Leuven Surgical Trial

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Van den Berghe G, et al. "Intensive Insulin Therapy in Critically Ill Patients". The New England Journal of Medicine. 2001. 345(19):1359-1367.
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Clinical Question

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

Bottom Line

Among surgical ICU patients, intensive glycemic control improves survival compared to standard therapy.

Major Points

The single center Leuven Surgical Trial in 2001, so named because it took place in the Belgian city and involved predominantly surgical patients, randomized 1,548 surgical ICU patients to intensive glycemic control (goal glucose 80-110 mg/dL) vs. conventional glycemic control (180-200 mg/dL). This trial demonstrated a significantly lower ICU mortality in the intensive glycemic control arm, particularly among patients who were in the ICU for 5 days or longer. This mortality benefit was not replicated in the same Leuven center in medical ICU patients in the 2006 Leuven Medical Trial.

However, the largest multicenter trial looking at intensive glycemic control, NICE-SUGAR (2009), actually demonstrated increased mortality among medical and surgical ICU patients who received intensive glycemic control. NICE-SUGAR contradicted and overrode the trend towards intensive glycemic control that began with the Leuven Surgical Trial. As a result, intensive glycemic control in the ICU to a goal <110 mg/dL is no longer recommended. Although the ideal target glucose remains unclear, the standard of care in most centers targets 140-180 mg/dL among medical and surgical ICU patients.

Guidelines

Surviving Sepsis Campaign severe sepsis and septic shock (2016, adapted)[1]

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

Design

  • Single center, non-blinded, parallel-group, randomized, controlled trial
  • N=1,548
    • Intensive (n=765)
    • Conventional (n=783)
  • Setting: Single center in Belgium
  • Enrollment: February 2000 to January 2001
  • Primary outcome: ICU mortality

Population

Inclusion Criteria

  • Adult patients
  • Receiving mechanical ventilation

Exclusion Criteria

  • Participation in another trial
  • Patients in terminal decline
  • DNR status

Baseline Characteristics

  • Age: 63 vs. 62 years
  • Male sex: 71%
  • BMI: 26.2 vs. 25.8
  • ICU indication:
    • Cardiac surgery: 62% vs. 63%
    • Neurologic disease, cerebral trauma, brain surgery: 4%
    • Thoracic surgery, respiratory insufficiency: 9% vs. 7%
    • Abdominal surgery or peritonitis: 6% vs. 7%
    • Vascular surgery: 4% in each
    • Multiple trauma, severe burns: 4% in each
    • Transplantation: 6% in each
    • Other: 5% vs. 4%
  • APACHE II score:
    • First 24h: 9 in each
    • Second 24h: 9 in each
    • Score >9 in first 24h: 56% vs. 58%
  • TISS-28 score:
    • First 24h: 43 in each
    • Second 24h: 38 in each
  • Tertiary referral: 16% vs. 17%
  • History of cancer: 16% vs. 15%
  • History of diabetes: 13% in each
    • Treated with insulin: 5% vs. 4%
    • Treated with oral agent, diet, or both: 8% vs. 9%
  • Blood gulcose:
    • >110 mg/dl: 73% vs. 76%
    • >200 mg/dl: 11% vs. 13%

Interventions

  • Patients randomly assigned to intensive (goal 80-110 mg/dl) vs. conventional (goal 180-200 mg/dl) glycemic therapy
  • In the conventional group, insulin infusion started if blood glucose (BG) >215 mg/dl and adjusted to maintain BG 180-200 mg/dl
  • In the intensive group, insulin infusion started if BG >110 mg/dl and adjusted to maintain BG 80-110 mg/dL; maximum insulin infusion rate was 50 units/hr
  • All infusion rates were managed by ICU nurses and study physician not involved in the clinical care of the patient
  • On ICU day #1, both arms received 200-300 g of IV glucose
  • On ICU day #2, majority of patients received parenteral nutrition (TPN or PPN) in addition to enteral nutrition if necessary to achieve caloric goals

Outcomes

Comparisons are intensive vs. conventional.

Primary Outcome

ICU mortality
4.6% vs. 8% (RR 0.42; 95% CI 22-62%; P<0.04)

Secondary Outcomes

5-day mortality
1.7% vs. 1.8% (P=0.9)
>5-day mortality
10.6% vs. 20.2% (P=0.005)
In-hospital death
7.2% vs. 10.9% (P=0.01)
In-hospital death among those in ICU for >5 days
16.8% vs. 26.3% (P=0.01)

Criticisms

  • Non-blinded design
  • Predominantly surgical rather than medical patients

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

  1. 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.