Leuven Medical Trial

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Van den Berghe G, et al. "Intensive insulin therapy in the medical ICU". New England Journal of Medicine. 2006. 354(5):449-461.
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Clinical Question

In medical ICU patients, how does intensive glycemic control compare to conventional glycemic control in reducing mortality?

Bottom Line

In contrast to the Leuven Surgical Trial (2001), which showed significantly lower mortality in the intensive control arm, there was no significant difference in the primary outcome of total death from any cause in the hospital (40.0% in the conventional vs. 37.3% in the control arm, p=0.33, HR 0.94) in these medical ICU patients.

Major Points

The single center Leuven Medical Trial in 2006 randomized 1200 medical ICU patients to intensive glycemic control (goal glucose 80-110 mg/dL) vs. conventional glycemic control (180-200 mg/dL). A predefined subgroup analysis was also performed on patients who stayed in the ICU for > 3 days.

  • In contrast to the Leuven Surgical Trial (2001), which showed significantly lower mortality in the intensive control arm, there was no significant difference in the primary outcome of total death from any cause in the hospital (40.0% in the conventional vs. 37.3% in the control arm, p=0.33, HR 0.94).
  • The authors highlighted that there was a significantly higher mortality rate in the conventional arm in the pre-specified subgroup of patients who stayed in the ICU for > 3 days: 52.5% vs. 43.0%, p=0.009, HR 0.84.
  • They also reported a lower mortality rate in the conventional control group in patients who stayed in the ICU for < 3 days as part of non-pre-specified subgroup analysis (19% vs. 27%; in Appendix)
  • The authors also emphasized that intensive control significantly reduced morbidity, specifically via lower rates of acquired kidney injury, accelerated weaning from mechanical ventilation, and accelerated discharge from the ICU and the hospital, but all of these were secondary outcomes.

Because of the conflicting conclusions of the Leuven Medical and Leuven Surgical Trials, these trials were followed up by the NICE-SUGAR trial (2009), which definitively demonstrated increased mortality among medical and surgical ICU patients who received intensive glycemic control.

Guidelines

Surviving Sepsis Campaign severe sepsis and septic shock (2016, adapted)

  • Recommend a glucose control protocol targeting levels ≤180 mg/dL rather than ≤110 mg/dL (strong recommendation, high quality of evidence)

Design

Single center, prospective, non-blinded, parallel-group, randomized, controlled trial

  • N=1200
  • Intensive (n=595)
  • Conventional (n=605)
  • Setting: Single center in Belgium
  • Enrollment: March 2002 to May 2005
  • Intention-to-treat analysis
  • Pre-defined subgroup analysis of patients who stayed in the ICU for >3 days: intensive (n=381) vs. conventional (n=386)

Outcomes

  • Primary outcome: Death from any cause in the hospital
  • Secondary outcomes: Mortality in the ICU, 90-day mortality, days to weaning from mechanical ventilation, days in the ICU and in the hospital, the initiation of dialysis, new kidney injury during intensive care (defined as either a level of serum creatinine twice that present on admission to the ICU or a peak level of serum creatinie of >2.5mg/dL), days of inotropic or vasopressor support, presence or absence of hyperinflammation (defined as CRP>150mg/dL), presence or absence of bacteremia, prolonged (>10 days) use of antibiotics, and the presence or absence of hyperbilirubinemia (defined as bilirubin level of >3mg/dL

Population

Inclusion Criteria

  • Adult patients
  • Assumed to require at least 3 days of ICU care

Exclusion Criteria

  • Able to receive oral nutrition
  • Active DNR order
  • Immediately postoperative

Baseline Characteristics (conventional vs. intensive) -- all appropriately matched with non-significant p-values

  • Male sex (%): 63.1 vs. 60
  • Age 64 vs. 63
  • BMI 24.8 vs 25.1
  • ICU indication (%): matched for respiratory, GI or liver, hematologic or oncologic, other sepsis, cardiovascular, neurologic, renal, metabolic, or other causes
  • History of cancer (%): 21.2 vs 22.5
  • Kidney failure on admission to ICU (%): 19.8 vs. 20.0
  • History of diabetes (%): 16.0 vs. 17.8
    • Treated with insulin: 8.4 vs. 10.9
    • Treated with oral antidiabetic agent, diet or both: 7.6 vs. 6.9
  • Baseline APACHE II score
    • Mean: 23 vs. 23
    • Score>40 (%): 3.0 vs 4.4
  • Baseline TISS-28 score
    • Mean: 29 vs. 29
    • Score>33 (%): 20.6 vs. 26.6 [p=0.02]
  • Matched patients on admission blood glucose (162 mg/dl vs. 162 mg/dL), HbA1c (6.2 vs. 6.3), Cr, BUN, ALT, and CRP

Interventions

  • In the conventional-treatment group, continuous insulin infusion was started when BG>215 mg/dL and was adjusted to maintain BG 180-200 mg/dL. When BG<180, insulin infusion was tapered and eventually stopped
  • In the intensive-treatment group, insulin infusion was started when BG>110 mg/dL and was adjusted to maintain 80-110 mg/dL. Maximal continuous IV insulin infusion was arbitrarily set at 50 IU/hour
  • At patient's discharge from ICU, a conventional approach was adopted (maintenance of BG<200 mg/dL)
  • Adjustments were made by nurses using titration guidelines adapted from the Leuven Surgical ICU study.
  • Enteral feeding was started according to routine guidelines

Outcomes

(conventional vs. intensive)

Primary Outcome

  • Total death from any cause in hospital (%): 40.0 vs. 37.3, p=0.33, HR 0.94
    • Diagnostic categories (%): Respiratory (44.1 vs. 39.0), GI or liver (32.3 vs. 45.6), hematologic or oncologic (64.7 vs. 60.9), other sepsis (28.9 vs. 42.2), cardiovascular (33.3 vs. 53.8), neurologic (29.0 vs. 30.0), renal (40.0 vs. 25.0), metabolic (36.4 vs. 22.2), other (30.0 vs. 50.0). Individual p-values not calculated
    • APACHE II quartile (%): <17 (19.5 vs 19.7), 17-22 (37.1 vs. 32.1), 23-29 (44.6 vs. 44.0), >29 (58.1 vs. 55.3)
    • +/- Diabetes (%): No history of diabetes (40.9 vs. 36.8), History of diabetes (35.0 vs. 39.6)

Secondary Outcomes

  • Mortality in the ICU (%): 26.8 vs. 24.2, p=0.90
  • 90-day mortality (%): 37.7 vs. 35.9

Subgroup analysis

ICU for >3 days

  • Total death from any cause in hospital (%): 52.5 vs. 43.0, p=0.009, HR 0.84
  • Mortality in the ICU (%): 38.1 vs. 31.3, p=0.05
  • 90-day mortality (%): 49.1 vs. 42.2, p=0.06

Criticisms

  • Improvements in morbidity were secondary endpoints and were marginally significant
  • Post hoc analysis has limited usefulness for clinicians, since patients requiring stays of three days or longer in the medical ICU cannot be accurately identified prospectively
  • Lack of blinding
  • Publication bias: Studies that showed increased harm with intensive glycemic control are often stopped early and never make it to publication.
  • See editorials

Funding

Funded by the University of Leuven, the Belgian Fund for Scientific Research, the Belgian Foundation for Research in Congenital Heart Disease, and an unrestricted grant from Novo Nordisk.

Further Reading

Rhodes A, et al. "Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016." Critical Care Medicine. 2017;45(3)1-67.