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CRITICAL CARE AND TRAUMA

The Good, the Bad, and the Ugly: Should We Completely Banish Human Albumin from Our Intensive Care Units?

Department of Anesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Ludwigshafen, Germany

Address correspondence and reprint requests to Joachim Boldt, MD, Department of Anesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Bremserstr. 79, 67063 Ludwigshafen, Germany. Address e-mail to BoldtJ{at}gmx.net

	Abstract

Top Abstract Introduction What Is so Specific... Specification of Albumin... Pros and Cons of... Indications for Albumin... What Does the Literature... What Can We Conclude... References

 

Implications: Human albumin is still widely used in critically ill patients for volume replacement therapy or for correcting hypoproteinemia. Most meta-analyses on the value of albumin administration are over 15 yr old and raise more questions than they answer. With the help of a MEDLINE analysis, we examined more recent studies in humans using albumin. Most of these studies have recommended a very cautious use of albumin in critically ill patients.

	Introduction

Top Abstract Introduction What Is so Specific... Specification of Albumin... Pros and Cons of... Indications for Albumin... What Does the Literature... What Can We Conclude... References

 
Hypovolemia is a consequence of a variety of pathophysiological processes, and it is common in intensive care patients. Intravascular fluid deficits occur in the absence of obvious fluid loss, most likely secondary to generalized modification of endothelial barriers resulting in capillary leaks. Hypovolemia is a potential killer in any disease process (1) and IV fluids are required to adequately increase the circulating blood volume. The restoration of flow is essential to avoid tissue ischemia and subsequent multiple organ failure. Because maintenance of cardiovascular stability and prevention of microvascular disorder are related, both systemic hemodynamics and microcirculatory stability need to be optimal (2).

Controversy still persists over the best choice of fluid to use for intravascular volume restoration. Increasing hemoglobin concentrations to more than 7 to 10 g/dL is of little or no benefit for oxygenation/tissue perfusion and/or outcome in intensive care unit (ICU) patients (2,3). Furthermore, transfusion of allogenic blood of as little as 1–2 units was an independent predictor of infection (4,5). Thus, allogeneic blood should only be given to patients who have severe anemia.

The use of albumin continues to be controversial (6,7). Albumin solutions have been and are still used for critically ill ICU patients (8–10). Approximately 300–400 tons of albumin were administered during 1998 world-wide (personal communication). In the United States approximately 100 tons were given (Europe: also approximately 100 tons)—equivalent to 4 million bottles of 5% albumin 500 mL or 4 million bottles of 25% albumin 100 mL. As demonstrated in earlier studies, albumin accounts for up to 30% of the total pharmacy budget in many hospitals (11). In today’s climate of cost consciousness and cost containment, is there still any place for the use of such a high-priced substance?

The use of meta-analyses and evidence-based medicine analyses is common. Most of these analyses have only produced more confusion, however, concerning the best choice of the ideal intravascular volume replacement regimen. Although there are several negative studies on the use of albumin, the controversy has not been solved (12). It is not the aim of this overview to create another meta-analysis or evidence-based medicine analysis on albumin, but to present pros and cons on the use of albumin with respect to the ICU patient. Additionally, more actual studies on albumin in the ICU patient should be analyzed to formulate possible recommendations for albumin in this particular setting.

	What Is so Specific About the ICU Patient?

Top Abstract Introduction What Is so Specific... Specification of Albumin... Pros and Cons of... Indications for Albumin... What Does the Literature... What Can We Conclude... References

 
Patients should be characterized by their underlying diseases (e.g. sepsis, burns, trauma). However, most critically ill ICU patients have a common pathophysiological process. Infection, trauma, or major surgery initiate an inflammatory cascade leading to an activation of regulatory mechanisms that are aimed at control in the intensity of inflammatory response (13). Release of various inflammatory mediators (e.g. various cytokines) and leukocyte activation have been implicated in the pathogenesis of the inflammatory process (14). This cascade becomes self-perpetuating and may result in a damaged endothelial integrity, increasing microvascular permeability and promote extravasation of fluids into the tissue. Thus, one major problem in fluid management of the ICU patient is the generalized increase in capillary permeability (15,16). The definitive etiology of endothelial cell damage in this situation has not been fully elucidated. The direct effects of hypoxia caused by microcirculatory abnormalities, release of proteinases from activated white cells, activation of mediator systems, and activation of coagulation cascade all may contribute to endothelial function abnormalities (17–19). Microcirculatory dysfunction may result in reduced arteriolar pressure and endothelial swelling. Poorly perfused capillaries are associated with the risk of liberation of various mediators by which cell adhesion and vasoconstriction is promoted, and a vicious cycle of progressive tissue damage is instituted (20).

In healthy conditions, increased capillary pressure results in increased filtration of water and low molecular weight solutes out of the intravascular space into the tissue. By the subsequent dilution of the interstitial matrix and the increased concentration of capillary proteins, water is pulled back into the intravascular compartment. In "leaky conditions" (e.g. in inflammation) increased capillary pressure results in an increased shift of water and larger molecules (e.g. albumin) into the interstitium. Because of the increased concentration of protein in the interstitial space and the "relative" dilution of protein in the capillary space, colloid oncotic pressure (COP) is reduced, with subsequent less movement of water from the tissue.

	Specification of Albumin Solutions

Top Abstract Introduction What Is so Specific... Specification of Albumin... Pros and Cons of... Indications for Albumin... What Does the Literature... What Can We Conclude... References

 
Albumin is a naturally occurring plasma protein and has long been thought to be the kind of solution by which patients would most profit (defined as the "gold-standard"). Commercially available human albumin solutions (HA) contain approximately 96% albumin, purified protein fraction contains approximately 83% albumin, the remainder in both products being globulins. Although albumin is derived from pooled human plasma, there should be no risk of disease transmission because albumin is heated and sterilized by ultrafiltration. Thus, albumin is generally considered safe (21). The future production of recombinant albumin may be an alternative to today’s production process.

The molecular weight of albumin is approximately 69,000 Daltons. Albumin 4% is slightly hypooncotic, 5% albumin is isooncotic, whereas 20% and 25% solutions are markedly hyperoncotic, so that total plasma volume is expanded by shifting of fluid from the interstitial/intercellular to the intravascular compartment. One hundred milliliters of albumin 25% increases intravascular volume to a total volume of approximately 450 mL (22). Albumin 5%, 500 mL, expands plasma volume by approximately 490 mL or 750 mL. The volume effect of albumin is not predictable and depends on blood volume, proteins levels, and capillary permeability.

	Pros and Cons of Albumin Application

Top Abstract Introduction What Is so Specific... Specification of Albumin... Pros and Cons of... Indications for Albumin... What Does the Literature... What Can We Conclude... References

 
Benefits of Albumin
Maintenance of COP is a desirable goal of intravascular volume replacement in the critically ill patient. In "old" studies, the oncotic force of concentrated HA (e.g. 20%) reduces tissue edema (e.g. pulmonary tissue edema) (23–25). These beneficial effects of albumin greatly vary with regard to the patient’s disease. In patients with altered vascular endothelial integrity (e.g. in septic patients), albumin may pass into the interstitial space, by which fluid shift from the intravascular compartment may be promoted, interstitial volume substantially increased, and tissue perfusion altered ["overalbuminization" (26)]. The importance of maintaining or increasing COP is not certain. In a randomized study of 220 patients, COP was modified perioperatively (27). Albumin was added when the COP was <19 mm Hg. In another group, albumin was given more liberally (when COP was <23 mm Hg). The two groups did not differ in mortality, length of ventilation, renal function, and outcome. Others (28,29) have demonstrated that an acute reduction of plasma COP, while maintaining pulmonary capillary hydrostatic pressure in sepsis states, resulted in fluid retention, weight gain, peripheral edema, and ascites, but no pulmonary edema. These studies suggest that sepsis leads to pulmonary dysfunction but that this dysfunction appears to be independent of colloid oncotic forces.

Albumin may also have some additional specific effects related to its transport function for various drugs and endogenous substances (e.g. bilirubin, free fatty acids) (30,31). Many drugs used in critically ill patients bind to albumin, and drug toxicity is partly attributable to altered binding capacity. Albumin may also have protective properties caused by free radical scavenging by which membrane permeability is beneficially modified (32). In an in vitro study, the effects of different resuscitation fluids (e.g. dextran, hetastarch, albumin) on neutrophil activation was examined (33). Neutrophil activation and expression of neutrophil adhesion molecules was least pronounced with albumin. However, others found a significant increase in expression of endothelial cell adhesion molecules with albumin (34). All possibly beneficial effects of albumin were only shown experimentally, no study has shown any of these beneficial effects in the ICU patient.

Side-Effects of Albumin
All fluids used for intravascular volume replacement have merits and demerits—also the natural colloid albumin. One of the most threatening problems with the use of synthetic colloids is the occurrence of (severe) anaphylactoid reactions. This appears to be less frequent when using albumin (35). Certain commercially available albumins contain remarkable quantities of ions from the preparation process. In patients with acute renal failure, potentially toxic concentrations of aluminum occur after massive albumin administration (36). Hypotension has occurred after albumin administration and is most likely caused by vasoactive peptides (37). Other side effects were demonstrated only in animal experiments. By using isolated rabbit myocardium, the addition of albumin caused a more pronounced depression in myocardial contractility than hydroxyethyl starch (38). This may be explained by the increased binding between albumin and Ca⁺⁺. Although considered to be the colloid with the least influence on coagulation, albumin may exert coagulatory or anticoagulatory effects (e.g., by inhibiting platelet aggregation and enhancing the inhibition of factor Xa by antithrombin III) (39,40). Tobias et al. (41) showed in an in vitro study using serial hemodilution (11%, 25%, 33%, 50%, and 75%) and thromboelastography that albumin may also produce early and profound hypocoagulable effects. Using in vitro bleeding time to test primary hemostasis albumin showed an increased bleeding time (42). Finally, certain batches of albumin preparations affect the expression of endothelial cell adhesion molecules (34). The mechanism and importance of this effect is uncertain, although increased plasma levels of endothelial adhesion molecules in the circulating blood may be regarded as markers of nonsurvival (43). However, overall side effects of albumin are rare, and there are no absolute contraindications for the use of HA.

	Indications for Albumin Administration

Top Abstract Introduction What Is so Specific... Specification of Albumin... Pros and Cons of... Indications for Albumin... What Does the Literature... What Can We Conclude... References

 
Albumin for Intravascular Volume Replacement in the ICU Patient?
Adequate volume replacement is a cornerstone for managing the ICU patient. Most of these patients (e.g. patients with sepsis/septic shock) show large fluid deficits. In approximately half of septic patients, adequate volume replacement may reverse hypotension and restore hemodynamics (44). In the United States, approximately 26% of all albumin is given to treat acute hypovolemia (e.g. surgical blood loss, trauma, hemorrhage). Approximately 12% of all albumin is used to treat hypovolemia for other reasons (e.g. infection). Hypovolemia is thus an important reason to administer albumin.

The effects of albumin depend on its movement between the intravascular and extravascular compartments. Albumin is considered necessary to increase COP to prevent extravasation of fluid from the intravascular space. It may, however, aggravate interstitial edema because it is not confined to the vascular space. Thus, the retention of infused albumin in the intravascular compartment, and therefore its hemodynamic efficacy, greatly vary with regard to the patient’s disease. When using low molecular weight colloids (e.g. gelatins [35,000 Daltons] or albumin [69,000 Daltons]) larger volumes will be required because of the failure of the colloid to remain in the intravascular space. Because these colloids tend to leak from the vascular compartment, interstitial edema will be worsened (45). Consequently, albumin may be without benefit as a plasma substitute in patients showing capillary leakage. Whether all colloids (including synthetic colloids with a higher molecular weight) are contraindicated in patients with capillary leak, or whether some may even prevent further leakage ["plugging the leak" (46)] is intensively discussed. Weaver et al. (47) demonstrated that albumin molecules may extravasate into the interstitium and thus may favor fluid movement out of the capillaries. In contrast, narrow range hydroxyethyl starch [HES] (molecular weight 250.000 Daltons) was reported to be effective in reducing capillary edema in experimental (48) and clinical models of increased permeability (49). Despite some promising results with the use of this specific volume replacement regimen, this area of speculation requires further investigation.

Hypoalbuminemia: To Treat or not to Treat?
One important rationale for using albumin in the ICU patient appears to be the correction of hypoalbuminemia. Surgery, trauma, or infection decrease albumin plasma levels. Interestingly, administration of excess albumin does not alter albumin synthesis but increases the rate of degradation (50). Intravascular infused albumin is completely distributed within the extravascular space in 7 to 10 days (50). Injury and infection result in a decrease of serum albumin level of approximately 1.0 to 1.5 g/dL within 3 to 7 days (50). Because the half-life of albumin is approximately 20 days, this decrease cannot be explained by a reduced albumin synthesis. Vascular leakage associated with increased distribution to the extravascular space seems to be most important for decreasing albumin concentrations in inflammatory states (e.g. sepsis, trauma) (51). Ten percent of the infused albumin leaves the vascular space within two hours (52). More rapid equilibration occurs in capillary leakage: in an animal experiment using Escherichia coli, capillary permeability to albumin has increased 13-fold; permeability to dextran was only one-third as great (53).

Several studies have demonstrated that low serum albumin is associated with poor outcome (22,30,50,54). A serum albumin level of <2.0 g/dL was associated with a mortality of nearly 100% (55). Albumin appears to be a nonspecific marker of the seriousness of an illness. However, changes to its value are the result of pathological events, and not the cause of them (30). Thus, hypoalbuminemia can be regarded as a "normal" phenomenon in the critically ill ICU patient (56). Supplementation of albumin in patients who have hypoalbuminemia has no apparent effect on morbidity and outcome (22). In a randomized, prospective study in 219 critically ill surgical ICU patients, Golub et al. (57) either supplemented low albumin plasma concentration (<3.0 g/dL) or not (control group). There were no differences with regard to morbidity and mortality between supplemented and nonsupplemented patients. The authors concluded that albumin should be abandoned in the treatment of these patients. Rubin et al. (58) also did not demonstrate any benefit on patient outcome after albumin supplementation in severe hypoalbuminemic patients (albumin plasma level < 2.5 g/dL) receiving total parenteral nutrition (TPN). In another study, Foley et al. (59) used concentrated albumin to correct hypoalbuminemia and achieve serum albumin levels of 2.5 g/dL or greater in the critically ill patient. They failed to show that this regimen has beneficially influenced patient morbidity or mortality. Albumin supplementation during TPN in patients showing albumin plasma levels < 3 g/dL had no apparent effect on free water excretion or electrolyte-free water resorption (60).

The question is whether we should support a particular range of serum albumin levels. Is there a specific dangerous level of albumin concentration? Because knowledge of serum albumin levels provides no useful additional diagnostic and prognostic information, determination of serum albumin on the ICU should be strictly limited (30). Interestingly, people have been born without albumin (congenital analbuminemia), and several patients are remarkably asymptomatic (61). What is the role of albumin: vital component or place-holder, hero or poseur?

Possible and Controversial Indications for Albumin Use
Some possible indications for the use of albumin outside "standard" intensive care management have been formulated:

Neonatology ICU,

ICU patients after liver transplantation, and

Severely burned ICU patients.

It is beyond the intention of this overview to deepen the discussion on these problems because no, or only very few, controlled studies are available, and conclusive results are lacking. However, some of the possible indications have already been questioned. When using albumin in burn patients, synthetic colloids (e.g., MMW-HES) have been shown to be as effective or even superior in increasing central venous pressure, (CVP), pulmonary capillary wedge pressure, (PCWP), DO₂, and VO₂ (62). No attempt should be made to normalize albumin levels in burns (63): albumin plasma levels of 15 g/L have been well tolerated.

Some very controversial indications for administration of albumin in the ICU patient have been defined:

Liver disease, ascites, paracentesis,

Malnutrition, starvation,

Nephrotic syndrome, and

Pancreatitis, peritonitis.

Management of patients with ascites is often considered an indication for the use of albumin. Plasma volume expansion using albumin in patients with cirrhosis and spontaneous bacterial peritonitis resulted in a smaller incidence of renal impairment than in a group of patients without additional volume therapy (64). In a study of patients who have cirrhosis with ascites, it was assessed whether IV diuretics plus intravascular volume expansion with albumin exert beneficial effects compared with diuretic therapy alone (65). The cumulative rate of response to diuretics plus albumin treatment of ascites was larger than in the diuretic group alone. Survival, however, was similar in the two groups. In a study of patients who have liver cirrhosis and hypovolemia and comparing two volume replacement strategies (gelatin vs albumin), it has been demonstrated that the infusion of a synthetic colloid (gelatin) showed no differences to treatment with albumin (66). Also others showed no benefit of albumin administration in cirrhotic patients undergoing paracentesis in comparison to patients treated with synthetic colloids (67,68). Thus, there appears to be no rational reason to use albumin-containing solutions under these circumstances.

	What Does the Literature Tell Us About Albumin in the ICU Patient?

Top Abstract Introduction What Is so Specific... Specification of Albumin... Pros and Cons of... Indications for Albumin... What Does the Literature... What Can We Conclude... References

 
Despite several meta-analyses, evidence-based medicine analyses, and consensus conferences (69–72), confusion has increased concerning the use of albumin. In 1998, the Cochrane Injuries Group published a meta-analysis comparing the use of albumin with other regimens of volume replacement (crystalloids, synthetic colloids) (6). The analysis included 30 studies of 1419 patients. The pooled results showed an overall excess mortality of 6.8% (or approximately 6 additional deaths for every 100 patients treated with albumin).

Important problems with all meta-analyses have been the mixing of patients with different diseases (e.g. trauma, burns, surgery), including patients with varying degrees of severity of illness, and merging different kinds of fluids that were infused. Only one meta-analysis distinguished between studies in critical care patients (n = 3) and other kinds of patients (73). Two of the three analyzed studies were more than 15 yr old. One more recently published study from 1994 included (non-ICU) patients undergoing interleukin-2-based therapy for metastatic cancer and volume therapy. All meta-analyses included several studies that are more than 20 yr old (6,7,71). However, there have been several innovative strategies in managing the ICU patient in the past years (e.g. improved monitoring, ventilation strategies, feeding) which also may have influenced disease and outcome. A precise and guiding definition of sepsis/septic shock making studies on sepsis more comparable was not available until 1992 (74). The varying physicochemical properties of the different colloids have also been neglected in most of the meta-analyses. It is not appropriate to summarize all colloids to a "colloid group" because of the differences between individual colloids.

In a MEDLINE-based analysis, more actual studies (1985–1999) on the use of albumin in the adult ICU patients were performed. Only studies in humans were included, because extrapolation from animal models to critically ill patients must always be done with caution. Only studies comparing different kinds of solutions for volume therapy were included. Abstracts and articles not written in English were not included. From 1985, only 10 studies comparing albumin with other kinds of solutions for volume replacement in the adult ICU patient were identified (Tables 1 and 2) (75–85). The study populations of the analyzed studies differ from 6 to 249 patients in each volume group. Patient population included septic patients, long-term posttrauma patients, and ICU patients who were not specified. In most studies, therapy with albumin was compared with synthetic colloids (e.g. HES, gelatins). Infused volume ranged from 500 mL to 30 L (76,77). The follow-up period after volume administration ranged from 45 min (76) to 87 days (77). Current evidence indicates that the efficacy of different volume replacement regimens cannot be assessed when only short-term use of volume infusion (e.g. more than 45 min) is studied. No differences in outcome between two different volume therapy strategies were found in short-term studies using only limited doses of volume (up to 1000 mL). It is doubtful whether 500 mL of any fluid may alter the outcome of the ICU patient.

Some studies were designed only to show possible side effects on hemostasis, organ function (e.g. kidney or pulmonary function), or inflammatory response. None of the studies on hemostasis (75,76,82,84) demonstrated significant differences between albumin-treated patients and those patients treated with synthetic colloids (e.g. HES). Renal function was also not negatively influenced by HES (84) or gelatin (77,78) compared to albumin-treated patients. Pulmonary function remained almost unaffected by either albumin or synthetic colloids (HES or gelatin).

In most meta-analyses too much emphasis has been placed on outcome. Most of the actual studies comparing different volume replacement strategies were not focused on outcome. Outcome was not even documented in several of these studies. Consequently, the influence of albumin on outcome in comparison to other volume replacement regimens cannot be definitely determined.

	What Can We Conclude for Our ICU Patients?

Top Abstract Introduction What Is so Specific... Specification of Albumin... Pros and Cons of... Indications for Albumin... What Does the Literature... What Can We Conclude... References

 
To use (albumin) or not to use? This question has been discussed very emotionally, since some very controversial comments on this topic have been published (see Ref. 86 or 87). The theoretical pharmacological benefits of albumin do not justify its use in the ICU patient because they are without consequences in the clinical setting. More actual data from the literature do not support the role of albumin as a plasma substitute in the ICU patient. Thus, the use of albumin should be strictly revised. Apart from fractionated HA solutions, various synthetic colloidal plasma substitutes are available for volume restoration and appear to be appropriate alternatives for this indication. The use of albumin to correct hypoalbuminemia is also not justified. It is even doubtful whether knowledge of serum albumin concentrations provides useful additional diagnostic information in the critically ill patient (30).

Interpretation of the literature is made difficult by variations in patients, targets, additive therapy, and other factors. Most meta-analyses must be viewed with skepticism because they were mainly focused on mortality (88). Mortality does not seem to be an appropriate end-point when comparing different volume replacement regimens, because mortality was never an end-point of any of the analyzed studies. When selecting a specific fluid, consideration should be focused on organ function, endothelial inflammation, or tissue perfusion.

A major challenge is to decide which kind of therapeutic strategy is associated with the greatest benefit and fewest disadvantages for the ICU patient. In the absence of supportive data in the literature, albumin-containing solutions are still widely used for volume replacement in the ICU patient. Interestingly, despite several advices not to use albumin, the plasma products industry has launched a 1.4 million British Pound international program to promote albumin (88a).

Cost-containment is becoming an increasingly important factor in medical decision making (89). The costs of albumin are tremendous, and acceptable alternatives would be favorable. Frequency of allergic reaction and other side effects seems extremely low with the use of albumin solutions. Modern synthetic colloids are as effective as albumin and have a very low risk of side effects. They do, however, have enormous economic advantages over albumin solutions. Reduction of albumin use resulted in a saving of US $7,000 each month in a small, seven-bed ICU (90). A switch to the cheapest, fully approved colloid on the US market has been projected to save some $300 million annually (91).

A few years ago it was suggested that "to withhold albumin therapy...is neither logical nor appropriate" (92) and that "albumin is a useful colloid for intravascular volume expansion" (56). To summarize actual data on the use of albumin in the ICU patient, there is no evidence support the widespread use of albumin. There are no convincing data justifying administration of albumin either for treating hypovolemia or for correcting hypoalbuminemia. More well designed studies are necessary to reevaluate the administration of albumin in the ICU patient. Until convincing data pro albumin is presented, very restrictive use of albumin is recommended.

	References

Top Abstract Introduction What Is so Specific... Specification of Albumin... Pros and Cons of... Indications for Albumin... What Does the Literature... What Can We Conclude... References

 

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