Review article

Journal of the Intensive Care Society

2021, Vol. 22(3) 248–254
! The Intensive Care Society 2020
Human albumin solutions in intensive Article reuse guidelines:
sagepub.com/journals-permissions
care: A review DOI: 10.1177/1751143720961245
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David Melia1 and Benjamin Post2

Abstract
Albumin plays a key role in the critically ill patient acting as a prognostic marker and as a therapy in the form of human
albumin solutions. However, the use of human albumin solution has varied over time with notable differences between
health systems. Whilst its use is widely accepted for some clinical indications, its role has not always been clear in the
critically ill and has been found to be harmful in some cohorts. Numerous studies have showed conflicting results and
critical care clinicians have not always been guided by robust evidence. Nonetheless, at present the use of human albumin
solution appears to be increasing again in the United Kingdom. Below, we discuss the latest evidence base for its use in
critically ill patients.

Keywords
Albumin, hypoalbuminaemia, colloids, crystalloid solutions

indicative price),11 compared to crystalloid solutions

Introduction
A stable solution of human albumin was first devel-
oped in the 1940s yet, even today, few therapeutic
interventions polarise critical care physicians more.1
Interest in albumin solution as a plasma expander has
been great, and by the turn of the century was used in
greater volume than any other biopharmaceutical
solution available on the market.2 However, the first
prospective randomised controlled trial was not
reported until 1975,3 and after numerous small studies
with conflicting results,4–6 the publication of a meta-
analysis by the Cochrane Collaboration, concluded
that albumin use may increase mortality in the critic-
ally ill.4 Despite these results, and increasing compe-
tition from the synthetic colloid market,7 human
albumin solution (HAS) remains in use in the critical
care environment. Colloid use has diminished overall
but HAS use has proportionally increased8 (Figure 1).
The use of albumin varies greatly between geo-
graphical locations and health systems; one trial
reported no use in Switzerland, whilst in the United
States it accounted for 100% of colloid used9
(Figure 2). Despite a reliable safety profile,2,10
human albumin solution’s use is still minimal in the
United Kingdom compared to other areas of the
world.8,9 Acquisition cost is potentially prohibitive;
a 500 mL bottle of 4.5% solution costing as much as
55.02 (Zenalb 4.5% solution for infusion 500 mL
bottles (Bio Products Laboratory Ltd) NHS
that can be purchased for a fraction of the cost.12
Coupled with a lack of proven superiority in the gen-
eral intensive care unit (ICU) population,13 some may
find it difficult to justify the expense. And yet, inter-
national guidelines, developed and endorsed, by inter-
national critical care societies, suggest that albumin
solution could be used after administration of ‘sub-
stantial amounts’ of crystalloid, when resuscitating
patients.14 The absence of specific recommendations
on dose and timing likely reflects heterogeneity in the
published literature.
Hypoalbuminaemia and the use of human albumin
solution in acutely unwell patients has been investi-
gated for decades. Here, we aim to briefly provide an
overview of the available clinical evidence in specific
conditions seen in ICU.
Hypoalbuminaemia
Hypoalbuminaemia is associated with worse out-
comes across a myriad of patient cohorts, including
1
Whipps Cross University Hospital, London, UK
2
Department of Bioengineering and Department of Computing,
Imperial College, London, UK
Corresponding author:
David Melia, Whipps Cross University Hospital, London E11 1NR, UK.
Email: DavidJohn.Melia@nhs.net
Melia and Post 249

Figure 1. Proportion of all fluid resuscitation episodes given in 2007 and 2014 in 84 ICUs (courtesy of Hammond et al.8).

Figure 2. Type of colloid used as a percentage of all colloid episodes by country (courtesy of Finfer et al.9).

trauma,15 major surgery,16 emergency medical admis-
sions17 and the ICU population.18
Hypoalbuminaemia, defined as a serum albu-
min < 35 g/L,19,20 is common in the ICU, with a
reported incidence of up to 76% in critically unwell
children,21 and 82% in certain adult groups.22
Mechanisms for this phenomenon are complex and
multifactorial, but the predominant syndrome
encountered in the critical care population is one of
increased capillary leak.23 Increased renal losses (e.g.
nephrotic syndrome), bleeding, protein losing enter-
opathy, increased catabolism, reduced hepatic synthe-
sis and malnutrition can all potentially contribute, but
are much less common.24
A 2003 meta-analysis of almost 100 studies, includ-
ing over 290,000 patients, demonstrated that as the
severity of hypoalbuminaemia increased, so too did
mortality, morbidity, length of stay and cost. For
each 10 g/L reduction in serum albumin concentration
a 137% increase in mortality was observed. The role
of albumin as a therapy is less clear; recipients of
human albumin solution had a reduced pooled odds
ratio of morbidity, but this failed to reach statistical
significance.
Dubois et al. tested the theory that supplementing
serum albumin with hyperoncotic solutions daily, in
patients who were hypoalbuminaemic, would result in
better outcomes. In this single centre, open label, pilot
study, 100 patients with serum albumin concentra-
tions of <31 g/dL, were randomised to receive
300 mL 20% HAS on day 1, then 200 mL 20% HAS
on each subsequent day, or to receive no albumin
250
therapy. They found that mean delta SOFA score was
greater in the albumin group than in the control (3.1
vs. 1.4; p ¼ 0.03), during days 1 to 7, concluding that
supplementation of albumin improves organ dysfunc-
tion, and results in less positive fluid balance, but were
unable to find any difference in survival, or sustained
improvement in organ dysfunction at days 14, 21 and
28.25 However, it is worth noting that there was no
statistically significant difference in absolute SOFA
scores between the two groups. A subsequent large,
randomised controlled trial, failed to replicate these
promising results26 – discussed further below.
Use as a resuscitation fluid
Intravenous fluid therapy is one of the most common
interventions in critical care,27 and human albumin
solutions may have a role in certain syndromes and
cohorts.
In 2004, the SAFE trial, of 6997 critical care
patients in 16 academic centres in Australia and
New Zealand, compared 4% HAS to 0.9% saline as
a resuscitation fluid in a heterogeneous group of
intensive care patients. Exploring all-cause mortality
at 28 days, no statistically significant difference was
found between the groups. Similar outcomes were
observed in terms of length of stay, duration of mech-
anical ventilation and incidence of renal replacement
therapy. Sub-group analysis of patients with trauma
revealed a trend towards increased mortality (13.6%
vs. 10.0% (RR 1.36; 0.99 to 1.86; p ¼ 0.06).13
This finding led Myburgh et al. to perform a post
hoc follow-up study of 460 patients from the original
SAFE trial, who had sustained a traumatic brain
injury. A significantly higher mortality (33.2% vs.
20.4%), and fewer favourable neurological outcomes
(47.3% vs. 60.6%) were observed at 24 months post
randomisation, in the albumin group, compared to
those that received saline.28 An additional post-hoc
analysis of patients who received intracranial pressure
monitoring (ICP), found that those in the albumin
group received more interventions to treat raised
ICP, and in the group where ICP monitoring was
discontinued in the first week after randomisation,
there were significantly more deaths in the albumin
group compared to saline (34.4% vs. 17.4).29 The
authors hypothesised this could be the result of
harm associated with interventions to treat ICP, or
albumin-associated coagulopathy leading to second-
ary haemorrhage. It is worth emphasising that these
are post hoc analyses, but in the absence of large
randomised controlled trials, it seems prudent to
avoid the use of albumin in the brain injured patient.
The observation of a less positive fluid balance
when using hyperoncotic human albumin solutions
sparked interest in the critical care community and
led to the concept of ‘small volume resuscitation.’30
This concept utilises the greater oncotic properties of
hyperoncotic solutions, to maximise the proportional
Journal of the Intensive Care Society 22(3)
volume of fluid administered to remain in the intra-
vascular compartment, and also to draw interstitial
fluid intravascularly. This combined effect allows
the achievement of the same haemodynamic end-
points for significantly smaller volumes of fluid
administered. When using 20% HAS, patients require
one quarter of the volume compared with balanced
crystalloid.31 Research has repeatedly demonstrated
an association with net positive fluid balance and
adverse outcomes, in both septic,25,32 and non-
septic,33,34 populations, and thus the concept of
‘small volume resuscitation’ is an attractive one.
In 2018, Martensson et al. published The SWIPE
trial,35 comparing patients resuscitated with 20%
albumin versus 4–5% albumin solutions, and found
that at 48 h the volume of fluid administered was
lower (median difference 600 mL (800 to 400;
p ¼ <0.001)), and a lower cumulative fluid balance
(mean difference 576 mL (1033 to 119;
p ¼ 0.01) was observed in the 20% albumin group
compared to the group resuscitated with 4–5% albu-
min. No difference in adverse events were found and,
thus, the authors concluded that the findings support
further exploration of ‘small volume resuscitation’ in
larger randomised trials.35 Importantly, this theory
has not yet been tested against balanced crystalloid
solutions in a similar manner.
In the general ICU population, HAS is a safe intra-
venous fluid, but without proven superiority over
0.9% saline. However, it should be avoided in those
patients who have suffered a traumatic brain injury.
Its role in ‘‘small volume resuscitation’’ appears pro-
mising but requires further large-scale research.
Use in sepsis and septic shock
Intravenous fluid therapy has been researched exten-
sively in the treatment of sepsis and septic shock.27
Albumin has received particular attention as a ther-
apy in sepsis, both as a resuscitation fluid, and in the
prevention of hypoalbuminaemia.
Both the Society of Critical Care Medicine (USA),
and the European Society of Intensive Care Medicine,
endorse the Surviving Sepsis Campaign recommenda-
tion of albumin as the colloid of choice, when resus-
citating patients with sepsis and septic shock.14,36
Again, guidance on when to move from crystalloid
to colloid, during resuscitation, is left to individual
clinician discretion.
The SAFE Study Investigators performed an a
priori, post hoc analysis of 1218 patients with severe
sepsis from their original dataset. Following multi-
variate analysis, and after adjustment for baseline
characteristics, albumin therapy was independently
associated with a decreased odds ratio for death.37
Curiously, important secondary outcome measures,
including length of ICU and hospital stay, duration
of mechanical ventilation, and incidence of renal
replacement therapy, did not differ between the groups.
Melia and Post
The results of the EARSS Study were presented by
J Charpentier, at LIVES 2011, in Berlin, Germany.
This multi-centre, open-label, randomised trial, in 29
French ICUs, looked at whether infusion of 100 mL
of 20% albumin, every 8 h, for three days, would
result in superior outcomes, compared to infusing
100 mL 0.9% saline, at the same intervals. Mortality
did not differ significantly between the two groups
(24.1% vs. 26.3%), but catecholamine requirement
was significantly reduced in the albumin group.38 It
should be noted, however, that this dataset is, as yet,
unpublished, and thus has not undergone the scrutiny
of peer review.
Following Dubois et al.’s initial results, using 20%
albumin to treat hypoalbuminemia, Caironi and col-
leagues performed the ALBIOS trial, a prospective,
multi-centre, randomised, open-label trial, of over
1800 critically unwell adults with severe sepsis, in
100 Italian ICUs. Patients were randomised to receive
either 20% albumin and crystalloid, to maintain
serum albumin levels of 30 g/L or greater, or crystal-
loid solutions alone, for the first 28 days of their ICU
stay, or until ICU discharge. Mortality at 28 days did
not differ between the two groups. During the first
seven days the albumin group had a significantly
lower cumulative net fluid balance (median 347 mL
vs. median 1220 mL; p ¼ 0.004), and quicker reso-
lution of shock (median days to suspension of vaso-
pressors 3 vs. 4; p ¼ 0.007).26
Subsequent meta-analyses have yielded mixed
results. In 2014, Patel et al. published a meta-analysis
of 16 randomised trials exploring the impact of albu-
min on mortality in critically ill adults, and found that
compared to control fluid groups, there was little dif-
ference in outcomes (RR 0.94; 95% CI 0.87–1.01;
p ¼ 0.11).39 It is worth noting here that of the
16 trials included, all but three had fewer than
60 patients. One trial included in the meta-analysis,
performed by Joachim Boldt, has since been retracted
by Anesthesia & Analgesia, after Justus-Liebig
Universität Giessen reported evidence of data
manipulation.40
In the same year, Wiedermann and Joannidis sub-
mitted a brief communication to the New England
Journal of Medicine in response to the ALBIOS
Figure 3. Meta-analysis of mortality in large-scale randomized trials comparing albumin with crystalloids in adult patients with severe
sepsis (courtesy of Wiedermann and Joannidis41).
251
trial.41 They presented their meta-analysis, including
only large scale, randomised trials of albumin ther-
apy. They concluded that, although not reaching stat-
istical significance in the individual SAFE, ALBIOS
or EARRS trials, the pooled relative risk when small
trials were excluded, indicated a significant reduction
in mortality with albumin use. This analysis excluded
all works performed by Boldt et al., and all other
trials with fewer than 60 patients included in the
meta-analysis above. It is critical to note, this is not
a formal meta-analysis, presented as original research.
However, based on these results, a formal analysis is
needed urgently (Figure 3).
Human albumin solutions have been extensively
researched in sepsis, and may have benefit over
other intravenous fluid therapies, but this has never
been definitely proven in a large-scale RCT.
Use as an adjunct to furosemide
Diuretics are used in almost 50% of critical care
admissions, with furosemide accounting for almost
95% of diuretic use.42 The diuretic effect of furosem-
ide is diminished in the setting of hypoalbuminae-
mia43 so it would appear rational to administer both
hyperoncotic albumin solution and furosemide
together, in patients who are albumin deficient.
Two small prospective trials have addressed this
question in the critical care population. In 2005,
Martin et al. published the results of a randomised,
double-blinded, placebo-controlled trial, of mechanic-
ally ventilated patients with lung injury. Patients ran-
domised to the treatment arm received 100 mL 25%
albumin, a loading dose of furosemide, followed by
the initiation of a furosemide infusion. Repeated
doses of albumin were administered every 8 h for
three days. The control group received an identical
loading dose, and infusion, of furosemide, but received
100 mL 0.9% saline every 8 h. At the end of the study
period, the albumin group had a significantly greater
mean net negative fluid balance (5480 mL vs.
1490 mL; p ¼ <0.01), and greater improvement in
their oxygenation index.44 These results should be
interpreted in the context that this multi-centre trial
consisted of only 40 patients across two sites.
252
Oczkowski et al. performed a pilot, feasibility
study, to assess whether hyperoncotic albumin, in add-
ition to furosemide, improves diuresis and enables lib-
eration from mechanical ventilation. Unfortunately,
the study did not meet its feasibility criteria, but in
the limited physiological data acquired, outcomes
were similar between the groups. The authors con-
cluded that, although feasibility with their model
was not proven, the design could help inform the
planning of future, definitive, trials.45
Furosemide potency is reduced in hypoalbuminae-
mia, but as a target for therapeutic intervention,
research so far is limited.
Use in liver disease
Patients with acute, or progressive, liver disease
account for more than 3% of all admissions to critical
care beds in the United Kingdom.46 Therefore, it is
important that the intensivist is aware of the indica-
tions and limitations of albumin therapy in liver
disease.
Paracentesis is the cornerstone of treatment of
tense, symptomatic, ascites in patients with liver
cirrhosis.47 On removal of large volumes of fluid,
circulatory dysfunction is prevalent in approximately
80% of cases, if adjunctive plasma expansion is
not performed.48 A meta-analysis, performed by
Kwok et al., of 16 randomised trials, found that
albumin use was associated with a significant reduc-
tion in post-paracentesis circulatory dysfunction
(OR 0.26 95% CI 0.08–0.93), but conferred no benefit
over synthetic colloids.49 This is in contrast with
numerous small studies that have shown benefit of
albumin therapy over synthetic colloids in this con-
text.50–52 This phenomenon is commonly observed in
critical care research, where large analyses fail to
replicate outcomes of smaller studies. The likely
explanation of this is a combination of the inherent
heterogeneity of the critical care population, com-
bined with non-uniform trial design and outcome
measures.53
The British Society of Gastroenterology (BSG) rec-
ommend that large volume paracentesis (>5000 mL)
be performed in one episode, and patients should
receive plasma expansion after completion of the pro-
cedure, using 8 g albumin per litre of ascites removed.
This equates to one 100 mL bottle of 20% human
albumin solution per 3 L of ascites drained.47
The BSG also make recommendations for its use in
high risk patients with spontaneous bacterial periton-
itis (SBP) and raised/rising creatinine; albumin
1.5 g/kg within the first 6 h, and 1 g/kg on day 3.47
A paper published by Salerno et al. in 2013, presented
the results of a systematic review and meta-analysis of
four randomised controlled trials, with a total of 270
patients. The pooled odds ratio for a reduction in
renal impairment, in patients treated with albumin,
was 0.21 (0.11–0.42), and 0.34 (0.19–0.60) for a
Journal of the Intensive Care Society 22(3)
reduction in mortality.54 Albumin’s benefit in patients
with advanced liver disease and other infections, has
traditionally, been less clear. In 2014, Thevenot et al.
published the results of a multicentre randomised con-
trolled trial, of 193 patients with severe liver disease,
and sepsis unrelated to SBP. Patients were rando-
mised to receive either antibiotics plus albumin, or
antibiotics alone. Albumin delayed the onset of
renal failure (mean time to onset, ALB: 29.0  21.8
vs. 11.7  9.1 days, p ¼ 0.018), but had no effect in
the incidence of established renal failure at three
months, or mortality.49
However, this is in contrast to those patients with
cirrhosis and ascites who receive ‘long-term’ albumin
replacement therapy. The ANSWER trial, published
in 2018 by Caraceni et al., sought to compare
standard medical therapy (anti-aldosterone drugs
and furosemide), with standard medical therapy in
combination with human albumin solution, in
patients with liver cirrhosis and ascites. Participants
in the albumin arm received 50 mL 20% HAS, twice
per week for the first week, then once weekly for up to
18 months thereafter. Patients who received albumin
therapy had a reduced risk of death of 38%, com-
pared to those who received standard medical therapy
alone (OR 0.62 CI 95% 0.40–0.95).55
Human albumin solution is a well-established ther-
apy in patients with liver disease. Although the benefit
demonstrated in smaller studies is not replicated in
larger analyses, consensus opinion favours the use of
albumin in large volume paracentesis, and in spontan-
eous bacterial peritonitis. Its acute use in other hep-
atic syndromes is less clear.
Conclusions
Albumin may have an important role within certain
facets of critical care medicine. It is recommended to
avoid circulatory dysfunction after large volume para-
centesis and is beneficial in hepatic decompensations
due to SBP. Its use in sepsis and septic shock remains
debated; reducing administered fluid volumes, but
with inconclusive effects on mortality outcomes.
Further investigation into ‘small volume resuscitation’
is urgently required. However, albumin solutions
should not be administered to patients who have sus-
tained a traumatic brain injury, and the routine cor-
rection of hypoalbuminaemia in critically ill patients
is not advised.
In summary, hypoalbuminaemia is associated with
worse mortality, which is not improved by replace-
ment. HAS is useful as an intravenous therapy in
aspects of hepatic failure and may still be shown to
have a role in sepsis, pending a formal meta-analysis
of large albumin trials. Whilst its use in the United
Kingdom pales in comparison to the United States,
Australia and New Zealand, its use continues to climb
in proportion to other colloids. Knowledge of its uses
and evidence base are paramount, allowing the critical
Melia and Post
care physician to make safe and effective, clinical and
economic decisions.
Authors’ Note
David Melia and Benjamin Post are also affiliated with
Barts Health NHS Trust, London, England.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of
this article.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
ORCID iD
David Melia https://orcid.org/0000-0001-9335-4024
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