TATM 2003;5(4):397-400

Should Albumin Be Used to )

(
Correct Hypoalbuminemia
in the Critically Ill? Yes

SUMMARY

Hypoalbuminemia is frequent in critically ill patients and is associated with worse

J EAN -L OUIS V INCENT, MD , PhD
DEPARTMENT OF INTENSIVE CARE
ERASME HOSPITAL
FREE UNIVERSITY OF BRUSSELS
BRUSSELS, BELGIUM
outcomes. From the limited clinical data available, it would seem that replenishing
low albumin levels in hypoalbuminemic critically ill patients may be of benefit.
Nevertheless, deciding exactly which patients to treat and what level of serum
albumin to aim for remains uncertain. The results of prospective, randomized
controlled trials are urgently needed to provide intensivists with sufficient, high-

grade evidence on which to base decisions regarding albumin use. In the meantime,

however, there is no reason to ban the use of albumin in the critically ill patient.

• Albumin
• Hypoalbuminemia
• Critically ill
• Safety

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Albumin in the Critically Ill: Pro J E A N -L O U I S V I N C E N T

Recent years have seen increasing debate and controversy over frequently occurs in the critically ill patient, passage of fluid into
the use of albumin in critically ill patients. Meta-analyses have the interstitial space increases considerably, and maintenance of
been published with apparently conflicting conclusions,1,2 oncotic pressure becomes relatively more important. In patients
moratoriums on the use of albumin have been called for by some3 with hypovolemic shock, colloid infusion, including albumin, is
while others have leapt honorably to its defense,4 and the associated with less edema formation than crystalloid infusion.10
intensivist is left trying to weigh up the evidence. Although some
questions had been raised earlier,5 the story really kick-started Substance Binding
with the publication in 1998 of a meta-analysis by the respected
In addition to the effects of albumin on COP, albumin has many
Cochrane group on the administration of albumin solutions.1 The
other physiological properties, which make it a valuable
authors concluded that the overall relative risk of death in patients
resuscitation fluid. Albumin functions as the principal binding
receiving albumin solutions was 1.68 compared with non-albumin
protein of various endogenous and exogenous substances,
recipients, suggesting that for every 17 critically ill patients treated
including drugs and metabolites. Albumin is also a secondary or
with albumin there is one additional death. This study attracted
tertiary carrier for some substances that have specific binding
considerable media attention with headlines such as “Burns
proteins, for example, steroids, including derivatives such as
treatment ‘kills thousands’” (Daily Telegraph, UK). However,
vitamin D and thyroxine.11 For drugs that are strongly linked to
albumin has been used widely around the world for more than
albumin and those with narrow therapeutic ranges,
60 years. Should we discard it on the basis of this one, highly
hypoalbuminemia will increase the free fraction of the drug,
criticized article? Let us briefly look at some of the evidence in
potentially leading to an increased or even toxic effect.12,13
support of albumin.
Metabolic and Antioxidant Activities
Properties of Albumin Albumin is involved in the metabolism of endogenous
substances such as lipids and eicosanoids. Albumin can stabilize
Maintenance of Oncotic Pressure some eicosanoids during metabolism, such as prostaglandin I2
and thromboxane A2; it can increase the release of arachidonate
Albumin accounts for about 80% of the normal oncotic
from macrophages; and it seems to favor lipo-oxygenase over
pressure.6 Critically ill patients have a lowered COP, and this is
cyclo-oxygenase.11 Albumin also has important oxygen free radical
associated with worsened outcome.7 When capillary permeability
scavenging properties, with albumin able to inhibit the production
is normal, a decreased COP is associated with an increased
of oxygen free radicals by polymorphonuclear leucocytes14 and
filtration rate across the capillaries, resulting in edema in most
in septic patients albumin administration can increase plasma
tissues, although the lung is relatively insensitive to extravascular
thiol levels,15 thiols, themselves, being scavengers of reactive
fluid shifts caused by lowering of the COP, due to the efficacy of
oxygen and nitrogen species. Although the clinical significance
the pulmonary lymph drainage and the high pulmonary interstitial
of these effects remains untested, hypoalbuminemic patients may
protein concentration.8 The main determinant of fluid exchange
thus have reduced potential for oxygen free scavenging and
in the lung is the hydrostatic force, and when pulmonary
increased susceptibility to the effects of these toxic agents.
hydrostatic pressure is normal, a fall in oncotic pressure is of little
importance;9 however, when hydrostatic pressure increases, as
Antithrombotic Properties
Table 1.
Albumin influences coagulation in a similar way to heparin,
Suggested Beneficial and Harmful Effects of Albumin possibly related to the similarity in the structure of the two
Potentially beneficial molecules.11 Albumin decreases platelet aggregation16 and has
• Decreased edema antithrombotic effects.17 There is an intimate connection between
– improved gas exchange
– improved wound healing the coagulation system and the inflammatory response, supported
– earlier mobilization by the fact that the only immunomodulating therapy so far shown
– improved tolerance to feeding to be effective in treating sepsis is drotrecogin alfa (activated), a
• Anti-platelet effects
• Anti-thrombotic effects recombinant form of the natural anticoagulant, activated protein
• Improved microcirculation C.18 The effects of albumin on this interaction may be important.
Potentially harmful
• Fluid overload – pulmonary edema Effects of Albumin on the Microcirculation
• Altered myocardial contractility (decreased calcium availability)
• Worsening of edema (leakage of larger molecules in the interstitium) There is evidence that albumin might beneficially influence the
• Increased blood losses (anti-hemostatic and anti-platelet effects)
microcirculation, although this remains controversial. Albumin
• Impaired water and sodium excretion/renal failure
• Altered immune response seems to reduce increases in capillary permeability; the

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 Albumin in the Critically Ill: Pro J E A N -L O U I S V I N C E N T

mechanisms behind these effects are unclear but may be related beneficial, and indeed this approach has been evaluated in a
to the size of the albumin molecule simply blocking the channels, number of studies.34-39 However, these studies focused on specific
or some effect of the strong negative charge repelling other populations and extrapolation to the general ICU patient may be
negatively charged particles in the capillary membrane.11 In a rat difficult. Nevertheless, a recent randomized controlled trial of
model of hemorrhagic shock, Horstick et al. noted markedly albumin administration in critically ill hypoalbuminemic patients
reduced rolling and adherent leukocytes, maximum velocity, and does support a beneficial effect of albumin replacement,40 and a
shear rate in the mesenteric microcirculation after administration recent meta-analysis assessed the effects of correcting
of albumin.19 hypoalbuminemia as reported in 9 prospective studies involving
535 patients.27 Analysis of dose-dependency in these controlled
Anti-Apoptotic Effects trials of albumin therapy suggested that complication rates may
be reduced when the serum albumin level attained during
Some of the effects on the microcirculation may be related to
albumin administration exceeds 30 g/L. In addition, if correction
the anti-apoptotic effects of albumin. Apoptosis is a normal
of hypoalbuminemia is considered, the optimal albumin
phenomenon involved in vascular remodeling, but it may be
concentrations to which therapy should be targeted by have not
disturbed in certain situations. Several studies have demonstrated
been clearly defined.
anti-apoptotic effects of albumin,20,21 possibly mediated in part by
Liver disease, and particularly cirrhosis, is frequently associated
its effects on calcium metabolism.20
with hypoalbuminemia. In a study of 126 patients with cirrhosis
and spontaneous bacterial peritonitis, Sort et al.41 randomized
patients to receive treatment with cefotaxime or cefotaxime plus
Adverse Events intravenous albumin. The results showed a reduced incidence of
renal impairment and reduce mortality rates in the group treated
Albumin solutions have an excellent long-term safety profile.22,23
with intravenous albumin in addition to the antibiotic. In 126
A recent study covering 1.62 x 107 albumin doses noted that
patients with cirrhosis and ascites, albumin was shown to be
despite likely increased reporting of adverse events since the
effective in improving the rate of response to diuretic therapy and
Cochrane meta-analysis,1 the incidence of all serious adverse
preventing recurrence of ascites.42
events was 5.28 per 106 doses, and no patient death was classified
The use of albumin as a general resuscitation fluid in all critically
as probably related to albumin administration.23
ill patients is less obvious and results of randomized controlled
studies, such as that recently completed in Australasia (the Saline
versus Albumin Fluid Evaluation [SAFE] study) where saline was
Use of Albumin in Critically Ill Patients compared with albumin in the fluid resuscitation of critically ill
patients, are urgently awaited, although this may not provide all
Hypoalbuminemia is frequent in the critically ill patient,24 and
the answers as it studied albumin as a resuscitation fluid rather
may be the result of a variety of factors including decreased
than specifically to correct hypoalbuminemia.
synthesis or increased catabolism, renal or gut losses, dilution
secondary to fluid infusion, and redistribution secondary to
increased vascular permeability.25 Hypoalbuminemia is associated
with worse outcomes in intensive care unit patients. In a review
Conclusion
of the literature, mortality was reported to increase by 24 to 56%
Albumin has well-established, unique and wide-ranging
for each 2.5 g/L decrease in albumin concentration,26 and more
properties, and hypoalbuminemia is associated with poorer
recently, in a meta-analysis of 90 cohort studies including a total
outcomes. From the limited clinical data available, it would seem
of 291,433 patients, for each 10 g/L decrease in albumin, the
that replenishing low albumin levels in hypoalbuminemic critically
mortality was increased by 137%, morbidity by 89%, and ICU
ill patients may be of benefit. Nevertheless, deciding exactly which
and hospital lengths of stay by 28% and 71%, respectively.27 In
patients to treat and what level of serum albumin to aim for
this study, the association between hypoalbuminemia and poor
remains uncertain. The results of prospective, randomized
outcome was independent of the patient’s nutritional and
controlled trials are urgently needed to provide intensivists with
inflammatory status. Other studies have also demonstrated a link
sufficient, high-grade evidence on which to base decisions
between hypoalbuminemia and various outcome measures
regarding albumin use. In the meantime, however, there is no
including mortality,28-30 ICU length of stay,31 ventilator
reason to ban the use of albumin in the critically ill patient
dependency,31,32 and the development of acute respiratory distress
syndrome (ARDS) in patients with sepsis.33
The poor prognosis associated with hypoalbuminemia suggests
that raising serum albumin levels back towards normal may be

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Albumin in the Critically Ill: Pro J E A N -L O U I S V I N C E N T
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