A Comparison of Albumin and Saline for Fluid Resuscitation in

the Intensive Care UnitThe SAFE Study Investigators

N Engl J Med 2004: 350:2247-56.

Background

• Conflicting results from meta-analyses comparing saline to albumin on survival of critically ill patients exist.

• Cochrane Injuries Group Albumin Reviewers’ meta-analysis of 24 studies and 1419 patients suggested albumin increased the absolute risk of death by 6 percent compared to crystalloid.

• No adequately powered randomized, controlled trials have examined the effects of fluid choice on the survival of patients in the ICU.

NEJM 2004 350;22:2247-56.

Hypothesis

• When 4% albumin is compared to 0.9% sodium chloride for intravascular resuscitation in the ICU there will be no difference in 28 day rate of death from any cause.

NEJM 2004 350;22:2247-56.

Methods

• 16 ICUs in Australia and New Zealand• 6997 patients

– 3497 received albumin, 3500 received saline

• Randomized, blinded• Inclusion criteria

– Fluid replacement needed and 4% albumin or 0.9% sodium chloride acceptable

– At least one clinical sign of hypovolemia

• Exclusion criteria– A/E human albumin, religion, plasmapheresis, cardiac surgery,

burns, liver transplantation, < 18 years, brain death, moribund, previous enrollment, previous fluid resuscitation.

NEJM 2004 350;22:2247-56.

Outcome Measures

• Primary outcome measures– 28 day all cause mortality

• Secondary outcome measures– 28 day survival time– Number of new organ failures– Duration of mechanical ventilation– Duration of renal replacement therapy– Duration of ICU and hospital LOS

• Subgroup comparison– Trauma, sepsis, ARDS

NEJM 2004 350;22:2247-56.

Outcome Albumin(3473) Saline(3460) RR (95% CI) P valueStatus at 28 days: No.(%)

Death 726(20.9) 729(21.1) 0.99 (0.91 to 1.09) 0.87Alive in ICU 111(3.2) 87(2.5) 1.27 (0.96 to 1.68) 0.09Alive in HOS 793(22.8) 848(24.5) 0.93 (0.86 to 1.01) 0.10

Outcome Albumin(3473) Saline(3460) AD (95% CI) P valueICU LOS (d) 6.56.6 6.26.2 0.24 (-0.06 to

0.54) 0.44HOS LOS (d) 15.39.6 15.69.6 -0.24 (-0.70 to

0.21) 0.30Vent days 4.56.1 4.3±5.7 0.19 (-0.08 to 0.47) 0.74RRT days 0.482.28 0.392.0 0.09 (-0.0 to 0.19) 0.41

No difference in 0-5 new organ failures (p=0.85)

Results- Primary and Secondary Outcomes

NEJM 2004 350;22:2247-56.

Results- New Organ FailuresNew organ failure-no. (%) p=0.85*

No (%) Albumin Saline

1 organ 1397 (52.7) 1424 (53.3)

2 organs 795 (30.0) 796(29.8)

3 organs 369 (13.9) 361 (13.5)

4 organs 68 (2.6) 75 (2.8)

5 organs 2 (0.1) 0*The P value pertains to the comparison between the albumin and saline groupsIn the numbers of patients who had no new organ failure of new failure of one,Two, three, four, or five organs. NEJM 2004 350;22:2247-56.

Probability of Survival Results

NEJM 2004 350;22:2247-56.

Death within 28 days by subgroup: No./total (%) Albumin Saline RR (95% CI) P

valueTrauma 81/596 (13.6) 59/590 (10.0) 1.36 (0.99 to 1.86)

0.06

Severe Sepsis 185/603 (30.7) 217/615 (35.3) 0.87 (0.74 to 1.02) 0.09

ARDS 24/61 (39.3) 28/66 (42.4) 0.93 (0.61 to 1.41) 0.72

Study had insufficient power to detect small differences in mortality among subgroups.

Results- Mortality by Subgroup

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Relative Risk of Death

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Summary

• 4 percent albumin or normal saline for intravascular volume resuscitation in a heterogeneous population resulted in equivalent rates of death at 28 days.

• Mechanical ventilation, ICU and hospital days and renal replacement therapy needs were equivalent.

• Findings do not support Cochrane Injuries Group Albumin Reviewers meta-analysis.

NEJM 2004 350;22:2247-56.

Conclusion

• “ Our study provides evidence that albumin and saline should be considered clinically equivalent treatments for intravascular volume resuscitation in a heterogeneous population of patients in the ICU. Whether albumin or saline confers benefit in highly select populations of critically ill patients requires further study.”

NEJM 2004 350;22:2247-56.