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Clin Perinatol 31 (2004) 475 – 488
Clin Perinatol 31 (2004) 475 – 488

The albumin controversy

Michael R. Uhing, MD

Division of Neonatology, Medical College of Wisconsin, Neonatal Intensive Care Unit, Children’s Hospital of Wisconsin, 9000 West Wisconsin Avenue Milwaukee, WI 53226, USA

A recent meta-analysis of 90 studies in critically ill patients showed that each

1 g/dL decrease in serum albumin concentration increases the odds of morbidity and mortality by 89% and 137%, respectively [1] . Similarly, in the National Veterans Administration Surgical Risk Study of 54,215 major noncardiac surgery cases, preoperative serum albumin concentrations were the strongest predictor of surgical mortality and morbidity [2] . Based on this correlation between hypoalbuminemia and adverse outcome, it would seem prudent to treat patients who are hypoalbuminemic or at risk for developing hypoalbuminemia with exogenous albumin. A meta-analysis of 30 randomized controlled trials by the Cochrane Injuries Group, however, showed that the risk for death was increased in critically ill patients treated with albumin for hypovolemia, burns, or hypoalbuminemia [3] . Albumin treatment was associated with one additional death for every 17 patients treated and the study concluded that albumin should be given only in ‘‘the context of rigorously conducted, randomized controlled trials’’ [3] . Several limitations of the Cochrane analysis have been outlined, however, including (1) the lack of a homogenous patient population, (2) the lack of consistency in disease severity and treatment

regimens, (3) the lack of correlation between time of death and time of albumin administration, and (4) mortality was used as the primary endpoint for the

Cochrane analysis but was not the primary endpoint for many of the studies in the analysis [4– 6] .

A larger meta-analysis of 55 randomized controlled trials involving trauma,

surgery, hypoalbuminemia, neonates, and ascites found that albumin supplemen- tation did not increase mortality [7] . Although suggesting that albumin supple-

E-mail address: muhing@mcw.edu

0095-5108/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.clp.2004.03.018

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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].

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Colloid oncotic pressure and edema formation

The flow of fluid across the capillary membrane (J v ) is described by the Starling equation as follows [16] :

J v = L p ½ð P c P i Þ r ðp c p i Þ

where L p is the hydraulic permeability coefficient of the capillary wall, P c is the capillary hydrostatic (hydraulic) pressure, P i is the interstitial hydrostatic pressure

(tissue turgor), r is the oncotic reflection coefficient, p c is the capillary osmotic pressure, and p i is the interstitial osmotic pressure. L p reflects the permeability of the membrane to water and small solutes and is affected by the conductance of the capillary wall and the ease of movement of fluid in the interstitial space. s is a measure of permeability to proteins, with a value of 1 indicating that the mem- brane is impermeable to proteins and a value of 0 indicating that the membrane

is permeable to proteins. As evident from the Starling equation, the absolute values of capillary osmotic

pressure and interstitial osmotic pressure are not important; the osmotic gradient

is important for the development of edema. In addition, alterations in permeabil-

ity (either L p or s ) may lead to edema formation without changes in either hydrostatic or osmotic pressure. Albumin is the major determinant of colloid oncotic pressure in normal patients. Many of the theoretical arguments supporting albumin use are based on this strong relationship. In critically ill patients, however, the correlation between serum albumin concentration and colloid oncotic pressure is low [17 – 20] . There is a stronger relationship between colloid oncotic pressure and total protein concen- tration that may be related to the rise in acute phase – reactant proteins or immunoglobulins in these patients [18,21] . Because the relationship between albumin concentration and colloid oncotic pressure is low in critically ill patients, the correlation between hypoalbuminemia and edema formation is also low [22] . Analbuminemia is a rare congenital condition in which patients do not synthesize albumin. Most of these patients do not have major clinical sequelae [23,24] . Only 50% develop mild edema and mild abnormalities in lipid metabolism. The other 50% are asymptomatic. The benign course of this con- dition suggests that the role of albumin in the maintenance of colloid oncotic pressure and prevention of edema is not understood completely. The role of lymphatic function is also important in the development of edema.

A high flow of fluid across the capillary membrane (J v ) will not result in edema

formation if there is a compensatory increase in lymphatic flow [16] . Conversely, a normal J v may be associated with edema if there is lymphatic dysfunction in critically ill patients [25,26] .

Mechanisms causing hypoalbuminemia

The causes of hypoalbuminemia can be divided into four general categories:

decreased synthesis, increased catabolism, increased loss, and altered distribution

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[27] . Because serum albumin has a long half-life of 17 to 20 days, hypoalbu- minemia secondary to decreased synthesis (liver failure, starvation) or increased catabolism of albumin tends to occur over a relatively long period of weeks to months. Furthermore, because only 20% to 30% of hepatocytes are producing albumin at any one time, there is a large reserve capacity for albumin synthesis. Loss of albumin occurs with hemorrhage, nephrotic syndrome, protein-losing enteropathy, and exudative losses, such as with burn injury or surgical drains. Significant decreases in serum albumin concentrations as a result of loss of albumin can occur over a few hours. These losses can be particularly pronounced if they are accompanied by rapid infusion of crystalloid fluids during resuscitation. Altered distribution of albumin between the intravascular and extravascular compartments is probably the most frequent cause of hypoalbuminemia in critically ill patients. Increased vascular permeability, such as in capillary leak syndromes, leads to increased protein flow into the extravascular compartment. Decreased lymphatic function may lead to decreased lymph flow and, therefore, a decrease in protein return to the vascular compartment. Because alteration of capillary permeability may lead to rapid leak of albumin into the interstitial space and the circulation half-life of albumin is only 16 hours, changes in the distribution of albumin also may lead to the development of hypoalbuminemia in hours.

Normal albumin concentrations

Crucial to the discussion of albumin use in neonates is the knowledge of the normal serum albumin concentrations in preterm and term newborns. Mean albumin concentrations at birth increase from 1.9 g/dL at 25 weeks’ gestation to 3.1 g/dL at 42 weeks’ gestation [22,28] . Postnatally, serum albumin concen- trations in preterm infants rise at a similar rate as the intrauterine rate up to 8 weeks of age [28] . The relatively low normal serum albumin concentrations in preterm and term newborns are unrelated to the development of edema [22,29] . The lower normal serum albumin concentrations in newborns compared with adults must be considered when analyzing adult studies of albumin supplemen- tation. Many of the studies in adults target specific albumin concentrations that may not apply to preterm or term infants.

Albumin in specific disease states and patient populations

Critically ill patients

Hypoalbuminemia in critically ill patients is related most commonly to an increase in capillary permeability and altered albumin distribution. Barle and colleagues [30] found that albumin synthesis was higher in critically ill adults compared with healthy adults. The correlation between colloid osmotic pressure and serum albumin levels in critically ill patients is poor. In a retrospective review of 145 adult intensive-care

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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

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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

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albumin levels [57] . The investigators hypothesized that an exchange occurred between the albumin and other molecules containing thiol groups. In rats with endotoxin-primed lungs subjected to hemorrhagic shock, treatment with 25% albumin decreased lung injury as measured by decreased neutrophil sequestra- tion, decreased lipid peroxidation, and decreased nuclear factor-kB translocation [58] . Albumin modified with N-ethylmaleimide to decrease its antioxidant activity reduced this beneficial effect. The clinical significance in humans of this potential antioxidant role of albumin is not known.

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 H 2 O compared with above 24 cm H 2 O 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

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supported by the decrease in systemic and pulmonary edema after albumin infusion in hypoproteinemic dogs after plasmaphoresis [40] . In neonates, hypoalbuminemia has been associated with an increased risk for necrotizing enterocolitis [66] and anastomotic dehiscence following enterostomy

closure after surgically treated necrotizing enterocolitis [67] . This is consistent with studies in adults showing poorer outcomes in hypoalbuminemic patients. The effect of exogenous albumin in these patients has not been studied. There are few studies of albumin treatment in pediatric surgical patients. Kenny and colleagues [68] found that hypoalbuminemia occurred in 27% of postoperative neonates. The mortality in the hypoalbuminemic infants was greater but unrelated to the albumin level or albumin treatment. Ford and colleagues [69] showed that in pediatric patients 3 months to 12 years of age a serum albumin below 3 g/dL was associated with a greater number of episodes of feeding intolerance. In a follow-up study of 20 patients ranging from 4 months to

14 years of age, patients with a serum albumin below 3 g/dL were treated with

exogenous albumin. The incidence of feeding intolerance decreased to the same rate as that in the patients with the higher albumin levels in the initial study [69] . The use of historical controls limits the validity of this study, however. A prospective randomized trial in adults failed to show any effect of albumin supplementation in postoperative patients with hypoalbuminemia on length of postoperative ileus or feeding tolerance [61] .

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

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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

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group. Oxygenation in the control group also improved by 72 hours, however. The study identified differences between the control group and the treatment group in oxygenation, weight loss, or serum total protein by 1 week of age. Therefore, although the combination of albumin and furosemide accelerated the improvement in the patients’ pulmonary status, overall outcome was not affected. In addition, the study did not evaluate the effect of furosemide alone. Therefore, whether albumin administration led to the improvement is not clear. Finally, the inclusion of only relatively stable patients who were likely to improve despite different therapies makes extrapolation of the data to more unstable patients with ongoing capillary leak difficult.

Partial exchange transfusion

A study of 102 full-term infants with polycythemia found that partial exchange transfusions using isotonic saline or 5% albumin were equally ef- fective. There were no differences between the groups in blood pressure, decrease in hematocrit, serum electrolytes, or bilirubin concentrations. They concluded that in view of the lack of differences, use of 0.9% NaCl was the preferred re- placement fluid [91] .

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.

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