; P .462).
After the rst diagnosis of SBP, the duration of hospitalization was higher in the NSBB group (NSBB: 33.4 days
per person-year; 95% CI: 31.934.9 vs no-NSBB: 28.8 days
per person-year; 95% CI: 27.629.9). The duration of elective hospitalizations was comparable between both treatment groups (NSBB: 3.6 days per person-year; 95% CI:
3.14.1 vs no-NSBB: 3.9 days per person-year; 95% CI:
3.54.3). In contrast, a higher duration of nonelective hospitalizations was observed in the NSBB group (NSBB: 29.6
days per person-year; 95% CI: 28.231 vs no-NSBB: 23.7
days per person-year; 95% CI: 22.724.8).
In multivariate analysis, NSBB treatment was associated
with impaired transplant-free survival after SBP diagnosis
(HR 1.644; 95% CI: 1.1452.361; P .007), after adjusting
for CPS stage (stage B: HR 1.642; 95% CI: 0.5075.314;
P .408; stage C: HR 3.318; 95% CI: 1.03610.627;
P .043) and the presence of varices (HR 0.695; 95% CI:
0.457-1.057; P .089) at the time of SBP development
(Model 3, Table 3, Figure 3). Rates of transplant-free survival
after SBP development are shown in Table 3.

Inuence of Nonselective b Blocker Treatment on

Hepatorenal Syndrome and Acute Kidney Injury
Development After the First Spontaneous
Bacterial Peritonitis Diagnosis
A total of 11 patients were excluded from the analysis
of HRS development because of evidence for shock, hypovolemia, or chronic kidney disease other than HRS. In
addition, 6 patients without HRS, liver transplantation, or

Figure 3. Inuence of NSBB treatment on transplant-free

survival after the rst SBP diagnosis.

death were excluded because of a follow-up period of <90

days after the rst SBP diagnosis. Among the remaining
165 patients, HRS was observed in 18% (29 of 165) of
patients within 90 days after the SBP diagnosis. The rate of
HRS development was signicantly higher in patients with
(24% [20 of 83]) when compared with patients without
NSBB treatment (11% [9 of 82]; P .027) (Figure 4).
Eighty percent (16 of 20) of patients with NSBB treatment
developing HRS died within 90 days after the HRS
diagnosis.
Six patients without HRS, liver transplantation, or death
were excluded from the analysis of AKI development because
of a follow-up period of <90 days after the rst SBP diagnosis. Grade C AKI was observed in 14% (24 of 176) of the
patients included in this analysis. Patients with NSBB treatment (20% [17 of 86]) showed a higher rate of grade C AKI
development when compared with patients without NSBB

Table 3.Inuence of Nonselective b Blocker Treatment on Transplant-Free Survival After the First Spontaneous Bacterial
Peritonitis Diagnosis (Model 3) and Survival Rates After Spontaneous Bacterial Peritonitis Development
95% CI
HR
Patient characteristics
Varices, yes
CPS stage B
CPS stage C
NSBB, yes

0.97
1.478
2.954
1.539

Lower

Upper

Univariate (n 182)
0.657
1.432
0.459
4.757
0.932
9.365
1.095
2.164

95% CI
P value
.88
.512
.066
.013

HR
0.695
1.642
3.318
1.644

no-NSBB (n 96)
Estimate
Time point
1 month
6 month
12 month

0.713
0.495
0.358

95% CI
Lower
0.627
0.403
0.271

Upper
0.81
0.608
0.472

Lower

Upper

Multivariate (n 182)
0.457
1.057
0.507
5.314
1.036
10.627
1.145
2.361
NSBB (n 86)

Estimate

0.566
0.279
0.227

95% CI
Lower
0.47
0.198
0.152

Upper
0.682
0.393
0.338

P value
.089
.408
.043
.007

Figure 4. Inuence of NSBB treatment on HRS and grade C

AKI development within 90 days after the rst SBP diagnosis.

treatment (8% [7 of 90]; P .021) (Figure 4). Eighty-eight

percent (15 of 17) of patients with NSBB treatment did not
survive the 90-day period after grade C AKI development.

Discussion
A recent landmark study by Serste et al12 demonstrated
reduced survival in patients with refractory ascites who were
treated with NSBBs and has initiated a lively debate among
gastroenterologists on the appropriate use of NSBBs in patients with advanced cirrhosis. In summary, the editorial30
and various other responses to this study brought up concerns about the unequal distribution of esophageal varices
between the NSBB and no-NSBB group. In addition, the
trends toward a higher prevalence of CPS stage C and HCC in
patients with NSBB treatment31,32 and the lack of consecutive
patient enrollment33 were highlighted as factors signicantly
limiting the conclusions drawn within the study. We aimed to
address these limitations in our study by adjusting for the
presence of varices in all analyses of transplant-free survival.
In addition, all analyses were adjusted for CPS stage, as at the
rst SBP diagnosis, there was a trend toward a lower prevalence of CPS stage B and a higher prevalence of CPS stage C
among patients with NSBB treatment. Except for a higher
proportion of females in the NSBB group at the rst paracentesis and higher bilirubin levels in the NSBB group at the
rst SBP diagnosis, no other statistically signicant differences in patient characteristics were observed. In order to
avoid multicollinearity, bilirubin was not considered as a
covariate, as it is a component of the CPS. As our study
population comprises consecutive patients meeting the inclusion and exclusion criteria of this study, our results are
based on a large, representative cohort treated at a single
academic center.
Another response by Senzolo et al11 addressed a potential benecial effect of NSBB treatment on SBP development, highlighting a positive meta-analysis by the same
author.11 In our study, no statistically signicant effect of
NSBB treatment on SBP incidence was observed. As patients who had only one paracentesis and patients with
SBP at their rst paracentesis were excluded and the

b Blockers in Spontaneous Bacterial Peritonitis 1687

follow-up duration was limited to the last paracentesis for

statistical reasons, a lack of statistical power of Model 1 to
detect a clinically signicant effect of NSBB treatment on
SBP development cannot be excluded. However, these
limitations do not apply to the analyses of SBP incidence
rates, which were comparable between patients with and
without NSBB treatment. The proportion of CPS stage C
patients in our study was substantially higher when
compared with previous studies designed for the assessment of the effect of NSBB treatment on variceal
bleeding,13 and all patients included in our study had
previously developed ascites. As NSBB treatment has been
shown to reduce the risk of developing ascites in patients
with compensated cirrhosis,9 the overall effect of NSBB
treatment initiated before the rst decompensation cannot
be assessed in our study. Our results provide a rationale
for additional meta-analyses assessing the effect of NSBB
treatment on SBP development in patients with more
advanced stages of cirrhosis.
Nearly half of the patients included in the study by
Serste et al12 received a comparatively high daily propranolol dose of 160 mg. In a consecutive crossover study,
propranolol treatment was found to be associated with a
higher risk for paracentesis-induced circulatory dysfunction
in patients with refractory ascites and cirrhosis.34 Seven of
10 patients included in this study received 160 mg propranolol. Because high NSBB doses have profound effects on
systemic circulation and might not be well tolerated by
hemodynamically compromised patients, such as patients
with advanced cirrhosis, Robins et al35 suggested that the
use of lower NSBB doses is safe among patients with refractory ascites. In contrast, substantially lower NSBB doses
were administered in our study. However, carvedilol might
not only be more efcient in decreasing portal pressure by
additional a1 adrenoreceptor inhibition,36,37 it might also
lead to a more pronounced decrease in MAP.36
The efcacy of NSBB treatment for the prevention of
variceal bleeding has primarily been studied in patients
without ascites, and meta-analysis suggests that the benecial effect in the prevention of variceal bleeding might be
lower among patients with ascites.14 The characteristics or
our study population might explain the low rates of variceal
bleeding during follow-up observed in our study. There was
a signicant proportion of patients without varices in the
no-NSBB group, and the proportion of patients with previous variceal bleeding included in this study was low. When
comparing bleeding rates between patients with and
without NSBB treatment, the unequal distribution of varices
has to be considered.
Patients with more advanced liver disease, such as patients with cirrhosis and refractory ascites or bacterial infections have yet not been specically addressed in clinical
trials investigating the effectiveness of NSBB treatment.4
Our study assessed the effect of NSBB treatment in a
cohort of patients with cirrhosis undergoing their rst
paracentesis and considered the incidence of SBP as a timedependent covariate. Thus, our study comprised an internal
control group of patients with ascites who yet have not
developed SBP. This study design is in accordance with the

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1688 Mandorfer et al

CLINICAL LIVER

common understanding of cirrhosis as a dynamic process

and facilitates the design of prospective studies to validate
our observations. Although up to the development of SBP,
NSBB treatment had a benecial effect on transplant-free
survival and was associated with a reduction in mortality
risk of 25%, transplant-free survival was worse in SBP patients receiving NSBB treatment with an increase in mortality risk of 58%. We also conrmed this observation in an
additional analysis with patients entering the model with
the rst development of SBP. These observations suggest
that NSBB treatment should be discontinued at the rst
development of SBP, raising the question of whether to
permanently discontinue or to restart NSBB treatment after
resolving the SBP episode. Based on the slope of the KaplanMeier curves, the higher hazard in the NSBB patients was
limited to the rst 6 months after SBP development, with
curves converging toward the end of follow-up. However,
this observational data must be interpreted with caution, as
signicant bias can arise from the high rate of early mortality observed in the NSBB group, leading to the selection of
patients with better prognosis and therefore lower hazard
or with improvement of hepatic function during follow-up.
In addition, the development of additional SBP episodes
was not considered in this model. Arvaniti et al have
demonstrated that following the occurrence of bacterial
infections, 30% of patients with cirrhosis patients die within
1 month, and another 30% die within 1 year.15 The development of bacterial infections might dene a distinct group
of critically ill patients with cirrhosis with a highly restricted
prognosis in which maintaining the circulatory reserve is
crucial not only during the acute phase of infection but also
later on. This hypothesis is supported by recent data on
mortality in patients with cirrhosis admitted to the intensive
care unit for severe sepsis or septic shock in which NSBB
treatment was discontinued during the period of hemodynamic instability. Although intensive care unit mortality was
comparable, higher mortality rates at 3 and 6 months were
observed among patients discharged from the intensive care
unit with re-established NSBB treatment.38
Similar to our observations on transplant-free survival,
NSBB treatment had a detrimental effect on nonelective and
overall hospitalization after SBP development. NSBB treatment might not only lead to increased mortality, but also to
increased morbidity and burden of disease in this subgroup
of patients.
NSBB treatment had only a moderate effect on systemic
hemodynamics at the time of the rst paracentesis and
therefore did not increase the proportion of hemodynamically compromised patients. In contrast, at the time of the
rst SBP diagnosis, there was a substantially increased proportion of hemodynamically compromised patients in the
NSBB group, dened as SAP <100 mm Hg or MAP <82 mm
Hg. MAP <82 mm Hg39 or impaired cardiac output19 have
been found to be associated with substantially increased
mortality in patients with cirrhosis or both cirrhosis and
ascites, respectively. Also, patients with SBP and low cardiac
output have been shown to be at high risk for HRS,18 and
NSBB treatment has previously been found to further deteriorate cardiac output in patients with cirrhosis.21 These

Gastroenterology Vol. 146, No. 7

results provide a pathophysiologic explanation for the

detrimental effect of NSBB treatment after SBP development,
compromising systemic hemodynamics and predisposing for
HRS and AKI development, as observed in our study population. Our study supports previous hypotheses with observational data.40,41 Because we only considered group C AKI in
our analyses, there was a substantial overlap of AKI and HRS.
However, the proportion of patients who fullled the criteria
for group C AKI was numerically smaller than the proportion
of patients with HRS, which might be explained by the
restrictive time criterion included in the diagnostic criteria of
AKI and the higher creatinine increase threshold for the
diagnosis of group C AKI.
The main limitations of our study arise from the retrospective design. As patients have not been prospectively
followed, drug adherence and intermittent interruptions in
NSBB treatment cannot be ruled out entirely. However, the
benecial effect of transplant-free survival in the no-SBP
group can serve as an internal validation for our approach.
This is the rst study to provide observational evidence
for the detrimental effect of NSBB treatment after SBP
development. It supports the pathophysiologically compelling window hypothesis by Krag et al,13 dening SBP as a
clinical event that closes the therapeutic window for NSBB
treatment. However, whether the therapeutic window for
NSBB treatment reopens after resolving the SBP episode
remains unclear. Prospective studies are highly encouraged
to investigate the appropriate, stage-dependent use of this
cornerstone in the treatment of portal hypertension.

Supplementary Material
Note: To access the supplementary material accompanying
this article, visit the online version of Gastroenterology at
www.gastrojournal.org, and at http://dx.doi.org/10.1053/
j.gastro.2014.03.005.

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Author names in bold designate shared co-rst authors.

Gastroenterology Vol. 146, No. 7

Received December 23, 2013. Accepted March 7, 2014.
Reprint requests
Address requests for reprints to: Thomas Reiberger, MD, Division of
Gastroenterology and Hepatology, Department of Internal Medicine III,
Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna,
Austria. e-mail: thomas.reiberger@meduniwien.ac.at; fax: (43) 1 40400 4735.
Conicts of interest
The authors disclose no conicts.

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June 2014

Supplementary Figure 1. Inuence of NSBB treatment on

SBP incidence.

b Blockers in Spontaneous Bacterial Peritonitis 1690.e1