VISEP: Hydroxyethyl Starch and Intensive Insulin in Sepsis (2008)

“In patients with severe sepsis, resuscitation with hydroxyethyl starch as compared with Ringer’s lactate resulted in a higher rate of acute kidney injury and a greater need for renal-replacement therapy. Intensive insulin therapy did not reduce mortality and was associated with a higher rate of severe hypoglycemia.”

— The VISEP Investigators

1. Publication Details

  • Trial Title: Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis.
  • Citation: Brunkhorst FM, Engel C, Bloos F, et al; for the German Competence Network Sepsis (SepNet). Efficacy of volume substitution and insulin therapy in severe sepsis. N Engl J Med. 2008;358(2):125-139. doi:10.1056/NEJMoa070716.
  • Published: January 10, 2008, in The New England Journal of Medicine.
  • Author: Frank M. Brunkhorst, M.D.
  • Funding: German Ministry of Education and Research and others.

2. Keywords

Severe Sepsis, Septic Shock, Fluid Resuscitation, Hydroxyethyl Starch (HES), Crystalloids, Ringer’s Lactate, Intensive Insulin Therapy, Glycemic Control.

3. The Clinical Question

In adult patients with severe sepsis or septic shock (Population), does fluid resuscitation with 10% hydroxyethyl starch (HES) compared to Ringer’s lactate (Intervention 1 vs Comparison 1) or does intensive insulin therapy compared to conventional insulin therapy (Intervention 2 vs Comparison 2) reduce 90-day mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The optimal fluid for resuscitation in sepsis was debated. Colloids like HES were thought to be more effective at volume expansion than crystalloids. Separately, a single-center trial (Leuven I) had suggested that intensive insulin therapy (IIT) to maintain tight glycemic control dramatically reduced mortality in surgical ICU patients.
  • Knowledge Gap: There were concerns about the safety of HES, particularly its effects on the kidneys. The benefit of IIT needed confirmation in a multicenter trial and in a medical ICU population. A large trial was needed to clarify both of these common ICU practices.
  • Proposed Hypothesis: The authors hypothesized that both HES and intensive insulin therapy would be superior to their respective comparators (Ringer’s lactate and conventional insulin therapy) in reducing mortality.

5. Study Design and Methods

  • Design: A prospective, multicenter, randomized, 2×2 factorial design trial. The intensive insulin therapy comparison was stopped early for safety concerns.
  • Setting: 26 university and 26 community hospitals in Germany.
  • Trial Period: Enrollment from October 2003 to November 2007.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with severe sepsis or septic shock diagnosed within the previous 24 hours.
    • Exclusion Criteria: Pre-existing end-stage kidney disease, pregnancy, or known contraindications to any of the study interventions.
  • Intervention: Patients were randomized in a factorial design to:
  • Fluid Therapy: 10% pentastarch (HES 200/0.5) vs. modified Ringer’s lactate.
  • Insulin Therapy: Intensive insulin therapy (target blood glucose 80-110 mg/dL) vs. conventional insulin therapy (target 180-200 mg/dL).
  • Control: Ringer’s lactate and conventional insulin therapy.
  • Management Common to Both Groups: All other aspects of sepsis care were managed according to the discretion of the treating physicians, guided by international guidelines.
  • Power and Sample Size: The trial was powered to detect a 7.5% absolute reduction in 28-day mortality for each intervention, requiring 534 patients for the insulin comparison and 600 for the fluid comparison.
  • Outcomes:
    • Primary Outcome: 90-day mortality for the fluid comparison; 28-day mortality for the insulin comparison.
    • Secondary Outcomes: Incidence of acute kidney injury (AKI), need for renal replacement therapy (RRT), and incidence of severe hypoglycemia.

6. Key Results

  • Enrollment and Baseline: 537 patients were randomized to the insulin comparison, and 600 to the fluid comparison. The groups were well-matched.
  • Trial Status: The intensive insulin therapy arm was stopped early by the data and safety monitoring committee due to a high rate of hypoglycemia and lack of benefit. The fluid therapy comparison was completed.
  • Primary Outcome:
    • Fluid Therapy: There was no significant difference in 90-day mortality between the HES and Ringer’s lactate groups (31.0% vs 25.8%; P=0.13).
    • Insulin Therapy: There was no significant difference in 28-day mortality between the intensive and conventional insulin groups (24.7% vs 26.0%; P=0.74).
  • Secondary Outcomes:
    • Fluid Therapy: The incidence of AKI and the need for RRT were significantly higher in the HES group compared to the Ringer’s lactate group.
    • Insulin Therapy: The rate of severe hypoglycemia was significantly higher in the intensive insulin group (17.0% vs 4.1%; P<0.001).
  • Adverse Events: HES was associated with more renal failure. Intensive insulin therapy was associated with more severe hypoglycemia.

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcomes were analyzed using a chi-square test.
  • Primary Outcome Analysis: The proportion of deaths at the specified time point was compared between the groups for each intervention.
  • Key Statistic(s) Reported (Fluid Therapy): Relative Risk (RR) for death at 90 days with HES: 1.20 (95% CI, 0.96 to 1.51; P=0.13).
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: The paper reports the RR as 1.20.
      • Clinical Meaning: An RR of 1.20 means there was a 20% higher relative risk of death in the HES group compared to the Ringer’s lactate group, but this difference was not statistically significant.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The reported 95% CI was 0.96 to 1.51.
      • Clinical Meaning: Since this confidence interval crosses the line of no effect (1.0), it indicates no statistically significant difference. The true effect is likely somewhere between a 4% benefit and a 51% harm.
    • P-value:
      • Calculation: The reported p-value was 0.13.
      • Clinical Meaning: The p-value of 0.13 is above the conventional threshold of 0.05, confirming that the observed difference is likely due to chance. A result is conventionally considered statistically significant if the p-value is less than 0.05.
  • Clinical Impact Measures: Not applicable for the primary outcome as no benefit was shown.
  • Subgroup Analyses: No significant benefit was found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, randomized design with a factorial approach was a methodologically strong and efficient way to test two important interventions.
  • Generalizability: The inclusion of both university and community hospitals increases the external validity of the findings.
  • Important Safety Data: The trial provided definitive evidence of harm for both interventions (renal failure with HES, hypoglycemia with IIT).

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded for the fluid intervention, which could introduce bias, though the primary outcome of mortality is objective.
  • External Validity (Generalizability): The type of HES used (pentastarch) may not be generalizable to other HES formulations, although subsequent trials have confirmed harm with other types as well.
  • Other: The early termination of the insulin arm limited the precision of that comparison, though the safety signal was clear.

10. Conclusion of the Authors

“Neither hydroxyethyl starch nor intensive insulin therapy improved the outcome in patients with severe sepsis and septic shock. Intensive insulin therapy was associated with a significantly increased risk of hypoglycemia, and resuscitation with HES was associated with a significantly increased rate of acute kidney injury and renal-replacement therapy.”

11. To Summarize

  • Impact on Current Practice: The VISEP trial was a landmark “double-negative” study that was profoundly practice-changing. It provided strong evidence that HES is not only ineffective but also harmful (nephrotoxic) in sepsis, contributing to the near-total abandonment of synthetic colloids for sepsis resuscitation. It was also a key multicenter trial that refuted the findings of the original Leuven study on IIT, demonstrating that tight glycemic control is dangerous and does not improve survival in sepsis.
  • Specific Recommendations:
    • Patient Selection: For adult patients with severe sepsis or septic shock.
    • Actionable Intervention: Do not use HES for fluid resuscitation; use crystalloids instead. Do not use intensive insulin therapy to target tight glycemic control (80-110 mg/dL); a more moderate target is safer.
    • Expected Benefit: Avoiding HES reduces the risk of AKI. Avoiding IIT reduces the risk of severe hypoglycemia.
  • What This Trial Does NOT Mean: This trial does not mean that glycemic control is unimportant in the ICU, but rather that the target should be more conservative.
  • Implementation Caveats: The findings provide clear, strong recommendations against the use of two common interventions.

12. Context and Related Studies

  • Building on Previous Evidence: VISEP was a key trial that challenged the findings of the Leuven I trial (2001)on IIT and added to the growing safety concerns about HES.
  • Influence on Subsequent Research: The findings on HES were confirmed and strengthened by subsequent large trials like 6S (2012) and CHEST (2012). The findings on IIT were confirmed by the definitive NICE-SUGAR trial (2009), which showed that tight glycemic control actually increased mortality.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: After this trial, the major questions were definitively answered.
  • Future Directions: Research in fluid resuscitation has focused on the type of crystalloid (e.g., SMART trial) and fluid stewardship. Research in glycemic control has focused on defining the optimal moderate glucose target.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The trial addressed two of the most critical and debated questions in sepsis management at the time.
  • Methods: The large, multicenter, randomized factorial design was methodologically excellent.
  • Results: The trial had clear and robustly negative results for both interventions. The safety findings of increased renal failure with HES and increased severe hypoglycemia with IIT were critically important.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The results are highly applicable to the global ICU community and provided definitive, evidence-based directives to abandon two widely used therapies, thereby significantly improving patient safety.

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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