Annals of Emergency Medicine
Volume 54, Issue 1 , Pages 114-116, July 2009

Albumin Administration in the Management of Critically Ill Patients: Is It Safe?

  • Lauralyn McIntyre, MD, FRCPC, MSc

      Affiliations

    • University of Ottawa, Department of Medicine (Division of Critical Care), Ottawa Health Research Institute, Center for Transfusion and Critical Care Research, Ottawa Hospital, Ottawa, Ontario, Canada
    • ,
  • Robert S. Green, MD, BSc, FRCPC, DABEM

      Affiliations

    • Dalhousie University, Department of Emergency Medicine, Department of Internal Medicine, Division of Critical Care Medicine, Halifax, Nova Scotia, Canada

published online 24 September 2008.

Article Outline

 

[Ann Emerg Med. 2009;54:114-116.]

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Systematic Review Source 

This is a systematic review abstract, a regular feature of the Annals' Evidence-Based Emergency Medicine (EBEM) series. Each features an abstract of a systematic review from the Cochrane Database of Systematic Reviews and a commentary by an emergency physician(s) knowledgeable in the subject area.

The source for this systematic review abstract is: Alderson P, Bunn F, Li Wan Po A, et al; Albumin Reviewers. Human albumin solution for resuscitation and volume expansion in critically ill patients. Cochrane Database Syst Rev. 2004;(4):CD001208. doi:10.1002/14651858.CD001208.pub2. The Annals' EBEM editors assisted in the preparation of the abstract of this Cochrane systematic review, as well as the Evidence-Based Medicine Teaching Points.

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Objective 

To quantify the effect on mortality of human albumin and plasma protein fraction administration on the management of critically ill patients.

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Data Sources 

The authors searched MEDLINE, EMBASE, and BIDS Index to Scientific and Technical Proceedings; reference lists of trials and review articles were reviewed, and authors of identified trials were contacted (search last updated August 2004).

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Study Selection 

Randomized controlled trials comparing albumin/plasma protein fraction with no albumin/plasma protein fraction, or with a crystalloid solution, in critically ill patients with hypovolemia, burns, or hypoalbuminemia.

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Data Extraction and Analysis 

Two reviewers extracted data and assessed quality independently. The analysis was stratified according to patient type. Relative risks (RRs) and 95% confidence intervals (CIs) for mortality were calculated for each trial on an intention-to-treat basis. Heterogeneity between trials was tested using an I2 test. Where possible, summary RRs and 95% CIs were calculated using a fixed-effects model. If the source of heterogeneity could obviously be related to patient type or allocation concealment, then the analysis was stratified on this dimension.

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Main Results 

Thirty-two trials met the inclusion criteria and reported death as an outcome. There were 1,632 deaths among 8,452 trial participants. For hypovolemia, albumin use did not reduce mortality (RR=1.01; 95% CI 0.92 to 1.10). This estimate was heavily influenced by the results of the Saline versus Albumin Fluid Evaluation (SAFE) trial, which contributed 91% of the information (based on weighted meta-analysis). For burns, albumin use increased mortality (RR=2.40; 95% CI 1.11 to 5.19); for hypoalbuminemia, albumin's increase in mortality was not statistically significant (RR=1.38; 95% CI 0.94 to 2.03). There was no substantial heterogeneity between the trials in the various categories (I2=0%). The pooled RR of death with albumin administration was 1.04 (95% CI 0.95 to 1.13).

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Conclusions 

There is no evidence that albumin reduces mortality compared with cheaper alternatives such as saline solution for patients with hypovolemia. There is also no evidence that albumin reduces mortality in critically ill patients with burns and hypoalbuminemia. However, selected populations of critically ill patients in which albumin may be beneficial remains to be determined. In view of the absence of evidence of a mortality benefit from albumin and its increased cost compared to alternatives, such as saline solution, it would seem reasonable that albumin should be used only within the context of well-concealed and adequately powered randomized controlled trials.

Systematic Review Author Contact 


Ian Roberts, MB, BCh, MRCP, PhD

London School of Hygiene & Tropical Medicine

London, UK

E-mail Ian.Roberts@lshtm.ac.uk

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Commentary: Clinical Implication 

The administration of resuscitation fluids to the critically ill patient for volume resuscitation is a cornerstone of management. Two main classes of fluid expand the plasma volume: colloid and crystalloid solutions. The most commonly used crystalloid fluids are normal saline solution and Ringer's lactate. Colloid fluids include hydroxyethyl starch solutions, albumin (5% and 25%), gelatins, and dextrans, with hydroxyethyl starch fluids being the dominant colloid used for resuscitation in North America and Europe.1, 2 Until recently, there has been insufficient evidence of benefits and harms to guide the use of fluids in resuscitation.3, 4

Clinicians who favor the use of colloid fluids argue that hypo-oncotic crystalloids leak from the plasma to excessively expand the interstitial fluid volume and create peripheral edema.5 In contrast to crystalloid solutions, colloid solutions are macromolecules that under normal physiologic conditions do not pass through the endothelial layer and into the interstitial space.6 Thus, colloids have the potential advantage of requiring much less volume to expand the intravascular space. Critically ill patients are often in a physiologically compromised state, however, resulting in endothelial injury and microcirculatory dysfunction. In these circumstances, colloid solutions may freely pass from intravascular to interstitial spaces.6 Albumin may act as an antioxidant and influence vascular permeability, but none of these purported benefits have translated into improved outcomes.7 In fact, a systematic review in 1998 suggested a 6% excess risk of death for critically ill patients resuscitated with albumin.8 This led to a reduction in albumin use in the United Kingdom and likely elsewhere.9

This updated Cochrane Review included 32 trials involving 8,452 participants. The review concludes that albumin is not associated with a reduced risk of death overall or in the specific setting of hypovolemia. In the subgroups of patients who were burned or hypoalbuminemic, albumin was associated with a significant increase and a trend toward an increased risk of death, respectively. These findings should be considered hypothesis generating, requiring confirmation through large randomized controlled trials. The authors conclude that because albumin is not associated with a mortality benefit, and because it is more expensive than crystalloids, it should be used only in the context of adequately powered randomized controlled trials. They also acknowledge that the results of the systematic review were heavily influenced by a single randomized controlled trial of 6,997 heterogeneous critically ill patients resuscitated with 4% albumin versus normal saline solution. This trial failed to identify a difference between the resuscitation strategies (RR=0.99; 95% CI 0.91 to 1.09). One a priori subgroup analysis of patients with severe sepsis3 suggested a trend toward reduced mortality (RR=0.87; 95% CI 0.74 to 1.02). Conversely, a post hoc subgroup analysis of patients with traumatic brain injury10 revealed an increased risk of death associated with albumin use (RR=1.63; 95% CI 1.17 to 2.26). These findings illustrate that fluid selection may have disparate effects in different critically ill patients. Editorialists agree that future randomized controlled trials examining albumin's effects are required in specific critically ill populations.11, 12

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Take-Home Message 

Early fluid resuscitation is the cornerstone of management for the patient who requires volume resuscitation. Resuscitation with albumin fluid for critically ill patients who are hypovolemic and in need of volume resuscitation is not associated with increased survival. Until further evidence emerges on the role of albumin in specific critically ill patient populations, emergency physicians should use crystalloids for resuscitation and restrict the use of albumin.

EBEM Commentator Contact 


Lauralyn McIntyre, MD, FRCPC, MSc

Center for Transfusion and Critical Care Research

Ottawa Hospital, Ottawa, ON, Canada

E-mail lmcintyre@ottawahospital.on.ca

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EBEM Teaching Point 

Role of Industry Funding 

The pharmaceutical industry funds more than 70% of drug trials.13 There is strong suspicion that this industry funding may bias the trial results reported and the interpretation of these results. In our examination of the funding source for the 32 trials included in this review, only 1 trial was provided with industry and nonindustry funding; a further 18 trials received nonindustry funding. The remaining 12 trials did not reveal a funding source, and hence it is unclear whether industry sponsored these studies.

Several systematic reviews of randomized controlled trials have examined the role of industry funding and authors' conclusions; most have found that industry sponsorship is associated with proindustry results and conclusions.14, 15 The reasons for these positive associations are not clear. Although industry-funded trials appear to be of equal or higher methodological quality than nonindustry-funded trials,14 research results and conclusions may be influenced by ghost management and authorship,16 publication bias, or other design biases that are not identified or explained by an examination of trial quality or disclosure of the funding source.14

Additional research is required to understand why industry-sponsored trials appear more likely to be associated with publications supporting their treatment interventions. Readers of reviews should be cognizant of the potential bias introduced by industry funding, and the medical literature should be interpreted with the funding source in mind.

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References 

  1. Schortgen F, Deye N, Brochard L, et al. Preferred plasma volume expanders for critically ill patients: results of an international survey. Intensive Care Med. 2004;30:2222–2229
  2. Miletin M, Steward T, Norton PG. Influence on physicians' choices of intravenous colloids. Intensive Care Med. 2002;28:917–924
  3. 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
  4. Brunkhorst F, Engel C, Bloos F, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358:125–139
  5. Marik PE, Iglesias J. Would the colloid detractors please sit down!. Crit Care Med. 2000;28:2652–2654
  6. Vercueil A, Grocott MP, Mythen MG. Physiology, pharmacology, and rationale for colloid administration for the maintenance of effective hemodynamic stability in critically ill patients. Transfus Med Rev. 2005;19:93–109
  7. American Thoracic Society. Evidence-based colloid use in the critically ill: American Thoracic Society consensus statement. Am J Respir Crit Care Med. 2004;170:1247–1259
  8. Cochrane Injuries Group Albumin Reviewers. Human albumin administration in critically ill patients: systematic review of randomised controlled trials (Cochrane Injuries Group Albumin Reviewers). BMJ. 1998;317:235–240
  9. Roberts I, Edwards P, McLelland B. More on albumin (Use of human albumin in UK fell substantially when systematic review was published). BMJ. 1999;318:1214–1215
  10. Safe Study Investigators. Saline or albumin for fluid resuscitation in patients with traumatic brain injury. N Engl J Med. 2007;357:874–884
  11. Cook D. Is albumin safe?. N Engl J Med. 2004;350:2294–2296
  12. Fan E, Stewart TE. Albumin in critical care: SAFE, but worth its salt?. Crit Care. 2004;8:297–299
  13. Sismondo S. Pharmaceutical company funding and its consequences: a qualitative systematic review. Contemp Clin Trials. 2008;29:109–113
  14. Sismondo S. How pharmaceutical industry funding affects trial outcomes: causal structures and responses. Soc Sci Med. 2008;66:1909–1914
  15. Clifford TJ, Barrowman NJ, Moher D. Funding source, trial outcome and reporting quality: are they related? Results of a pilot study. BMC Health Serv Res. 2002;2:18
  16. Gotzsche PC, Hrobjartsson A, Johansen HK, et al. Ghost authorship in industry-initiated randomised trials. PLoS Med. 2007;4:e19

PII: S0196-0644(08)01584-9

doi:10.1016/j.annemergmed.2008.07.047

Annals of Emergency Medicine
Volume 54, Issue 1 , Pages 114-116, July 2009

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