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Albumin administration - what is the evidence of clinical benefit? A systematic review of randomized controlled trials

Haynes, G. R.*; Navickis, R. J.; Wilkes, M. M.

European Journal of Anaesthesiology (EJA): October 2003 - Volume 20 - Issue 10 - p 771-793
Original Article
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Background and objective: The advantages of albumin over less costly alternative fluids continue to be debated. Meta-analyses focusing on survival have been inconclusive, and other clinically relevant end-points have not been systematically addressed. We sought to determine whether albumin confers significant clinical benefit in acute illness compared with other fluid regimens.

Methods: Database searches (MEDLINE, EMBASE, Cochrane Library) and other methods were used to identify randomized controlled trials comparing albumin with crystalloid, artificial colloid, no albumin or lower-dose albumin. Major findings for all end-points were extracted and summarized. A quantitative meta-analysis was not attempted.

Results: Seventy-nine randomized trials with a total of 4755 patients were included. No significant treatment effects were detectable in 20/79 (25%) trials. In cardiac surgery, albumin administration resulted in lower fluid requirements, higher colloid oncotic pressure, reduced pulmonary oedema with respiratory impairment and greater haemodilution compared with crystalloid and hydroxyethylstarch increased postoperative bleeding. In non-cardiac surgery, fluid requirements, and pulmonary and intestinal oedema were decreased by albumin compared with crystalloid. In hypoalbuminaemia, higher doses of albumin reduced morbidity. In ascites, albumin reduced haemodynamic derangements, morbidity and length of stay and improved survival after spontaneous bacterial peritonitis. In sepsis, albumin decreased pulmonary oedema and respiratory dysfunction compared with crystalloid, while hydroxyethylstarch induced abnormalities of haemostasis. Complications were lowered by albumin compared with crystalloid in burn patients. Albumin-containing therapeutic regimens improved outcomes after brain injury.

Conclusions: Albumin can bestow benefit in diverse clinical settings. Further trials are warranted to delineate optimal fluid regimens, in particular indications.

*Medical University of South Carolina, Department of Anesthesia and Perioperative Medicine, Charleston, South Carolina;Hygeia Associates, Grass Valley, California, USA

Correspondence to: Mahlon Wilkes, Hygeia Associates, 17988 Brewer Road, Grass Valley, California 95949, USA. E-mail: mwilkes@hygeiaassociates.com; Tel: +1 530 268 2300; Fax: +1 530 268 2301

Accepted for publication January 2003 EJA 1387

The first evidence that exogenous purified albumin is effective and safe for fluid management in the acutely ill was furnished by the report of a 200 patient multicentre clinical trial published in 1942 [1]. Marked and rapid improvement was documented after albumin administration in most patients requiring fluid resuscitation for hypovolaemic shock due to trauma, surgery or others causes of haemorrhage, and no adverse events were encountered. A subsequent 600 patient multicentre safety trial was reported in 1944, indicating the absence of adverse reactions to albumin, and pathologic studies of necropsy material from albumin recipients failed to reveal significant changes attributable to albumin (such as storage disease, renal glomerular damage or periarteritis nodosa) [2]. Since these early investigations, albumin has served as a common option for fluid management in acute illness and has been the subject of much further clinical investigation including numerous randomized controlled trials (RCTs) comparing albumin with alternative fluids, such as crystalloids or artificial colloids.

Despite more than 60 yr of extensive clinical investigation, the value of albumin administration is frequently questioned, primarily because of cost concerns. While beneficial effects have been consistently demonstrated in certain indications, such as ascites, for other indications results from clinical trials often appear to have been conflicting. Such apparent inconsistencies may have arisen at least partly from the small size of most studies and poor quality of some as well as differences in effects of albumin across varying clinical indications and patient populations. Compounding the uncertainty has been the frequent appearance of review articles challenging the appropriateness of albumin therapy based on selective citations from the literature [3]. As a result, the appropriate place of albumin in fluid management remains controversial.

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 crystalloid, no albumin or lower-dose albumin [4,5]. Neither meta-analysis could detect a significant overall survival benefit. Indeed, the first of the two meta-analyses to appear even indicated increased mortality among albumin recipients. However, this possibility was not supported by the second meta-analysis, which encompassed a body of randomized trial evidence approximately threefold the size of that in the first meta-analysis, or by a large-scale pharmacovigilance study demonstrating that fatal adverse events in albumin recipients are extremely rare [6]. The second meta-analysis also revealed that the overall results were misleading due to contamination by the contribution of poorer-quality trials. Higher-quality trials, such as those with blinding and larger patient populations, suggested a survival benefit of albumin.

A major limitation of both meta-analyses was the exclusive reliance on survival as the end-point. More than half the randomized trials were not designed to assess this end-point, and those trials differed markedly in their results from the trials that did include survival as a study end-point [5]. Moreover, because of the relatively low underlying mortality rate among acutely ill patients under contemporary intensive care regimens, mortality is a relatively insensitive end-point. Further reducing the sensitivity of this end-point is the common use of numerous concomitant procedural interventions, medications and fluids that can obscure the effect of albumin on a remote outcome, such as death.

Additional clinically relevant outcomes, such as morbidity, length of stay and costs of care, should also be considered when appraising the clinical utility of albumin. Morbidity, for example, is a more sensitive end-point than mortality and is a major concern of patients [7]. Higher morbidity is likely also to prolong stay and increase costs.

In this systematic review, comprehensive evidence was assembled and summarized from randomized trials on effects of administered albumin in the acutely ill. Data were extracted on multiple clinically relevant end-points that the trials were designed to assess.

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Methods

Inclusion criteria

In this systematic review, the aim was to identify all RCTs comparing albumin administration with a control regimen in the following seven categories of clinical indications: cardiac surgery, non-cardiac surgery, hypoalbuminaemia, ascites, sepsis, burns and brain injury. The control regimen must have consisted of crystalloids; artificial colloids (such as hydroxyethylstarch (HES), dextran or gelatin); no albumin or lower-dose albumin.

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Search techniques

Published and unpublished RCTs fulfilling the inclusion criteria were identified by computer searches of the MEDLINE and EMBASE bibliographic databases, the Cochrane Controlled Trials Register and the Cochrane Medical Editors Trial Amnesty of unpublished trials. No language restrictions were applied. General medical journals and Index Medicus were hand searched. The authors of published controlled trial reports related to albumin and the medical directors of albumin suppliers were contacted and the reference citations examined from completed reviews and protocols in the Cochrane Database of Systematic Reviews, other meta-analyses, review articles and reports of controlled and uncontrolled studies involving albumin.

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Data extraction and summarization

Data were extracted independently by two investigators, and inconsistencies in interpretation were resolved through discussion. Extracted data pertained to clinical setting, fluid regimen and major results. Statistically significant between-group differences, or lack thereof, were summarized. Due to the diversity of end-points addressed, a quantitative meta-analysis was not attempted. For purposes of summarizing RCT findings, account was taken of potential confounding factors, for example, higher hydrostatic pressure in the albumin than the control group.

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Statistical analysis

Descriptive statistics were calculated using Stata® 7.0 statistical software (Stata Corp., College Station, TX, USA).

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Results

The numbers of trials identified, screened and included in the systematic review are presented in Figure 1. Seventy-nine RCTs with a total of 4755 patients were included [8-89]. One trial was excluded because of fluid overload in the albumin group [90]. The median number of patients in the included trials was 40 (range 12-300).

Figure 1

Figure 1

As detailed below, in the majority of trials there was evidence of clinical benefit in some form resulting from albumin administration. However, there was no effect in 20/79 (25%) trials [10-12,18,23-25,37,44,47,48,54,56,66,67,70,78-80,82,83,87,89]. Deleterious effects of albumin were reported in one trial [36]; however, the control patients had received large doses of albumin, and their mean colloid oncotic pressure (COP) was actually higher than that of the albumin group.

One or more potential confounding factors were apparent in 14/79 (18%) trials. Such factors included the administration of concomitant albumin to all groups for intra- and/or postoperative volume expansion [13,34,35,55,59] or as a constituent of the extracorporeal circuit priming fluid [2,31,35,61], of large crystalloid volumes in all groups [24,31] or of similar albumin and crystalloid volumes to maintain stable haemodynamics [10,11]. Other potential confounding factors were significantly higher baseline serum albumin in the control group [18], administration of albumin sufficient to elevate hydrostatic pressure to a significantly greater extent than that in the control group [16,20] and use of albumincontaining blood products in all groups [19]. These factors are likely to have masked or diminished true treatment effects.

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Cardiac surgery

Thirty-one included trials with 1559 patients involved cardiac surgery (Table 1). The median number of patients in these trials was 47 (range 14-105). Of these trials, 17 with 914 patients focused on pump priming and 14 with 645 patients on volume expansion.

Table 1

Table 1

Table 1

Table 1

Table 1

Table 1

Table 1

Table 1

Table 1

Table 1

Among the pump priming trials, crystalloid use increased intra- [22,43,59] and postoperative fluid requirements [21], and resulted in positive fluid balance [13,55,71] and weight gain [34]. COP [21,22,34,59] and the gradient between COP and pulmonary arterial wedge pressure (PAWP) [53] was maintained at more nearly normal values in patients receiving albumin than crystalloid. Pulmonary shunt fraction [34] and extravascular lung water accumulation [53] were increased by crystalloid but not albumin (Fig. 2). Crystalloid was also less effective than albumin for achieving haemodilution [13,22,43]. HES decreased platelet concentrations [28,34,59] and aggregation [55], and prolonged prothrombin time (PT) [34] and activated partial thromboplastin time (aPTT) [59].

Figure 2

Figure 2

In the trials of volume expansion, intraoperative fluid requirements were greater with crystalloid than albumin [73]. Albumin maintained COP [31,73] and COP-PAWP gradient [73] at more nearly normal levels than crystalloid. Additionally, albumin was more efficacious than crystalloid for haemodilution [73]. HES reduced platelet count [26] and aggregation [61], prolonged PT [29,74] and aPTT [29] and increased postoperative bleeding (Fig. 3)[61,68].

Figure 3

Figure 3

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Non-cardiac surgery

There were 17 trials of non-cardiac surgery with 999 total patients (Table 2). The median number of patients in these trials was 29 (range 17-220).

Table 2

Table 2

Table 2

Table 2

Fourfold more crystalloid (approximately 15 L) than albumin was necessary in trauma patients to attain haemodynamic end-points [12]. Inefficient blood oxygenation and possible pulmonary oedema due to crystalloid was suggested by elevated alveolar-arterial oxygen difference and venous admixture [14]. Albumin prevented the fall in COP observed in surgical patients receiving crystalloid [16,19,20,33]. In patients undergoing caesarean section, albumin was more effective than crystalloid in preventing hypotension resulting from spinal anaesthesia and increasing the Apgar scores of the infants [17]. In a trial of surgery and trauma patients, administration of albumin to maintain higher serum albumin concentrations significantly lowered the frequency of re-operations [32]. In abdominal surgery patients, albumin reduced intraoperative intestinal oedema compared with either crystalloid or HES (Fig. 4)[50].

Figure 4

Figure 4

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Hypoalbuminaemia

Nine RCTs with 536 total patients focused on the correction of hypoalbuminaemia (Table 3). The median number of patients per trial was 36 (range 24-219). Three of the trials involved high-risk neonates and the rest adults.

Table 3

Table 3

Table 3

Table 3

Results in these trials exhibited a consistent dose dependency. While between-group differences could not be detected when attained serum albumin concentrations during albumin therapy remained below 30 g L−1, clinical benefit was consistently demonstrable when attained serum albumin exceeded 30 g L−1. Thus, in trials with >30 g L−1 attained serum albumin; morbidity was reduced by albumin therapy (Fig. 5)[8,39]. In hypoalbuminaemic high-risk neonates albumin therapy accelerated time to regain birth weight [8,58], reduced oedema [64] and improved pulmonary function [64].

Figure 5

Figure 5

There was evidence of benefit in all three RCTs of high-risk neonates, and the possibility could be entertained that different pathophysiological mechanisms operating in these patients, as contrasted with those in adults, might account for the effects of administered albumin rather than dose per se. However, in a controlled trial of 53 low birth weight premature infants, which was not included in this systematic review because of its non-randomized design, attained serum albumin concentration was 29 g L−1 during albumin supplementation, and there was no evidence of accelerated weight gain or diminished complications [91]. A meta-analysis regression reported elsewhere indicates a significant quantitative correlation between increasing attained serum albumin concentration and decreasing morbidity in controlled trials on the correction of hypoalbuminaemia among both high-risk neonates and adults [92].

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Ascites

Ten RCTs in a total of 942 cirrhotic patients with ascites were included in the systematic review (Table 4). The median number of patients per ascites trial was 74 (range 18-289).

Table 4

Table 4

Table 4

Table 4

Albumin in conjunction with repeated large-volume paracentesis reduced complications, impairment of systemic haemodynamics and activation of the renin-angiotensin system compared with paracentesis alone [41]. As an adjunct to total therapeutic paracentesis albumin averted hypovolaemia, haemodynamic derangements and activation of the renin-angiotensin system [63,72]. Post-paracentesis circulatory dysfunction was less frequent with albumin than with either dextran 70 or gelatin [75]. Albumin was more effective than HES in reducing weight and, unlike HES, was not subject to a paracentesis volume limitation [84].

In refractory ascites, inpatient albumin plus diuretics increased response rate, shortened hospital stay and lowered overall costs vs. diuretics alone (Fig. 6); whereas outpatient albumin in conjunction with diuretics reduced ascites recurrence and hospital readmission compared with diuretics alone [85]. Albumin in conjunction with cefotaxime reduced both mortality and renal impairment in patients with spontaneous bacterial peritonitis compared with cefotaxime alone (Fig. 7)[86].

Figure 6

Figure 6

Figure 7

Figure 7

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Sepsis

Four trials of 104 patients evaluated the effects of albumin in sepsis (Table 5). In these trials, the median number of patients was 23 (range 12-46).

Table 5

Table 5

Compared with crystalloid, albumin markedly reduced the incidence of pulmonary oedema (Fig. 8)[27] and also diminished intrapulmonary shunt fraction [30]. HES prolonged PTT [40] and decreased platelet count [40] and factor VIII:C [46] in patients with sepsis.

Figure 8

Figure 8

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Burns

Thermal injury was the subject of four trials in 197 patients (Table 6). The median number of patients per trial was 49.5 (range 19-79). Albumin reduced complications in burn patients compared with crystalloid (Figs. 9, 10)[9,15].

Table 6

Table 6

Figure 9

Figure 9

Figure 10

Figure 10

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Brain injury

The median patients per trial in the four trials of brain injury (Table 7) was 50 (range 18-300). There were a total of 418 patients in these trials.

Table 7

Table 7

Haemodilution with albumin in patients with acute ischaemic stroke and normal haematocrit reduced both mortality and disability (Fig. 11)[57]. High oncotic pressure therapy with albumin prevented serious neurological deficits in patients with closed head injury [69]. In neonates with asphyxia and brain oedema, albumin reduced cerebral oedema, improved Apgar score and shortened hospital stay (Fig. 12)[88].

Figure 11

Figure 11

Figure 12

Figure 12

It should be recognized that all four trials in this category involved distinct types of brain insults. The varying pathologic mechanisms at work in these groups of patients are likely to require different approaches to fluid management, for instance, due to increased intracranial pressure in patients with head trauma.

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Discussion

This systematic review revealed evidence of clinical benefit due to albumin administration, for instance by reducing morbidity in a variety of clinical settings. Cardiac surgery is among the predominant indications of albumin administration. In cardiac surgery, albumin was devoid of the detrimental effects exerted by crystalloids, such as respiratory impairment and pulmonary oedema, which may be attributable to crystalloid-mediated reductions in COP and COP-PAWP gradient [93,94].

Impaired haemostasis was a consistent finding in cardiac surgery patients exposed to HES. Excessive postoperative bleeding is a frequent [95], serious [96,97] and unpredictable [98] complication of cardiac surgery. Nevertheless, significant differences in clinical bleeding between albumin and HES were infrequently demonstrable within individual trials. However, based upon the results of a recent meta-analysis of 16 RCTs comparing albumin with HES in cardiac surgery patients [99], the lack of statistically significant difference in bleeding in most trials was due to the small numbers of patients enrolled and, therefore, limited statistical power to detect such differences. For 88% of randomized comparisons in the meta-analysis, postoperative bleeding was lower in the albumin group, and the pooled between-group difference in average bleeding was statistically significant. For the adult trials included in the meta-analysis, the estimated percentages of albumin and HES recipients experiencing excessive postoperative bleeding were 19% and 33%, respectively [99]. The reported average cost to manage a single case of excessive bleeding after cardiac surgery was $US 16 654 (approximately €15 373), an amount substantially exceeding the difference in acquisition cost between albumin and HES [100]. Consequently, albumin probably is capable of exerting a favourable pharmacoeconomic impact in the setting of cardiac surgery as contrasted with HES. More generally, it is important to consider the effects of albumin on overall costs of care, including the potential to reduce morbidity and shorten length of stay, rather than focusing solely on the acquisition cost of albumin as compared with that of alternative fluids [101].

Advantages of albumin vis-à-vis crystalloid were also apparent in non-cardiac surgery trials. Both pulmonary and intestinal oedema were reduced by albumin. Far lower volumes of albumin than crystalloid were needed to reach haemodynamic targets, and hence it is feasible to attain these targets more rapidly with albumin.

The hypoalbuminaemia trials were instructive, in that dose effects were remarkably effective in resolving apparent inconsistencies in results. Indeed, these inconsistencies have often prompted the interpretation that albumin is of little value when administered for correction of hypoalbuminaemia. However, in this review albumin clearly bestowed clinical benefit when administered in doses adequate to raise the serum albumin concentration above 30 g L−1. The therapeutic rationale for correcting hypoalbuminaemia rests upon the well-recognized association between lower serum albumin and poor outcome. Multivariate models derived from the results of numerous cohort studies have revealed hypoalbuminaemia to be a potent independent predictor of mortality, morbidity and other adverse outcomes, suggesting that serum albumin exerts a direct protective effect. For instance, in one such study involving 54 215 non-cardiac surgery patients, both mortality and morbidity increased progressively as serum albumin decreased over the range of albumin concentrations between 22 and 46 g L−1[102].

In no category is the evidence of clinical benefits due to albumin more consistent than ascites. These benefits include reduced morbidity, length of stay and treatment cost. In ascites patients progressing to spontaneous bacterial peritonitis, a significant survival benefit of albumin has also been demonstrated [86].

It is often recommended that albumin be administered with caution in states of increased endothelial permeability, such as sepsis. However, a previous review of preclinical and clinical evidence failed to support the concept of increased lung water or compromised lung function with the administration of colloids [103]. On the contrary, among the RCTs included in this review there was evidence of reduced pulmonary oedema and improved respiratory function in sepsis patients receiving albumin. Deleterious effects of HES on coagulation function were also apparent in this indication.

The optimal time for albumin administration in burn patients remains unresolved. In this review, albumin reduced morbidity in burned patients. Furthermore, this benefit was attained with immediate use of albumin. Delaying albumin administration for 24 h is commonly advocated for fluid management of thermal injury.

In patients with brain injury, albumin-containing regimens reduced mortality, disability and neurological deficits. By contrast, serious safety problems associated with HES have been reported in this setting [104,105]. For instance, two RCTs of HES for acute ischaemic stroke had to be stopped prematurely due to unexpected morbidity and mortality in HES recipients [106,107]. Indeed, the consistent evidence of adverse effects attributable to HES in this review clearly indicates that all colloids are not equal.

What mechanisms might account for the observed benefits of albumin? The role of albumin in maintaining COP is well recognized. However, this ability is shared by other colloids, such as HES, which nevertheless fail to confer comparable clinical benefit. This may in part be attributed to side-effects of artificial colloids, such as interference with coagulation by HES through reductions in factor VIII, von Willebrand factor and platelets, impairment of platelet function and enhancement of fibrinolysis, as elsewhere reviewed [108].

Besides the absence of deleterious effects due to artificial colloid, some of the additional protective properties of albumin are likely to be of importance, e.g. its antioxidant activity and binding affinity for lipids, drugs, toxic substances and other ligands. Other potential protective effects of albumin are inhibition of apoptosis [109] and, probably of greater importance, modulation of inflammatory response [110].

As an example of the binding properties of albumin, in cardiac surgery patients albumin prevented erythrocyte crenation that may compromise microcirculatory performance, and the effect was apparently due to the ability of albumin to bind free fatty acids that would otherwise be incorporated in the erythrocyte membrane [111]. Drug binding by albumin can both modulate pharmacological activity and promote delivery of drugs to their site of action, and these processes may be disrupted by hypoalbuminaemia. For instance, albumin co-administration has been shown to potentiate the diuretic and natriuretic actions of furosemide in nephrotic syndrome patients [112]. Both phenytoin [113] and midazolam [114] toxicity have been observed in association with hypoalbuminaemia. Albumin infusion might be considered to reduce such toxicity. In any case, albumin should be administered with cognizance of its drug-binding properties to avoid unintended interference with the desired actions of co-administered pharmacological agents.

In this review, all RCTs comparing albumin with various control regimens were considered, rather than the subset of trials reporting data with respect to a particular end-point, such as mortality. Consequently, the scope of this review - 79 trials with 4755 total patients - is far larger than that of any prior review on this topic, including the previous meta-analyses on survival after albumin therapy [4,5]. This review also focused exclusively on end-points that the included trials were designed to assess, thereby avoiding the potential distortions of investigating an outcome such as death a posteriori in trials not designed to address this end-point.

A substantial number of included trials failed to detect differences between albumin and control with respect to clinically important end-points, hence supporting the contention that albumin therapy is without benefit. However, because of the small size of most included trials, failure to detect benefit might be due to lack of statistical power rather than of albumin effectiveness. Another likely explanation for absence of between-group differences in some trials was the presence of confounding factors [10,11,18,24].

Importantly, clear evidence of unfavourable effects attributable to albumin has rarely been reported. If albumin were devoid of overall benefit, a population of trials such as that in this review would be expected to yield favourable, neutral and unfavourable effects of albumin. The infrequency of unfavourable results is consistent with the conclusion that the overall impact of albumin therapy is beneficial.

The potential contribution of publication bias must be considered. It is possible that trials demonstrating statistically significant benefits of albumin were more likely to be reported than those that did not. However, publication bias can operate in either direction, i.e. over-reporting or under-reporting of beneficial results. The potential for under-reporting of benefit arises from the design of many RCTs, which were undertaken to demonstrate the equivalence of albumin with less expensive alternative fluids. Indeed, in the most recent meta-analysis of survival after albumin administration, significant publication bias was observed [5]. In that meta-analysis trials with mortality results favourable to albumin were more likely to be unreported. Consequently, in the present review publication bias, if any, might tend to cause albumin benefit to be under- rather than overestimated.

Based on this systematic review of RCTs, beneficial effects of albumin are apparent in a wide array of clinical settings. Nevertheless, the results of the review, particularly in the hypoalbuminaemia and burn trials, suggest that optimal dose and administration schedules for albumin remain to be delineated, and further investigations are warranted to address these issues, as well as to define more precisely the appropriate roles for albumin in particular indications and patient populations.

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Acknowledgement

This work was supported through an unrestricted grant from the Plasma Protein Therapeutics Association.

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Keywords:

BRAIN INJURIES; CARDIAC SURGICAL PROCEDURES; INFECTION, sepsis; PATHOLOGICAL PROCESSES, ascites; PROGNOSIS, treatment outcome; RANDOMIZED CONTROLLED TRIALS; SERUM ALBUMIN; SURGERY; VITAL STATISTICS, morbidity; WOUNDS AND INJURIES, burns

© 2003 European Academy of Anaesthesiology