Albumin Infusion in Patients Undergoing Large-Volume

Paracentesis: A Meta-Analysis of Randomized Trials

Mauro Bernardi,1 Paolo Caraceni,1 Roberta J. Navickis,2 and Mahlon M. Wilkes2

Albumin infusion reduces the incidence of postparacentesis circulatory dysfunction among

patients with cirrhosis and tense ascites, as compared with no treatment. Treatment alter-
natives to albumin, such as artificial colloids and vasoconstrictors, have been widely inves-
tigated. The aim of this meta-analysis was to determine whether morbidity and mortality
differ between patients receiving albumin versus alternative treatments. The meta-analysis
included randomized trials evaluating albumin infusion in patients with tense ascites. Pri-
mary endpoints were postparacentesis circulatory dysfunction, hyponatremia, and mortality.
Eligible trials were sought by multiple methods, including computer searches of biblio-
graphic and abstract databases and the Cochrane Library. Results were quantitatively com-
bined under a fixed-effects model. Seventeen trials with 1,225 total patients were included.
There was no evidence of heterogeneity or publication bias. Compared with alternative treat-
ments, albumin reduced the incidence of postparacentesis circulatory dysfunction (odds ratio
[OR], 0.39; 95% confidence interval [CI], 0.27-0.55). Significant reductions in that compli-
cation by albumin were also shown in subgroup analyses versus each of the other volume
expanders tested (e.g., dextran, gelatin, hydroxyethyl starch, and hypertonic saline). The
occurrence of hyponatremia was also decreased by albumin, compared with alternative treat-
ments (OR, 0.58; 95% CI, 0.39-0.87). In addition, mortality was lower in patients receiving
albumin than alternative treatments (OR, 0.64; 95% CI, 0.41-0.98). Conclusions: This meta-
analysis provides evidence that albumin reduces morbidity and mortality among patients
with tense ascites undergoing large-volume paracentesis, as compared with alternative treat-
ments investigated thus far. (HEPATOLOGY 2012;55:1172-1181)

patients with cirrhosis and ascites.3 Therapeutic para-

A
scites, the most common major complication of
cirrhosis, is associated with a poor prognosis.1
As ascites progresses, abdominal distension
becomes more marked, and in the advanced grades, the
patient can experience major discomfort and impaired
breathing, often necessitating hospitalization.2 Spontane-
ous bacterial peritonitis develops in 25%-30% of
Abbreviations: CI, 95% confidence interval; LVP, large-volume paracentesis;
OR, odds ratio; PCD, postparacentesis circulatory dysfunction; RAAS, renin-
angiotensin-aldosterone system; RCT, randomized, controlled trial; SNS,
sympathetic nervous system.
1
Dipartimento di Medicina Clinica, Alma Mater Studiorum–Universita` di
Bologna, Semeiotica Medica–Policlinico S. Orsola-Malpighi, Bologna, Italy; and
2
Hygeia Associates, Grass Valley, CA.
Received August 16, 2011; accepted October 15, 2011.
This investigation was supported through an unrestricted grant from CSL
Behring, King of Prussia, PA.
Address reprint requests to: Mauro Bernardi, M.D., Dipartimento di
Medicina Clinica, Alma Mater Studiorum–Universita` di Bologna, Semeiotica
Medica–Policlinico S. Orsola-Malpighi, Via Albertoni 15, I-40138 Bologna,
Italy. E-mail: mauro.bernardi@unibo.it; fax: (þ39) 051 636 2930.
Copyright VC 2011 by the American Association for the Study of Liver Diseases.
View this article online at wileyonlinelibrary.com.
DOI 10.1002/hep.24786
Potential conflict of interest: Dr. Navickis and Dr. Wilkes received grants
from CSL Behring.
1172
centesis has become the first line of treatment for
patients with tense (i.e., grade 3) and refractory asci-
tes.4-6 Large-volume paracentesis (LVP) is faster and less
likely to exert unwanted side effects than diuretics.7,8
One drawback of LVP without adjunctive treatment is
the associated risk of postparacentesis circulatory dysfunc-
tion (PCD). Even before paracentesis, patients with asci-
tes are subject to marked circulatory dysfunction, most
notably splanchnic arteriolar vasodilation, hyperdynamic
circulation, and decreased effective arterial blood volume.
Accompanying activation of the renin-angiotensin-aldo-
sterone system (RAAS) and sympathetic nervous system
(SNS) and increase in antidiuretic hormone levels result
in sodium and water retention and renal vasoconstriction.
Paracentesis substantially influences systemic hemo-
dynamics.9 In the majority of patients not receiving
adjunctive treatment, removal of large ascitic fluid
volumes, by reducing intra-abdominal pressure, boosts
venous return to the heart. As a result, right atrial
pressure decreases and cardiac output and stroke vol-
ume increase. However, because of an excessive drop
in peripheral vascular resistance, effective circulating

HEPATOLOGY, Vol. 55, No. 4, 2012
volume further declines, leading to a reduction in arte-
rial pressure.10-12 In the days after paracentesis, a pro-
nounced reactivation of RAAS and SNS ensues that can
persist for months. These events represent the pathophys-
iological background of PCD, which is usually defined as
an increase in plasma renin activity of 50% or greater.
This complication is associated with a high rate of ascites
recurrence, development of hepatorenal syndrome, dilu-
tional hyponatremia, and decrease in survival.13,14
It was first demonstrated in the 1980s that adjunc-
tive albumin infusion favorably influences circulatory
function after LVP and prevents the subsequent reacti-
vation of vasoconstrictor systems and occurrence of
PCD.2 The value of adjunctive albumin treatment in
this setting has been recognized in both European and
American clinical practice guidelines, which recom-
mend the administration of albumin when the volume
of ascites removed during paracentesis exceeds 5 L.4-6
Since the early 1990s, less-costly alternatives to albu-
min have been sought, such as artificial colloid volume
expanders and vasoconstrictors. Despite numerous
randomized trials, it remains uncertain whether the
effectiveness of such alternative treatments is compara-
ble to that of albumin. This uncertainty, in part,
reflects the limited size and statistical power of the
randomized trials reported so far. Quantitatively com-
bining results of all relevant trials by meta-analysis
could help resolve this uncertainty. The aim of this
meta-analysis was to determine the comparative effective-
ness of albumin and alternative treatments in minimizing
PCD, hyponatremia, and mortality among ascites
patients undergoing LVP. The specific null hypothesis
tested was that the effects of albumin infusion in cir-
rhotic patients with tense ascites undergoing LVP are
equivalent to those of alternative treatments.
Materials and Methods
The primary endpoints of the meta-analysis were
PCD, hyponatremia, and mortality. Secondary end-
points consisted of ascites recurrence, renal impair-
ment, hepatic encephalopathy, portal hypertensive
bleeding, and hospital readmission. A subsidiary aim
was to quantify, as precisely as possible, the magnitude
of albumin effects versus no treatment.
Study Selection. Randomized, controlled trials
(RCTs) were eligible for inclusion if they specifically
evaluated albumin in the acute treatment of cirrhotic
patients with tense ascites undergoing LVP and fur-
nished data for one or more primary endpoints of the
meta-analysis. Eligible trials could compare LVP plus
albumin with LVP plus an alternative treatment, such
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BERNARDI ET AL. 1173
as another volume expander or a vasoconstrictor. Trials
assessing the combined effect of LVP plus albumin
versus a control drug, such as diuretic, or nonparacent-
esis procedure, such as shunting, were not eligible. Tri-
als with ascites fluid withdrawal, concentration by
ultrafiltration ex vivo, and reinfusion of the concentrate
as the control treatment were excluded. To quantify
the effect size of albumin, compared with no treat-
ment, trials were also sought that evaluated LVP plus
albumin versus LVP without adjunctive treatment.
Both published and unpublished trials could be
included, and no limitations were placed on trial size,
time period, or language of reporting.
Search Strategy. Eligible trials were identified by
multiple methods, including computer searches of
MEDLINE, EMBASE, the Cochrane Library, the
ClinicalTrials.gov website, and the abstract databases
from major meetings in hepatology. Full-text searches
with the Google search engine were also performed.
Search terms included the following: ascites; cirrhosis;
paracentesis; albumin; colloid; dextran; gelatin; hydrox-
yethyl starch; HES; saline; crystalloid; vasoconstrictor;
terlipressin; midodrine; norepinephrine; postparacente-
sis circulatory dysfunction; plasma renin activity; hypo-
natremia; mortality; survival; and RCTs. Roots and
variants of the search terms were also sought. Refer-
ence lists in primary study publications and review
articles were examined and online contents of specialty
journals in hepatology were consulted.
Data Extraction. Determinations of trial eligibility
and extraction of data were performed independently
by at least two investigators. In the case of differences
in interpretation, consensus was reached through dis-
cussion. The investigators, time periods, patients, and
methods were closely compared between candidate trial
reports to avoid inclusion of redundant data and
ensure the most complete possible data set. Data
extracted from the trial reports included, as available,
numbers of patients allocated to each study group,
year of reporting, methods of randomization, alloca-
tion concealment, and blinding, duration of follow-up,
age, gender, baseline serum albumin level, indication
for treatment, refractoriness of ascites to treatment,
Child-Pugh score, etiology of cirrhosis, baseline renal
dysfunction, albumin and control treatment regimens,
concomitant diuretics, type of paracentesis and volume
of ascites fluid removed, study definitions of PCD,
hyponatremia, and renal impairment, day of PCD assess-
ment, numbers of patients developing PCD, hyponatre-
mia, renal impairment, hepatic encephalopathy, or
portal hypertensive bleeding, experiencing ascites recur-
rence, or requiring hospital readmission, mortality, and
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1174 BERNARDI ET AL. HEPATOLOGY, April 2012

criterion for statistical significance. Subgroup analyses

were performed on the effects of trial quality, as judged
by the randomization method, allocation concealment,
and blinding.16 All analyses were performed using R ver-
sion 2.13.0 (The R Foundation for Statistical Comput-
ing, Vienna, Austria) statistical software.

Fig. 1. Process of RCT selection.
numbers of patients at risk for each outcome. Indi-
vidual patient and summary data reported in the
form of graphical displays were captured by computer
digitization.
Statistical Analysis. Heterogeneity was assessed by
the Cochran Q test and the I2 statistic. Publication bias
was evaluated by linear regression of standardized effect
versus precision.15 In the analysis of publication bias,
precision was defined as the inverse of the standard error.
Upon confirmation that significant heterogeneity was
absent, trials were combined under a fixed-effects model,
and the pooled odds ratio (OR) and its 95% confidence
interval (CI) were computed. The significance of effect
size differences between subgroups was determined by
meta-regression. An a level of 0.05 was adopted as the
Results
Included Trials. The process of RCT selection for
the meta-analysis is outlined in Fig. 1. After the
screening of 126 candidate clinical study reports, 41
reports were examined in detail. The most common
reasons for the exclusion of reports at that stage were
ineligible control treatment (e.g., concentrated ascitic
fluid) or a study design that did not specifically test the
effect of albumin on outcome (e.g., paracentesis þ
albumin versus diuretics or shunting). Seventeen candi-
date RCTs reported from 1988 to 2010 with 1,225
total patients met all selection criteria and were included
in the meta-analysis.2,17-32 None was unpublished. The
median number of patients per trial was 54, with an
interquartile range of 40-88. In three trials, more than
100 patients each were enrolled (Table 1).
The mean age of the study population ranged from
46.9 to 61.4 years. The pooled mean proportion of
male patients enrolled was 73.6% (range, 60.0%-
90.0%). In 11 of the 17 RCTs, mean baseline serum
albumin ranged from 26 to 29 g
L1 (Table 1). The
respective minium and maximum values for the
remaining RCTs were 20.9 and 31.9 g
L1. In two tri-
als, ascites was characterized as refractory.18,32
Renal dysfunction and gastrointestinal bleeding were
study-exclusion criteria in all 17 trials. Nonetheless, in

Table 1. Included Trials*

Trial n Age (Years) Serum Albumin (g
L1) Ascites Volume Removed (L) Control
2
Ginès et al., 1988 105 57.0 29.0 11.9 No treatment
Planas et al., 199017 88 59.0 27.7 9.4 6% dextran 70
Salerno et al., 199118 54 54.4 31.4 8.6 3.5% gelatin
Fassio et al., 199219 41 54.0 26.5 11.9 6% dextran 70
Garcı́a-Compeán et al., 199320 35 55.9 20.9 8.3 No treatment
Luca et al., 199521 18 58.5 26.0 8.8 No treatment
Ginès et al., 199622 289 57.7 26.3 7.8 6% dextran 70 or 3.5% gelatin
Altman et al., 199823 60 56.0 26.8 7.1 6% HES 200/0.62
Garcı́a-Compeán et al., 200224 96 58.0 29.5 5.5 10% dextran 40
Moreau et al., 200225 20 54.0 29.0 5.5 3 mg terlipressin
Sola-Vera et al., 200326 72 61.4 26.1 6.4 3.5% saline
Moreau et al., 200627 68 55.1 25.4 — 3.5% gelatin
Singh et al., 200628 40 48.2 27.0 7.0 0.5-3 mg norepinephrine
Singh et al., 200629 40 47.0 26.2 5.9 3 mg terlipressin
Appenrodt et al., 200830 24 56.3 23.0 6.2 12.5 mg midodrine TID
Singh et al., 200831 40 46.9 31.9 6.3 5-10 mg midodrine TID
Abdel-Khalek and Arif, 201032 135 47.0 29.0 15.9 6% HES 200/0.5

*Presented data for serum albumin are at baseline. Age, serum albumin, and ascites volume values are pooled means for the total study populations. Abbrevi-
ations: HES, hydroxyethyl starch; TID, three times daily.

HEPATOLOGY, Vol. 55, No. 4, 2012
six trials, at least some degree of renal dysfunction was
present at baseline in 9.7%-35.1% of patients. Other
common patient-exclusion criteria were infection,
including spontaneous bacterial peritonitis and sepsis,
in 16 trials, liver cancer in 14, hepatic encephalopathy
in 13, low prothrombin activity percentage (<25%-
40%) or prolonged prothrombin time in 11, thrombo-
cytopenia (<30,000-50,000 mm3) in 10, marked
hyperbilirubinemia (>5-10 mg
dL1) in eight, and
severe hyponatremia (<120-125 mEq
L1) in four.
Mean Child-Pugh score was reported for 11 trials,
and values ranged from 8.8 to 11.0. Alcoholism was
the etiology of cirrhosis for a pooled mean 71.3% of
patients enrolled in the included trials (range, 38.9%-
94.1%).
Random numbers from a table or computer-generated
sequence were used for randomization in 10 trials.
Method of randomization was not indicated for the
remaining seven trials. Concealment of allocation to
randomized groups was adequate for five trials and was
unspecified for 12. Both the physician and patient
were blinded in two trials and the laboratory in one.
Blinding procedures, if any, were not described for any
of the remaining trials.
Diuretics were discontinued before study treatment
in 16 trials, whereas in the remaining trial, the pre-
study diuretic regimen could be continued without
change. Total paracentesis was performed in 13 trials
and repeated LVP in three. Type of paracentesis was
unspecified for one trial. The mean volume of ascites
fluid removed during paracentesis ranged from 5.5 to
15.9 L (Table 1).
In 12 trials, albumin was administered at a dose of 8
g per L ascites fluid removed. The dose in two trials
was 6 g
L1, and in one trial each 5 g
L1, 10 g
L1
and, depending on ascites volume removed, 7-10 g
L1.
The concentration of albumin infused was 20% in 12
trials, 25% in one trial, and unspecified in four trials.
The control group received no treatment in three
trials, an artificial colloid or hypertonic saline in nine
trials, or a vasoconstrictor in five. The nine trials com-
paring albumin with other volume expanders formed
the predominant category, accounting for 74% (903 of
1,225) of all patients in the meta-analysis, compared
with 13% each for trials with no treatment or vasco-
constrictor as the control regimen. Artificial colloids
were the control volume expanders in eight of nine tri-
als, namely, dextran in three trials, gelatin in two trials,
either of those two artificial colloids in one trial, and
hydroxyethyl starch in two trials. In only one trial did
hypertonic (3.5%) saline serve as the control volume
expander. Vasoconstrictors evaluated in the control
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BERNARDI ET AL. 1175
group were terlipressin and midodrine in two trials
each and norepinephrine in one trial.
Length of follow-up was reported for eight trials.
Median follow-up for those eight trials was 76 days
(range, 6-426).
PCD. Data for the PCD endpoint were available
from all the included trials except one.27 Across all 16
included trials with PCD data, there was no significant
heterogeneity (P ¼ 0.31; I2, 12.8%) or detectable pub-
lication bias (P ¼ 0.87).
Among the three trials comparing albumin with no
treatment,2,20,21 31 of the 44 untreated control patients
(72.7%) developed PCD, compared with 7 of 41 albu-
min recipients (17.1%). In these trials, albumin reduced
the odds of PCD by 93% (pooled OR, 0.07; CI, 0.02-
0.22). The OR for each of the three individual trials
were remarkably consistent: 0.07 (CI, 0.02-0.28),2 0.07
(CI, 0.00-1.50),20 and 0.08 (CI, 0.01-0.75).21
Thirteen trials comparing albumin with alternative
treatments provided PCD data (Fig. 2). Across those
trials, 148 of 471 patients receiving other treatments
(31.4%) developed PCD, compared with 58 of 386
albumin-treated patients (15.0%). Albumin reduced
the odds of PCD by 61% versus alternative treat-
ments. In subgroup analyses, the reductions in odds of
PCD by albumin were comparable across strata
defined by age, refractory ascites, baseline serum albu-
min level, type of control volume expander, day of
PCD assessment, paracentesis regimen, ascites volume
removed, trial quality, control group mortality, and
time period (Table 2).
The effects of albumin versus other volume expan-
ders were highly consistent, with OR for all eight trials
in this subgroup falling within the comparatively tight
range of 0.17-0.80 (Fig. 2). Albumin significantly
reduced the odds of PCD, in comparison with each of
the four other volume expanders evaluated, and the
magnitudes of the OR were similar for all four com-
parisons (Table 2).
All five trials in the subgroup comparing albumin
with vasoconstrictor were relatively small, with the
total enrolled population in no cases exceeding 40
patients. Results were more variable in this subgroup,
as evidenced by the broad range of individual trial OR
from 0.30 to 5.54. Although the pooled OR for the
subgroup (0.79) was higher than that for the subgroup
comparing albumin with other volume expanders
(0.34), the difference in effect sizes between the two
subgroups was not statistically significant (P ¼ 0.10).
Hyponatremia. Data on hyponatremia were avail-
able for all 17 included trials. However, in one trial
comparing albumin with vasoconstrictor,31 there were

1176 BERNARDI ET AL.
no cases of hyponatremia in either study group, and so
the OR for that trial could not be computed or included
in the calculation of pooled OR. Across the other 16
included trials there was no evidence of significant heter-
ogeneity (P ¼ 0.97; I2, 0%) or publication bias (P ¼
0.24) with respect to the hyponatremia endpoint.
In the three trials comparing albumin with no treat-
ment, 13 of 79 untreated control patients (16.5%)
developed hyponatremia versus 3 of 77 patients receiv-
ing albumin (3.9%). Albumin reduced the odds of
hyponatremia by 80%, compared with no treatment
(pooled OR, 0.20; CI, 0.05-0.74).
Over all 14 trials evaluating alternative treatments, 86
of 577 control patients (14.9%) and 39 of 478 patients
allocated to albumin treatment (8.2%) experienced hypo-
natremia. Among 13 of those trials with at least one case
of hyponatremia, albumin decreased the odds of hypona-
tremia by 42% (Fig. 3). The effects of albumin on the
odds of hyponatremia were similar across strata of age,
refractory ascites, baseline serum albumin level, type of
control volume expander, day of PCD assessment, para-
centesis regimen, ascites volume removed, trial quality,
control group mortality, and time period (Table 2).
Mortality. Data on mortality were unavailable for
four trials, and in one trial,20 there were zero deaths.
Across the remaining 12 trials, the mortality endpoint
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HEPATOLOGY, April 2012
Fig. 2. PCD in trials comparing
albumin with alternative treat-
ments. Error bars depict CI. Point
estimates for individual trials
scaled in proportion to meta-ana-
lytic weight.
did not exhibit significant heterogeneity (P ¼ 0.91; I2,
0%) or publication bias (P ¼ 0.24). Only 1 of the 12
trials compared albumin with no treatment,2 and there
was no significant effect of albumin on mortality in
that trial (P ¼ 0.37).
In 11 trials with mortality data comparing albumin
with alternative treatments, 74 of 513 control patients
(14.4%) died versus 50 of 414 assigned to albumin
infusion (12.1%). The odds of death were lower by
36% in the albumin group (P ¼ 0.038; Fig. 4). Differ-
ences in the effect of albumin on mortality between
subgroup strata of age, refractory ascites, baseline serum
albumin level, type of control volume expander, day of
PCD assessment, paracentesis regimen, ascites volume
removed, trial quality, control group mortality, and time
period were minor (Table 2).
Secondary Endpoints. Of the trials comparing albu-
min with alternative treatments, the number with avail-
able data for a particular secondary endpoint and at
least one event ranged from 6 to 11 (Table 3). Albumin
administration was associated with 15%-19% reductions
in the odds of acites recurrence, renal impairment, and
hospital readmission. Smaller reductions were observed
for hepatic encephalopathy and portal hypertensive
bleeding. However, none of these effects with respect to
secondary endpoints were statistically significant.
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HEPATOLOGY, Vol. 55, No. 4, 2012 BERNARDI ET AL. 1177

Table 2. Subgroup Analyses of Albumin Effects Versus Alternative Treatments

PCD Hyponatremia Mortality

Variable Trials Odds Ratio (CI) Trials Odds Ratio (CI) Trials Odds Ratio (CI)

Age (y)
55 7 0.61 (0.33-1.10) 6 0.68 (0.31-1.48) 5 0.85 (0.42-1.75)
>55 6 0.31 (0.20-0.48) 7 0.55 (0.34-0.89) 6 0.54 (0.31-0.93)
Type of ascites
Not specified as refractory 11 0.38 (0.26-0.56) 11 0.57 (0.37-0.87) 9 0.56 (0.35-0.92)
Refractory 2 0.43 (0.20-0.95) 2 0.72 (0.23-2.21) 2 1.00 (0.39-2.55)
Serum albumin (g
L1)*
<27 6 0.38 (0.24-0.61) 7 0.55 (0.34-0.91) 5 0.52 (0.23-1.18)
27 7 0.40 (0.24-0.67) 6 0.65 (0.32-1.33) 6 0.69 (0.42-1.14)
Control volume expander
Dextran 4 0.34 (0.20-0.57) 4 0.62 (0.35-1.09) 4 0.60 (0.35-1.03)
Gelatin 2 0.43 (0.24-0.78) 3 0.66 (0.37-1.17) 3 0.64 (0.29-1.43)
Hydroxyethyl starch 2 0.29 (0.12-0.71) 2 0.51 (0.11-2.44) 1 0.98 (0.13-7.20)
Hypertonic saline 1 0.26 (0.08-0.93) 1 0.34 (0.06-1.90) 1 0.94 (0.06-15.7)
Day of PCD assessment
1-5 5 0.50 (0.22-1.12) — — — —
6 8 0.37 (0.25-0.55) — — — —
Paracentesis
Total 11 0.39 (0.27-0.56) 10 0.57 (0.36-0.90) 9 0.64 (0.40-1.01)
Repeated LVP 2 0.36 (0.09-1.46) 2 0.91 (0.22-3.70) 1 0.74 (0.20-2.78)
Ascites volume removed (L)
5.5-8.0 9 0.42 (0.28-0.65) 8 0.52 (0.31-0.87) 6 0.48 (0.24-0.94)
>8 4 0.33 (0.18-0.60) 4 0.85 (0.38-1.87) 4 0.82 (0.46-1.46)
Randomization method
Adequate 6 0.31 (0.21-0.47) 7 0.56 (0.35-0.89) 6 0.57 (0.34-0.97)
Unspecified 7 0.77 (0.38-1.53) 6 0.66 (0.29-1.52) 5 0.78 (0.37-1.64)
Allocation concealment
Adequate 4 0.44 (0.27-0.73) 4 0.55 (0.32-0.95) 5 0.47 (0.17-1.28)
Unspecified 9 0.34 (0.21-0.56) 9 0.62 (0.34-1.16) 6 0.69 (0.43-1.11)
Blinding
Adequate 2 0.51 (0.15-1.80) 3 0.52 (0.19-1.48) 3 0.47 (0.10-2.19)
Unspecified 11 0.38 (0.27-0.55) 10 0.59 (0.38-0.92) 8 0.65 (0.42-1.02)
Control group mortality (%)
<25 6 0.40 (0.26-0.62) 6 0.56 (0.33-0.93) 7 0.51 (0.22-1.20)
25 4 0.34 (0.17-0.66) 4 0.80 (0.38-1.71) 4 0.69 (0.42-1.13)
Year reported
Before 2000 5 0.37 (0.23-0.58) 5 0.67 (0.40-1.13) 4 0.71 (0.41-1.24)
2000 or after 8 0.43 (0.25-0.73) 8 0.46 (0.24-0.89) 7 0.54 (0.27-1.06)

*At baseline.

Discussion the development of PCD and hyponatremia and

Though PCD is clinically silent, it is the most
powerful independent predictor of mortality in patients
with tense ascites treated by LVP.22 In three trials
included in the meta-analysis comparing albumin with
no treatment, 73% of the untreated patients developed
PCD, and albumin reduced the odds of this complica-
tion by 93%, confirming the value of adjunctive treat-
ment in patients undergoing LVP. Albumin also reduced
the odds of hyponatremia 80% versus no treatment.
The clinical question addressed in 14 of the 17
included trials was whether there may be alternative
treatments of comparable effectiveness to albumin.
However, this meta-analysis indicates that adjunctive
albumin infusion is significantly more effective than
alternative treatments evaluated to date in preventing
reducing mortality after LVP. Effect sizes were substan-
tial, with albumin reducing the odds of PCD by
66%, hyponatremia by 42%, and death by 36%. In
subgroup analyses, albumin was significantly superior
to each of the four other volume expanders tested in
averting PCD. Oncotic forces exerted by 20%-25%
albumin, and hence effectiveness in draining water and
sodium from the extravascular space, may be greater
than those of the alternative volume expanders.33 It is
also possible that nononcotic properties contribute to the
observed effects of albumin. For instance, evidence in
patients with spontaneous bacterial peritonitis suggests
that albumin may modulate endothelial cell function.34
No particular volume of ascites removed was required
for eligibility in this meta-analysis. Nevertheless, in all

1178 BERNARDI ET AL.
eligible trials identified and included, average volume
removed exceeded 5 L, the customary cutoff below which
albumin infusion is not recommended. Within the range
of volumes removed among the included studies, no major
differences in the effects of albumin were apparent
between 5.5 and 8.0 L of ascites fluid removed and >8 L.
In the majority of included studies, albumin was
administered at a dose of 8 g per L of ascites fluid
removed, although doses as low as 5 or 6 g
L1 were
also evaluated in three trials. Lower albumin doses, if
effective, might aid in reducing treatment costs. A
pilot study directly comparing 4- and 8-g
L1 doses
has recently been reported.35
The pathogenesis of PCD is not completely under-
stood, but it is thought to be secondary to accentuation
of already established arteriolar vasodilation. This con-
cept has prompted the evaluation of the vasoconstrictors
vasopressin, midodrine, and norepinephrine, as alterna-
tives to albumin. The systematic search process under-
taken as part of this meta-analysis revealed that random-
ized trial evidence on the clinical utility of vasopressors
in ascites patients undergoing LVP is limited to small tri-
als with 40 or fewer total patients each, and the results
were variable. On the other hand, the combination of al-
bumin and vasoconstrictors is the first-line treatment for
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HEPATOLOGY, April 2012
Fig. 3. Hyponatremia in trials
comparing albumin with alternative
treatments. Graphic conventions as
in Fig. 2.
type-1 hepatorenal syndrome and is being tested in
patients awaiting liver transplantation. The possibility
that such combination treatment might benefit ascites
patients needing LVP has not been investigated thus far.
Although some data have suggested that hyponatremia
may occur less frequently in patients receiving albumin
as an adjunct to LVP, such an effect has not previously
been established. The present meta-analysis provides
clear-cut evidence that albumin effectively prevents
hyponatremia, compared with alternative treatments.
This finding is of potential clinical importance, because
hyponatremia is a risk factor for hepatic encephalopathy
and death.36-38 Patients with hyponatremia also display
greater susceptibility to the development of refractory
ascites, lower responsiveness to diuretics in terms of
change in body weight, higher requirement for LVP to
manage their ascites, and a shorter interval between
needed paracentesis procedures.39 Hyponatremia devel-
ops because of an impairment in the renal capacity to
eliminate solute-free water, causing disproportionate
retention of water relative to sodium and thereby reduc-
ing serum sodium concentration. Arterial underfilling
unloads high-pressure baroreceptors, stimulating a non-
osmotic hypersecretion of vasopressin and inducing sol-
ute-free water retention and dilutional hyponatremia.
 15273350, 2012, 4, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.24786 by Readcube (Labtiva Inc.), Wiley Online Library on [25/02/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
HEPATOLOGY, Vol. 55, No. 4, 2012 BERNARDI ET AL. 1179

Fig. 4. Mortality in trials com-

paring albumin with alternative
treatments. Graphic conventions as
in Fig. 2.

Albumin infusion has yielded favorable results as a as a detoxification agent is severely compromised in
treatment for hyponatremia in patients with cirrhosis.40,41 patients with cirrhosis.44 The combination of hypoal-
In one RCT, daily albumin infusion for severe hypona- buminemia and impaired albumin function leads to a
tremia in patients with refractory ascites increased serum marked disturbance in the transport, metabolism, and
sodium levels and reduced the incidence of infection, excretion of many endogenous and exogenous substan-
hepatic encephalopathy, and in-hospital mortality.41 ces. One consequence is alteration in the pharmacoki-
The clinical value of albumin administration as an netics and pharmacodynamics of many drugs, thus
adjunct to LVP has been questioned because a survival affecting their efficacy and side-effect profile.45 Infu-
benefit could not previously be shown.5,42 Individual sion of exogenous albumin in ascites patients may
trials have not been powered to detect a survival benefit. serve the dual purposes of repleting the levels of circu-
By ‘‘borrowing strength’’ from all available RCTs, this lating albumin and the functional activity of the albu-
meta-analysis has provided evidence that albumin can min pool. These are effects specific to albumin not
indeed bestow a survival benefit, compared with alterna- shared by alternative treatments and may contribute to
tive treatments in ascites patients undergoing LVP. the superior effectiveness of albumin documented in
The mechanisms underlying the therapeutic effects this meta-analysis.
exerted by albumin in liver failure are not fully under- The trials included in the meta-analysis concern
stood, but multiple mechanisms appear to be at work. acute treatment with albumin at the time of LVP. But,
Albumin, the most abundant circulating protein in the albumin has also shown promise for the management
plasma, is endowed with an array of nononcotic prop- of ascites as a weekly or biweekly long-term treatment
erties beyond its role as the predominant plasma col-
loid and its capacity to expand intravascular volume.43 Table 3. Other Effects of Albumin Versus Alternative
These include ligand binding and antioxidant and Treatments
anti-inflammatory activity. Patients with ascites are Endpoint Trials Odds Ratio (CI)
usually hypoalbuminemic as a consequence of reduced
Ascites recurrence 11 0.85 (0.61-1.18)
hepatic synthesis and secretion, dilution by increased Renal impairment 10 0.83 (0.49-1.42)
intravascular and interstitial volume, and loss to the Hepatic encephalopathy 7 0.91 (0.50-1.66)
ascites fluid. Moreover, the ability of albumin to Portal hypertensive bleeding 7 0.97 (0.45-2.11)
Hospital readmission 6 0.81 (0.56-1.18)
transport protein-bound substances and drugs and act

1180 BERNARDI ET AL.
in combination with diuretics.46-48 The data are much
more limited for this indication, however. In an RCT
of 100 patients, long-term albumin administration in
combination with diuretics to cirrhotic patients after
their first ascitic episode significantly improved trans-
plant-free survival and decreased the risk of ascites recur-
rence, compared with diuretics alone.48 A large, multi-
center RCT in Italy is evaluating the effects of the
addition of weekly albumin infusion to diuretic treat-
ment in patients with uncomplicated ascites (Clinical-
Trials.gov identifier NCT01288794). Primary outcome
measures are survival and incidence of refractory ascites.
This meta-analysis is the first to focus on the com-
parative effectiveness of albumin as an adjunct to ther-
apeutic paracentesis. A 2008 systematic review on
diagnostic paracentesis also summarized data on hypo-
natremia, survival, and certain other endpoints, though
not PCD, in patients receiving albumin after therapeu-
tic paracentesis.49 Results of albumin infusion were
not quantitatively combined across different control
treatments in that review, however. By combining
results of all available RCTs comparing albumin with
alternative treatments, it has been possible, in the
present meta-analysis, to show significant reductions
in PCD, hyponatremia, and mortality in patients
receiving albumin. Thus, the meta-analysis provides
evidence-based support for the well-accepted clinical
practice of infusing albumin as the first choice in
adjunctive treatment for patients requiring LVP.
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