Deleterious Effects of Beta-Blockers on Survival in

Patients With Cirrhosis and Refractory Ascites

Thomas Serste ,
1,2,3
Christian Melot,
4
Claire Francoz,
1,2,5
Franc ois Durand,
1,2,5
Pierre-Emmanuel Rautou,
1,2
Dominique Valla,
1,2,5
Richard Moreau,
1,2,5*
and Didier Lebrec,
1,2,5*
Beta-blockers may have a negative impact on survival in patients with cirrhosis and refrac-
tory ascites. The aim of this study was to evaluate the effect of the administration of beta-
blockers on long-termsurvival in patients with cirrhosis and refractory ascites. We performed
a single-center, observational, case-only, prospective study of patients with cirrhosis and re-
fractory ascites who did or did not receive beta-blockers for the prevention of gastrointestinal
bleeding; 151 patients were included. The mean Model for End-Stage Liver Disease score was
18.8 6 4.1. All patients regularly underwent large-volume paracentesis and intravenous al-
bumin administration. Seventy-seven patients (51%) were treated with propranolol (113 6
46 mg/day). The median follow-up for the whole group was 8 months. The median survival
time was 10 months [95% condence interval (CI) 58-12 months]. The probability of sur-
vival at 1 year was 41% (95% CI 5 33%-49%). The clinical characteristics and laboratory
values at enrolment were not signicantly different between patients who were receiving pro-
pranolol and those who were not. The median survival time was 20.0 months (95% CI 5
4.8-35.2 months) in patients not treated with propranolol and 5.0 months (95% CI 5 3.5-
6.5 months) in those treated with propranolol (P 5 0.0001). The 1-year probability of sur-
vival was signicantly lower in patients who received propranolol [19% (95% CI 5 9%-
29%)] versus those who did not [64%(95%CI 552%-76%), P < 0.0001]. The independent
variables of mortality were Child-Pugh class C, hyponatremia and renal failure as causes of
refractory ascites, and beta-blocker therapy. Conclusion: The use of beta-blockers is associ-
ated with poor survival in patients with refractory ascites. These results suggest that beta-
blockers should be contraindicated in these patients. (HEPATOLOGY 2010;00:000-000)
R
efractory ascites occurs in less than 10% of
patients with cirrhosis and ascites.
1
Refractory
ascites is dened as a lack of response to high
doses of diuretics or as the recurrence of side effects
when lower doses of diuretics are given.
2,3
Patients with
refractory ascites have a poor outcome.
2-4
The rst-line
treatment for refractory ascites is repeated large-volume
paracentesis.
2-4
In patients with cirrhosis, the adminis-
tration of nonselective beta-blockers for the prevention
of gastrointestinal hemorrhaging is frequent when
esophageal varices are present.
5-7
However, this treat-
ment may have deleterious effects on patients with asci-
tes treated by large-volume paracentesis. In particular, it
may contribute to limiting the compensatory increase
in cardiac output.
8,9
The aim of the present study was
to evaluate the effect of the administration of nonselec-
tive beta-blockers on long-term survival in patients with
cirrhosis and refractory ascites. In addition, the predic-
tive factors of mortality in these patients were studied.
Patients and Methods
Study Population. The study was a single-center,
observational, case-only, prospective study. From
Abbreviations: CI, condence interval; HR, hazard ratio; HVPG, hepatic
venous pressure gradient; MELD, Model for End-Stage Liver Disease; MELD-
Na, Model for End-Stage Liver Disease with sodium.
From the
1
Institut National de la Santeet de la Recherche Medicale Unite773,
Centre de Recherche Biomedicale Bichat Beaujon, Paris, France;
2
Service
dHepatologie, Hopital Beaujon, Clichy, France;
3
Hepato-Gastroenterologie,
Hopital Saint-Pierre, Bruxelles, Belgium;
4
Service des Urgences, Hopital
Universitaire Erasme, Bruxelles, Belgium; and
5
Universite Denis Diderot-Paris
7, Site Bichat, France.
Received March 23, 2010; accepted May 11, 2010.
*These authors contributed equally to this work.
Richard Moreau received an Interface Institut National de la Sante et de la
Recherche Medicale/Assistance PubliqueHopitaux de Paris fellowship.
Address reprint requests to: Didier Lebrec, INSERM, Hopital Beaujon, 110
Boulevard du General Leclerc, 92118 Clichy, France. E-mail: didier.lebrec@
inserm.fr.
Copyright VC
2010 by the American Association for the Study of Liver Diseases.
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hep.23775
Potential conict of interest: Nothing to report.
1
January 2004 to December 2008, all consecutive
patients who had cirrhosis, were older than 18 years,
and were admitted to our liver unit for refractory ascites
were studied. The criteria for refractory ascites were
based on International Ascites Club criteria.
2,3
Patients
were considered to have refractory ascites when they
had either diuretic-resistant or diuretic-intractable asci-
tes. Refractory ascites was qualied as diuretic-resistant
when ascites could not be stabilized despite intensive di-
uretic therapy (e.g., 400 mg of spironolactone with 160
mg of furosemide per day) associated with dietary so-
dium restriction (90 mmol of sodium per day). Refrac-
tory ascites was qualied as diuretic-intractable when
metabolic disturbances made it impossible to adminis-
ter or increase diuretic therapy. For the purpose of this
study, these metabolic abnormalities were diuretic-
induced hepatic encephalopathy, hyponatremia (dened
as a serum sodium level 125 mmol/L), renal impair-
ment (dened as a serum creatinine level 1.5 mg/
dL), and abnormal serum potassium levels (dened as a
serum potassium level 3 or 6 mmol/L).
The time of entry into the study was the date on
which the criteria for refractory ascites were rst ful-
lled. Patients were divided into two groups according
to whether they were receiving beta-blockers or not.
Study Variables. The following information was
collected at entry: demographic data, etiology of cir-
rhosis, physical examination ndings, biochemical val-
ues, Child-Pugh score, Model for End-Stage Liver Dis-
ease (MELD) score, presence of diabetes, and type of
treatment. In addition, because both the MELD score
and serum sodium levels were available for all patients,
the newly described Model for End-Stage Liver Disease
with sodium (MELD-Na) score
10
was calculated. The
hospital course, laboratory values, and outcomes (renal
dysfunction development, liver transplantation, or
death) were determined during regular follow-up.
Wedged and free hepatic venous pressures were meas-
ured, and the hepatic venous pressure gradient
(HVPG) was calculated for 27 patients receiving beta-
blockers and for 29 patients who did not receive beta-
blockers.
Statistical Analysis. Continuous data that were not
normally distributed are reported as median and ranges
(minimum to maximum). The distribution of the vari-
ables was tested with the Shapiro-Wilk test. Group
comparisons were made with the Wilcoxon-Mann-
Whitney test. Categorical variables are reported as
counts and percentages. Group comparisons were
made with the v
2
test or Fishers exact test. Survival
was assessed with the Kaplan-Meier nonparametric sur-
vivorship function, and group comparisons were made
with the log-rank test. Univariate and multivariate Cox
regression analyses were performed to detect the inde-
pendent predictors of survival. In all survival analyses,
the follow-up period ended either on the day of the
last visit for nontransplant patients or on the day of
transplantation for transplant patients. The multivari-
ate model was built with the backward elimination
technique with P < 0.10 for entering the model and
P < 0.05 for staying in the model. The results are pre-
sented as crude hazard ratios (HRs) with 95% con-
dence intervals (CIs) in univariate analyses and as
adjusted HRs with 95% CIs in multivariate analyses.
Crude HRs indicate the relationship between mortality
and a single predictor. Adjusted HRs indicate the rela-
tionship between mortality and a predictor and take
into account the other independent predictors. A P
value < 0.05 was considered signicant. Analyses were
performed with the PASW statistical package (SPSS
version 18.0, SPSS, Chicago, IL).
Results
Characteristics of the Patients. A total of 151
patients were enrolled. Clinical characteristics, bio-
chemical values, and treatment at inclusion are sum-
marized in Table 1. One hundred four patients
(68.9%) had diuretic-intractable ascites: renal dysfunc-
tion was found at entry in 46 patients (30.5%), and
hyponatremia was found in 58 patients (38.4%).
None of the patients had diuretic-intractable ascites
due to abnormal serum potassium levels. Forty-seven
patients (31.1%) had diuretic-resistant ascites. All
patients were regularly treated with large-volume para-
centesis and intravenous albumin. Seventy-seven
patients (51%) were treated with nonselective beta-
blockers (propranolol) for the prevention of gastroin-
testinal hemorrhage. Among these patients, 9 (11.7%)
were given 40 mg of propranolol per day, 31 (40.3%)
were given 80 mg, 1 (1.3%) was given 120 mg, and
36 (46.7%) were given 160 mg.
Outcome and Follow-Up of the Whole Group of
Patients. The median follow-up time was 8 months
(1-47 months). The median survival time was 10
months (95% CI 8-12 months). The probability of
survival was 41% at 1 year (95% CI 33%-49%)
and 28% at 2 years (95% CI 20%-36%; Fig. 1).
Ninety-seven patients (64.2%) died. Causes of death
were sepsis in 50 patients (spontaneous bacterial peri-
tonitis in 11 cases) and progression of hepatocellular
carcinoma in 13. Twenty-ve patients died at home of
unspecied causes. Twenty-six patients underwent liver
transplantation during the study period.
2 SERSTE

ET AL. HEPATOLOGY, Month 2010

Outcome According to Beta-Blocker Therapy. At
enrollment, no signicant difference was observed
between the two groups except for serum bilirubin and
esophageal varices, which were present in all patients
treated with beta-blockers and in only three patients in
the other group (Table 1). The frequency of paracente-
sis was not signicantly different between patients
treated with beta-blockers (2.0 6 1.1 per month) and
those who were not (2.0 6 1.8 per month). The heart
rate and arterial pressure were also signicantly differ-
ent between the two groups. The HVPG was not sig-
nicantly different between the two groups; it was
20.0 6 4.5 mm Hg in patients treated with beta-
blockers and 19.1 6 5.0 mm Hg in those who were
not (P 0.49).
Sixty-three patients treated with beta-blockers died,
and 34 patients died in the other group. The median
survival time was 5.0 months (95% CI 3.5-6.5
months) in patients treated with beta-blockers and
20.0 months (95% CI 4.8-35.2 months) in patients
Table 1. Patient Characteristics at Enrollment
Whole Group (n 5 151) NoBeta-Blocker Group (n 5 74) Beta-Blocker Group (n 5 77) P Value
Gender, male 122 (80.8) 60 (81.1) 62 (80.5) 0.93
Age, years 60.4 6 11.8 59.8 6 11.4 60.9 6 12.2 0.56
Weight, kg* 75.0 (40-132) 75.5 (51-132) 74 (40-103) 0.87
Heart rate, bpm 70 (54-89) 77 (63-89) 65 (54-79) <0.0001
Arterial systolic pressure, mm Hg 114 (91-139) 123 (11-139) 103 (91-119) <0.0001
Arterial diastolic pressure, mm Hg 73 (55-89) 73 (64-89) 73 (55-89) 0.95
Cause of cirrhosis 0.32
Hepatitis C virus 30 (19.9) 13 (17.6) 17 (22.1)
Hepatitis B virus 17 (11.3) 5 (6.8) 12 (15.6)
Alcoholic 85 (56.3) 49 (66.2) 36 (46.8)
Child-Pugh score 0.083
B 49 (32.5) 29 (39.2) 20 (26.0)
C 102 (67.5) 45 (60.8) 57 (74.0)
MELD score 18.8 6 4.1 18.9 6 4.2 18.8 6 4.0 0.89
MELD-Na score* 22 (11-31) 22 (11-31) 22 (14-30) 0.69
Presence of hepatocellular carcinoma 41 (27.2) 17 (23) 24 (31.2) 0.26
Presence of esophageal varices 74 (49) 3 (4.1) 77 (100) <0.001
Presence of hepatic encephalopathy 57 (37.8) 24 (32.4) 33 (42.8) 0.38
Diabetes 32 (21.2) 15 (20.3) 17 (22.1) 0.78
Prothrombin time, % of normal 45 (30-90) 45 (31-90) 45 (30-90) 0.69
International normalized ratio 1.80 (1.00-2.50) 1.8 (1-2.5) 1.8 (1.0-2.5) 0.15
Platelet count, 10
3
/mm
3
78 (27-359) 74 (29-359) 78 (27-270) 0.92
White cell count, 10
3
/mm
3
6.8 (0.25-26) 6.9 (0.34-26) 6.7 (0.25-12.3) 0.69
Creatinine, mg/dL 0.89 (0.42-3.40) 0.86 (0.45-3.40) 0.89 (0.42-2.56) 0.83
Renal dysfunction 51 (33.8) 30 (41) 21 (27.3) 0.07
Serum sodium, mmol/L 132 (112-145) 133 (118-140) 125 (112-145) 0.09
Serum potassium, mmol/L 4 (2.5-5.4) 4.1 (2.5-5.1) 4.0 (2.9-5.4) 0.29
Total bilirubin, mg/dL 53 (11-340) 48 (11-340) 56 (17-125) 0.01
Serum albumin, g/L 28 (4-47) 29 (20-42) 26 (4-47) 0.12
Aspartate aminotransferase, U/L 56 (21-360) 54 (21-360) 58 (22-142) 0.16
Alanine aminotransferase, U/L 48 (11-183) 45 (12-183) 49 (11-156) 0.68
Ascitic uid protein concentration, g/L 11 (0.9-25) 12 (0.9-22) 11 (0.9-25) 0.12
Data are presented as n (%), mean 6 standard deviation, or median (range), unless otherwise indicated. The MELD-Na score was calculated according to Kim
et al.
10
*Median (95% CI).
Fig. 1. Kaplan-Meier curve for the survival of the 151 patients with
cirrhosis and refractory ascites.
HEPATOLOGY, Vol. 000, No. 000, 2010 SERSTE

ET AL. 3
not treated with beta-blockers. The difference was sig-
nicant between the two groups (P < 0.0001).
In patients not treated with beta-blockers, the 1-year
probability of survival was 64% (95% CI 52%-
76%), and in patients treated with beta-blockers, it was
19% (95% CI 9%-29%; Fig. 2). In patients not
treated with beta-blockers, the 2-year probability of sur-
vival was 45% (95% CI 31%-59%), and in patients
treated with beta-blockers, it was 9% (95% CI 0%-
19%; Fig. 2). The differences were signicantly differ-
ent (P < 0.0001). The causes of death were not signi-
cantly different between the two groups.
Factors Associated With Mortality. Results of the
univariate analysis of factors associated with mortality
are found in Table 2. Signicant univariate predictors
of death were introduced into the multivariate Cox
regression model. The independent factors predicting
death were the presence of hepatocellular carcinoma,
Child-Pugh class C, underlying etiologies of refractory
ascites, and beta-blocker therapy (Fig. 3).
Fig. 2. Kaplan-Meier curves for the survival of patients with cirrhosis
and refractory ascites who received beta-blockers and those who did
not.
Table 2. Univariate Cox Regression Predicting Mortality
(Crude HRs with 95% CIs)
Variable HR (95% CI) P Value
Age, years 1.02 (1.00-1.03) 0.0402
MELD-Na score 1.11 (1.01-1.21) 0.0254
Esophageal varices, presence of 2.11 (1.70-2.61) <0.0001
Beta-blockers, presence of 4.00 (2.58-6.20) <0.0001
Child-Pugh class C 2.41 (1.51-3.85) 0.0002
Hepatocellular carcinoma, presence of 2.13 (1.39-3.26) 0.0005
Cause of cirrhosis 1.15 (1.05-1.25) 0.0028
Prothrombin time, % of normal 0.98 (0.96-0.99) 0.0132
International normalized ratio 2.46 (1.44-4.20) 0.0010
Serum bilirubin concentration, mg/dL 1.01 (1.00-1.01) 0.0201
Etiology of refractory ascites 3.03 (2.28-4.02) <0.0001
Renal impairment 3.10 (1.65-5.85) 0.0005
Severe hyponatremia (125 mEq/L) 9.26 (5.05-16.98) <0.0001
Ascitic uid protein concentration, g/L 0.93 (0.88-0.98) 0.0072
Serum sodium concentration, mEq/L 0.92 (0.89-0.95) <0.0001
Heart rate, bpm 0.94 (0.91-0.96) <0.0001
Arterial systolic blood pressure, mm Hg 0.97 (0.95-0.98) <0.0001
Fig. 3. Independent predictors of death in the Cox multivariate regression. Filled squares indicate point estimates (with the area proportional
to the number of events). Horizontal lines indicate 95% CIs. The different etiologies of refractory ascites have been divided into the subcategories
renal impairment (HR 3.27) and hyponatremia (dened as a sodium level 125 mmol/L; HR 7.07), with maximal diuretic treatment
used as the reference category (not shown; HR 1).
4 SERSTE

ET AL. HEPATOLOGY, Month 2010

Discussion
The present prospective observational study shows
that patients with cirrhosis and refractory ascites who
were treated with beta-blockers had a signicantly
higher mortality rate than those who were not. In addi-
tion, the median survival time was four times lower in
the group with beta-blockers versus the group without
beta-blockers. This difference was highly signicant.
The median survival time for all patients was 10
months, and this period was similar to those observed
in previous studies.
11,12
There is no clear explanation
for our nding of deleterious effects of beta-blocker
treatment on mortality in patients with cirrhosis and re-
fractory ascites. However, certain comments can be
made. In fact, the effects of beta-blocker treatment in
these patients have never been studied. Only one meta-
analysis of four trials of beta-blockers in the prevention
of initial episodes of gastrointestinal bleeding has been
reported, and it showed that advanced cirrhosis and
especially the presence of ascites were associated with
death in both treated and untreated patients and that
the mortality rate in the treated group was signicantly
lower than that in the placebo group.
13
Patients with
refractory ascites were not, however, included in these
four trials. In the present series of patients, the severity
of cirrhosis estimated by the Child-Pugh score and
MELD score and the etiology of cirrhosis were not dif-
ferent between the two groups. The degree of portal
hypertension estimated by the HVPG also does not
explain the difference in mortality because the HVPG
values were not different between the two groups. The
slightly elevated serum bilirubin levels observed in
patients treated with beta-blockers suggest subtle differ-
ences in liver function but cannot explain the higher
mortality rate in beta-blockertreated patients. Simi-
larly, the presence of esophageal varices in treated
patients does not seem to explain the higher mortality
rate in this group. Although the occurrence of varices is
associated with the severity of cirrhosis, in this study,
the severity of cirrhosis was similar in the two groups.
In contrast, the low arterial pressure measured in
patients treated with beta-blockers may explain, at least
in part, the higher mortality rate because it has been
shown that low arterial pressure is an independent pre-
dictor of death in patients with cirrhosis and ascites.
14
In the present study, our nding of low arterial pressure
in patients with refractory ascites treated with beta-
blockers is in contrast to observations in most patients
with cirrhosis, in whom beta-blockers have no effect on
arterial pressure.
15
The relationship between low arterial
pressures and mortality risk, independent of the severity
of cirrhosis, remains, however, to be determined.
Finally, beta-blocker administration may contribute to
the development of postparacentesis-induced circulatory
dysfunction, a syndrome associated with low survival in
patients with cirrhosis and tense ascites.
16-19
In patients
with cirrhosis treated with beta-blockers, the develop-
ment of the postparacentesis circulatory dysfunction
may be secondary to the limitation of increased cardiac
output. The survival rate in patients with refractory as-
cites and esophageal varices treated by band ligation is
unknown. If beta-blockers are responsible for postpara-
centesis-induced circulatory dysfunction, the survival
rate of patients treated by band ligation should be bet-
ter than that of those treated with beta-blockers. The
present study, however, makes it impossible to respond
to this hypothesis and indicates that studies are needed
to compare the two groups of treated patients.
Multivariate analysis showed that there were four in-
dependent predictors of death for the whole group of
patients: the presence of hepatocellular carcinoma,
Child-Pugh score class C, underlying etiologies of re-
fractory ascites, and beta-blocker therapy. It should be
emphasized that, unlike the Child-Pugh score, neither
the MELD score nor the MELD-Na score was able to
predict mortality in patients with cirrhosis and refrac-
tory ascites. In fact, in this series of patients, the
MELD score was relatively low, whereas more than
two-thirds of the patients had Child-Pugh class C cir-
rhosis. The discordance between these two prognostic
indicators may be explained by the fact that ascites is
taken into account in the Child-Pugh score but not in
the MELD score.
20,21
In fact, patients with refractory
ascites may have an elevated or low MELD score.
Thus, the risk of premature death in patients with cir-
rhosis, refractory ascites, and preserved liver function is
underestimated by the MELD score.
21,22
In other
words, the MELD score cannot be used to predict
mortality in patients with cirrhosis and refractory asci-
tes. Because there is a strong correlation between the
presence of ascites and hyponatremia in patients with
cirrhosis, previous studies have shown that the serum
sodium concentration has an independent prognostic
value.
23,24
Several alternative models have suggested
that the incorporation of sodium into the MELD
score provides a more accurate prediction of survival
than the MELD score alone in patient with asci-
tes.
10,23
However, these new models do not take into
account ascites itself and have been developed only for
patients on the list for liver transplantation.
In multivariate analysis, severe hyponatremia (a rea-
son for not using diuretic therapy) was a signicant
predictor of mortality. Even if hyponatremia has been
HEPATOLOGY, Vol. 000, No. 000, 2010 SERSTE

ET AL. 5
clearly identied as a poor prognostic factor in cirrho-
sis,
21,23,25,26
the exact relationship between hyponatre-
mia and the prognosis of cirrhosis remains unclear.
Hyponatremia could be a reection of systemic hemo-
dynamic disorders related to the severity of cirrhosis.
11
In addition, renal impairment (a reason for not using
diuretic therapy) was an independent predictor of
mortality. Renal impairment is known to be an indica-
tor of poor prognosis in cirrhosis.
4
Together, these
ndings suggest that diuretic-intractable refractory asci-
tes (due to severe hyponatremia or renal impairment)
may be worse than diuretic-resistant refractory ascites.
In conclusion, the present study shows that the use
of nonselective beta-blockers is associated with poor
survival in patients with cirrhosis and refractory ascites
and suggests that these drugs should be contraindi-
cated in these patients. This study also shows that the
Child-Pugh score (but not MELD score) is a predic-
tive factor of mortality in patients with cirrhosis and
refractory ascites.
References
1. Stanley MM, Ochi S, Lee KK, Nemchausky BA, Greenlee HB, Allen
JI, et al. Peritoneovenous shunting as compared with medical treatment
in patients with alcoholic cirrhosis and massive ascites. Veterans Admin-
istration Cooperative Study on Treatment of Alcoholic Cirrhosis with
Ascites. N Engl J Med 1989;321:1632-1638.
2. Arroyo V, Gines P, Gerbes AL, Dudley FJ, Gentilini P, Laf G, et al.
Denition and diagnostic criteria of refractory ascites and hepatorenal
syndrome in cirrhosis. International Ascites Club. HEPATOLOGY 1996;
23:164-176.
3. Moore KP, Wong F, Gines P, Bernardi M, Ochs A, Salerno F, et al.
The management of ascites in cirrhosis: report on the consensus confer-
ence of the International Ascites Club. HEPATOLOGY 2003;38:258-266.
4. Gine`s P, Cardenas A, Arroyo V, Rodes J. Management of cirrhosis and
ascites. N Engl J Med 2004;350:1646-1654.
5. Lebrec D. Pharmacological treatment of portal hypertension: present
and future. J Hepatol 1998;28:896-907.
6. de Franchis R. Updating consensus in portal hypertension: report of
the Baveno III consensus workshop of denitions, methodology and
therapeutic strategies in portal hypertension. J Hepatol 2000;33:
846-852.
7. Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W. Prevention and man-
agement of gastroesophageal varices and variceal hemorrhage in cirrho-
sis. HEPATOLOGY 2007;46:922-938.
8. Vila MC, Sola R, Molina L, Andreu M, Coll S, Gana J, et al. Hemo-
dynamic changes in patients developing effective hypovolemia after
total paracentesis. J Hepatol 1998;28:639-645.
9. Moreau R, Asselah T, Condat B, de Kerguenec C, Pessione F, Bernard
B, et al. Comparison of the effect of terlipressin and albumin on arte-
rial blood volume in patients with cirrhosis and tense ascites treated by
paracentesis: a randomised pilot study. Gut 2002;50:90-94.
10. Kim WR, Biggins SW, Kremers WK, Wiesner RH, Kamath PS, Ben-
son JT, et al. Hyponatremia and mortality among patients on the liver-
transplant waiting list. N Engl J Med 2008;359:1018-1026.
11. Moreau R, Delegue P, Pessione F, Hillaire S, Durand F, Lebrec D,
et al. Clinical characteristics and outcome of patients with cirrhosis and
refractory ascites. Liver Int 2004;24:457-464.
12. Salerno F, Camma C, Enea M, Rossle M, Wong F. Transjugular intra-
hepatic portosystemic shunt for refractory ascites: a meta-analysis of
individual patient data. Gastroenterology 2007;133:825-834.
13. Poynard T, Cales P, Pasta L, Ideo G, Pascal JP, Pagliaro L, et al. Beta-
adrenergic-antagonist drugs in the prevention of gastrointestinal bleed-
ing in patients with cirrhosis and esophageal varices. An analysis of
data and prognostic factors in 589 patients from four randomized clini-
cal trials. N Engl J Med 1991;324:1532-1538.
14. Llach J, Gines P, Arroyo V, Rimola A, Tito L, Badalamenti S, et al.
Prognostic value of arterial pressure, endogenous vasoactive systems,
and renal function in cirrhotic patients admitted to the hospital for the
treatment of ascites. Gastroenterology 1988;94:482-487.
15. Lebrec D, Hillon P, Munoz C, Goldfarb G, Nouel O, Benhamou JP.
The effect of propranolol on portal hypertension in patients with cir-
rhosis: a hemodynamic study. HEPATOLOGY 1982;2:523-527.
16. Ruiz-del-Arbol L, Monescillo A, Arocena C, Valer P, Gines P, Moreira
V, et al. Circulatory function and hepatorenal syndrome in cirrhosis.
HEPATOLOGY 2005;42:439-447.
17. Pozzi M, Osculati G, Boari G, Serboli P, Colombo P, Lambrughi C,
et al. Time course of circulatory and humoral effects of rapid total par-
acentesis in cirrhotic patients with tense, refractory ascites. Gastroenter-
ology 1994;106:709-719.
18. Panos MZ, Moore K, Vlavianos P, Chambers JB, Anderson JV, Gimson
AE, et al. Single, total paracentesis for tense ascites: sequential hemody-
namic changes and right atrial size. HEPATOLOGY 1990;11:662-667.
19. Gines A, Fernandez-Esparrach G, Monescillo A, Vila C, Domenech E,
Abecasis R, et al. Randomized trial comparing albumin, dextran 70,
and polygeline in cirrhotic patients with ascites treated by paracentesis.
Gastroenterology 1996;111:1002-1010.
20. Durand F, Valla D. Assessment of the prognosis of cirrhosis: Child-
Pugh versus MELD. J Hepatol 2005;42(Suppl):S100-S107.
21. Heuman DM, Abou-Assi SG, Habib A, Williams LM, Stravitz RT,
Sanyal AJ, et al. Persistent ascites and low serum sodium identify
patients with cirrhosis and low MELD scores who are at high risk for
early death. HEPATOLOGY 2004;40:802-810.
22. Biggins SW, Kim WR, Terrault NA, Saab S, Balan V, Schiano T, et al.
Evidence-based incorporation of serum sodium concentration into
MELD. Gastroenterology 2006;130:1652-1660.
23. Biggins SW, Rodriguez HJ, Bacchetti P, Bass NM, Roberts JP, Terrault
NA. Serum sodium predicts mortality in patients listed for liver trans-
plantation. HEPATOLOGY 2005;41:32-39.
24. Londono MC, Cardenas A, Guevara M, Quinto L, de Las Heras D,
Navasa M, et al. MELD score and serum sodium in the prediction of
survival of patients with cirrhosis awaiting liver transplantation. Gut
2007;56:1283-1290.
25. Luca A, Angermayr B, Bertolini G, Koenig F, Vizzini G, Ploner M,
et al. An integrated MELD model including serum sodium and age
improves the prediction of early mortality in patients with cirrhosis.
Liver Transpl 2007;13:1174-1180.
26. Angeli P, Wong F, Watson H, Gines P. Hyponatremia in cirrhosis: results
of a patient population survey. HEPATOLOGY 2006;44:1535-1542.
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ET AL. HEPATOLOGY, Month 2010