SAFE Study

SAFE: A Comparison of Albumin and Saline for Fluid Resuscitation in the Intensive Care Unit

The SAFE Study Investigators. N Engl J Med 2004; 351:1905-1908.

Clinical Question

  • Does fluid resuscitation with albumin, compared to saline, affect mortality for patients in the ICU?


  • Randomised controlled trial
  • Stratified by centre and according to whether there was a diagnosis of trauma
  • Double Blinded


  • 16 ICUs in Australasia
  • November 2001 – June 2003


  • Adult patients admitted to academic tertiary ICUs who were judged to require fluid administration to maintain or increase intravascular volume
  • Excluded post-op cardiac surgery, liver transplantation, burns
  • 6997 patients randomised


  • Resuscitation with 4% albumin


  • Resuscitation with 0.9% sodium chloride


  • Comparing 4% albumin to 0.9% sodium chloride
    • Primary outcome: all cause mortality at 28-days
      • 20.9% vs. 21.1%, Relative risk of death 0.99 (95% C.I. 0.91-1.09, P=0.87)
    • Secondary outcomes
      • There was no difference in length of ICU stay, duration of mechanical ventilation or renal replacement therapy
      • Mortality at 28 days in patients with severe sepsis
        • 30.7% vs 35.3% (RR 0.87, 95% C.I. 0.74 – 1.02), P=0.09
      • Mortality at 28 days in patients with trauma
        • 13.6% vs. 10% (RR 1.36, 95% C.I 0.99 – 1.86), P=0.06
    • Post-hoc analysis: mortality at 28 days in patients with brain injury
      • 24.5% vs. 15.1% (RR 1.62, 95% C.I 1.12-2.34), P=0.009

Authors’ Conclusion

  • Use of 4% albumin or 0.9% sodium chloride for fluid resuscitation results in similar  outcomes at 28 days


  • Multi-centre
  • Large number of patients included – a huge trial which demonstrates the importance of collaborative research
  • Double blinded – specifically designed fluid containers and administration sets were used
  • Robustly defended the short term safety profile of 4% albumin after concerns were raised by the Cochrane Injuries Group Albumin Reviewers


  • Minimal weaknesses. This was a great trial. The authors note that the sub-group analyses had insufficient power.

The Bottom Line

  • Overall there is no difference when 4% albumin is used for fluid resuscitation when compared to 0.9% sodium chloride. 4% albumin should be avoided in head injuries. A further study in patients with severe sepsis would be beneficial – hence the ALBIOS study.

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