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JAIN, N. CHAKRAVORTY, D. CHAKRAVORTY, BHATTACHARYA, YADAVA, AGARWAL : ALBUMIN : AN OVERVIEW. 433 Indian J. Anaesth. 2004; 48 (6) : 433-438

1. M.D., Asso. Prof.2. M.D., Asst. Prof.

3. M.D., P.D.C.C., Asst. Prof.

4. M.D., Asst. Prof.

5. M.D., Asst. Prof.

6. M.D., D.A., Prof. and HeadDepartment of Anaesthesiology and Critical Care,

Bhopal Memorial Hospital and Research Centre,

Bhopal, M.P.- 462038.

Correspond to :

Dr. Rajnish K. JainE-mail : [email protected]

(Accepted for publication on 27-10-2004 )

ALBUMIN : AN OVERVIEW OF ITS PLACE IN

CURRENT CLINICAL PRACTICEDr. Rajnish K. Jain1 Dr. N. Chakravorty2 Dr. D. Chakravorty3

Dr. P. K. Bhattacharya4 Dr. A. Yadava5 Dr. R. C. Agarwal6

SUMMARY

It is very difficult to comment on the rational of use of albumin in clinical practice. Interpretation of the literature is made difficult

by variations in patients, targets, additive therapy, and other factors. When selecting a specific fluid, consideration should be focussed

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 critically ill patient. In the absence of supportive data in

literature, albumin containing solutions are still widely used for volume replacement in these patients. 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! There are no convincing data justifying administration of albumin either for treating hypovolemia or for correcting

hypoalbuminemia.

Introduction

As our understanding of the pathophysiology of the

critically ill patients has increased, the subject of the use

of albumin in clinical practice has become more and

more controversial.1,2 Albumin has several physiological

functions, and is being widely used in anaesthetic and

intensive care practice for a range of indications. Despite

more than 60 years of extensive clinical investigations,

the value of albumin administration is increasingly

being questioned. Clinical studies conducted so far are

fraught with inconsistencies, and do not readilydemonstrate the cited theoretical benefits of albumin

replacement. Approximately 300-400 tons of albumin

were administered during 1998 worldwide,3 and

accounts for up 30% of the total pharmacy budget in

many hospitals.4 In today’s climate of cost consciousness

and cost containment, the indiscriminate use of such

expensive treatment modalities is debatable.

This article strives to discuss what is known so far

in the literature on the use of albumin with respect to the

critically ill patient.

Pathophysiology in critically ill patients

Most critically ill patients have a common

pathophysiological process. Infection, trauma, or major

surgery initiates an inflammatory cascade leading to the

release of various inflammatory mediators (e.g. cytokines)

and activation of leukocytes. This is a self perpetuating

cascade, which results in damaged endothelial integrity,

increasing microvascular permeability and promotes

extravasation of fluids (including albumin) into the

tissue. Such mediators may also reprioritize hepatic

protein synthesis in favor of acute phase reactants at theexpense of albumin production. C- reactive protein, an acute

phase protein produced by the liver, is one marker of

inflammation that has been proposed to account for the

association between hypoalbuminaemia and poor outcome.5

Specifications of albumin preparations

Albumin is a naturally occurring plasma protein

and has long been considered the “gold-standard”, the

kind of solution by which patients would most profit.

Commercially available human albumin solutions contain

approximately 96% albumin, the remainder being

globulins. Although albumin is derived from pooled

human plasma, there is no risk of disease transmission

because it is heated and sterilized by ultrafiltration. Thus,

albumin is generally considered safe. At present the ultra

high pure recombinant human albumin (Recombumin 20%)

developed by biotechnology is under clinical trial and will

be available for clinical use in the near future.

The molecular weight of albumin is approximately

69,000 Daltons. It is commercially available as 4.5%, 20%

and 25% solutions, the later being hyperoncotic, so that

basically it functions as a colloid and expands the plasma

volume by shifting of fluid from the interstitial / intracellular

REVIEW ARTICLE



INDIAN JOURNAL OF ANAESTHESIA, DECEMBER 2004434

compartment to the intravascular compartment. 100 ml of

2% albumin increases intravascular volume to a total of

approximately 450 ml.6 However, the volume effect of

albumin is not predictable and depends on blood volume,protein levels, and capillary permeability.

Indications for albumin administration

The many indications for albumin administration

quoted in literature are as follows:

1. Volume replacement therapy

Should albumin be given for intravascular volume

replacement in the critically ill patient?

Hypovolemia is a consequence of a variety of

pathophysiological processes, and it is common in intensive

care patients. Intravascular fluid deficits occur even 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 and intravenous 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. Hypovolemia is thus an

important reason to administer albumin in the Intensive

Care unit.

In the United States, approximately 26% of all

albumin is given to treat acute hypovolemia, (e.g. surgical

blood loss, trauma, haemorrhage) and 12% to treathypovolemia for other reasons (e.g. infection). In Australia,

human albumin is supplied free of charge to hospitals through

Red Cross and is widely used as a resuscitation fluid in the

intensive care units.

The effects of albumin depend on its movement

between the intravascular and extravascular compartments.

Albumin is considered necessary to increase colloid

oncotic pressure 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 haemodynamic efficacy,greatly varies 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. 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”], is intensively discussed. Weaver

et al7 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 (molecular weight 250,000 Daltons) was reported tobe effective in reducing capillary edema in experimental8

and clinical models of increased permeability.9

2. Support of colloid oncotic pressure

Maintenance of colloid oncotic pressure is of essence

during intravascular volume replacement in the critically

ill patient. It is believed that the oncotic force of

concentrated human albumin may help reduce tissue

oedema. Grundmann et al10 have demonstrated that though

colloid oncotic pressure is modified perioperatively by

albumin, administration of albumin showed no difference

in mortality, length of ventilation, renal function, andoutcome of patients. Recent literature states that albumin

may exert a direct protective effect in the critically ill

patient, and it’s ability to sustain oncotic pressure may only

be one of many possible mechanisms.11

3. Maintenance of serum albumin levels

Hypoalbuminemia: To treat or not to treat?

The normal serum concentration of albumin in healthy

adults is approximately 35 to 50 gL-1. Hypoalbuminaemia is

common in seriously ill patients. Herrmann et al12 have

reported the frequency of hypoalbuminaemia (serum albumin

concentration of less than 34 gL-1) as 21% at the time of

admission in adult hospitalized patients. After admission,

worsening of existing and development of de novo

hypoalbuminaemia are both frequently encountered.

Albumin appears to be a nonspecific marker of the

seriousness of an illness. Because of its importance as

an outcome predictor, serum albumin level has been added

as one of the component parameters in the APACHE III

score. However, it is to be remembered that changes in its

values are the result of pathological events, and not the

cause of them.13

Several studies have demonstrated that low serum

albumin is associated with poor outcome in acutely ill

patients.6,13,14 The results of a meta-analysis by Vincent et al11

incorporating 90 cohort studies with a total of 2,91,433

patients, show that hypoalbuminaemia was a potent dose

dependent, independent predictor of poor outcome. Each

10 gL-1 decline in serum albumin concentration significantly

raised the odds of mortality by 137%, morbidity by 89%,

prolonged the ICU and hospital stay by 28% and 71%

respectively, and increased resource utilization by 66%. A

serum albumin level of <2.0 gdL-1 in critically ill patients

has been shown to be associated with a mortality of nearly

100%.15



JAIN, N. CHAKRAVORTY, D. CHAKRAVORTY, BHATTACHARYA, YADAVA, AGARWAL : ALBUMIN : AN OVERVIEW. 435

The association between hypoalbuminaemia and poor

outcomes has long motivated clinicians in administering

exogenous albumin to hypoalbuminaemic patients. Several

studies16,17,18 have demonstrated that supplementation of albumin in patients who have hypoalbuminemia had no

apparent effect on morbidity and mortality and concluded

that albumin should be abandoned in the treatment of

these patients.16

In the interim, there is no compelling basis to

withhold albumin therapy if it is judged clinically appropriate.

Because of the strength of the association and low cost of

serum albumin assays, monitoring albumin levels has

been advocated as a prognostic tool to identify higher risk

patients.12,19

As a transport moleculeAlbumin may also have some additional specific

effects related to its transport function for various drugs

and endogenous substances (e.g. bilirubin, free fatty acids).

Many drugs (e.g. warfarin, digoxin, midazolam, thiopentone)

used in critically ill patients bind to albumin, and drug

toxicity is partly attributable to altered binding capacity.

It is also involved in the inactivation of a small group of

drugs and endogenous substances and acts as an effective

plasma buffer.

To assist in coagulation

Albumin is involved in the coagulation pathways,

and has an anticoagulant effect, which is probablyantithrombotic in nature, possibly mediated via inhibition

of platelet aggregation.

4. Free radical scavenging and maintenance of

membrane integrity

Albumin may have protective properties due to

its property of free radical scavenging by which it

modifies membrane permeability. The effects of different

resuscitation fluids (e.g. dextran, hetastarch, albumin)

on neutrophil activation were examined in an in vitro

study by Rhee et al.20 Neutrophil activation and

expression of neutrophil adhesion molecules was leastpronounced with albumin. However, others have found a

significant increase in expression of endothelial cell

adhesion molecules with albumin in experimental studies,21

and their increased plasma levels may be regarded as

markers of non survival.

5. Management of fluid shifts

i . As an osmotic agent (to pull fluid from the interstitium).

ii . To redistribute fluid during dialysis.

ii i. To improve oxygenation.

Albumin offers several advantages compared with

artificial colloids, including less restrictive dose limitations,

lower risk of impaired haemostasis, absence of tissue

deposition, reduced incidence of anaphylactoid reactions,and ease of monitoring to prevent fluid overload.

6. Miscellaneous indications

Treatment of metabolic acidosis (neonates) and

prevention of ileus.

Some other indications of albumin:

Some possible and controversial indications for the

use of albumin outside “standard” intensive care management

have been formulated:

a. Neonatology ICU, extracorporeal prime during

cardiopulmonary bypass in children5% albumin in the priming of extracorporeal

circuits during cardiopulmonary bypass particularly in

infants may attenuate the extravasation of fluid out of the

vascular space, but it may be associated with an increased

transfusion rate. The risks of transfusion and added costs of

albumin may preclude any benefit to this intervention.22

b. Severely burned ICU patients

Burn patients are a specific group in whom albumin

may have a beneficial role. Though it is reported to be

harmful in the first 24 hrs, its use is justified after 24 hrs

in profoundly hypoalbuminaemic patients, as it favorsreabsorption of oedema. In burns covering <15% of the

body surface area, it may not be necessary, but its use is

justified in >50% burns.23 When using albumin in burn

patients, synthetic colloids (e.g., MMW-HES) have been

shown to be as effective or even superior in increasing

CVP, PCWP, DO2and VO

2.24 Surprisingly, one study says

that no attempt should be made to normalize serum albumin

levels in burns.25 Albumin plasma levels as low as 15 gL-1

have been seen to be well tolerated in these patients.

c. Liver disease, ascites, paracentesis

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 when compared with a

group of patients without additional volume therapy, and

demonstrated superior outcomes in terms of both

morbidity and mortality.26 In a study of patients who had

cirrhosis with ascites, it was assessed whether intravenous

diuretics plus intravascular volume expansion with albumin

exert beneficial effects compared with diuretic therapy

alone.27 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 had liver cirrhosis and

hypovolemia, two volume replacement strategies werecompared (gelatin and albumin), and it was demonstrated

that the infusion of gelatin showed no difference when

compared to treatment with albumin.28 Another group

who have been shown to benefit from albumin therapy are

cirrhotic patients with ascities requiring paracentesis.

Post paracentesis circulatory dysfunction, defined as an

increased in plasma renin activity is associated with

poor outcome. Albumin was shown to be more effective

than either dextran or polygeline in preventing this

complication.29

d. Miscellaneous indications• ICU patients after liver transplantation

• Malnutrition, starvation

• Nephrotic syndrome

• Pancreatitis, peritonitis

Side effects of albumin

There are several reasons why albumin

supplementation might make things worse for critically ill

patients.30

a. Cardiac decompensation may occur after rapid

volume replacement with 20% albumin since thisleads to a four fold increase in volume retention.

b. In patients with capillary leak syndrome, albumin

may become detrimental when albumin and water

cross the capillary membrane and cause or worsen

pulmonary edema, thus compromising tissue

oxygenation and finally leading to multiorgan failure.

c. The antihaemostatic and platelet lowering properties

of albumin may increase blood loss in post surgical or

trauma patients.

d. Albumin administration in the resuscitation of

hypovolaemic shock may impair sodium and water excretion and worsen renal failure.

e. Certain commercially available preparations of albumin

contain remarkable quantities of ions generated

during the preparation process. In patients with acute

renal failure, potentially toxic concentrations of

aluminium may accumulate after massive albumin

administration. Hypotension has been reported to

occur after albumin administration and is most likely

caused by vasoactive peptides.

Other side effects have been demonstrated only in

animal experiments.

• The addition of albumin caused the depression of

isolated rabbit myocardium.31 This has been explained

by the increased binding between albumin and Ca++

ions.

• Although considered to be the colloid with the least

influence on coagulation, albumin may exert

procoagulatory or anticoagulatory effects (e.g., by

inhibiting platelet aggregation and enhancing

the inhibition of factor Xa by antithrombin III),

which may be detrimental in patients with

haemorrhagic hypovolaemia. Tobias et al32 showed

in an in vitro study using serial haemodilution

and thromboelastography that albumin may alsoproduce early and profound hypocoagulable effects.

Administration of albumin showed an increased

bleeding time in a study using in vitro bleeding time

to test primary haemostasis.33 In diabetes mellitus,

glycosylated albumin may increase the incidence of

thrombotic events and atherosclerosis.

However, overall side effects of albumin are rare,

and do not pose absolute contraindications for the use of

human albumin.

Review of literature

Despite a growing body of systematic reviews,evidence based medicine analyses, and consensus

conferences,34,35 the utility and safety profile of albumin is

still under dispute.

Two meta analyses of randomized trials have

broadly assessed the effects of albumin on survival in a

range of indications as compared with those of crystalloids,

no albumin or lower dose albumin.1,36 Neither could detect

a significant overall survival benefit. Indeed, the first of

the two meta analyses even indicated increased mortality

amongst albumin recipients (6.8%). However, the second

meta analysis has not supported the fact. The evidence of the Cochrane review has also been questioned by other

authors.37Another large scale pharmacovigilance study has

also demonstrated that fatal adverse events in albumin

recipients are extremely rare.38

A major limitation of both meta analyses is the

exclusive reliance on survival as the end point. Survival

does not seem to be an appropriate end point when comparing

different volume replacement regimens, because more than

half of the randomized trials were not designed to assess

this end point.



JAIN, N. CHAKRAVORTY, D. CHAKRAVORTY, BHATTACHARYA, YADAVA, AGARWAL : ALBUMIN : AN OVERVIEW. 437

Another meta analysis39 used different selection

criteria and included only studies using purified

albumin (The Cochrane review also included older

studies using less pure plasma protein fraction) and a widespectrum of patients. It included 55 trials involving

3504 patients. Overall, this analysis detected no difference

in mortality between patients treated with albumin and

other fluids.

A recent systematic review, which included 79

randomized trials with a total of 4755 patients showed

definite beneficial effects of albumin in both cardiac and

non cardiac surgery.40 The authors analyzed the results

of albumin administration in diverse clinical settings like

hypoalbumenemia, ascites, sepsis, burn patients and

outcomes after brain injury. This review concludes that

albumin does bestow benefit in terms of decreased morbidityin a wide array of clinical settings. However, the results

also suggest that optimal dose and administration schedule

for albumin remain to be delineated and further investigations

are warranted to address these issues.

Recently, the Australian and New Zealand

Intensive Care Society,the institute for International Health

of the University of Sydney, and the Australian Red Cross

Blood Service, have initiated the largest ever multicentric,

double blind, randomized controlled trial of Saline versus

Albumin Fluid Evaluation (SAFE) for fluid resuscitation of

critically ill patients in intensive care. This study is being

conducted in 7000 adult patients from 16 intensive careunits in Australia and New Zealand over an 18 month

period. The authors hope that the uncertainty about the use

of human albumin in critically ill patients will be resolved

by the end of the year 2004.41

Conclusions

It is very difficult to comment on the rational of use

of albumin in clinical practice. Interpretation of the

literature is made difficult by variations in patients, targets,

additive therapy, and other factors. When selecting a specific

fluid, consideration should be focussed 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 critically ill patient. In the absence

of supportive data in literature, albumin-containing solutions

are still widely used for volume replacement in these

patients. 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!

Cost containment is becoming an increasingly

important factor in medical decision making. The costs of

albumin are tremendous, and acceptable alternatives would

be favorable. 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 albuminsolutions.

As yet there is no evidence to support the widespread

use of albumin. There are no convincing data justifying

administration of albumin either for treating hypovolemia

or for correcting hypoalbuminemia. However, serious

nonfatal and fatal events after administration of albumin

appear to be rare. There is a growing body of existing

evidence indicating human albumin to be remarkably safe,

and its beneficial effects in a wide variety of clinical

settings.

Until convincing data pro albumin is presented,injudicious use of albumin is not to be recommended. Further

trials are required to form optimal fluid regimens, and

indications.

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albumin an overview of its place in

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