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A Comparison of Albumin and Saline for Fluid Resuscitation in the Intensive Care Unit.The SAFE Study Investigators. N Engl J Med 2004;350:2247-2256 (accompanying editorial by Cook D. N Engl J Med 2004;350:2294-2296)Reviewer: Bernhard Riedel, MBChB, MMed, FCA, FAHA
Background: It remains uncertain whether the choice of resuscitation fluid for patients in intensive care units (ICUs) significantly affects patient outcome.1-7 The absence of adequately powered randomized, controlled trials, and the conflicting results of meta-analyses examining how the choice of crystalloid or colloid solution and of albumin-containing or albumin-free fluid affects survival in critically ill patients 1-3, 7 have left many clinicians unsure about the effect of albumin-containing fluids on survival in critically ill patients. To address this uncertainty, the Saline versus Albumin Fluid Evaluation (SAFE) Study tested the hypothesis that when 4% albumin is compared with 0.9% sodium chloride (normal saline) for intravascular-fluid resuscitation in patients in the ICU, there is no difference in the 28-day rate of death from any cause. Methods: Adult patients admitted to closed, multidisciplinary ICUs of 16 academic tertiary hospitals in Australia and New Zealand between November 2001 and June 2003 were assessed for eligibility for the study. Eligible patients were those whom the treating clinician judged to require fluid administration to maintain or increase intravascular volume, with this decision supported by the fulfillment of at least one objective criterion (e.g., heart rate >90 beats per minute, a systolic blood pressure <100 mm Hg). Patients admitted to the ICU after cardiac surgery, after liver transplantation, or for the treatment of burns were excluded. Eligible patients were randomly assigned to receive either 4% albumin or normal saline in a double-blind fashion. Randomization, using a minimization algorithm, was centrally accessed through a secure internet-based Web site, and stratified according to institution and according to whether there was a diagnosis of trauma on admission to the ICU. The allocated study treatment was used for all fluid resuscitation in the ICU until death, or discharge, or until 28 days after randomization. The administration of maintenance fluids, specific replacement fluids, enteral or parenteral nutrition, and blood products, as well as the monitoring of central venous pressure, pulmonary-artery catheterization, and all other aspects of patient care were performed at the discretion of the treating clinicians. The primary outcome measure was death from any cause within 28 days after randomization. Secondary outcome measures were the survival time during the first 28 days, the proportion of patients who had new organ failure, the duration of mechanical ventilation, the duration of renal-replacement therapy, and the duration of the ICU and hospital stay. The trial was designed to detect a 3% difference in absolute mortality rates between the two groups from an estimated baseline mortality rate of 15% at a power of 90%. Results: Of the 6,997 patients who underwent randomization, 94.7percent were enrolled with the use of the provision for delayed consent, 3,497 were assigned to receive albumin and 3,500 were assigned to receive saline. Compliance was excellent; more than 97 percent of patients received their assigned fluid. Information on vital status 28 days after randomization was unavailable for 67 patients (1.0%). Patients randomly assigned to receive albumin received significantly less study fluid during the first four study days, with an overall ratio of volume of albumin to volume of saline administered approximating 1:1.4. Thereafter, there were no differences between the two groups with regards to volume of study fluids administered. There were 726 (20.9%) deaths in the albumin group, as compared with 729 (21.1%) deaths in the saline group (relative risk of death, 0.99; 95% CI, 0.91 to 1.09; P=0.87). At 28 days, 111 patients in the albumin group (3.2%) and 87 patients in the saline group (2.5 %) remained in the ICU (relative risk, 1.27; 95% CI, 0.96 to 1.68; P=0.09). There were no significant differences with regards to the mean (±SD) number of days spent in the ICU (6.5±6.6 vs. 6.2±6.2 days; P=0.44), days spent in hospital (15.3±9.6 vs. 15.6±9.6 days; P=0.30), days of mechanical ventilation (4.5±6.1 vs. 4.3±5.7 days; P=0.74), or days of renal-replacement therapy (0.5±2.3 vs. 0.4±2.0 days; P=0.41) between the albumin group and the saline group, respectively. The number of patients with new single- or multiple-organ failure was similar in the two groups (P=0.85). In a subgroup analyses of patients with trauma, 13.6% (81/596) patients assigned to receive albumin compared with 10.0% (59/590) patients assigned to receive saline died (relative risk, 1.36; 95% CI, 0.99 to 1.86; P=0.06). This difference in the relative risk of death was due to the greater number of patients with trauma and an associated brain injury who died after random assignment to albumin as opposed to saline: 24.5% (59/241) patients assigned to receive albumin compared with 15.1% (38/251) patients assigned to receive saline (relative risk, 1.62; 95% CI, 1.12 to 2.34; P=0.009). Among patients who had trauma without brain injury, there was no difference between the groups in terms of mortality. In a subgroup analysis of patients with severe sepsis, 30.7% (185/603) of patients assigned to receive albumin compared with 35.3% (217/615) of patients assigned to receive saline died (relative risk, 0.87; 95% CI, 0.74 to 1.02; P=0.09). Discussion and Comments: The SAFE Study investigators concluded that in a heterogeneous population of critically ill patients who require fluid resuscitation that the use of 4% albumin or normal saline for intravascular volume resuscitation resulted in equivalent rates of 28-day mortality from any cause. Rates of secondary outcomes - survival time, organ dysfunction, the duration of mechanical ventilation, the duration of renal-replacement therapy, and the length of stay in the intensive care unit and in the hospital - were also similar. These results challenge some polarized convictions and fail to support the results of the Cochrane Injuries Group Albumin Reviewers' meta-analysis, which suggested that the use of albumin was associated with an increased mortality rate among critically ill patients.1 In the context of the overall results, what do the subgroup analyses suggest? Given that the study had insufficient power to detect small but important differences in mortality among the predefined subgroups, cautious interpretation of these findings is warranted. Patients with traumatic brain injury constituted only 7% of the study population, and the excess number of deaths in the albumin group was only 21. Accordingly, the trend, in the albumin treated group, toward increased mortality among patients with brain injury associated with trauma and toward reduced mortality among patients with severe sepsis requires further investigation by specifically designed and appropriately powered studies. This study by the Australian and New Zealand Intensive Care Society Clinical Trials Group heralds a new era in critical care. The SAFE study,8 a large, simple, randomized, concealed, blinded trial that examined a ubiquitous intervention in the intensive care unit: intravenous fluid - one of the most fundamental and contentious issues in critical care, was commendably conducted, carefully analyzed, and transparently reported. As a consequence this study, by using multidisciplinary implementation strategies and Web-based management and by demonstrating excellent protocol adherence in thousands of patients, has raised the bar for future trials. The SAFE Study is not only a landmark trial; it is also a milestone for the discipline of critical care medicine.9 From the perspective of clinical practice, some clinicians will point to the overall absence of harm associated with albumin in the SAFE Study and use it on the basis of pathophysiological rationale and favorable trends in selected studies. Others will conclude that without proof of benefit, routine use of albumin is hard to justify; for similar clinical outcomes at a lower cost, crystalloids may suffice in most circumstances. Additional influences will include patient-specific conditions, clinicians' preferences, perceptions regarding safety of biologic fluids, availability, and cost. The affair with albumin in the intensive care is not over.9 References:
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