ALBIOS: Albumin Replacement in Severe Sepsis (2014)

“In patients with severe sepsis, albumin replacement in addition to crystalloids, as compared with crystalloids alone, did not improve survival at 28 and 90 days.”

  • The ALBIOS Study Investigators

1. Publication Details

  • Trial Title: Albumin Replacement in Patients with Severe Sepsis or Septic Shock
  • Citation: Caironi P, Tognoni G, Masson S, et al. Albumin Replacement in Patients with Severe Sepsis or Septic Shock. N Engl J Med. 2014;370(15):1412-1421. DOI: 10.1056/NEJMoa1401682
  • Published: April 10, 2014, in The New England Journal of Medicine
  • Author: Pietro Caironi, M.D.
  • Funding: Italian Medicines Agency; and others.

2. Keywords

  • Severe Sepsis, Septic Shock, Fluid Resuscitation, Albumin, Crystalloids, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with severe sepsis or septic shock (Population), does fluid resuscitation with 20% albumin and crystalloids (Intervention) compared to crystalloids alone (Comparison) reduce 28-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The optimal fluid for resuscitation in sepsis was a major debate. While crystalloids were standard, it was hypothesized that albumin, by maintaining oncotic pressure, might reduce edema and improve outcomes. The landmark SAFE trial (2004) showed no overall difference between albumin and saline in a general ICU population, but a subgroup analysis suggested a possible benefit in patients with severe sepsis.
  • Knowledge Gap: A large, dedicated trial was needed to specifically test the hypothesis that albumin administration improves survival in patients with severe sepsis.
  • Proposed Hypothesis: The authors hypothesized that administering albumin to maintain a serum level of 30 g/L, in addition to crystalloids, would be superior to crystalloids alone in reducing mortality.

5. Study Design and Methods

  • Design: A multicenter, open-label, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 100 intensive care units (ICUs) in Italy.
  • Trial Period: Enrollment ran from February 2008 to December 2012.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) admitted to the ICU with severe sepsis or septic shock for less than 24 hours.
    • Exclusion Criteria: Included traumatic brain injury, burns, and contraindications to albumin.
  • Intervention: Patients received 20% albumin and crystalloids to target a serum albumin level of 30 g/L or more for the first 28 days or until ICU discharge.
  • Control: Patients received crystalloid solutions alone for fluid resuscitation.
  • Management Common to Both Groups: All other aspects of sepsis management, including the use of vasopressors and antibiotics, were at the discretion of the treating clinicians according to international guidelines.
  • Power and Sample Size: The authors calculated that a sample size of 1800 patients would provide 80% power to detect a 7.5% absolute risk reduction in 28-day mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: All-cause mortality at 28 days.
    • Secondary Outcomes: Included 90-day mortality, organ dysfunction scores, and length of stay.

6. Key Results

  • Enrollment and Baseline: 1818 patients were randomized (910 to the albumin group and 908 to the crystalloid group). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in 28-day mortality. 285 of 895 patients (31.8%) in the albumin group died, compared with 288 of 900 patients (32.0%) in the crystalloid group (p=0.94).
  • Secondary Outcomes: There was no significant difference in 90-day mortality (41.1% in the albumin group vs. 43.6% in the crystalloid group). However, in a pre-specified subgroup of patients with septic shock, 90-day mortality was lower in the albumin group.
  • Adverse Events: There were no significant differences in adverse events between the groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death between the two groups.
  • Key Statistic(s) Reported: Relative Risk (RR) for death at 28 days: 0.99 (95% CI, 0.87 to 1.14; P-value: 0.94).
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: The paper reports the result as 0.99.
      • Clinical Meaning: An RR of 0.99 indicates virtually no difference in the risk of death between the two groups.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.87 to 1.14.
      • Clinical Meaning: Since this range crosses the line of no effect (1.0), it confirms that the result is not statistically significant. Clinically, this means the true effect could range from a 13% benefit to a 14% harm.
    • P-value: The p-value of 0.94 is much higher than the 0.05 threshold, indicating the result is not statistically significant and very likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial was neutral, ARR and NNT are not applicable.
  • Subgroup Analyses: In the pre-specified subgroup of patients with septic shock (n=1121), those in the albumin group had a lower 90-day mortality rate than those in the crystalloid group (43.5% vs. 49.9%), but this finding was not statistically significant after adjustment for multiple comparisons and should be considered hypothesis-generating.

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, randomized, controlled design provides a high level of evidence.
  • Generalizability: The pragmatic design across 100 Italian ICUs increases the applicability of the findings.
  • Statistical Power: The study was large and adequately powered to detect a clinically meaningful difference.
  • Patient-Centered Outcomes: The primary outcome of 28-day mortality is a robust and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label (unblinded), which introduces a risk of performance bias, as clinicians’ knowledge of the fluid type could have influenced other aspects of care.
  • External Validity (Generalizability): The results may not be applicable to settings where different types of crystalloids (e.g., balanced solutions vs. saline) are used.
  • Other: The control group received a larger total volume of fluid than the albumin group, which could have independently influenced outcomes.

10. Conclusion of the Authors

  • In patients with severe sepsis, albumin replacement in addition to crystalloids did not improve survival at 28 and 90 days as compared with crystalloids alone.

11. To Summarize

  • Impact on Current Practice: This large, high-quality trial provided strong evidence that the routine administration of albumin to all patients with severe sepsis does not improve survival.
  • Specific Recommendations:
    • Patient Selection: For the general population of adult patients with severe sepsis.
    • Actionable Intervention: The results do not support the routine, protocolized use of albumin to target a level of 30 g/L in all patients with severe sepsis.
  • What This Trial Does NOT Mean: This trial does NOT mean that albumin has no role in the ICU. The subgroup analysis suggests a potential benefit in patients with established septic shock, though this requires further confirmation.
  • Implementation Caveats: Crystalloids remain the first-line fluid for resuscitation in severe sepsis. The decision to use albumin may be considered in specific circumstances, such as in patients with septic shock who have received large volumes of crystalloids.

12. Context and Related Studies

  • Building on Previous Evidence: The ALBIOS trial (2014) was a direct follow-up to the hypothesis-generating subgroup analysis of the SAFE trial (2004).
  • Influence on Subsequent Research: The neutral overall result of ALBIOS, combined with the positive signal in the septic shock subgroup, has kept the debate about albumin’s role alive. It has influenced subsequent guidelines, which generally do not recommend routine albumin use but suggest it may be considered in septic shock.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question is whether the signal of benefit in the septic shock subgroup is real.
  • Future Directions: Future research is needed to confirm or refute the potential benefit of albumin specifically in patients with septic shock, perhaps guided by biomarkers or other physiological parameters.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a common and expensive intervention with an uncertain evidence base.
  • Methods: The multicenter RCT design was appropriate. The main methodological weakness is the open-label (unblinded) design, which introduces a risk of performance bias. The fact that the control group received more fluid is a potential confounder.
  • Results: The study reported a clear neutral finding for its primary outcome. The subgroup analysis for patients with septic shock is intriguing but should be interpreted with caution as it was not the primary question and was not powered for this analysis.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The high external validity of this pragmatic trial means its findings are broadly applicable. The trial provides strong evidence to discourage the routine use of albumin in all patients with severe sepsis.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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