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2004; 48 (6) : 433-438




Dr. Rajnish K. Jain1 Dr. N. Chakravorty 2 Dr. D. Chakravorty3 Dr. P. K. Bhattacharya 4 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 readily demonstrate 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 todays 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.
1. 2. 3. 4. 5. 6. M.D., Asso. Prof. M.D., Asst. Prof. M.D., P.D.C.C., Asst. Prof. M.D., Asst. Prof. M.D., Asst. Prof. M.D., D.A., Prof. and Head Department of Anaesthesiology and Critical Care, Bhopal Memorial Hospital and Research Centre, Bhopal, M.P.- 462038. Correspond to : Dr. Rajnish K. Jain E-mail :
(Accepted for publication on 27-10-2004 )

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 the expense 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



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 treat hypovolemia 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 patients 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 to be 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, and outcome of patients. Recent literature states that albumin may exert a direct protective effect in the critically ill patient, and its 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



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 molecule 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). 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 probably antithrombotic 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 least pronounced 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. iii. 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 children 5% 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 favors reabsorption 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, DO2 and VO2.24 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 were compared (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 this leads to a four fold increase in volume retention. 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. The antihaemostatic and platelet lowering properties of albumin may increase blood loss in post surgical or trauma patients. Albumin administration in the resuscitation of hypovolaemic shock may impair sodium and water excretion and worsen renal failure. 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 also produce 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.37 Another 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.







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 wide spectrum 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 morbidity in 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 care units 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 albumin solutions. 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. References
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