European Journal of Internal Medicine 24 (2013) 721–728

Contents lists available at ScienceDirect

European Journal of Internal Medicine

journal homepage: www.elsevier.com/locate/ejim

Review article

Clinical indications for the albumin use: Still a controversial issue

Paolo Caraceni ⁎, Marco Domenicali, Alessandra Tovoli, Lucia Napoli, Carmen Serena Ricci,
Manuel Tufoni, Mauro Bernardi
U.O. Semeiotica Medica, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Human serum albumin (HSA) is the most abundant circulating protein and accounts for about 70% of the
Received 13 May 2013 plasma colloid osmotic pressure. Beside the well known capacity to act as plasma-expander, HSA is provid-
Received in revised form 21 May 2013 ed of many other properties which are unrelated to the regulation of fluid compartmentalization, including
Accepted 24 May 2013
binding and transport of many endogenous and exogenous substances, antioxidant function, immuno-
Available online 20 June 2013
modulation, anti-inflammatory activity, and endothelial stabilization.
Keywords:
Treatment (hepatorenal syndrome) or prevention (renal failure after spontaneous bacterial peritonitis and post-
Albumin paracentesis circulatory dysfunction after large volume paracentesis) of severe clinical complications in patients
Liver cirrhosis with cirrhosis and fluid resuscitation in critically ill patients, when crystalloids and non-proteic colloids are not
Ascites effective or contra-indicated, represents the major evidence-based clinical indications for HSA administration.
Fluid resuscitation However, a large proportion of HSA prescription is inappropriate. Despite the existence of solid data against a
Sepsis real benefit, HSA is still given for nutritional interventions or for correcting hypoalbuminemia per se (without
hypovolemia). Other clinical uses for HSA administration not supported by definitive scientific evidence are
long-term treatment of ascites, nephrotic syndrome, pancreatitis, abdominal surgery, acute distress respira-
tory syndrome, cerebral ischemia, and enteric diseases.
HSA prescription should be not uncritically restricted. Enforcement of clinical practice recommendations has
been shown to allow a more liberal use for indications supported by strong scientific data and to avoid the futile
administration in settings where there is a lack of clinical evidence of efficacy. As a result, a more appropriate HSA
use can be achieved maintaining the health care expenditure under control.
© 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

1. Introduction 2. The molecule of albumin

Human serum albumin (HSA) is the most abundant circulating pro-
tein in the body provided of both oncotic and non-oncotic properties.
Administration of exogenous HSA dates back in the World War II when
it was used for fluid resuscitation. Since then, the use of HSA has been ex-
tended to many other diseases since physicians commonly believe in its
efficacy. However, beside some clinical indications supported by solid
scientific evidence, the administration in many other settings is still
under debate or has been disproved by evidence-based medicine. As a
result, clinical practical recommendations have been proposed to ratio-
nalize the prescription of HSA and avoid its futile use.
2.1. Structure
HSA is the main circulating protein in healthy individuals (3.5–5 g/dl),
representing about 50% of the total protein content in the plasma. HSA is a
small protein with a molecular weight of 66.5 kDa, consisting of a single
chain of 585 amino acids organized in three repeated homologue
domains (sites I, II, and III), each of which comprised of two separate
sub-domains (A and B). In the human body, HSA assumes a globular
heart-shaped conformation formed by α-helices for about 67%. Of the
35 cysteine residues of the albumin molecule, 34 are involved in internal
disulfide bonds which stabilize the spatial conformation of the molecule,
while the cysteine at position 34 (Cys-34) remains free [1–3].

Abbreviations: HRS, hepatorenal syndrome; HSA, human serum albumin; ICU, intensive
care unit; NO, nitric oxide; PPCD, post-paracentesis circulatory dysfunction; SBP, spontane-
ous bacterial peritonitis; TNF-α, tumor necrosis factor-α.
⁎ Corresponding author at: U.O. Semeiotica Medica, Department of Medical and Surgical
Sciences, Alma Mater Studiorum, University of Bologna, Via Albertoni15, 40138 Bologna,
Italy. Tel.: +39 051 6362919; fax: +39 051 6362930.
E-mail address: paolo.caraceni@unibo.it (P. Caraceni).
2.2. Synthesis
HSA is synthesized in the liver through the transcription of its gene
on the long arm of chromosome 4. Under physiological conditions,
20–30% of the hepatocytes are implicated in the synthesis and about
10–15 g are produced and released in the circulation every day, with

0953-6205/$ – see front matter © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ejim.2013.05.015
722 P. Caraceni et al. / European Journal of Internal Medicine 24 (2013) 721–728
none or a very low intracellular storage. However, under certain
circumstances, the HSA production can increase even up to 3–4 folds,
thus exploiting a large functional reserve [3,4]. Its synthesis is stimulat-
ed by hormonal factors, such as insulin, cortisol and growth hormone,
while pro-inflammatory mediators, including cytokines, such as
Interleukin-6 and Tumor Necrosis Factor-α, exert an inhibitory effect
[4,5].
2.3. Metabolism
Once produced, HSA is quickly released in the blood through the
sinusoids. Approximately 30–40% is maintained in the blood stream,
while the remaining pool is distributed in the interstitium, where its
concentration is low (1.4 g/dl), as well as in the muscles and the skin.
The protein leaves the vascular compartment at a rate of 5% per hour
(transcapillary escape rate), returning to it via the lymphatic system
in an amount comparable to the output. The circulatory half-life of
HSA, which is approximately 16–18 h, is therefore much shorter
than its total half-life, which varies from about 12 to 19 days in a
healthy young adult. Although its catabolism is a widespread process
involving many tissues, HSA is mainly degraded by the muscles, liver
and kidneys, while a little amount is lost into the gastrointestinal
tract [3–6].
3. The functions of albumin
Beside the well known oncotic function, HSA is provided of many
other properties which are unrelated to the regulation of fluid compart-
mentalization, the so-called non-oncotic properties.
3.1. Oncotic properties
HSA is the main modulator of fluid distribution in the various com-
partments of the body as it accounts for about 70–80% of the plasma
oncotic pressure. The oncotic property derives for 2/3 from the direct
osmotic effect related to its molecular mass and for 1/3 from the
Gibbs–Donnan effect, due to the negative net charge of the molecule
at physiological pH that allows the protein to attract positively charged
molecules (i.e. sodium and, therefore, water) into the intravascular
ROS
ONOO-
hydroperoxide
Endogenous
molecules
Bilirubin
Biliary salts
Fatty acids
Binding/Transport
Nitric oxide
Exogenous
molecules
Benzene
Aflatossin G
Drugs
NSAIDs
Warfarin
Antibiotics
Furosemide
Metals
Cu, Ni, Co, Fe
Fig. 1. Human serum albumin is provided of a series of oncotic and non-oncotic properties (right side). A major function is the binding and transport of many endogenous and
exogenous substances (left side), which are capable to interact with several specific sites of the albumin molecule.
compartment. As a result of its osmotic effect, most of the clinical use
of HSA is based on the capacity to act as a plasma-expander [4].
3.2. Non-oncotic properties
Many non-oncotic properties, mostly related to the peculiar struc-
ture and conformation of the albumin molecule, have been identified
in the last two decades (Fig. 1).
A large number of binding sites with different affinities for plasmatic
compounds have been identified: the major domains are capable of fold-
ing into hydrophobic pockets, which can open and close, and accommo-
date large insoluble anions; furthermore, cationic groups located on the
surface of the molecule allow the formation of ionic bonds with many
different ligands. As a result, HSA binds and carries a great variety of hy-
drophobic molecules, such as endogenous (i.e., cholesterol, fatty acids, bil-
irubin, thyroxine) or exogenous substances (i.e., drugs), transition metal
ions, and gas (nitric oxide [NO]), with consequent implications on their
solubilization, transport and metabolism [3,6]. Structural and conforma-
tional changes at the molecular level have been demonstrated to occur
during chronic diseases, producing an impairment of the binding, trans-
port and detoxification capacity of HSA [7,8].
3.2.1. Antioxidant activity
HSA is the major source of extracellular reduced sulfhydryl groups,
which act as potent scavengers of reactive oxygen species (ROS), thus
constituting the main circulating antioxidant system in the body.
According to the redox state of the sulfhydryl group in the Cys-34 posi-
tion, three albumin isoforms can be identified. Under physiological con-
ditions, about 70–80% of albumin contains the Cys-34 residue with a
free sulfhydryl group (known as human mercaptalbumin). In 25–30%
of albumin, the Cys-34 site is reversibly bound with other small
sulfhydril compounds, such as homocysteine or glutathione, forming
the non-mercaptalbumin 1 isoform, which is provided of a reduced
redox potential. Finally, less than 5% circulates with the residue
Cys-34 completely and irreversibly oxidized (non-mercaptalbumin 2),
with a permanent loss of its antioxidant activity [8]. In acute and chronic
disease states characterized by a pro-oxidant and pro-inflammatory cir-
culatory microenvironment (myocardial infarction [9], diabetes [10,11],
renal failure [12,13], liver cirrhosis [14]), the amount of the totally
Oncotic
pressure
Solubilization
III B IB Transport
Metabolism
IA
Antioxidant
Functions
SH
Immuno-
modulation
III A
II A
Endothelial
stabilization
NH2
Capillary
II B
permeability
Hemostasis
 P. Caraceni et al. / European Journal of Internal Medicine 24 (2013) 721–728
oxidized HSA is increased several folds and correlates with poor clinical
outcome and patient survival [15].
Finally, the antioxidant function of HSA resides also on the capability
to bind at the N-terminal portion of the molecule several metal ions, in-
cluding copper, cobalt, nickel, zinc and iron, which are therefore inhibited
to catalyze many chemical reactions generating free radicals [3,16,17].
3.2.2. Antithrombotic effects
These proprieties are mostly due to the capacity to bind NO at the
Cys-34 site, with subsequent formation of the complex albumin-NO,
also known as nitroso-albumin. This new compound, whose physiolog-
ic and pathologic functions are still partially determined, seems to pre-
vent the rapid inactivation of NO thus prolonging its anti-aggregant
effect on platelets [18,19].
3.2.3. Anti-inflammatory effect
HSA appears to inhibit the secretion of pro-inflammatory cytokines
(TNF-α) and complement factors (C5a) through the modulation of
the signaling systems between inflammatory cells, such as neutrophils
and endothelial cells [20,21].
3.2.4. Capillary permeability and endothelial stabilization
HSA contributes to the integrity of the vessels, by binding the in-
terstitial matrix and interacting with the sub-endothelial space, thus
participating in the maintenance of the normal capillary permeabil-
ity [22]. HSA may impact positively on endothelial function also by
reducing oxidative damage and modulating inflammation [23].
4. Clinical applications of albumin
HSA is largely used in clinical practice, but its administration is often
inappropriate. Indeed, physicians commonly believe in its efficacy al-
though many indications are still under debate or have been disproved
by evidence-based medicine.
Hepatology is a setting where HSA is recommended by international
guidelines, since randomized clinical trials and meta-analyses have dem-
onstrated its efficacy to prevent or treat some severe complications of
cirrhosis. In critically ill patients, HSA is also widely used for fluid resus-
citation, although non-protein colloids and crystalloids are considered
the first-line treatment. Furthermore, HSA is prescribed for some other
specific conditions, such as nephrotic syndrome, pancreatitis, major sur-
gery, kernicterus, plasmapheresis, and graft versus host disease, even
though these indications are not supported by definite scientific evi-
dence. Finally, the most common inappropriate use occurs when HSA
is given to correct hypoalbuminemia per se (i.e. not associated with
hypovolemia) or for nutritional intervention.
4.1. HSA in liver cirrhosis
Hypoalbuminemia is a typical feature of cirrhosis and represents an
independent adverse prognostic factor. Beside the decreased hepato-
cyte synthesis, the low serum albumin concentration results from the
dilution of the extracellular fluid protein content, due to the plasma vol-
ume expansion consequent to renal sodium and water retention, and
from the increased trans-capillary escape rate towards the extravascu-
lar space, at least in the most advanced stage of cirrhosis [24].
The therapeutic use of HSA in cirrhosis started more than 50 years
ago, when hypoalbuminemia was thought to be crucial for the develop-
ment of ascites, due to the alteration of Starling force balance in the
intrahepatic microcirculation. However, the net fluid flow from the intra-
vascular compartment to the interstitium is regulated by the colloid
osmotic gradient rather than by the absolute level of intrasinusoidal os-
motic pressure. Interestingly, it has been shown that the intravascular–
interstitial colloid osmotic gradient did not significantly differ between
healthy controls and patients with cirrhosis and ascites [25].
723
Today, we know that the cardiovascular abnormalities occurring in
advanced cirrhosis are the essential background for the development
of ascites formation and other severe clinical complications of the dis-
ease [26,27]. The schematic representation of the underlying patho-
physiological events is described in Fig. 2. Thus, the preservation of
the effective blood volume has emerged as a primary goal in the man-
agement of patients with advanced cirrhosis [28]. Based on its capacity
to act as a plasma-expander, the use of HSA is currently proposed by the
international guidelines to treat or prevent clinical complications of cir-
rhosis all characterized by extreme effective hypovolemia, such as in
preventing post-paracentesis circulatory dysfunction (PPCD) and the
renal failure induced by spontaneous bacterial peritonitis (SBP) and in
treating hepatorenal syndrome (HRS), in association with vasoconstric-
tor drugs [29,30] (Fig. 3).
Beside these universally accepted indications, the use of HSA has been
proposed in patients with cirrhosis for the chronic treatment of ascites,
hypervolemic hyponatremia and hepatic encephalopathy, although all
these indications await to be supported by a clear scientific evidence
[6,28].
A final assumption deriving from the pathophysiological scenario
is that serum albumin concentration should not be a guide for its
use and the correction of hypoalbuminemia per se should not be a
goal to pursue.
4.1.1. Prevention of PPCD after large volume paracentesis
Paracentesis is the current first-line treatment for patients with tense
and refractory ascites [29,30]. The removal of large volumes of ascites
CIRRHOSIS
PORTAL
HYPERTENSION
CIRRHOTIC
SPLANCHNIC
VASODILATION
CARDIOMIOPATHY
(end-stage disease)
EFFECTIVE HYPOVOLEMIA
ACTIVATION OF
COMPENSATORY REDUCED
NEURO-HORMONAL RENAL PERFUSION
SYSTEMS
RENAL RETENTION RENAL RETENTION RENAL PERFUSION
Na+ and H2O Na+ and H2O
ASCITES HYPERVOLEMIC HEPATORENAL
HYPONATREMIA SYNDROME
DISEASE SEVERITY
Fig. 2. Cardiovascular abnormalities in cirrhosis. An imbalance of the vasoactive systems
with a predominance of vasodilators (i.e. nitric oxide, carbon monoxide, endocannabinoids)
reduces the tone of resistance vessels and hampers their response to vasoconstrictors, induc-
ing vasodilation, mainly located in the splanchnic area. This leads to a reduction in the central
effective volemia, which, in turn, evokes the compensatory activation of neuro-humoral
systems, such as the renin–angiotensin–aldosterone axis (RAAS), the sympathetic nervous
system (SNS) and arginine–vasopressin (ADH), ultimately promoting renal sodium and
water retention. In the advanced stages of cirrhosis, effective hypovolemia is further im-
paired by cardiac dysfunction, as witnessed by a relative reduction in cardiac output. These
events represent the pathophysiological background for the development of clinical compli-
cations of cirrhosis, including ascites, hyponatremia, and renal failure.
724 P. Caraceni et al. / European Journal of Internal Medicine 24 (2013) 721–728

Evidence based clinical indications for albumin admistration in cirrhosis

Spontaneous Hepatorenal syndrome

Paracentesis bacterial
peritonitis Diagnosis Treatment

Cr > 1.5 mg/dL

Prevention Prevention of renal Exclusion of Type I HRS

of PPCD failure hypovolemia

8 g/liter ascites Day 1: 1.5 g/kg 1 g/kg per day Day 1: 1g/kg (max 100 g),
removed Day 3: 1 g/kg (at least two days) then 20-40 g/day
+ antibiotics + diuretics + vasoconstrictors in HRS 1
withdrawal

Ascites
Bacterial
Hepatic encephalopathy
infections (other than SBP)
Hypervolemic hyponatremia

grey zone
Lack of evidences to make recomendations

Fig. 3. Evidence-based and controversial clinical indications (gray zone) for the use of human serum albumin in patients with complicated liver cirrhosis. HRS: hepatorenal syndrome;
PPCD: post-paracentesis circulatory dysfunction; SBP: spontaneous bacterial peritonitis.

(>5 l) has been associated with an increased risk to develop PPCD, which
is diagnosed by a significant increase (>50%) in plasma renin activity
6 days after paracentesis. PPCD is a circulatory dysfunction characterized
by an exacerbation of arteriolar vasodilatation, reduction of effective
blood volume, rapid re-accumulation of ascites, increased risk of HRS,
dilutional hyponatremia, and increased mortality [31,32]. In several ran-
domized trials, administration of HSA at the time of paracentesis was
able to reduce significantly the incidence of PPCD, showing also its supe-
riority when compared with other plasma expanders or vasoconstrictors
[33–35]. Importantly, a recent meta-analysis has shown that HSA not only
reduces the occurrence of PPCD more efficiently than any other plasma
expander, but is also superior to either artificial plasma expanders or va-
soconstrictors in lowering the incidence of hyponatremia and mortality
[36]. On the basis of such evidences, international guidelines recommend
the administration of 8 g of HSA per liter of ascites removed, with a great-
er strength of recommendation for paracentesis of at least 4–5 l [29,30].
4.1.2. Prevention of renal failure after SBP
SBP is a frequent and life-threatening infection of ascitic fluid that oc-
curs in patients with advanced cirrhosis and requires prompt recognition
and treatment. Diagnosis is based on the presence of >250 polymorpho-
nuclear cells/mmc of ascites, in the absence of an intra-abdominal source
of infection or malignancy [37]. Even in absence of septic shock, SBP may
trigger hemodynamic decompensation precipitating renal failure that
can become progressive as type 1 HRS. Thus, despite infection resolution,
SBP still carries approximately a 10–30% hospital mortality [38–40].
A prospective randomized comparative study reported that adminis-
tration of high-dose of HSA (1.5 g/kg at diagnosis of SBP and 1 g/kg on
day 3), together with antibiotic treatment, decreased the incidence of
type 1 HRS (from 30% to 10%) and improved in-hospital and 3-month
survival [39]. Whether all patients with SBP should be treated with anti-
biotics and HSA is still matter of debate. Indeed, available data suggest
that the most striking effects are obtained in patients with liver failure
(serum bilirubin > 4 mg/dl) and renal dysfunction (serum creatinine
greater than 1 mg/dl) at the time of diagnosis, suggesting that HSA ad-
ministration could be restricted to these high-risk patients [39,41]. How-
ever, two large subsequent retrospective studies showed a not negligible
incidence of poor outcome in low-risk patients not treated with albumin
[42,43]. Similarly, the dose of HSA proposed is arbitrary and chosen
based on pathophysiological considerations and not according compara-
tive clinical studies. At this regard, a reduced-dose regimen of albumin
(1.0 g/kg on day 1 and 0.5 g/kg on day 3) seemed to be as effective as
the standard regimen in preventing renal failure and HRS [44].
Until more information are available, the Clinical Practice Guidelines
of the European Association for the Study of the Liver (EASL) recom-
mend that all patients who develop SBP should be treated with broad
spectrum antibiotics and HSA (1.5 g/kg on day 1 and 1 g/kg on day 3)
[29]. Supporting this recommendation, a very recent meta-analysis
from Salerno at al. has confirmed the capacity of HSA to improve out-
comes in patients with SBP [45].
4.1.3. Diagnosis and treatment of HRS
HRS is a potentially reversible renal failure developing in patients
with advanced cirrhosis and ascites and it is characterized by marked
renal hypoperfusion related to the extreme effective hypovolemia, due
to splanchnic vasodilatation and cardiac dysfunction, and the conse-
quent overactivation of compensatory mechanisms that induce severe
intrarenal vasoconstriction [26,46].
The diagnostic criteria for HRS have been published in 2007 by the In-
ternational Club of Ascites (Table 1). HRS is diagnosed in patients with cir-
rhosis and ascites and the exclusion of organic and other functional forms
of renal failure. At this regard, diuretic withdrawal and HSA administra-
tion (1 g/kg of body weight per day up to a maximum of 100 g/day) for
at least 2 days are recommended to exclude hypovolemic renal failure
[46]. The expert panel of the International Club of Ascites agreed that vol-
ume expansion should be performed with HSA rather than saline, be-
cause of its greater and more sustained expansion [46].
Once diagnosis in established, the current therapeutic approach in-
cludes the administration of both vasoconstrictors and HSA with the
aim of improving effective volemia. Several vasoconstrictors have
been used in the management of type 1 HRS, but terlipressin, which
mainly acts on the splanchnic vascular bed where vasodilation is maxi-
mal, is the most studied and widely used [47–51]. As recently shown by
a systematic review of randomized studies, terlipressin is able to resolve
HRS in about 40% of the cases and to improve patient survival [52]. In
 P. Caraceni et al. / European Journal of Internal Medicine 24 (2013) 721–728
Table 1
Diagnostic criteria and classification of hepatorenal syndrome (HRS) in cirrhosis according
the International Club of Ascites [46].
Diagnostic criteria
• Cirrhosis with ascites
• Serum creatinine > 1.5 mg/dl (133 mmol/l)
• Absence of shock
• Absence of hypovolemia as defined by no sustained improvement of renal function
(creatinine decreasing to b1.5 mg/dl–133 mmol/l) following at least 2 days
of diuretic withdrawal (if on diuretics), and volume expansion with albumin
at 1 g/kg/day up to a maximum of 100 g/day
• No current or recent treatment with nephrotoxic drugs
• Absence of parenchymal renal disease as defined by proteinuria b0.5 g/day,
no microhematuria (b50 red cells/high powered field), and normal renal
ultrasonography
Classification
• Type 1 HRS: a rapid progressive renal failure as defined by doubling of the initial
serum creatinine concentration to a level greater than 2.5 mg/dl in less than
2 weeks. It often appears after a precipitating event, most frequently spontaneous
bacterial peritonitis.
• Type 2 HRS: a moderate renal failure (serum creatinine from 1.5 to 2.5 mg/dl), with
a steady or slowly progressive course. It often appears spontaneously and is
typically associated with refractory ascites.
contrast, the use of vasoconstrictors and albumin in type 2 HRS is still
controversial [29,30].
4.1.4. Other potential indications for the use of HSA in cirrhosis
4.1.4.1. Long-term treatment of ascites. The chronic and prolonged use
of HSA to treat ascites is still debated, due to the lack of a definitive
evidence showing a clinical benefit and an adequate assessment of
the cost/effectiveness ratio.
So far, the effect of the combination of HSA and diuretics has only been
assessed in two controlled clinical trials conducted in Italy and involving a
relatively small number of patients. In the first study, two groups of pa-
tients with cirrhosis and ascites were randomized to receive diuretics
with or without daily infusion of 12.5 g of albumin during hospitalization
followed by 25 g/week after discharge, with a median follow-up of
20 months [53]. The treatment with diuretics plus HSA was overall
more effective than diuretics alone in resolving ascites and reducing the
length of the hospital stay. However, these results were only achieved
in the subset of patients receiving a low dose of diuretics, while the ad-
vantage was lost when higher doses were needed [53]. In a subsequent
study, a cohort of patients was randomized to receive chronic treatment
with either diuretic alone or diuretic plus HSA (25 g/week for the first
year, then 25 g every 2 weeks) (median follow up 84 months) [54].
The recurrence rate of moderate to severe ascites and mortality were sig-
nificantly reduced in patients supplemented with HSA; however, the rel-
atively low sample size prevented to reach firm conclusions [54].
In order to fill this gap of knowledge, an open-label, multicenter,
randomized clinical trial (NCT01288794, www.clinicaltrials.gov, the
“ANSWER Study”) that will enroll more than 400 patients is currently
ongoing in Italy. This study has the potential to assess the effective-
ness of long-term administration of HSA in improving ascites treat-
ment and patient mortality.
4.1.4.2. Bacterial infections other than SBP. Even less defined is the indi-
cation on the prophylactic use of HSA in patients with bacterial infec-
tions other than SBP. In a recent randomized controlled trial, HSA
administration together with antibiotics, as compared with standard
antibiotic therapy alone, had some beneficial effects on the renal and
circulatory functions, showing also a potential survival benefit at least
in high-risk patients. However, due to the relatively low sample size, a
clear recommendation cannot be given as yet [55].
4.1.4.3. Hypervolemic hyponatremia. Hyponatremia (serum sodium b
135 mmol/l) frequently complicates advanced cirrhosis and its de-
velopment is associated to the use of diuretics, paracentesis without
725
albumin, bacterial infections, refractory ascites and renal failure [56].
Hypervolemic hyponatremia in cirrhosis is the result of effective
hypovolemia that leads to greater free water reabsorption mediated
by the non-osmotic secretion of vasopressin [56]. Although some physi-
cians prescribe HSA to correct moderate (serum sodium b 130 mmol/l)
or severe (serum sodium b 125 mmol/l) hyponatremia with the aim to
expand the central volume and suppress the ADH release, there is no ac-
tual recommendation about its use because of the lack of clinical studies
specifically dedicated to this topic.
4.2. Albumin in critically ill patients
Fluid resuscitation is widely practiced in intensive care units (ICU)
for the treatment of critically ill patients. Although HSA has been
given for many decades in a large number of diseases, including
shock, sepsis, trauma, acute respiratory distress syndrome, burns or
acute clinical situations associated with hypoproteinemia, a long de-
bate is still ongoing since the choice of fluid is controversial with crys-
talloids and non-protein colloids being also proposed for treatment.
In 1998, a Cochrane meta-analysis of 30 randomized clinical trials
strongly suggested that the infusion of HSA solutions in the management
of patients with hypovolemia from injury or surgery, burns and
hypoproteinemia increased the risk of death by 6% (pooled relative
risk: 1.68) [57]. However, few years later, a meta-analysis including 55
trials on the comparison of HSA therapy with crystalloid therapy, no
HSA or lower HSA doses in patients with trauma or surgery, burns,
hypoalbuminemia, ascites or high-risk neonates found no significant ef-
fect of HSA on mortality [58]. The latter finding was then confirmed by
the third meta-analysis published on this topic by the Cochrane group
in 2004 [59]. At the same time, the Saline versus Albumin Fluid Evalua-
tion (SAFE study) evaluating 6997 patients admitted to the ICU and ran-
domized to receive saline or 4% HSA solution for fluid resuscitation
demonstrated that the 28-day mortality was similar in the two groups,
supporting the safety use of HSA in critically ill patients [60]. More re-
cently, in 2011, another Cochrane meta-analysis on 38 trials, comparing
HSA or plasma protein fraction with no HSA or plasma protein fraction or
with a crystalloid solution in critically ill patients with hypovolemia,
burns or hypoalbuminemia, showed no evidence of survival benefit of
HSA compared to the other cheaper alternatives [61].
However, all these studies included a very heterogeneous population
of critically ill patients, while the effect of HSA may be quite different
depending on the specific clinical conditions. Indeed, while consistent
evidence have indicated that HSA administration for resuscitation of
patients with traumatic brain injury is associated to an increased risk of
mortality, accumulating data support its use in patients with sepsis
[62,63]. Indeed, the SAFE group in a pre-defined subgroup analysis of
1218 patients with severe sepsis randomized to receive HSA or saline
showed that, at multivariate analysis, those treated with HSA administra-
tion may have a decreased risk of death with an adjusted odd ratio of 0.71
[63]. Similarly, a meta-analysis by Delaney et al. comparing crystalloid
and albumin in septic patients showed a survival benefit with HSA [64].
Furthermore, besides acting as plasma-expander, HSA might exert an ad-
ditional beneficial effect in these patients by increasing the plasma
anti-oxidant and anti-inflammatory capacity and by reducing the capil-
lary permeability and thus the fluid loss towards the interstitium [6]. As
a result, the most recent guidelines of the surviving sepsis campaign sup-
port, even if the level of recommendation is still low, the use of HSA for
fluid resuscitation in patients with severe sepsis and septic shock when
substantial amount of crystalloids are required, suggesting also to avoid
the use of hydroxyethyl starch [65]. A definitive indication on the use of
HSA in this specific clinical setting will be hopefully provided by a ran-
domized prospective multicenter clinical trial, actually ongoing in Italy,
comparing HSA with crystalloids among patients with severe sepsis
(NCT00707122, www.clinicaltrials.gov, “the ALBIOS study”).
Thus, if HSA administration for resuscitation is now considered safe
in critically patients except for those with traumatic brain injury, its
726 P. Caraceni et al. / European Journal of Internal Medicine 24 (2013) 721–728
benefit above cheaper alternatives (crystalloids and non-proteic col-
loids) has not been unequivocally demonstrated. However, recent
evidence indicate that HSA could be instead more effective at least in
some specific clinical conditions, such as sepsis, severe sepsis and septic
shock [63,64].
4.3. Other clinical indications and inappropriate use of albumin
Beside liver cirrhosis and critical care illnesses, some niche indica-
tions for the appropriate use of HSA can reflect the peculiar settings of
highly specialized centers. An example is the extracorporeal liver sup-
port device Molecular Adsorbant Recirculating System (MARS), which
is based on the binding and detoxification capacity of albumin, for the
treatment of advanced liver failure, hepatic encephalopathy and intrac-
table cholestatic pruritus [66–68].
However, there is no doubt that, in many other clinical conditions, the
lack of definitive scientific evidence have produced some confusion and a
great variability regarding which indication is perceived to be appropri-
ate. As a result, a consistent part of the HSA prescription, ranging from
40% up to 90%, is not supported by clinical evidence, guidelines or prac-
tical recommendations, as it has been consistently revealed by several
studies and surveys in different countries [69–73].
Most of the inappropriate HSA prescription derives from the use for
nutritional interventions or for correcting hypoalbuminemia per se
(without hypovolemia) that still occurs in many clinical areas (i.e. sur-
gery, internal medicine, geriatrics, oncology), despite the existence of
solid data against a real benefit. Other clinical uses for HSA administra-
tion not supported by solid scientific evidence are nephrotic syndrome,
pancreatitis, abdominal surgery, acute distress respiratory syndrome,
cerebral ischemia, and enteric diseases [69–73].
Finally, inappropriate prescription can also occur even in presence of
clinical guidelines and recommendations, i.e. when HSA is prescribed as
first-line treatment for fluid resuscitation even if other cheaper plasma-
expanders are not contraindicated or for chronic treatment of cirrhosis.
5. Impact of clinical recommendations for albumin prescription
Beside the high proportion of inappropriate use, the elevated cost,
the theoretical risk of disease transmission and the existence of more
economical alternatives of comparable efficacy have prompted several
clinical and economical evaluations aiming to rationalize and render
more appropriate the use of HSA [69–73].
Table 2
Practical recommendations for the prescription of human serum albumin at the S. Orsola-Malpighi University Hospital, Bologna, Italy [69].
Acute diseases First-line treatment
Hypovolemic shock Colloid/crystalloid solutions
Major surgery: Colloid/crystalloid solutions
• Cardiovascular
• Other surgery
Burns Colloid/crystalloid solutions
Paracentesis Human albumin 8 g/l of removed ascites if paracentesis >4 l
Spontaneous bacterial peritonitis Human albumin 1.5 g/kg at diagnosis and 1 g/kg on third
day + antibiotic therapy
Hepatorenal syndrome Human albumin 1 g/kg at diagnosis followed by
20–40 g/die + vasoconstrictors
Ascites Diuretic treatment
Plasmapheresis Human albumin if plasma changes >20 ml/kg per week
Protein wasting enteropathy/malnutrition Enteral or parenteral nutrition
We recently reported the impact of internal practice guidelines for the
appropriate use of albumin in the S. Orsola-Malpighi Academic Hospital
in Bologna, Italy, a third-level referral center for many diseases, including
liver cirrhosis and transplantation, with more than 1.700 beds and 70.000
admissions per year [69]. Due to the fact that HSA consumption and costs
had been relentlessly increasing in the period comprised between 1997
and 2003, practical recommendations were elaborated using a systematic
literature-based consensus method by a multi-disciplinary team, which
identified conditions where HSA had to be considered the first- or
the second-line treatment and others where HSA was formally not
recommended (Table 2) [69].
As a result of their implementation in 2003, the HSA consumption
and the related costs dropped suddenly about 20% to remain steady
over the following year. Even more interestingly, the decrease observed
in the “non-hepatological” units after guideline implementation was
mirrored by a parallel increase in the “hepatological” units of our hospi-
tal. Furthermore, no significant changes occurred in the prescription by
physicians working in ICUs, probably because they were already accus-
tomed to established international guidelines, despite the dispute on
the HSA administration in critically ill patients lasts almost two decades
[69].
In few words, the enforcement of in-hospital guidelines allowed a
more liberal use of HSA for indications supported by strong scientific
data and avoided its futile administration in settings where there is a
lack of clinical evidence of efficacy. As a result, a more appropriate
HSA prescription was achieved maintaining the health care expendi-
ture under control.
Learning points
• Clinical indications for HSA administration have emerged from
evidence-based medicine.
• HSA is the first choice to expand effective volemia in patients with
advanced cirrhosis and should be used to prevent renal failure
after spontaneous bacterial peritonitis and the post-paracentesis
circulatory dysfunction after large volume paracentesis or to diag-
nose and treat hepatorenal syndrome.
• HSA is also the second-line treatment for fluid resuscitation in critical-
ly ill patients when crystalloids and non-proteic colloids are not effec-
tive or contra-indicated. Among the heterogeneous population of ICU
patients, accumulating data indicate that those with sepsis, severe
sepsis, and septic shock benefit more from HSA administration.
Second-line treatment
Human albumin if:
• Sodium intake restriction
• Hypersensitivity to colloid or crystalloids
• Lack of response to combined use of colloids and crystalloid
Human albumin if:
• Lack of response to combined use of colloid/crystalloid
Human albumin plus crystalloid solutions if:
• Lack of response to colloid or crystalloid solutions alone
• Severe burns (>50% body surface)
Human albumin if:
• Ascites resistant to diuretics
Human albumin if:
• Severe diarrhea (>2 l/die)
• Albuminemia b 2 g/dl
• Clinical hypovolemia
 P. Caraceni et al. / European Journal of Internal Medicine 24 (2013) 721–728
• A large proportion of the HSA use is not supported by solid scientif-
ic evidence. Most of this inappropriate prescription derives from
the administration for nutritional interventions or for correcting
hypoalbuminemia per se (without hypovolemia), despite the exis-
tence of solid data against a real benefit.
• Clinical practical recommendations should be implemented to rational-
ize the prescription of HSA and avoid its futile use.
Conflict of interests
Paolo Caraceni has been a speaker for Grifols S.p.A.
Mauro Bernardi has been a speaker and consultant for Grifols Italia
S.p.A, CLS Behring GNBH, PPTA Europe.
Marco Domenicali, Alessandra Tovoli, Lucia Napoli, Carmen Serena
Ricci and Manuel Tufoni have no conflict of interest.
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