LEUVEN I: Intensive Insulin Therapy in Critical Illness (2001)

“We conclude that intensive insulin therapy to maintain normoglycemia substantially reduces mortality and morbidity among patients in the surgical intensive care unit.”

— Greet Van den Berghe, M.D., Ph.D., et al.

1. Publication Details

  • Trial Title: Intensive Insulin Therapy in Critically Ill Patients
  • Citation: van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345(19):1359-1367. DOI: 10.1056/NEJMoa011359
  • Published: November 8, 2001, in The New England Journal of Medicine
  • Author: Greet Van den Berghe, M.D., Ph.D.
  • Funding: The Research Foundation–Flanders, Belgium; and others.

2. Keywords

Intensive Insulin Therapy, Hyperglycemia, Glycemic Control, Critical Illness, Sepsis, Randomized Controlled Trial

3. The Clinical Question

In adult patients in a surgical intensive care unit (ICU) who are receiving mechanical ventilation (Population), does a strategy of intensive insulin therapy to maintain strict normoglycemia (Intervention) compared to a strategy of conventional glucose control (Comparison) reduce in-hospital mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Hyperglycemia is a very common finding in critically ill patients, even those without a history of diabetes, due to the stress response of illness. Observational data had suggested that the severity of hyperglycemia was associated with an increased risk of death and complications, particularly infections.
  • Knowledge Gap: It was unknown if actively and aggressively treating this “stress hyperglycemia” with intensive insulin therapy to maintain normal blood glucose levels would improve patient-centered outcomes, or if it would be a risky intervention due to the potential for hypoglycemia.
  • Proposed Hypothesis: The authors hypothesized that a strategy of intensive insulin therapy to maintain strict normoglycemia would be superior to a conventional glucose control strategy in reducing mortality and morbidity in critically ill patients.

5. Study Design and Methods

  • Design: A single-center, prospective, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: A single, large tertiary care surgical ICU in Leuven, Belgium.
  • Trial Period: Enrollment ran from February 2000 to January 2001.
  • Population:
    • Inclusion Criteria: Adult patients admitted to the surgical ICU who were receiving mechanical ventilation.
    • Exclusion Criteria: Included patients who were moribund (expected to die within 12 hours) or who had a history of diabetic ketoacidosis.
  • Intervention: An “intensive” insulin therapy strategy. Patients received a continuous intravenous insulin infusion, with the dose aggressively titrated to maintain a target blood glucose level between 80 and 110 mg/dL (4.4 to 6.1 mmol/L).
  • Control: A “conventional” strategy. Patients only received an insulin infusion if their blood glucose level exceeded 215 mg/dL, with a target of maintaining the glucose between 180 and 200 mg/dL.
  • Management Common to Both Groups: All patients received a standardized nutritional support regimen, which included early parenteral nutrition to provide a high caloric intake.
  • Power and Sample Size: The authors calculated that a sample size of 1500 patients would be required to have 80% power to detect a 25% relative risk reduction in ICU 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: Overall in-hospital mortality.
    • Secondary Outcomes: Included ICU mortality, incidence of bloodstream infections, acute kidney injury requiring dialysis, and duration of mechanical ventilation.

6. Key Results

  • Enrollment and Baseline: 1548 patients were randomized (765 to the intensive group and 783 to the conventional group). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in overall in-hospital mortality between the groups (10.9% in the intensive group vs. 11.0% in the conventional group). However, in a post-hoc analysis of patients who stayed in the ICU for more than 5 days, intensive therapy did reduce mortality.
  • Secondary Outcomes: ICU mortality was significantly lower in the intensive-therapy group (4.6% vs. 8.0%; p<0.04). The intensive-therapy group also had a significant reduction in the incidence of bloodstream infections, acute kidney injury requiring dialysis, and the duration of mechanical ventilation.
  • Adverse Events: Severe hypoglycemia (blood glucose < 40 mg/dL) was significantly more common in the intensive-therapy group (5.1% vs. 0.8%).

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary and secondary mortality outcomes were analyzed using a chi-square test.
  • Key Statistic(s) Reported: The key statistics were the absolute mortality rates and the associated P-values.
  • Interpretation of Key Statistic(s) for Secondary Outcome (ICU Mortality):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: RR = 4.6% / 8.0% = 0.575.
      • Clinical Meaning: An RR of 0.575 means there was a 42.5% lower relative risk of dying in the ICU in the intensive therapy group compared to the conventional therapy group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The paper did not report a CI, but based on the p-value, it would not have crossed 1.0.
      • Clinical Meaning: A 95% CI that does not cross 1.0 indicates that the result is statistically significant.
    • P-value:
      • Calculation: The reported p-value was <0.04.
      • Clinical Meaning: The p-value of <0.04 is below the conventional threshold of 0.05, indicating that the observed difference in ICU mortality is unlikely to be due to chance.
  • Clinical Impact Measures (for the secondary outcome of ICU mortality):
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group).
      • Calculation: ARR = 8.0% – 4.6% = 3.4%.
      • Clinical Meaning: For every 100 surgical ICU patients treated with intensive insulin therapy, about 3-4 additional deaths in the ICU were prevented.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR.
      • Calculation: NNT = 1 / 0.034 = 29.4, which is rounded to 29.
      • Clinical Meaning: You would need to treat 29 patients with intensive insulin therapy to prevent one additional death in the ICU.

8. Strengths of the Study

  • Study Design and Conduct: The large, randomized, controlled design provided a high level of evidence for a novel management strategy.
  • Statistical Power: The study was large and adequately powered for its primary outcome.
  • Patient-Centered Outcomes: The study focused on important patient-centered outcomes, including mortality and major morbidities.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which introduces a risk of performance bias.
  • External Validity (Generalizability): The single-center design is a major limitation, as the results from this highly specialized surgical ICU in Belgium may not be applicable to other centers. The patient population was almost exclusively post-cardiac surgery patients, and the nutritional strategy (high-calorie, early PN) was very aggressive and not typical of most ICUs.
  • Other: The trial was negative for its primary outcome of in-hospital mortality. The positive finding for the secondary outcome of ICU mortality, while statistically significant, must be interpreted with caution. The high rate of severe hypoglycemia in the intervention group is a major safety concern.

10. Conclusion of the Authors

The authors concluded that intensive insulin therapy to maintain normoglycemia reduces morbidity and mortality in a population of critically ill patients in a surgical ICU.

11. To Summarize

  • Impact on Current Practice: This was a profoundly practice-changing trial. Despite its limitations, the dramatic reduction in ICU mortality and morbidity led to the widespread, global adoption of “tight glycemic control” as a new standard of care in the ICU for nearly a decade.
  • Specific Recommendations:
    • Patient Selection: For adult patients in a surgical ICU who are expected to require prolonged mechanical ventilation.
    • Actionable Intervention: At the time, the trial supported the implementation of an intensive insulin protocol to target a blood glucose of 80-110 mg/dL.
  • What This Trial Does NOT Mean: As later trials showed, this trial did NOT mean that tight glycemic control is beneficial for all critically ill patients.
  • Implementation Caveats: The key takeaway is the significant risk of severe hypoglycemia associated with this strategy, which requires extremely frequent blood glucose monitoring and a dedicated nursing protocol to be implemented safely.

12. Context and Related Studies

  • Building on Previous Evidence: The LEUVEN I trial (2001) was a landmark study that provided the first high-quality evidence to support a specific, protocolized approach to glycemic control in the ICU.
  • Influence on Subsequent Research: The dramatic but controversial findings of this single-center trial led directly to numerous attempts at replication. The same group’s follow-up study in a medical ICU population (LEUVEN II, 2006) failed to show a mortality benefit. The definitive answer came from the very large, multicenter NICE-SUGAR trial (2009), which not only failed to show a benefit for tight glycemic control but demonstrated a significant increase in mortality, leading to the de-adoption of this practice.
  • Unresolved Questions & Future Directions:
    • Unresolved Questions: This trial left the key question of whether its remarkable findings were replicable in other, multicenter settings and in different patient populations (e.g., medical ICU patients).
    • Future Directions: The entire subsequent history of research into glycemic control in the ICU, culminating in the definitive NICE-SUGAR trial, can be seen as the future direction that followed from this pivotal but ultimately controversial study.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a very common and important aspect of ICU care.
  • Methods: The randomized controlled design was a strength. However, the single-center, unblinded design and the unique patient population (almost all cardiac surgery) and co-interventions (high-calorie, early PN) are major methodological limitations that severely reduce the external validity of the findings.
  • Results: The study was negative for its primary outcome but reported a statistically significant benefit for the secondary outcome of ICU mortality. This, combined with the significant increase in harm (hypoglycemia), makes the overall results complex to interpret.
  • Conclusions and Applicability: The authors’ conclusion, while a fair reflection of their secondary outcome data, was ultimately not supported by subsequent, more robust research. The trial is a classic example of a seminal, hypothesis-generating study whose dramatic findings from a single center could not be replicated in broader, multicenter trials. It serves as a powerful lesson in the importance of external validation before a new and risky therapy is widely adopted.

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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