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The albumin controversy

Created: 25/7/2005
Updated: 1/5/2012

SAFE study

The 1998 report of a meta-analysis by the Cochrane Injuries Group Albumin Reviewers presented an important public health issue and questioned the practices of many doctors in Australian intensive care units (ICUs). Using data from 24 studies involving 1419 patients, the meta-analysis reported that the administration of albumin-containing fluids to critically ill patients increased the absolute risk of death by 6%, suggesting one extra death for every 17 patients given albumin. The authors recommended that albumin should not be administered to critically ill patients outside the context of rigorously conducted, randomised trials. A subsequent meta-analysis did not resolve the issue of albumin safety in the critically ill.

Thus, the SAFE study demonstrated that, in this heterogeneous population of adult ICU patients, albumin can be considered safe, without demonstrating any clear efficacy advantage over saline. The SAFE study achieved its goal of providing a definitive answer to an important clinical question. The result is widely applicable in those ICUs around the world where purified albumin is available. In addition, the study has demonstrated that investigators in Australian and New Zealand ICUs are capable of conducting large-scale collaborative trials on modest budgets and in a realistic timeframe. The SAFE study has been described as a landmark study that heralds a new era in critical care. We hope that it will be only the first of many such studies.


[i] Finfer S, Bellomo R, Boyce N et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004; 350: 2247-2256

[ii] Finfer SR, Boyce NW, Norton RN. The SAFE study: a landmark trial of the safety of albumin in intensive care. Med J Aust 2004; 181: 237-238 

Albumin meta-analysis

Human albumin administration in critically ill patients: systematic review of randomised controlled trials. Cochrane Injuries Group Albumin Reviewers. BMJ 1998; 317: 235-240

Objective: To quantify the effect on mortality of administering human albumin or plasma protein fraction during management of critically ill patients.

Design: Systematic review of randomised controlled trials comparing the administration of albumin or plasma protein fraction with no administration or with the administration of crystalloid solution in critically ill patients with hypovolaemia, burns or hypoalbuminaemia.

Subjects: 30 randomised controlled trials including 1419 patients.

Main outcome measure: Mortality from all causes at end of follow-up for each trial.

Key learning points

  • Human albumin solution has been used in the treatment of critically ill patients for over 50 years.
  • Currently, the licensed indications for use of albumin are emergency treatment of shock, acute management of burns and clinical situations associated with hypoproteinaemia.
  • Our systematic review of randomised controlled trials showed that, for each of these patient categories, the risk of death in the albumin-treated group was higher than in the comparison group.
  • The pooled relative risk of death with albumin was 1.68 (95% confidence interval 1.26 to 2.23) and the pooled difference in the risk of death was 6% (3% to 9%) or six additional deaths for every 100 patients treated.
  • We consider that use of human albumin solution in critically ill patients should be urgently reviewed.

Readers' criticisms

  • Altogether, 30 randomised studies with population sizes ranging from 12 to 219 (over half had fewer than 30 patients) were assessed, with a total of 1419 patients. No account was taken of the purpose, design or specific end points of the studies.

  • The end point of the review, mortality, was not an end point in most studies, many of which took place over a period of less than five days.

  • Most deaths occurred outside the study times.

  • Variables ignored included age, medical conditions, severity of disease, dose of albumin, mode of administration and attributable mortality of the states of disease that were treated.

Authors' response

"On the basis of our systematic review of randomised trials we concluded that there is no evidence that albumin administration reduces mortality in critically ill patients, and a strong suggestion that it may increase mortality. We read with anticipation the letters in response to our review, but note with concern that none of the correspondents provide any evidence that albumin is beneficial in critically ill patients, in which case our conclusions stand."

Related examination questions

Human plasma albumin:

(a) is the greatest contributor to plasma oncotic pressure
(b) is produced in the liver
(c) carries carbon dioxide in the blood
(d) is an anion at pH 7.5
(e) is actively filtered by the glomerulus


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