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Controversias en Albumina PDF
Controversias en Albumina PDF
0095-5108/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.clp.2004.03.018
476 M.R. Uhing / Clin Perinatol 31 (2004) 475–488
mentation was safe, this analysis did not show that albumin supplementation
improved patient outcome. Considering the above issues, neonatologists often are
faced with the dilemma of whether albumin should be administered to their
patients. This dilemma is compounded because most literature regarding albu-
min supplementation involves adult patients. Indeed, the above meta-analyses
included relatively few neonatal patients [3,7].
This article reviews the physiology of albumin and the effects of albumin
administration in various disease processes. Because there are relatively few
studies of albumin administration in neonates, many studies of albumin use in
adult patients are included. Although not optimal, these studies offer the best
evaluation of the effects of albumin use in clinical situations common in sick
neonates and adults, such as sepsis and postoperative fluid management.
Albumin physiology
Albumin consists of 585 amino acids and has a relatively low molecular
weight of 66 kd [8,9]. In comparison, IgG and fibrinogen have molecular weights
of 150 kd and 340 kd, respectively [9]. Albumin’s relatively low molecular
weight accounts for its 75% to 80% contribution to plasma oncotic pressure
despite comprising only 50% of total plasma protein concentration [8].
Albumin is synthesized in the hepatocytes by the polysomes bound to the
endoplasmic reticulum as preproalbumin, a precursor protein possessing a 24
amino-acid extension on the N terminus [10,11]. Subsequently, 18 of these amino
acids are removed to form proalbumin. Albumin is formed when the remaining
6 amino acids are removed from proalbumin in the golgi apparatus. The primary
factor regulating the synthesis of albumin is the osmotic pressure and osmolality
of the extravascular space within the liver [12,13]. Other factors that regulate
synthesis are the availability of some essential amino acids and hormones [11,14].
Prealbumin is not a precursor to albumin. It is a different, unrelated protein
that derives its name from its having an earlier electrophoretic migration
compared with albumin.
Albumin is not stored in the liver. It is immediately excreted into the hepatic
lymph system or the sinusoids. Albumin has a circulation half-life of approxi-
mately 16 hours, in which it circulates from the intravascular space across the
capillary wall into the interstitial space, and returns to the intravascular space
through the lymphatic system [9]. Under normal conditions, the albumin
concentration in the interstitial space is half of that in the intravascular space.
Because the size of the interstitial space is twice as large the intravascular space,
interstitial spaces each contain approximately 50% of the total body’s pool of
albumin [9]. In healthy adults, the percentage of intravascular albumin leaking
into the interstitial space, or the transcapillary escape rate (TER) is 4% to 5% per
hour [15]. The TER depends on capillary permeability, capillary recruitment,
and hydrostatic pressure. The total degradation half-life of albumin is 17 to
20 days [8].
M.R. Uhing / Clin Perinatol 31 (2004) 475–488 477
unit (ICU) patients with critical illness of 7 or more days’ duration, daily
measurements of albumin and colloid osmotic pressure were correlated with
outcome [17]. Although nonsurvivors had lower mean albumin concentrations
and slower rate of normalization of albumin concentrations than survivors, colloid
osmotic pressure measurements were not different at anytime between the groups.
Furthermore, regression analysis found that serum albumin contributed only 17%
of the colloid osmotic pressure in these patients [17]. Therefore, although albumin
significantly contributes to the maintenance of colloid oncotic pressure in healthy
patients, the relationship in critically ill patients is less significant. This may be
related partially to an increased production of other proteins and acute-phase
reactants that increase colloid oncotic pressure in critically ill patients [31].
The lack of correlation of colloid oncotic pressure and albumin concentrations
in critically ill patients may explain why albumin supplementation for treatment
of hypoalbuminemia alone is ineffective. In the Cochrane meta-analysis, the
subgroup of studies on the use of albumin for treatment of hypoalbuminemia
showed the most significant increase in mortality [3]. Studies examining other
outcome measures, such as length of stay and ventilator dependence, also did
not show a significant benefit of treating hypoalbuminemia [32 – 34]. Similarly,
maintaining serum albumin levels above 2.5 g/dL compared with above 1.5 g/dL
in pediatric burn patients is not associated with an improvement in any clinical
outcome including fluid requirements, ventilator requirements, antibiotic treat-
ment, feeding tolerance, length of stay, or mortality [35].
Several studies in humans have examined the effect of resuscitation fluid on
pulmonary function in critically ill adults. Compared with crystalloids, albumin is
not more effective in preventing pulmonary dysfunction in trauma patients [36],
surgical patients [37,38], and patients with hypovolemic shock [39].
The etiology of the disease process and timing of treatment may influence
greatly the effects observed with albumin treatment. In dogs made hypopro-
teinemic with low colloid oncotic pressure (less than 40% of baseline) through
plasmapheresis, a sixfold greater amount of isotonic saline was required to reach
a pulmonary artery occlusive pressure of 10 mm Hg when compared with 5%
albumin [40]. In addition, the extravascular lung water was 52% greater in the
saline-treated animals. The study concluded that in hypoproteinemic animals,
crystalloid infusion is associated with systemic and pulmonary edema. In a
subsequent study by the same group in septic rats, extravascular lung fluid was
not different between saline- and colloid-treated animals [41]. These two studies
suggest that when albumin loss occurs in the presence of normal capillary
permeability, albumin supplementation may be beneficial, but when hypoalbu-
minemia is associated with increased capillary permeability, such as during
sepsis, the benefits of albumin supplementation disappear.
Sepsis/infection
Hypoalbuminemia during sepsis is most commonly secondary to albumin
redistribution associated with increased capillary permeability. Measurements of
480 M.R. Uhing / Clin Perinatol 31 (2004) 475–488
colloid osmotic pressure of the serum and edema fluid show that capillary
permeability is increased in patients with sepsis [42]. Direct measurements of
albumin permeability show that the TER is increased up to 300% [43 – 45]. The
increased TER and capillary permeability in sepsis are at least in part related to
cytokine release [46]. Subcutaneous injections of interleukin-2 in adult melanoma
patients have been shown to significantly increase the TER [47]. Endotoxin
administration in animals also is associated with an increased TER [48].
Contributing to the development of edema in septic patients is the propensity
for decreased lymphatic function, which leads to an inability to compensate for
the increased TER [25,26].
Significant hypoalbuminemia during sepsis unlikely is related to decreased
synthesis. Studies in animals [49] and humans [50] show that albumin synthesis
is not decreased after endotoxin administration. A cecal ligation and puncture
animal model of sepsis showed that liver albumin synthesis was decreased only
mildly [31]. Although chronic metabolic acidosis decreases albumin synthesis
[51], this has not occurred during processes with acute metabolic acidosis, such
as during sepsis [52].
In the presence of increased capillary permeability and TER, albumin infusion
expands the intravascular and interstitial space. A study of 18 septic adults found
that when 5% albumin was infused, the extracellular fluid volume increased by
224% of the volume infused. The interstitial space increased by 102% of the
infused volume and the plasma volume increased by 122% [53]. When isotonic
saline was infused, the extracellular fluid volume increased by 103% of the
volume infused with the interstitial and plasma volumes increasing by 83% and
21%, respectively. Therefore, although albumin was more effective in increasing
plasma volume, both contributed to expansion of the interstitial fluid volume
contributing to edema formation. Other outcome parameters, such as oxygen
delivery and cardiac index, were not different between the groups.
In one study in hypovolemic patients with septic shock, resuscitation with
crystalloids compared with albumin led to increased pulmonary edema as
determined by chest radiography [54]. In rats in the early stage of endotoxemia,
however, albumin administration was associated with an increased alveolar-
arterial oxygen difference [55]. In addition, the endotoxin-treated rats that
received albumin had greater levels of lung water content than rats treated with
only endotoxin or only albumin. The increase in heart and kidney water content
after endotoxin administration was not improved by infusion of albumin. This
study did not evaluate the effects of crystalloid infusion in endotoxin-treated
animals. Similarly, in baboons with sepsis there was no correlation between the
degree of pulmonary dysfunction and colloid oncotic forces [56].
Although most studies have concentrated on the role of albumin for cardio-
vascular support and development of pulmonary edema, several studies suggest
that albumin may have potential benefits as an antioxidant. In its reduced form,
albumin has a single exposed thiol group that may function as an antioxidant. In
critically ill adults, albumin administration resulted in increased plasma thiol
concentrations that were sustained despite subsequent decreases in plasma
M.R. Uhing / Clin Perinatol 31 (2004) 475–488 481
Surgical patients
Hypoalbuminemia in postoperative patients also is usually secondary to
redistribution of albumin between the intravascular and the extravascular spaces
or a result of protein losses during the surgical procedure. An analysis of
postoperative hypoalbuminemia in 17 adult patients undergoing either elective
aortic surgery or minor extra-abdominal surgery found that 77% of the decrease
in albumin was caused by redistribution, 18% caused by blood loss, and 6%
caused by increased catabolism [59]. Fleck and colleagues [43] showed that the
TER was increased 100% 7 hours after cardiac surgery in adult patients. In adults
with major abdominal surgery, cannulation of the thoracic duct revealed that
lymph volume and the concentration of lymph albumin increased during the
surgery, indicating a rising TER [60].
As in other critically ill patients, there is little correlation with colloid oncotic
pressure with either albumin or total protein concentrations in postoperative adult
ICU patients [19]. Grundmann and colleagues [19] found that treating patients
with albumin to maintain a colloid oncotic pressure above 29 cm H2O compared
with above 24 cm H2O did not alter outcome, including need for blood trans-
fusions, length of mechanical ventilation, length of ICU stay, kidney function, or
mortality. For patients with extremely low colloid oncotic pressure regardless of
their treatment group, mortality was higher, indicating that low colloid oncotic
pressure and low albumin concentrations are markers that reflect severity of
disease [19]. Similarly, in patients undergoing abdominal aortic aneurysm repair,
aortoiliac bypass grafts, or aortofemoral bypass grafts, maintenance of serum
albumin concentrations above 3.5 g/dL with exogenous albumin did not alter the
length of postoperative ileus or hospital stay [61]. Several other studies have
shown that although albumin supplementation leads to higher colloid oncotic
pressure and serum albumin concentrations, morbidity, including alterations in
pulmonary function, and mortality remain unchanged [36,38,39,62 – 64].
The effect of albumin treatment on postoperative hypoalbuminemia may
depend on the underlying cause. In the above studies, hypoalbuminemia was
related to redistribution. If hypoalbuminemia is a result of significant blood loss
or protein loss during surgery, however, albumin replacement may be beneficial.
In rats undergoing laparotomy and exteriorization of an ileal loop, albumin
replacement of plasma protein loss led to improved hemodynamics and abdomi-
nal blood flow compared with infusion of normal saline [65]. This also is
482 M.R. Uhing / Clin Perinatol 31 (2004) 475–488
Nutrition
Serum albumin concentrations are not a good indicator of nutritional status
[70,71]. Even in states of increased protein catabolism, albumin is relatively
spared [9]. In addition, because of its long half-life, serum albumin concen-
trations fall only after prolonged periods of inadequate caloric intake [72].
Conversely, when hypoalbuminemia is caused by malnutrition, serum albumin
concentrations normalize slowly after improved caloric intake [73]. A study of
16 adult postoperative patients found that despite adequate parenteral nutrition,
albumin concentrations did not normalize, whereas serum prealbumin concen-
trations significantly improved within 1 week [74].
Other investigators have examined the role of albumin administration in
nutritional support. Although one study suggests that albumin supplementation
may decrease pneumonia and sepsis [75], most studies show no benefit in terms
of morbidity and mortality [32,34,76 –78]. The only study in neonates also found
no differences [79].
Resuscitation/hypotension
Two randomized controlled studies comparing isotonic saline to 5% albumin
in hypotensive term and preterm neonates have been performed. A study of
hypotensive preterm infants less than 34 weeks’ gestation and less than 2 hours of
age found that isotonic saline and 5% albumin were equally effective in treating
M.R. Uhing / Clin Perinatol 31 (2004) 475–488 483
hypotension [80]. The albumin-treated infants had greater weight gain at 24 and
48 hours of age, indicating greater fluid retention. Oca and colleagues [81] found
similar results in term infants as well as preterm infants less than 24 hours of age.
A meta-analysis by the Cochrane reviewers found no benefit from early volume
expansion, regardless of the type of fluid used [82].
These studies are consistent with studies in adults [83]. Although resuscitation
with crystalloid solutions may require a twofold to threefold greater fluid volume
to reach the same physiologic endpoints, several meta-analyses have shown that
the type of fluid used does not affect long-term outcome in adult patients with
hypovolemia caused by trauma, surgery, or burns [84,85]. One randomized trial
found that use of albumin for treatment of hypovolemic shock impaired
respiratory function [86].
Respiratory disease
In premature neonates, albumin has been administered in an attempt to de-
crease pulmonary morbidity. Greenough and colleagues [87] hypothesized that
increasing albumin concentrations would improve diuresis, decreasing lung fluid
and improving pulmonary function. They administered 5 mL/kg of 20% albumin
versus 5 mL/kg maintenance fluids given as part of total maintenance fluids to
30 hypoalbuminemic (less than 3 g/dL), normotensive, ventilator-dependent neo-
nates between 24 and 34 weeks’ gestation and less than 7 days of age. Although
the albumin-treated infants demonstrated greater weight loss and higher albumin
concentrations, this was not associated with a significant decrease in ventilatory
support compared with the placebo group [87].
In a similar study in preterm infants with respiratory distress syndrome,
albumin was added to the total parenteral nutrition, providing a slower constant
rate of albumin infusion. Again, albumin supplementation improved weight gain
and was associated with higher blood pressure, but there were no effects on the
length of mechanical ventilation, duration of oxygenation, or time to full enteral
feedings [79]. A study of fluid intake in the first week of life in infants less than
33 weeks’ gestation found that larger amounts of colloid administration were
associated significantly with longer duration of oxygen dependency, even after
adjustment for disease severity [88]. Follow-up of these infants showed that
greater amounts of colloid infusion were associated significantly with abnormal
neurodevelopmental outcome at 1 to 2 years of age [89].
Often, albumin is administered with furosemide in hypoalbuminemic
newborns with other types of lung injury in an attempt to improve lung function.
This has not been investigated in newborns and only one study in adults has
addressed this issue directly. In this study of 37 adult patients with acute lung
injury requiring mechanical ventilation and hypoproteinemia (total protein 5 or
less g/dL), a 5-day protocol of 25 g of albumin in conjunction with a continuous
infusion of furosemide resulted in significant improvement in oxygenation
beginning 24 hours after initiation of therapy [90]. This improvement correlated
with increased serum total protein concentrations and weight loss in the treatment
484 M.R. Uhing / Clin Perinatol 31 (2004) 475–488
Summary
There are relatively few studies of albumin use in neonates and children, with
most showing no consistent benefit compared with the use of crystalloid
solutions. Certainly, albumin treatment is not indicated for treatment of hypo-
albuminemia alone. Studies also show that albumin is not indicated in neonates
for the initial treatment of hypotension, respiratory distress, or partial exchange
transfusions. In adults, albumin is not considered to be the initial therapy for
hypovolemia, burn injury, or nutritional supplementation [92].
Based on the evidence, albumin should be used rarely in the neonatal ICU.
Albumin may be indicated in the treatment of hypovolemia only after crystalloid
infusion has failed. In patients with acute hemorrhagic shock, albumin may be
used with crystalloids when blood products are not available immediately. In
patients with acute or continuing losses of albumin and normal capillary per-
meability and lymphatic function, such as during persistent thoracostomy tube or
surgical site drainage, albumin supplementation will prevent the development of
hypoalbuminemia, and possibly edema formation. This has not been studied
systematically, however. In patients with hypoalbuminemia and increased capil-
lary permeability, albumin supplementation often leads to greater albumin
leakage across the capillary membrane, contributing to edema formation without
improvement in outcome. As the disease process improves and capillary per-
meability normalizes, albumin supplementation may accelerate recovery, but
long-term benefits of albumin treatment usually cannot be demonstrated. These
patients will recover whether or not albumin is administered.
M.R. Uhing / Clin Perinatol 31 (2004) 475–488 485
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