NICE-SUGAR

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Finfer S, et al. "Intensive versus conventional glucose control in critically ill patients". The New England Journal of Medicine. 2009. 360(13):1283-1297.
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Clinical Question

In critically ill patients, how does intensive compare to conventional glycemic control in reducing the risk of mortality?

Bottom Line

In medical ICU patients, intensive glycemic control (target 81-108 mg/dL) led to more deaths compared to conventional control (target≤180).

Major Points

The impact of glycemic control on inpatient mortality has been long debated. The 2001 Leuven Surgical Trial[1] was one of the first to demonstrate a mortality benefit among predominantly surgical ICU patients treated with intensive glycemic control (targeting a blood glucose of 80-110 mg/dL). This mortality benefit with intensive glycemic control was not replicated in the same Belgian center among medical ICU patients in the 2006 Leuven Medical Trial.

The Normoglycemia in Intensive Care Evaluation and Surviving Using Glucose Algorithm Regulation (NICE-SUGAR) trial randomized 6,104 medical and surgical ICU patients to intensive glycemic control (target glucose 81-108 mg/dL) vs. conventional glycemic control (target glucose ≤180 mg/dL). Unexpectedly, the intensive glycemic control arm had a higher 90-day mortality and more hypoglycemic events. There was no difference between medical or surgical ICU patients, and there were no differences in LOS, duration of ventilator therapy, or need for renal replacement therapy. A 2012 follow-up publication by the authors [2] demonstrated that excess mortality was due to moderate-severe hypoglycemia, especially in patients with distributive shock.

As a result, NICE-SUGAR, the largest multi-center trial investigating glycemic control in ICU patients, contradicted and overrode the trend towards intensive glycemic control that began with the earlier Leuven single-center trials [3][4]. Intensive glycemic control in the ICU targeting glucose<110 mg/dL is no longer recommended. Although the ideal target glucose remains unclear, guidelines suggest glycemic target of 140-180 mg/dL.

Guidelines

Surviving Sepsis Campaign severe sepsis and septic shock (2016, adapted)[5]

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

Design

  • Multicenter, non-blinded, parallel group, randomized, controlled trial
  • N=6,104
    • Intensive (n=3,054)
    • Conventional (n=3,050)
  • Setting: 42 centers
  • Enrollment: 2004-2008
  • Analysis: Intention-to-treat
  • Primary outcome: 90-day mortality

Population

Inclusion Criteria

  • Expected to require ICU treatment for ≥3 consecutive days
  • Medical and surgical ICU patients

Exclusion Criteria

  • None identified

Interventions

  • Randomized to intensive glycemic control (goal 81-108 mg/dL) or conventional glycemic control (goal ≤180 mg/dL), stratified by type of admission (operative vs. non-operative) and region (Australia, New Zealand, or North America)
  • Glycemic control occurred with IV insulin infusion, and the blood was taken from arterial rather than from capillaries.
    • Conventional glycemic control group (goal ≤180 mg/dL) was started on IV insulin infusion for glucose levels >180 mg/dL and was discontinued for blood glucose <144 mg/dL, when the patient was eating, or was discharged from the ICU.

Outcomes

Comparisons are intensive vs. conventional glycemic control.

Primary Outcomes

90-day mortality
27.5% vs. 24.9% (OR 1.14; 95% CI 1.02-1.28; P=0.02)
After adjusting for predefined risk factors (OR 1.14; 95% CI 1.01-1.29; P=0.04)

Secondary Outcomes

90-day survival
HR 1.11; 95% CI 1.01-1.23; P=0.03
Cause-specific mortality
41.6% vs. 35.8% (P=0.02)

There was no difference in: overall LOS, ICU LOS, time on mechanical ventilation, or time on renal replacement therapy.

Tertiary Outcomes

There was no difference in 28-day all-cause mortality, incidence of new organ failure, positive blood cultures, or RBC transfusions.

Subgroup Analysis

There was no difference in operative vs. non-operative patients (P=0.10), patients with or without diabetes, with and without severe sepsis, treated with and without corticosteroids (P=0.06), or APACHE II scores ≥25 vs <25.

Adverse Events

Blood glucose ≤40 mg/dL
6.8% vs 0.5% (OR 14, 95% CI 9.0-25.9; P<0.001)

Criticisms

  • The target in NICE-SUGAR's conventional therapy arm (target 140-180 mg/dL) differs from the arm in the Leuven studies (target 180-215 mg/dL)[4]
  • Patients received enteral nutrition exclusively (compared to supplemental parenteral nutrition as in the Leuven studies), in which case undernourished patients may have been harmed by insulin administration[4]
  • Subjective inclusion criterion of expected length of stay
  • Inability to blind treating staff

Funding

  • Australian National Health and Research council grant
  • Health Research Council of New Zealand grant
  • Canadian Institutes for Health Research grant

Further Reading

  1. van den Berghe G, et al. "Intensive insulin therapy in critically ill patients." The New England Journal of Medicine.' 2001;345(19):1359-1367.
  2. Finfer S, et al. "Hypoglycemia and risk of death in critically ill patients." The New England Journal of Medicine. (2012)367.12:1108.
  3. Inzucchi SE, et al. "Glucose Control in the ICU — How Tight Is Too Tight?" N Engl J Med. 2009;360:1346-1349
  4. 4.0 4.1 4.2 "Correspondence: Glucose Control in Critically Ill Patients." N Engl J Med. 2009;361:89-92
  5. 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.