Impact of albumin compared to saline on organ function and mortality of patients with severe sepsis

Abstract

Purpose

To determine the effect of random assignment to fluid resuscitation with albumin or saline on organ function and mortality in patients with severe sepsis.

Methods

Pre-defined subgroup analysis of a randomized controlled trial conducted in the intensive care units of 16 hospitals in Australia and New Zealand.

Results

Of 1,218 patients with severe sepsis at baseline, 603 and 615 were assigned to receive albumin and saline, respectively. The two groups had similar baseline characteristics. During the first 7 days mean arterial pressure was similar in the two groups, but patients assigned albumin had a lower heart rate on days 1 and 3 (p = 0.002 and p = 0.03, respectively) and a higher central venous pressure on days 1–3 (p < 0.005 each day). There was no difference in the renal or total Sequential Organ Failure Assessment score of the two groups; 113/603 (18.7%) of patients assigned albumin were treated with renal replacement therapy compared to 112/615 (18.2%) assigned saline (p = 0.98).

The unadjusted relative risk of death for albumin versus saline was 0.87 [95% confidence interval (CI) 0.74–1.02] for patients with severe sepsis and 1.05 (0.94–1.17) for patients without severe sepsis (p = 0.06 for heterogeneity). From multivariate logistic regression analysis adjusting for baseline factors in patients with complete baseline data (919/1,218, 75.5%), the adjusted odds ratio for death for albumin versus saline was 0.71 (95% CI: 0.52–0.97; p = 0.03).

Conclusions

Administration of albumin compared to saline did not impair renal or other organ function and may have decreased the risk of death.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

References

  1. 1.

    Dellinger R, Levy M, Carlet J, Bion J, Parker M, Jaeschke R, Reinhart K, Angus D, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini J, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson B, Townsend S, Vender J, Zimmerman J, Vincent JL (2008) Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock. Intensive Care Med 34:17–60

    Article  PubMed  Google Scholar 

  2. 2.

    Schortgen F, Deye N, Brochard L (2004) Preferred plasma volume expanders for critically ill patients: results of an international survey. Intensive Care Med 30:2222–2229

    Article  PubMed  Google Scholar 

  3. 3.

    Miletin MS, Stewart TE, Norton PG (2002) Influences on physicians’ choices of intravenous colloids. Intensive Care Med 28:917–924

    Article  PubMed  Google Scholar 

  4. 4.

    Schortgen F, Lacherade JC, Bruneel F, Cattaneo I, Hemery F, Lemaire F, Brochard L (2001) Effects of hydroxyethyl starch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet 357:911–916

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, Moerer O, Gruendling M, Oppert M, Grond S, Olthoff D, Jaschinski U, John S, Rossaint R, Welte T, Schaefer M, Kern P, Kuhnt E, Kiehntopf M, Hartog C, Natanson C, Loeffler M, Reinhart K, the German Competence Network Sepsis (SepNet) (2008) Intensive Insulin Therapy and Pentastarch Resuscitation in Severe Sepsis. N Engl J Med 358:125–139

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Schortgen F, Girou E, Deye N, Brochard L (2008) The risk associated with hyperoncotic colloids in patients with shock. Intensive Care Med 34:2157–2168

    Article  PubMed  Google Scholar 

  7. 7.

    Maitland K, Pamba A, English M, Peshu N, Marsh K, Newton C, Levin M (2005) Randomized trial of volume expansion with albumin or saline in children with severe malaria: preliminary evidence of albumin benefit. Clin Infect Dis 40:538–545

    Article  PubMed  Google Scholar 

  8. 8.

    Akech S, Gwer S, Idro R, Fegan G, Eziefula AC, Newton CR, Levin M, Maitland K (2006) Volume expansion with albumin compared to gelofusine in children with severe malaria: results of a controlled trial. PLoS Clin Trials 1:e21

    Article  PubMed  Google Scholar 

  9. 9.

    Sort P, Navasa M, Arroyo V, Aldeguer X, Planas R, Ruiz-del-Arbol L, Castells L, Vargas V, Soriano G, Guevara M, Gines P, Rodes J (1999) Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 341:403–409

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    The SAFE Study Investigators (2004) A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 350:2247–2256

    Article  Google Scholar 

  11. 11.

    ANZICS Clinical Trials Group and Institute for International Health SAFE Study Investigators. The Saline vs. Albumin Fluid Evaluation (SAFE) Study (ISRCTN76588266): design and conduct of a multi-centre, blinded randomised controlled trial of intravenous fluid resuscitation in critically ill patients. http://bmj.com/cgi/content/full/326/7389/559/DC1 Accessed May 18 2010

  12. 12.

    Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ (1992) Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 101:1644–1655

  13. 13.

    Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher Jr CJ (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344:699–709

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Vincent JL, de Mendonca A, Cantraine F, Moreno R, Takala J, Suter PM, Sprung CL, Colardyn F, Blecher S (1998) Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on “sepsis-related problems” of the European Society of Intensive Care Medicine. Crit Care Med 26:1793–1800

    CAS  PubMed  Google Scholar 

  15. 15.

    TheSAFE Study Investigators (2006) 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 333:1044–1046

    Article  Google Scholar 

  16. 16.

    Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985) APACHE II: a severity of disease classification system. Crit Care Med 13:818–829

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Finfer S, Bellomo R, Lipman J, French C, Dobb G, Myburgh J, the ANZICS CTG Sepsis Investigators (2004) Adult population incidence of severe sepsis in Australian and New Zealand Intensive Care Units. Intensive Care Med 30:589–596

    Article  PubMed  Google Scholar 

  18. 18.

    Karlsson S, Varpula M, Ruokonen E, Pettila V, Parviainen I, la-Kokko TI, Kolho E, Rintala EM (2007) Incidence, treatment, and outcome of severe sepsis in ICU-treated adults in Finland: the Finnsepsis study. Intensive Care Med 33:435–443

    Article  PubMed  Google Scholar 

  19. 19.

    Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, Moreno R, Carlet J, Le G Jr, Payen D (2006) Sepsis in European intensive care units: results of the SOAP study. Crit Care Med 34:344–353

    Article  PubMed  Google Scholar 

  20. 20.

    NICE-SUGAR Study Investigators (2009) Intensive versus conventional glucose control in critically ill patients. N Engl J Med 360:1346–1349

    Article  Google Scholar 

  21. 21.

    Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M, the Early goal Directed Therapy Collaborative Group (2001) Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 345:1368–1377

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troche G, Chaumet-Riffaut P, Bellissant E (2002) Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 288:862–871

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R (2001) Intensive insulin therapy in critically ill patients. N Engl J Med 345:1359–1367

    Article  PubMed  Google Scholar 

  24. 24.

    Finfer S, Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Gardlund B, Marshall JC, Rhodes A (2008) Design, conduct, analysis and reporting of a multi-national placebo-controlled trial of activated protein C for persistent septic shock. Intensive Care Med 34:1935–1947

    Article  PubMed  Google Scholar 

  25. 25.

    Finfer S (2008) Corticosteroids in Septic Shock. N Engl J Med 358:188–190

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    The Australasian Resuscitation in Sepsis Evaluation (ARISE) Investigators and the Australian and New Zealand Intensive Care Society (ANZICS) Adult Patient Database (APD) Management Committee. The outcome of patients with sepsis and septic shock presenting to emergency departments in Australia and New Zealand (2007) Crit Care Resusc 9:8–18

  27. 27.

    Quinlan GJ, Mumby S, Martin GS, Bernard GR, Gutteridge JM, Evans TW (2004) Albumin influences total plasma antioxidant capacity favorably in patients with acute lung injury. Crit Care Med 32:755–759

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Zhang WJ, Frei B (2002) Albumin selectively inhibits TNF{alpha}-induced expression of vascular cell adhesion molecule-1 in human aortic endothelial cells. Cardiovasc Res 55:820–829

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Martin GS, Mangialardi RJ, Wheeler AP, Dupont WD, Morris JA, Bernard GR (2002) Albumin and furosemide therapy in hypoproteinemic patients with acute lung injury. Crit Care Med 30:2175–2182

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    The SAFE Study Investigators (2007) Saline or albumin for fluid resuscitation in patients with traumatic brain injury. N Engl J Med 357:874–884

    Article  Google Scholar 

  31. 31.

    Wills BA, Dung NM, Loan HT, Tam DTH, Thuy TTN, Minh LTT, Diet TV, Hao NT, Chau NV, Stepniewska K, White NJ, Farrar JJ (2005) Comparison of three fluid solutions for resuscitation in dengue shock syndrome. N Engl J Med 353:877–889

    Article  PubMed  Google Scholar 

  32. 32.

    McCann KB, Vucica Y, Famulari S, Bertolini J (2009) Effect of processing methods on colouration of human serum albumin preparations. Biologicals 37:32–36

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgments

Funding bodies are listed alphabetically (Australia unless otherwise stated): Auckland District Health Board, New Zealand; Australian Commonwealth Department of Health and Aged Care; CSL Limited, Melbourne, Victoria; Middlemore Hospital, New Zealand; Australian National Health and Medical Research Council; Health Department of Western Australia; Health Research Council of New Zealand; New South Wales Health Department; Northern Territory Health Services; Queensland Health Services Department; Royal Hobart Hospital, Tasmania; South Australian Department of Human Services; Victorian Department of Human Services. The funding bodies played no part in the conduct or analysis of the study, or the decision to publish the results.

Author information

Affiliations

Consortia

Additional information

The Saline versus Albumin Fluid Evaluation (SAFE) Study is a collaboration of the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG), the Australian Red Cross Blood Service, and the George Institute for International Health. The writing committee (Simon Finfer, Suzanne McEvoy, Rinaldo Bellomo, Colin McArthur, John Myburgh, and Robyn Norton) takes responsibility for the content of this article. The SAFE Study Investigators are listed in full in the Appendix.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 147 kb)

Appendix: SAFE Study Investigators

Appendix: SAFE Study Investigators

Writing Committee

Simon Finfer (Chair), Suzanne McEvoy, Rinaldo Bellomo, Colin McArthur, John Myburgh and Robyn Norton.

SAFE Study Management Committee

Robyn Norton (Chair), Julie French (Senior Project Manager), Rinaldo Bellomo, Simon Finfer, John Myburgh, Suzanne McEvoy, Gordon Doig, Mary Hayek and Sheridan O’Donnell.

SAFE Study Steering Committee

Simon Finfer (Chair), Anthony Bell, Rinaldo Bellomo, Neil Boyce, David Blythe, John Cade, Marianne Chapman, Louise Cole, D. James Cooper, Andrew Davies, Craig French, Julie French, Christopher Joyce, Colin McArthur, Stephen MacMahon, John Myburgh, Bruce Neal, Robyn Norton, Jeffrey Presneill, Peter Saul, Ian Seppelt, Dianne Stephens, Andrew Turner, Anthony Williams and Clive Woolfe.

SAFE Study External Safety and Data Monitoring Committee

Richard Peto (Chair), Peter Sandercock, Charles Sprung and J. Duncan Young.

Statistical analysis

The George Institute for International Health, University of Sydney, NSW.

Laurent Billot, Michael Fitzharris, Qiang Li, Suzanne McEvoy.

Site investigators

Alphabetically by institution and surname, Australia unless stated, NSW = New South Wales, NZ = New Zealand.

Alfred Hospital, Melbourne, Victoria: Julie Charlton, James Cooper, Andrew Davies, Catherine Harry, Lisa Higgins, Katherine Moulden, Shirley Vallance.

Auckland Hospital, Auckland (NZ): Janine Chadderton, Lynette Newby, Colin McArthur.

Austin & Repatriation Medical Centre, Melbourne, Victoria: Samantha Bates, Rinaldo Bellomo, Donna Goldsmith, Alison Voss.

Australian Red Cross Blood Service, Melbourne, Victoria: Neil Boyce.

Fremantle Hospital, Fremantle, Western Australia: David Blythe, Annamaria Palermo.

The George Institute for International Health, University of Sydney, NSW: Lesley Francis, Julie French, Michael Fitzharris, Mary Hayek, Kathy Jayne, Stephen MacMahon, Mamta Merai, Bruce Neal, Robyn Norton, Sameer Pandey, Sheridan O’Donnell, Manuela Schmidt, Siva Sivarajasingham, Mark Woodward.

John Hunter Hospital, Newcastle, NSW: Rosemary Carroll, Brett McFadyen, Peter Saul.

Middlemore Hospital, Auckland (NZ): Jane Clarke, Juliet Powell, Anthony Williams, Judi Tai.

Nepean Hospital, Penrith, NSW: Louise Cole, Iveta Hynesova, Ian Seppelt, Leonie Weisbrodt.

Princess Alexandra Hospital, Brisbane, Queensland: Lisa Bradley, Christopher Joyce, Theresa Kelly, Anthony Limpus, Robyn Moore.

Royal Adelaide Hospital, South Australia: Marianne Chapman, Stephanie Creed, Sandra Kaplan, Justine Rivett.

Royal Darwin Hospital, Northern Territory: Dianne Stephens, Jane Thomas.

Royal Hobart Hospital, Tasmania: Anthony Bell, Kathy Marsden, Andrew Turner.

Royal Melbourne Hospital, Victoria: Catherine Boyce, John Cade, Belinda Howe, Jeffrey Presneill, Megan Robertson.

Royal North Shore Hospital, Sydney, NSW: Gordon Doig, Simon Finfer, Anne O’Connor, Julie Potter, Naresh Ramakrishnan.

Royal Prince Alfred Hospital, Sydney, NSW: Catherine Powell, Dorrilyn Rajbhandari, Clive Woolfe.

St George Hospital, Sydney, NSW: Kathryn Girling, Marie Hodgetts, Alina Jovanovska, John Myburgh.

Western Hospital, Melbourne, Victoria: Craig French, Lorraine Little.

Competing interests and the role of SAFE study funders:

The SAFE study was part funded by CSL Limited. CSL Limited has acted as a sponsor for scientific meetings of the Australian and New Zealand Intensive Care Society and its Clinical Trials Group. CSL Limited has paid travel expenses for Professor Simon Finfer and Professor Rinaldo Bellomo to present the results of the SAFE study at scientific and industry sponsored meetings. In common with the other funders of the SAFE study, CSL Limited had no say in the design or conduct of the study, and no role or say in the analysis of the results, the preparation of manuscripts or the decision to submit results for publication.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

The SAFE Study Investigators. Impact of albumin compared to saline on organ function and mortality of patients with severe sepsis. Intensive Care Med 37, 86–96 (2011). https://doi.org/10.1007/s00134-010-2039-6

Download citation

Keywords

  • Critical care
  • Fluid therapy
  • Sepsis
  • Mortality
  • Multicenter randomized clinical trial