Vincent et al.

Critical Care 2014, 18:231

http://ccforum.com/content/18/4/231

REVIEW

Albumin administration in the acutely ill: what is

new and where next?
Jean-Louis Vincent1*, James A Russell2, Matthias Jacob3, Greg Martin4, Bertrand Guidet5,6, Jan Wernerman7,
Ricard Ferrer Roca8, Stuart A McCluskey9 and Luciano Gattinoni10

Abstract
Albumin solutions have been used worldwide for the treatment of critically ill patients since they became
commercially available in the 1940s. However, their use has become the subject of criticism and debate in more
recent years. Importantly, all fluid solutions have potential benefits and drawbacks. Large multicenter randomized
studies have provided valuable data regarding the safety of albumin solutions, and have begun to clarify which
groups of patients are most likely to benefit from their use. However, many questions remain related to where
exactly albumin fits within our fluid choices. Here, we briefly summarize some of the physiology and history of
albumin use in intensive care before offering some evidence-based guidance for albumin use in critically ill pa-
tients.

Introduction have limitations, including high costs relative to possible

Albumen is doubtless one of the most important of the alternatives, notably crystalloids, and potential (rare)
animal proximate principles. risks of transmission of microorganisms, anticoagulant,
and allergic effects [6-8]. Because there are no definitive
(Henry Ancell [1]) randomized controlled trials (RCTs) demonstrating an
Albumin solutions have been used worldwide for the outcome benefit of albumin in heterogeneous groups of
treatment of critically ill patients since they became critically ill patients, routine administration of albumin
commercially available in the 1940s. However, driven for fluid resuscitation is not warranted in all patients,
largely by the results of a widely publicized meta- but there is evidence to support its use in some patient
analysis in 1998 that reported increased mortality rates populations.
in patients who received albumin solutions [2], the role The purpose of this article is not to review in detail
of albumin administration in critically ill patients be- the multiple functions and roles of albumin or the many
came highly controversial. It is well known that albumin comparative studies and meta-analyses that have now
has multiple physiological effects [3], including regula- been performed, although we will briefly summarize this
tion of colloid osmotic pressure (COP), binding and information to provide some context. Rather, we wish to
transportation of various substances (for example, drugs, provide some clear suggestions and guidance for albu-
hormones) within the blood, antioxidant properties, ni- min use based on the current available evidence and
tric oxide modulation and buffer capabilities, which may highlight important areas for future research.
be of particular relevance in critically ill patients. It is
also well established that low serum albumin levels, a
common occurrence in critically ill patients, are associ- Some background
ated with worse outcomes [4,5]. There would therefore History
seem to be a good rationale for use of albumin infusions Albumin was one of the first human proteins to be iso-
in critically ill patients. However, albumin solutions also lated and extracted from plasma for clinical use. First crys-
tallized in 1934, a preparation was made available for
* Correspondence: [email protected] clinical use in the 1940s [9,10]. Early successful use in
1
Department of Intensive Care, Erasme Hospital, Université libre de Bruxelles,
route de Lennik 808, 1070 Brussels, Belgium
multi-trauma and severely burned patients led to rapid
Full list of author information is available at the end of the article expansion of the so-called human albumin program in the
© 2014 Vincent et al.; licensee BioMed Central Ltd. The licensee has exclusive rights to distribute this article, in any medium, for
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USA [11], and albumin use spread from the military set- interaction with plasma constituents, including albumin, to
ting to civilian hospitals and into regular use in operating form the endothelial surface layer, which is positioned on
and emergency rooms around the world. The first com- the luminal side of the endothelium with a thickness of up
mercially available preparations of intravenous human al- to 1 μm in humans [16-19]. A small space, situated on the
bumin solution were developed using the cold alcohol luminal side of the endothelium beneath this protein
fractionation technique created by Edwin Joseph Cohn sponge, is permanently cleared of passing protein molecules
[9,11]. Later developments and refinements in extraction by a protein-low resting flux through small breaks in the
and processing have resulted in increasingly pure solu- intercellular junction strands towards the tissues [18].
tions [12]. Accordingly, an inwardly-directed oncotic force, quantita-
tively opposite to the hydrostatically driven fluid filtration,
Physiological properties develops exclusively across the small space beneath the
Albumin is a natural plasma protein synthesized exclu- glycocalyx and the protein-loaded endothelial surface layer
sively by the liver at a rate of 9 to 14 g/day in healthy indi- (Figure 2).
viduals, with a median half-life of about 18 to 19 days Current understanding of optimal vascular barrier func-
(Figure 1) [9]. Albumin is catabolized in most organs of tion in the high-pressure segment of the vascular system in-
the body at a similar rate of about 9 to 14 g/day, by uptake cludes an intact glycocalyx combined with a minimum
into endocytotic vesicles on the endothelial surface [9,13]; concentration of plasma proteins [20]. Although albumin is
the final breakdown products are amino acids [13]. therefore a crucial part of the endothelial surface layer and
Albumin has well-known effects on maintaining fluid bal- infusing albumin may seem a reasonable suggestion to
ance, being responsible for 75 to 80% of COP in the basal improve and maintain vascular barrier competence, experi-
physiological state [9,10]. In critically ill patients, particularly ments in isolated organs have shown that the endothelial
those with sepsis, the relationship between COP and the al- surface layer appears to function well until the albumin con-
bumin concentration is complex, being influenced by altered centration falls to a value as low as around 10 g/l [21].
permeability and increased transcapillary escape rates Hence, the major insult when the vascular barrier fails to
[14,15]. Moreover, improved understanding of the endothe- function because of a severe acute illness is most probably
lial glyocalyx has altered our comprehension of the role of not hypoalbuminemia, but a breakdown of the molecular
COP in fluid balance [16]. Numerous experimental studies structure of the endothelial glycocalyx because of hypervole-
have confirmed that the traditional understanding of an mia or ischemia/reperfusion injury and other forms of
inwards-directed oncotic gradient between a protein-low systemic inflammation [22]. Nevertheless, below a certain
interstitial space and a protein-rich plasma, as suggested by threshold, artificial substitutes such as starches or gelatin are
Ernest Starling more than 100 years ago, is not correct; in- not sufficient to form an endothelial surface layer with a
deed, the interstitial compartment has high protein concen-
trations. Nevertheless, there is a functional vascular barrier,
created by the endothelial glycocalyx layer, a skeleton of gly-
coproteins, proteoglycans and glycosaminoglycans, and its

Figure 2 Schematic illustration of the current understanding of

vascular barrier function within the high-pressure segment of
the vascular system. For explanation, see text. White arrows,
hydrostatic pressure (HP) gradients towards the interstitial space;
thick black arrow, inward directed oncotic force across the
endothelial surface layer; thin black arrow, small flux of protein low
ultrafiltrate. EC, endothelial cell; EG, endothelial glycocalyx; ESL,
endothelial surface layer; IS, interstitial space; PF, protein free space
Figure 1 Schematic illustration of metabolism of albumin in beneath the endothelial surface layer; RC, red blood cell; VL,
healthy adults. GI, gastrointestinal. vascular lumen.
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resistance against pressure-dependent fluid and protein out- Clearly there is much about the physiologic effects of
flow comparable with albumin [21,23]. albumin that is not yet well understood [8]. These effects
Albumin has many other properties in addition to its are probably altered in various disease states, particularly
effects on intravascular volume, including transport and those associated with oxidant stress such as sepsis, but
antioxidant activities, but their importance in health and whether and how these changes are involved in the
disease are less well documented. pathogenesis of these conditions requires further eluci-
The antioxidant effects of albumin are, in brief, related dation. Administration of exogenous albumin may help
to its ability to bind certain ligands, notably iron and restore or provide additional antioxidant capacity, trans-
copper, which reduces the availability of these compounds port capabilities, and vascular barrier competence, which
for pro-oxidant reactions, and are related to an exposed may account for some of the beneficial effects of albu-
thiol group on the free cysteine residue, which acts as a min seen in specific patient populations, but it is difficult
free radical scavenger, able to interact with or trap reactive to differentiate these from albumin’s effects on intravas-
oxygen or nitrogen species, including nitric oxide, a key cular volume.
mediator in many conditions including sepsis [10,24-26].
In addition to the binding of iron and copper ions, albu- Hypoalbuminemia
min also transports multiple other endogenous and Hypoalbuminemia (generally defined as a serum albu-
exogenous substances (Figure 3) [13]. Changes in albumin min concentration ≤30 g/l) [5,30] is very common in
concentrations and structure during critical illness can critically ill patients, the main reasons probably being in-
therefore potentially have marked effects on normal homeo- creased albumin losses from bleeding and via the gastro-
stasis and metabolism and on drug delivery and efficacy intestinal tract [31], increased capillary permeability
[10,27]. In a systematic review, Ulldemolins and colleagues leading to a redistribution from the intravascular to the
reported that protein binding of antibacterials, including interstitial space (previously called third-spacing) [32],
ceftriaxone, ertapenem, teicoplanin, and aztreonam, was and dilution from intravenous fluid administration
frequently decreased in critically ill patients with hypoal- Moreover, in some patients – particularly older patients
buminemia, notably with increased volume of distribution – baseline albumin levels may already be low as a result
and drug clearance [27]. These changes could result in of poor nutritional status or altered liver function. Al-
suboptimal treatment, particularly for time-dependent an- though animal models suggested that albumin synthesis
tibiotics, and may necessitate dose adjustment. may be reduced in critical illness [33], synthesis appears
The balance of acidic to basic residues on albumin makes to be increased in critically ill humans [34].
it a weak acid in physiological concentrations [10,28], so that Importantly, whatever the underlying mechanisms,
a decrease in albumin concentration increases the anion gap. hypoalbuminemia is associated with worse outcomes in-
This passively increases bicarbonate concentration, and is cluding increased complications [5,35-38] and reduced
therefore associated with development of metabolic alkalosis. short-term [5,39-43] and longer-term [42,44] survival in
Albumin also has anticoagulant effects similar to, but critically ill patients. In a meta-analysis of 90 cohort stud-
much less potent than, those of heparin, and inhibits ies that had evaluated hypoalbuminemia as a prognostic
platelet aggregation [29]. biomarker in acutely ill patients, each 10 g/l decrease in
Finally, albumin can protect the microvasculature and serum albumin concentration was associated with a 137%
mitigate increased vascular permeability via its antioxidant, increase in the odds of death, an 89% increase in morbid-
anti-inflammatory effects, and anti-apoptotic effects [3]. ity, and a 71% increase in length of hospital stay [5]. There
is therefore a clear association between the albumin level
and the severity of the insult [45], but it remains uncertain
whether the effect of hypoalbuminemia on outcome is a
cause–effect relationship or whether hypoalbuminemia is
rather a marker of serious disease.

Early clinical trials

For resuscitation in heterogeneous groups of critically ill
patients
Although albumin solutions were first introduced in the
1940s, the first RCT of albumin administration was only
published some 30 years later in 1975 (Table 1). This early
RCT, conducted in just 16 patients undergoing abdominal
Figure 3 Some of the key substances transported by albumin.
aortic surgery, compared the effects of intraoperative use
NO, nitric oxide; NSAID, nonsteroidal anti-inflammatory drug.
of albumin solution with those of a sodium-rich fluid
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Table 1 Key points in the albumin story so far

Year Event Reference
1941 First clinical use of human albumin solution in a patient with multiple trauma and circulatory shock [7]
1943 One of the first published reports of human albumin use in 200 patients [50]
1975 First randomized controlled trial of human albumin in 16 patients undergoing abdominal aortic surgery [46]
1998 Cochrane meta-analysis including 30 randomized controlled trials and reporting increased mortality rates in critically ill patients [2]
who received albumin
1998 US Food and Drug Administration issued a ‘Dear Doctor’ letter to all healthcare providers expressing serious concern over the [51]
safety of albumin administration in the critically ill population, based on the findings of the Cochrane meta-analysis, and urging
physicians to exercise discretion in its use
1999 Expert Working Party of the Committee on Safety of Medicines in UK concluded that there was insufficient evidence of harm to [48]
warrant withdrawal of albumin products but large, purpose-designed, randomized, controlled clinical trials should be conducted
to answer questions about mortality effects
1999 Study in 126 patients with cirrhosis and spontaneous bacterial peritonitis randomized to treatment with intravenous cefotaxime or [52]
cefotaxime and intravenous albumin; hospital and 3-month mortality rates were lower in the patients who received albumin
2001 Wilkes and Navickis’ meta-analysis including 55 trials and reporting no overall effect of albumin on mortality [53]
2003 Meta-analysis of 90 cohort studies evaluating hypoalbuminemia as an outcome predictor by multivariate analysis and nine [5]
prospective controlled trials evaluating use of albumin to correct hypoalbuminemia; results showed hypoalbuminemia to be a
dose-dependent predictor of poor outcome and correction of serum albumin to >30 g/l associated with reduced complications
2004 Large SAFE study randomizing 6,997 patients to 4% albumin or normal saline when fluid challenge needed; results showed no [49,54,55]
difference in mortality rates among groups, and subgroup analyses suggested benefit in patients with severe sepsis and harm in
those with traumatic brain injury
2005 US Food and Drug Administration issued a notice stating that the SAFE study had resolved the prior safety concerns raised by the [56]
Cochrane Injuries Group in 1998
2005 Results of SOAP observational study showing that albumin use was associated with decreased mortality in critically ill patients [57]
using a Cox proportional hazard model and a propensity case-matching analysis
2006 Pilot study of 100 patients with serum albumin ≤30 g/l randomized to receive 300 ml of 20% albumin solution on the first day [30]
and then 200 ml/day if their serum albumin concentration remained <31 g/l, or to receive no albumin; organ function was
improved in patients treated with albumin
2011 Meta-analysis including 17 studies in patients with sepsis reporting a survival benefit for patients who received albumin [58]
2012 ESICM taskforce Consensus statement suggesting that albumin may be included in the resuscitation of severe sepsis patients [59]
(grade 2B)
2013 Surviving Sepsis Campaign guidelines for the first time specifically suggest (grade 2C) use of albumin in the fluid resuscitation of [60]
severe sepsis and septic shock when patients require substantial amounts of crystalloids
2013 EARSS randomized controlled multicenter study comparing 100 ml 20% albumin with normal saline in patients with early severe [61]
sepsis, showing no differences in mortality rates between groups
2014 ALBIOS randomized controlled multicenter study comparing 20% albumin plus crystalloid or crystalloid alone and then continuing [62]
albumin infusions to maintain serum albumin ≥30 g/l; no overall difference in 28-day or 90-day mortality rates but survival benefit
at 90 days in patients with septic shock

during surgery and showed that albumin infusion led to outcomes [48]. In 2004, the results of the Saline versus Al-
less extracellular fluid expansion [46]. Other relatively bumin Fluid Evaluation (SAFE) RCT in almost 7,000 crit-
small studies followed, so that by the time the Cochrane ically ill patients were published, showing that a 4%
meta-analysis [2] was published in 1998 the average albumin solution was as safe as normal saline when used
sample size of the 32 included studies was just 46 patients. as a resuscitation fluid [49].
Although the results of many studies take years to be
published and to change clinical practice – if indeed they For resuscitation in patients with sepsis
ever do – this Cochrane report influenced practice rapidly Subgroup analysis of the SAFE study suggested there
around the world, especially in the UK where use of albu- may be a benefit in patients with severe sepsis (35% of
min decreased by 40 to 45% in the 6 months after publica- whom had septic shock), with an adjusted odds ratio for
tion [47]. An Expert Working Party of the Committee death of 0.71 (95% CI, 0.52 to 0.97; P = 0.03) for albumin
on Safety of Medicines in the UK highlighted the thoughts compared with saline [54]. A subsequent meta-analysis
of many in the medical community that there was an that included 17 RCTs comparing albumin solutions
urgent need to conduct large multicenter RCTs to deter- with other fluids for fluid resuscitation in patients with
mine whether albumin administration did indeed worsen sepsis reported that albumin use was associated with
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decreased mortality (odds ratio, 0.82; 95% CI, 0.67 to In 1999 Sort and colleagues published the results of a
1.0; P = 0.047) [58]. Guidelines currently suggest (grade RCT in 126 patients with cirrhosis and spontaneous bac-
2C) that albumin use should be considered as a resusci- terial peritonitis comparing treatment with intravenous
tation fluid in patients with severe sepsis, particularly if cefotaxime or cefotaxime plus intravenous albumin for
those patients are not responding to crystalloid infusion plasma volume expansion [52]. Renal impairment devel-
[59,60], based on data from the meta-analysis [58] and oped in fewer patients in the patients who received albu-
preliminary data from a multicenter study in France that min (P = 0.002) and these patients also had reduced
suggested a nonsignificant reduction in mortality in pa- hospital and 3-month mortality rates (both P = 0.01). A
tients with septic shock who received albumin [61]. more recent RCT reported beneficial effects of albumin
plus antibiotic on renal and circulatory function in 110
For resuscitation in patients with traumatic brain injury patients with cirrhosis and infections other than spon-
In the SAFE trial, patients with traumatic brain injury taneous bacterial peritonitis; treatment with albumin
treated with albumin had worse outcomes than saline- was an independent predictive factor of survival [69]. A
treated patients [55]. Using pattern mixture modeling, meta-analysis of 16 RCTs also suggested that albumin
the probable mechanism for the increased mortality ap- use was associated with a significant reduction in mor-
peared to be albumin-induced increases in intracranial tality (odds ratio, 0.46; 95% CI, 0.25 to 0.86) and renal
pressure [63]. The hypotonic and hypooncotic nature of impairment (odds ratio, 0.34; 95% CI, 0.15 to 0.75) in
the albumin solution used may also have played a role patients with cirrhosis and any infection [70]. Two small
[64]. RCTs have also demonstrated improved renal function
in patients with cirrhosis and hepatorenal syndrome
For albumin replacement in patients with hypoalbuminemia treated with albumin and terlipressin [71,72].
The effects of increasing albumin concentrations by giving
exogenous albumin have also been investigated in the critic- Recent randomized controlled trial results
ally ill. A meta-analysis of nine prospective controlled trials Following the results of the SAFE study suggesting a
on correcting hypoalbuminemia in acutely ill patients sug- benefit of albumin administration in patients with sepsis,
gested that complication rates were reduced in patients who several groups designed RCTs to further evaluate albu-
achieved serum albumin concentrations >30 g/l after albu- min use in this specific group of patients.
min administration [5]. However, in a subgroup analysis of In the ALBIOS study, conducted in 100 ICUs in Italy
the SAFE study in patients with hypoalbuminemia, using a [62], 1,818 patients with severe sepsis or septic shock were
cutoff value of 25 g/l [4], there were no significant differ- randomized either to receive 300 ml of 20% albumin plus
ences in outcomes in hypoalbuminemic patients and nor- crystalloid or to receive crystalloid alone initially to achieve
moalbuminemic patients who received albumin. In a pilot the target resuscitation goals of the early goal-directed ther-
RCT of 100 hypoalbuminemic critically ill patients who apy protocol used by Rivers and colleagues [73]. Over the
were randomized either to receive 300 ml of 20% albumin subsequent 28 days, albumin infusions were adjusted to
solution on the first day and then 200 ml/day if the serum maintain serum albumin ≥30 g/l; crystalloid solutions were
albumin concentration remained <30 g/dl or to receive no given when considered clinically indicated by the attending
albumin, Dubois and colleagues reported that organ func- physician. More patients in the albumin group than in the
tion (as assessed by change in the Sequential Organ Failure crystalloid group reached the target mean arterial pressure
Assessment score) improved more in the albumin-treated within 6 hours after randomization (86% versus 82.5%, P =
patients (P = 0.03) [30]; these patients also had a less positive 0.04), and during the first 7 days the mean arterial pressure
fluid balance (P =0.04). There was also a beneficial effect on was higher and the net fluid balance lower in the albumin
cumulative calorie intake during the first week, suggesting group than in the crystalloid group [62], despite similar
that albumin may have helped decrease intestinal edema. amounts of fluid being administered to the two groups.
The effects of albumin administration may also depend There were, however, no overall differences in 28-day mor-
on the simultaneous use of diuretics to prevent an albu- tality rates (32% albumin vs 32% crystalloid; relative risk in
min infusion-induced increase in hydrostatic pressure, the albumin group, 1.00; 95% CI, 0.87 to 1.14; P = 0.94) or
which may increase (rather than decrease) edema forma- 90-day mortality rates (41% albumin vs 44% crystalloid;
tion. Some studies have suggested that the concurrent use relative risk, 0.94; 95% CI, 0.85 to 1.05; P = 0.29) between
of albumin may increase furosemide-induced diuresis the groups. Of the 1,818 patients, 579 (31.8%) were ran-
in hypooncotic patients with acute respiratory distress domized within 6 hours and 1,239 (68.2%) more than 6
syndrome/acute lung injury [65,66] and cirrhosis-induced hours after meeting the clinical criteria for severe sepsis;
ascites [67], although not in all critically ill patients [68]; there were no significant differences in outcomes according
whether this strategy has any effect on patient-centered to the interval between meeting clinical criteria and
clinical outcomes is unclear. randomization. In the subgroup of patients with septic
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shock at enrollment (n = 1,121), however, those who re- should be used has generated some debate. Direct blood
ceived albumin had significantly lower 90-day mortality volume measurements in humans have revealed that the
rates than those who received saline (44% versus 50%; rela- intravascular volume effect of isooncotic preparations of
tive risk, 0.87; 95% CI, 0.77 to 0.99; P = 0.03) [62]. human albumin solutions is much higher than that of crys-
In the multicenter EARSS study in France, so far published talloids (>80% vs <20%) [76]. However, the albumin concen-
only in abstract form [61], 798 patients with septic shock of tration chosen largely depends on whether other fluids,
less than 6 hours duration were randomized to receive 100 especially crystalloids, are administered simultaneously – a
ml of 20% albumin or 100 ml of 0.9% saline every 8 hours 20% (20 g in 100 ml) albumin solution given simultaneously
for 3 days. Almost all patients had severe hypoalbuminemia with 500 ml of normal saline solution is equivalent to a 3.3%
at study inclusion. There were no significant differences in (20/600) albumin solution. Nevertheless, hyperoncotic albu-
mortality rates between the two groups (24.1 vs 26.3%). min may be a better choice if edema is already present [77],
avoiding excessive sodium and chloride loads and their at-
Where next? tendant complications [78].
Having briefly reviewed the background to the albumin
story so far, where are we left? Who, if anyone, should Which dose of albumin?
be given albumin? Some answers will be provided from Determining the ideal dose or volume of albumin that
further analysis of the results from recent and ongoing should be used is difficult. Early physiological studies
studies, but in the meantime we believe there are six key demonstrated that administration of 5% albumin to septic
questions that need answering. patients expanded the plasma volume by an amount
equivalent to the volume infused [79]. Different studies
Resuscitation versus supplementation (medication)? have used different doses, and perhaps the dose should be
Initially considered largely as an acute resuscitation fluid for adjusted according to a target serum albumin concentra-
its beneficial short-term effects on COP and blood volume, tion, as in the ALBIOS study [62]. The dose chosen by
recognition of the adverse outcomes associated with hypoal- Mira and colleagues in the EARSS study (100 ml of 20%
buminemia and new knowledge about vascular barrier func- albumin 8 hourly for 3 days) achieved an increase in
tioning has led to an increased interest in use of albumin serum albumin to 25 to 29 g/l [61], raising the possibility
solutions as a supplement to correct and maintain albumin that the albumin dose used may have been too low to
levels. Nevertheless, it is difficult to separate volume effects show definite benefit – although this increase was similar
from the effects of maintenance of serum albumin – par- to that reported in the SAFE study subgroup analysis of
ticularly in critically ill patients, many of whom are hypoal- patients with sepsis, in whom a benefit was reported [54].
buminemic and in whom it is difficult to clearly relate the
timing of interventions to the onset of disease. Thus, most Should albumin infusions target albumin levels?
studies of albumin administration actually combine a degree The need to make decisions as to whether or not a par-
of resuscitation with a degree of supplementation/mainten- ticular patient should receive albumin based on their albu-
ance of serum albumin. As a resuscitation fluid, the major min level is related to whether the considered use is
benefit of albumin will be from its impact on COP, resulting targeted as resuscitation or supplementation. Most pa-
in a short-term increase in intravascular volume. As supple- tients requiring resuscitation fluids in the ICU are hypoal-
mentation, effects on COP are also important, potentially re- buminemic and, as mentioned earlier, the fluid will be
ducing the risk of interstitial edema, but some of albumin’s given largely for its effects on COP – that is, limiting
other actions, such as transport and antioxidant effects, may edema formation – provided that the hydrostatic pressure
also become important. does not increase excessively. In such patients, monitoring
Efforts to substitute synthetic colloids for albumin as the albumin concentration is probably of little value.
part of perioperative fluid therapy have not been very In more prolonged administration as supplementation,
successful. Hydroxyethylstarch solutions can persist for however, serum albumin levels may be a useful guide to
long durations in the skin, the liver and, most import- ongoing needs, in combination with disease severity,
antly, the kidney [74], with a potential risk of renal fail- hemodynamic status, and nutritional status; just as an ar-
ure and even increased mortality rates in septic patients bitrary cutoff hemoglobin concentration should not be
[75]. Gelatin solutions have been less well studied, in used to define absolute need for blood transfusion in all
part because they are not available in the United States, patients, so a specific serum albumin threshold for albu-
and their persistence is quite short. min administration is unlikely to be relevant to all. The
meta-analysis of nine prospective controlled trials on cor-
Which concentration of albumin solution? recting hypoalbuminemia in acutely ill patients mentioned
Albumin solutions are available in a variety of concentra- earlier suggested that complication rates were reduced in
tions, mainly 20 to 25% or 4 to 5%, and which concentration patients who achieved serum albumin concentrations >30
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g/l after albumin administration [5]. As a result, the effectiveness evaluations of albumin use in the ICU.
ALBIOS study protocol stipulated that albumin adminis- Guidet and colleagues assessed the cost-effectiveness of
tration should be titrated to maintain serum albumin ≥30 albumin as given in the SAFE study on patients with se-
g/l [62]. Albumin levels were measured on a daily basis vere sepsis and septic shock admitted to one of 35
and 200 or 300 ml of 20% albumin were administered in French ICUs [86]. Based on a presumed 4.6% reduction
patients with albumin levels between 25 and 30 g/l or <25 in mortality associated with albumin therapy (as shown
g/l, respectively. Following the time course of albumin in the SAFE study), 513 lives were saved among the
levels, especially in response to an albumin infusion, may 11,137 patients included, with an estimated life expect-
be more valuable than a single albumin level, but optimal ancy for each life saved of 9.8 years. The cost per life
albumin levels during critical illness are not clearly saved was estimated at €6,037 and the cost per life-year
defined. saved as €617. The authors therefore concluded that al-
bumin administration was a cost-effective intervention
What type of albumin preparation? in patients with severe sepsis or septic shock [86]. Most
Currently available human albumin solutions are devel- recently, a cost-effectiveness analysis in severe sepsis and
oped using various techniques, such that the various com- septic shock using an advanced Bayesian approach ob-
mercially available albumin solutions may differ in protein served life-years gained with albumin relative to crystal-
content and composition, binding capacity, metal ion con- loid therapy, and concluded that albumin may be the
tent, antioxidant properties, charge, capacity to bind most cost-effective intravenous solution in this patient
drugs, and so forth [80,81]. This is a difficult topic to population [87].
evaluate because there are few data available about the
precise composition of the different albumin solutions Recommendations and conclusions
and whether or how this may impact on its clinical prop- Many changes within intensive care medicine have come
erties [81,82], but the differences may help explain some as the result of the realization that traditional practices
of the different study results. One study comparing six dif- once thought to be therapeutic were in fact detrimental
ferent commercially available preparations of albumin [88]. Human albumin solutions have been available for
with serum albumin from healthy volunteers reported almost 60 years and provide effective resuscitation with less
large differences between the solutions, particularly in fluid required than for crystalloid solutions; for many years,
terms of the presence of oxidized cysteine 34 (23% in hu- however, albumin was widely and perhaps nondiscrimi-
man volunteer albumin vs 54 to 60% in commercial prep- nantly used as a resuscitation fluid with little realization
arations) [81], which may influence the properties and that it may not be appropriate in all patients. Although
hence the clinical impact of albumin solutions [82]. Pre- criticized for its methodology and the heterogeneity of the
cise compositions of albumin solution should be clearly studies included, the 1998 Cochrane meta-analysis brought
identified in future study reports. this possibility to the attention of the wider community
and stimulated the conduct of large, multicenter RCTs [2].
Is albumin cost-effective? As the results of these studies become available, the role of
Albumin solutions have a good safety record [83]. The albumin in today’s critical care unit is becoming clearer
large SAFE study reported that 4% albumin was as safe and several recommendations can be made:
as normal saline in a heterogeneous group of ICU pa-
tients [49] and meta-analyses have noted that albumin  Albumin administration, although unlikely to cause
has a better safety profile than other colloid solutions harm in most patients, is not necessary in all
[84,85]. Reports of adverse events, including anticoagu- critically ill patients and should be reserved for use
lant and allergic effects and transmission of microorgan- in specific groups of patients in whom there is
isms, are rare. In a study evaluating adverse event evidence of benefit.
reporting between 1998 and 2000, the incidence of all  A hypotonic albumin solution should be avoided as
reported serious nonfatal and fatal adverse events was a resuscitation fluid in patients with traumatic brain
just 5 per million doses, and no patient death was classi- injury, based on the results of the SAFE subgroup
fied as probably related to albumin administration [83]. analysis [55].
Albumin is, however, more costly than all other resus-  There is now enough evidence – albeit largely from
citation fluids, although prices have decreased relative subgroup analyses – and plausible biological
to other fluids over the last 10 years. Nevertheless, rationale to support use of albumin in patients with
if shown to reduce morbidity and mortality even by septic shock when a colloid is considered [54,62].
a small amount, it is likely that the cost-effectiveness  Albumin administration should be considered in
ratio would favor albumin because so many ICU inter- patients with cirrhosis and spontaneous bacterial
ventions are very costly. There have been very few cost- peritonitis [52], but possibly also other infections
Vincent et al. Critical Care 2014, 18:231 Page 8 of 10
http://ccforum.com/content/18/4/231

[69,70]; in hypooncotic patients with acute Pierre Louis d’Epidémiologie et de Santé Publique, F-75013 Paris, France.
7
respiratory distress syndrome [65,66]; and also in Department of Anesthesiology & Intensive Care Medicine, Karolinska
University Hospital, Huddinge, 14186 Stockholm, Sweden. 8Servei de
patients with cirrhosis and type 1 hepatorenal Medicina Intensiva, Hospital Universitari Mútua Terrassa, Universitat de
syndrome [89]. Barcelona, CIBER Enfermedades Respiratorias, 08221 Terrassa, Barcelona,
Spain. 9Department of Anesthesia and Pain Management, Toronto General
Hospital, University of Toronto, Toronto, Ontario, Canada M5G 2C4.
Future research should be focused on patients who are 10
Dipartimento di Anestesia, Rianimazione (Intensiva e Subintensiva) e
most likely to benefit from albumin administration in whom Terapia del Dolore, Fondazione IRCCS Ca' Granda – Ospedale Maggiore
the evidence is inadequate or controversial because of con- Policlinico, 20122 Milan, Italy.

flicting study results. In addition to observational cohort

studies and RCTs focusing on specific patient groups, mech- Published: 16 Jul 2014
anistic studies are necessary to further elucidate the molecu-
lar and physiologic rationale for the beneficial effects of
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