Hydroxyethyl Starch or Saline for Fluid Resuscitation in Intensive Care

Myburgh et al for the ANZICS Clinical Trials Group. NEJM 2012; 367:1901-11. doi:10.1056/NEJMoal209759

Clinical Question

  • In critically ill patients requiring fluid resuscitation, does 6% hydroxyethyl starch (6% HES) compared to 0.9% sodium chloride (Saline) reduce mortality at 90 days?


  • Randomised, controlled, double-blinded clinical trial
  • Computer generated randomisation via website providing complete concealment
  • Minimisation algorithm stratified by institution and admission diagnosis of trauma
  • A priori publication of trial protocol and statistical analysis plan
  • Intention-to-treat analysis
  • Powered at 90% to detect absolute difference of 3.5% difference in mortality at 90 days from baseline of 26%, with alpha significance of 0.05
    • Planned sample size of 7000, allowing 5% loss


  • 32 adult ICUs
  • Mixed medical and surgical
  • Australia and New Zealand
  • December 2009 to January 2012


  • Inclusion: Attending physician judged fluid resuscitation to be needed; age over 18 years
  • Exclusion: 1000ml or more 6% HES prior to ICU admission; impending or current renal replacement therapy; intracranial haemorrhage; women of child-bearing age unless known negative pregnancy state; cardiac surgery, burn injury or liver transplant.
  • 19,475 patients screened; 7000 randomised
    • Baseline characteristics were similar (6% HES vs Saline):
      • Age: 63.1 vs 62.9 years
      • Weight: 79.4 vs 78.6 kg
      • Admitted from ED: 27.7% vs 27.6%
      • APACHE 2 score: 17.0 vs 17.0
      • Sepsis diagnosis: 29.2 vs 28.4
      • RIFLE-injury at baseline: 36.0% vs 36.0%
      • 6% HES prior to randomisation: 15.2% vs 15.1%


  • 6% HES (Voluven, Fresenius Kabi as 500ml bags)


  • 0.9% Saline (identical 500ml bags)

Both groups managed as below:

  • Fluid administered at clinician’s discretion for all fluid resuscitation
    • To correct hypovolaemia
    • Supported by at least one objective physiological parameter
  • Continued until death, discharge or day-90
  • Limited at 50 ml/kg/day as per product license
    • Open-label saline as required after this limit
  • Change to open-label saline if renal replacement therapy required
  • Maintenance and replacement fluid not controlled; fluid outside of ICU not controlled


  • Primary outcome: there was no statistically significant difference in 90-day mortality between the two groups
    • 6% HES: 18.0%
    • Saline: 17.0%
    • Absolute risk increase: 1.0%
    • Relative risk: 1.06 (95% CI 0.96 to 1.18; p=0.26)
  • Secondary outcomes: comparisons are 6% HES vs Saline
    • Incidence of acute kidney injury (by RIFLE scoring): reduced risk and injury, but more failure associated with 6% HES (see table).
      • 6% HES associated with increased urine output but also increased serum creatinine
    • Renal replacement therapy use: 7.0% vs 5.8% (RR 1.21; 95% CI 1.00 to 1.45; p=0.04) favouring Saline
    • New organ failure (by SOFA scoring): less cardiovascular failure but more hepatic failure associated with 6% HES (see table)
    • Duration of mechanical ventilation: 6.0 vs 5.7 days (p=0.12)
    • Duration of renal replacement therapy: 5.6 vs 5.5 days (p=0.86)
    • Cause-specific mortality: no statistically significant differences (see table)
  • Tertiary outcomes:
    • Fluid administered during first 4 days: 6% HES group received significantly less fluid
      • 6% HES: 526 ml/day ± 425 ml/day (as mean ± SD)
      • Saline: 616 ml/day ± 488 ml/day
      • p<0.001
    • Blood products: 6% HES group received significantly more blood products
      • 6% HES: 78 ml ± 250 ml
      • Saline: 60 ± 190 ml
      • p<0.001
    • Haemodynamic parameters were not significantly different

Authors’ Conclusions

  • “Our study does not provide evidence that resuscitation with 6% HES (130/0.4) as compared with saline, in the ICU provides any clinical benefit to the patient. Indeed the use of HES resulted in an increased rate of renal replacement therapy.”


  • Well designed, large, multi-centre randomised, controlled trial
  • Biases minimised with double-blinding
  • Pragmatic design – administration at clinician’s discretion
  • A priori statistical plan and intention-to-treat analysis


  • 6% HES had been administered to 15% of patients in Saline group prior to randomisation. This small cross-over may bias towards a conclusion of ‘no difference’
  • 5% loss to follow-up – this is what the authors expected, and since it is less than the primary outcome rate, it is unlikely to change the conclusion either way.
  • The lower baseline mortality rate may have contributed to a false negative conclusion
  • The clinician-judged need for renal replacement therapy has been criticised by some, but given clinicians were blinded, this is unlikely to have biased the conclusion

The Bottom Line

  • This trial adds to the existing data: starch-based fluids do not provide a mortality benefit and lead to increased renal dysfunction requiring renal replacement therapy.
  • In the context of critically ill medical and surgical patients, starch-based fluids should not be used for volume resuscitation.


Leave a Reply

Your email address will not be published. Required fields are marked *

This site uses Akismet to reduce spam. Learn how your comment data is processed.