CHEST: HES vs. Saline in Critically Ill Adults (2012)

“In a heterogeneous population of patients in the ICU, the use of 6% HES (130/0.4) did not reduce 90-day mortality, as compared with the use of saline.”

  • The CHEST Investigators

1. Publication Details

  • Trial Title: A Comparison of Albumin and Saline for Fluid Resuscitation in the Intensive Care Unit
  • Citation: Myburgh JA, Finfer S, Bellomo R, et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012;367(20):1901-1911. DOI: 10.1056/NEJMoa1209759
  • Published: November 15, 2012, in The New England Journal of Medicine
  • Author: John A. Myburgh, M.B., B.Ch., Ph.D.
  • Funding: National Health and Medical Research Council of Australia; and others.

2. Keywords

  • Fluid Resuscitation, Critical Care, Hydroxyethyl Starch (HES), Saline, Crystalloids, Randomized Controlled Trial

3. The Clinical Question

  • In a general population of critically ill adult patients in the ICU (Population), does fluid resuscitation with 6% hydroxyethyl starch (HES) 130/0.4 (Intervention) compared to 0.9% saline (Comparison) affect 90-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The choice between colloid and crystalloid solutions for fluid resuscitation 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 (130/0.4) were safer and more effective than simple crystalloids in a broad population of critically ill patients, not just those with sepsis.
  • Proposed Hypothesis: The authors hypothesized that there would be no significant difference in 90-day mortality between patients resuscitated with HES 130/0.4 and those resuscitated with saline.

5. Study Design and Methods

  • Design: A multicenter, parallel-group, blinded, randomized controlled trial (used to test the effectiveness of interventions).
  • Setting: 32 intensive care units (ICUs) in Australia and New Zealand.
  • Trial Period: Enrollment ran from April 2007 to March 2012.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) admitted to the ICU who were judged by their treating clinician to require fluid resuscitation.
    • Exclusion Criteria: Included known contraindications to HES, pre-existing end-stage renal failure, and traumatic brain injury.
  • Intervention: Fluid resuscitation with 6% HES 130/0.4 in 0.9% saline.
  • Control: Fluid resuscitation with 0.9% saline.
  • Management Common to Both Groups: The assigned study fluid was used for all fluid resuscitation needs throughout the ICU stay. The choice of all other interventions was at the discretion of the treating clinicians.
  • Power and Sample Size: The authors calculated that a sample size of 7000 patients would provide 90% power to detect a 3.5% absolute risk reduction in 90-day mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: Death from any cause at 90 days after randomization.
    • Secondary Outcomes: Included the incidence of acute kidney injury, the need for renal-replacement therapy (RRT), and organ dysfunction scores.

6. Key Results

  • Enrollment and Baseline: 7000 patients were randomized (3500 to HES and 3500 to saline). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in 90-day mortality. 597 of 3315 patients (18.0%) in the HES group died, compared with 566 of 3336 patients (17.0%) in the saline group (p=0.26).
  • Secondary Outcomes: The use of renal-replacement therapy was significantly more common in the HES group (7.0% vs. 5.8%; p=0.04).
  • Adverse Events: The incidence of adverse events was similar in both groups, with the exception of the increased need for RRT 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: 1.06 (95% CI, 0.96 to 1.18; P-value: 0.26).
  • 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 1.06.
      • Clinical Meaning: An RR of 1.06 suggests a non-significant 6% higher relative risk of death in the HES group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.96 to 1.18.
      • 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 4% benefit to an 18% harm.
    • P-value: The p-value of 0.26 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: No significant differences were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The very large, multicenter, randomized, blinded design provided high-quality evidence and minimized bias.
  • Generalizability: The pragmatic design and inclusion of a very large, heterogeneous population of ICU patients make the findings highly generalizable to real-world practice.
  • Statistical Power: The study was very large and adequately powered to confidently rule out even a small mortality benefit.
  • 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 are specific to HES 130/0.4 and cannot be extrapolated to other colloids like albumin.
  • Other: The study used saline as the comparator, which has its own potential harms (e.g., hyperchloremic acidosis). A comparison to a balanced crystalloid might have yielded different results.

10. Conclusion of the Authors

  • In a heterogeneous population of patients in the ICU, the use of 6% HES (130/0.4) did not reduce 90-day mortality, as compared with the use of saline, and was associated with an increased use of renal-replacement therapy.

11. To Summarize

  • Impact on Current Practice: This large, high-quality trial provided definitive evidence that HES offers no survival benefit over saline in a general ICU population and is associated with an increased risk of requiring dialysis. This was a major practice-changing trial that solidified the move away from synthetic colloids.
  • Specific Recommendations:
    • Patient Selection: For the broad population of adult ICU patients requiring fluid resuscitation.
    • Actionable Intervention: Avoid the use of HES 130/0.4 for fluid resuscitation.
  • 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 and do not apply to albumin.
  • Implementation Caveats: Crystalloids (either saline or balanced solutions) should be the first-line fluid for resuscitation in the ICU.

12. Context and Related Studies

  • Building on Previous Evidence: The CHEST trial (2012) was designed to provide a definitive answer on the safety of newer HES solutions in a broad ICU population, following on from earlier studies like VISEP (2008) that had raised concerns in sepsis.
  • Influence on Subsequent Research: The findings of this trial, along with the concurrent 6S trial (2012) in septic patients, were instrumental in the development of clinical practice guidelines that now strongly recommend against the use of HES in critically ill 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 BaSICS trial (2021)).

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a very common intervention with major implications for patient safety and cost.
  • Methods: The very large, multicenter, randomized, and blinded design represents the highest level of evidence and was appropriate for minimizing bias. The pragmatic and inclusive nature of the patient population is a major strength.
  • Results: The study reported a clear neutral finding for its primary outcome of mortality, but a statistically significant and clinically important increase in harm for the secondary outcome of requiring 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. This is a classic example of a high-quality “negative” trial that was profoundly practice-changing by providing strong evidence to stop a common but harmful therapy.

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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