BMJ  2006;333:1029-1030 (18 November), doi:10.1136/bmj.39029.490081.80

Editorials

Resuscitation using albumin in critically ill patients

Research in patients at high risk of complications is now needed

Intravenous albumin has been widely used in the treatment of shock since the early 1940s. In a recent large European study on the occurrence of sepsis in acutely ill patients, 11% of patients received albumin at some point during their stay in intensive care.¹ Despite such widespread use, there are few randomised controlled trials on albumin administration in critically ill patients, and even fewer data on which subgroups of patients are likely to benefit most. Because low baseline serum albumin concentrations are associated with worse outcomes,^{2 3} data on the use of albumin in patients with low albumin are of considerable interest. In this week's BMJ a subgroup analysis of the saline versus albumin fluid evaluation (SAFE) study⁴ assesses the effect of baseline serum albumin concentration on outcomes of resuscitation.⁵

A meta-analysis published in the BMJ in 1998 suggested that resuscitation with albumin solutions rather than crystalloids increased the absolute risk of death by 6%.⁶ In 2004, prompted in part by the meta-analysis, the saline versus albumin fluid evaluation (SAFE) study compared 4% albumin with normal saline as the initial fluid for resuscitation in 7000 patients in intensive care.⁴ It found no significant difference in outcomes between treatments at 28 days.⁴

The results of the SAFE study are often interpreted to mean that albumin administration does not result in better outcomes than saline; however, the aim of the study was only to show that albumin administration is safe. All patients who needed a fluid challenge—for whatever reason—were therefore included, regardless of the underlying condition. In any unit using a logical clinical decision process, most patients randomised to the SAFE study would not receive albumin. It is therefore unreasonable to expect the study to show a benefit from albumin administration, except perhaps in subgroup analyses. The question that we need to answer is which subgroups of people are likely to benefit from such administration.

In this week's BMJ, a further analysis of the SAFE study assesses whether outcomes of resuscitation with saline or albumin are related to baseline serum albumin concentrations, predefined as serum albumin less than or greater than 25 g/l.⁵ The analysis confirmed the findings of previous studies,^{2 3} that a low albumin concentration is significantly associated with increased mortality after adjusting for baseline risk factors. This confirms the importance of assessing the effects of albumin administration in such patients. Patients with low serum albumin who received albumin tended to have a lower mortality rate than those who received saline (23.7% v 26.2%, odds ratio 0.87, 95% confidence interval 0.73 to 1.05), but the difference was not significant.

Some aspects of the study merit consideration. About 40% of patients had an albumin concentration below 25 g/l. Such patients were older and were more likely to have severe sepsis, acute respiratory distress syndrome, or renal replacement therapy than people with higher albumin values. They were also more likely to be admitted for surgical reasons (which may explain why they were also less likely to be treated by mechanical ventilation). Surprisingly they did not have higher acute physiology and chronic health evaluation (APACHE II) scores than patients with higher albumin concentrations. It would have been useful if sequential organ failure assessment scores had been reported so that the degree of organ dysfunction in the two groups could be compared.

The next logical question would be whether administration of albumin was beneficial in patients with hypoalbuminaemia and a high risk of complications, such as those with severe sepsis or a high sequential organ failure assessment score, or both. This would be an analysis of a subgroup within a subgroup, however, with double the limitations of subgroup analyses. Unfortunately, this latest study provides little information on the use of albumin in such patients.⁵

The authors are correct when they reject the routine use of albumin in adult patients in intensive care, but their interpretation of the data may be too restrictive when they conclude that albumin and saline have similar effects across the range of albumin concentrations. The results may suggest that patients with a low serum albumin who receive albumin have a lower mortality rate than those who receive saline. It should be remembered that the SAFE study was not designed to show the beneficial effects of albumin administration in any particular group of patients.

Imagine a study with an identical design that evaluated the safety of blood transfusions. Such a study would probably show no benefit and perhaps a harmful effect of blood transfusions in an unselected group of patients. This would not indicate that blood transfusions should be abandoned, but rather that studies should focus on the subgroup of patients with anaemia and a high risk of complications.

It is now time to conduct a randomised controlled trial to evaluate the effects of albumin versus saline administration in patients with hypoalbuminaemia and an increased risk of complications. In the meantime, insufficient evidence exists to support a ban on albumin administration in critically ill patients with hypoalbuminaemia.

¹ Department of Intensive Care, Erasme University Hospital, 1070 Brussels, Belgium

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Competing interests: None declared.

References

1. Vincent JL, Sakr Y, Reinhart K, Sprung CL, Gerlach H, Ranieri VM. Is albumin administration in the acutely ill associated with increased mortality? Results of the SOAP study. Crit Care 2005;9:R745-54.[CrossRef][ISI][Medline]
2. Vincent JL, Dubois MJ, Navickis RJ, Wilkes MM. Hypoalbuminemia in acute illness: is there a rationale for intervention? A meta-analysis of cohort studies and controlled trials. Ann Surg 2003;237:319-34.[CrossRef][ISI][Medline]
3. Goldwasser P, Feldman J. Association of serum albumin and mortality risk. J Clin Epidemiol 1997;50:693-703.[CrossRef][ISI][Medline]
4. Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004;350:2247-56.[Abstract/Free Full Text]
5. Saline versus Albumin Fluid Evaluation (SAFE) Study Investigators. Effect of baseline serum albumin concentration on outcome of resuscitation with albumin or saline in patients in intensive care units: analysis of data from the saline versus albumin fluid evaluation (SAFE) study. BMJ doi: 10.1136/bmj.38985.398704.7C
6. Cochrane Injuries Group. Human albumin administration in critically ill patients: systematic review of randomized controlled trials. BMJ 1998;317:235-40.[Abstract/Free Full Text]

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