6S: HES vs. Ringer’s Acetate in Sepsis (2012)

“In patients with severe sepsis, resuscitation with hydroxyethyl starch 130/0.42 was associated with a significantly increased risk of death at 90 days and a greater need for renal-replacement therapy, as compared with resuscitation with Ringer’s acetate.”

  • The 6S Trial Group and the Scandinavian Critical Care Trials Group

1. Publication Details

  • Trial Title: Hydroxyethyl Starch 130/0.42 versus Ringer’s Acetate in Severe Sepsis
  • Citation: Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl Starch 130/0.42 versus Ringer’s Acetate in Severe Sepsis. N Engl J Med. 2012;367(2):124-134. DOI: 10.1056/NEJMoa1204242
  • Published: July 12, 2012, in The New England Journal of Medicine
  • Author: Anders Perner, M.D., Ph.D.
  • Funding: Danish Research Council; Rigshospitalet; and others.

2. Keywords

  • Severe Sepsis, Septic Shock, Fluid Resuscitation, Hydroxyethyl Starch (HES), Crystalloids, Renal Replacement Therapy

3. The Clinical Question

  • In adult patients with severe sepsis in the ICU (Population), does fluid resuscitation with 6% hydroxyethyl starch (HES) 130/0.42 (Intervention) compared to Ringer’s acetate (Comparison) affect 90-day mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The choice between colloid and crystalloid solutions for fluid resuscitation in septic patients was a major clinical debate. Colloids like HES were thought to be more effective at plasma volume expansion, but concerns about adverse effects, particularly acute kidney injury and increased mortality with older HES solutions, were growing based on trials like VISEP (2008).
  • Knowledge Gap: It was unclear if the newer, lower-molecular-weight HES solutions (130/0.42) were safer and more effective than crystalloids in the setting of severe sepsis.
  • Proposed Hypothesis: The authors hypothesized that there would be no significant difference in 90-day mortality between patients resuscitated with HES 130/0.42 and those resuscitated with Ringer’s acetate.

5. Study Design and Methods

  • Design: A multicenter, parallel-group, blinded, randomized controlled trial (used to test the effectiveness of interventions).
  • Setting: 26 general intensive care units (ICUs) in Scandinavia (Denmark, Finland, Iceland, and Norway).
  • Trial Period: Enrollment ran from December 2009 to November 2011.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with severe sepsis requiring fluid resuscitation in the ICU.
    • Exclusion Criteria: Included pre-existing end-stage renal failure requiring dialysis, contraindications to HES (e.g., intracranial hemorrhage), and recent receipt of more than 1000 ml of colloid.
  • Intervention: Fluid resuscitation with 6% HES 130/0.42 in an acetate-containing solution.
  • Control: Fluid resuscitation with Ringer’s acetate (a balanced crystalloid).
  • Management Common to Both Groups: The study fluid was used for all fluid resuscitation needs up to a maximum of 33 ml/kg/day. The choice of all other interventions, including the use of vasopressors and other supportive care, was at the discretion of the treating clinicians according to local guidelines.
  • Power and Sample Size: The authors calculated that a sample of 800 patients would provide 80% power to detect a 7.5% absolute difference in 90-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: Death from any cause at 90 days after randomization.
    • Secondary Outcomes: Included the need for renal-replacement therapy (RRT), severe bleeding, and organ dysfunction scores.

6. Key Results

  • Enrollment and Baseline: 798 patients were randomized (400 to HES and 398 to Ringer’s acetate). The groups were well-matched at baseline.
  • Trial Status: The trial was stopped early by the data monitoring committee after the second planned interim analysis due to safety concerns (increased mortality) in the HES group.
  • Primary Outcome: Mortality at 90 days was significantly higher in the HES group: 201 of 398 patients (51%) died, compared with 172 of 400 patients (43%) in the Ringer’s acetate group (p=0.03).
  • Secondary Outcomes: Significantly more patients in the HES group received renal-replacement therapy (22% vs. 16%; p=0.04). There was no significant difference in the rates of severe bleeding.
  • Adverse Events: The primary adverse events were death and the need for RRT, both of which were more common in the HES group.

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 90 days: 1.17 (95% CI, 1.01 to 1.36; P-value: 0.03).
  • 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 1.17.
      • Clinical Meaning: The RR of 1.17 means that patients in the HES group had a 17% higher relative risk of dying at 90 days compared to the Ringer’s acetate group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 1.01 to 1.36.
      • Clinical Meaning: Since this entire range is above the line of no effect (1.0), it confirms that the result is statistically significant and suggests harm.
    • P-value: The p-value of 0.03 is below the 0.05 threshold, indicating the result is statistically significant and unlikely to be due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures:
    • Absolute Risk Increase (ARI):
      • Formula: ARI = (Risk in Intervention Group) – (Risk in Control Group)
      • Calculation: ARI = 51% – 43% = 8%.
      • Clinical Meaning: For every 100 patients with severe sepsis treated with HES instead of Ringer’s acetate, about 8 additional deaths occurred.
    • Number Needed to Harm (NNH):
      • Formula: NNH = 1 / ARI
      • Calculation: NNH = 1 / 0.08 = 12.5, which is rounded up to 13.
      • Clinical Meaning: You would only need to treat 13 patients with HES instead of Ringer’s acetate to cause one additional death.
  • Subgroup Analyses: The findings were consistent across all pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, blinded design provided high-quality evidence and minimized bias.
  • Generalizability: The pragmatic design across 26 ICUs increases the applicability of the findings to routine clinical practice.
  • Statistical Power: Although stopped early, the trial had a large enough sample size to detect a statistically significant difference.
  • Patient-Centered Outcomes: The primary outcome was 90-day mortality, a robust and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a low risk of bias.
  • External Validity (Generalizability): The results apply specifically to HES 130/0.42 and cannot be extrapolated to other colloids like albumin.
  • Other: The trial was stopped early for harm.

10. Conclusion of the Authors

  • Patients with severe sepsis who received fluid resuscitation with HES 130/0.42 had a higher risk of death at 90 days and were more likely to receive renal-replacement therapy than were those who received Ringer’s acetate.

11. To Summarize

  • Impact on Current Practice: This trial provided strong evidence of harm associated with even the newer generation of HES solutions in patients with severe sepsis. Along with other major trials, it led to a dramatic global shift away from the use of synthetic colloids in critical care.
  • Specific Recommendations:
    • Patient Selection: For adult patients with severe sepsis or septic shock.
    • Actionable Intervention: Avoid the use of HES 130/0.42 for fluid resuscitation.
    • Expected Benefit: Avoiding HES prevents one additional death for every 13 patients treated.
  • What This Trial Does NOT Mean: This trial does NOT mean that all colloids are harmful. Its findings are specific to this type of synthetic colloid (HES 130/0.42) and do not apply to albumin.
  • Implementation Caveats: Balanced crystalloids should be considered the first-line fluid for resuscitation in sepsis.

12. Context and Related Studies

  • Building on Previous Evidence: The 6S trial (2012) confirmed and strengthened the findings of earlier studies like VISEP (2008), which had raised concerns about kidney injury with older HES solutions.
  • Influence on Subsequent Research: The findings of this trial, along with the concurrent CHEST trial (2012), were instrumental in the development of clinical practice guidelines that now strongly recommend against the use of HES in septic patients.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial did not answer the question of whether other colloids, specifically albumin, are superior to, equivalent to, or inferior to crystalloids.
  • Future Directions: The results of this trial helped shift the focus of fluid resuscitation research towards the debate between balanced crystalloids and saline (e.g., SMART trial (2018)) and the role of albumin in specific subgroups (e.g., ALBIOS trial (2014)).

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question addressed a highly relevant and contentious issue in critical care with major implications for patient safety and cost.
  • Methods: The multicenter, randomized, and blinded design represents a high level of evidence and was appropriate for minimizing bias. The patient population was representative of general ICU patients with severe sepsis.
  • Results: The study reported a statistically significant and clinically important increase in harm (NNH of 13) for a major patient-centered outcome. The findings were consistent across both mortality and the need for renal-replacement therapy.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The high external validity of this pragmatic trial means its findings are broadly applicable to most ICUs, and they have been instrumental in changing global practice.

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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