The NICE-SUGAR study was a large randomized controlled trial that compared intensive glucose control (80-108 mg/dL) to conventional glucose control (≤180 mg/dL) in over 6,000 critically ill patients. The study found that intensive control was associated with a higher mortality rate (27.5% vs 24.9%) and more episodes of severe hypoglycemia. No differences were seen in other outcomes like length of stay. This significant study challenged prior evidence supporting tight glucose control in the ICU and suggests current practice of more moderate control is safest.

1. NICE-SUGAR
Intensive versus Conventional Glucose
Control in Critically Ill Patients
Stephen Wiseman
PGY-3 Anesthesiology Resident
Cleveland Clinic

2. Introduction
• Hyperglycemia is common in critically ill
patients.
• In 2001, blood glucose became a major
therapeutic target after a study showed a
decrease in mortality in SICU patients with
strict glucose control.
• Current literature shows conflicting results
on the effects of more intensive glucose
control versus conventional glucose control
in critically ill patients.

3. Van Den Berghe et al: Intensive Insulin Therapy in
Critically Ill Patients (2001)
• Prospective randomized controlled study.
• Enrolled 1548 SICU patients into 2 groups
• Intensive therapy targeted glucose between
80-110 and the conventional range was 180-200
• Primary outcome was death in ICU which was
4.6 percent in the Intensive Glucose control
group vs. 8.0 percent in Conventional glucose
control group which was statistically significant.

4. Figure 1. Kaplan–Meier Curves Showing Cumulative Survival of Patients Who Received
Intensive Insulin Treatment or Conventional Treatment in the Intensive Care Unit (ICU).

5. Van den Berghe et al 2
Intensive Insulin Therapy in the Medical
ICU
• Prospective, randomized, controlled study
of 1200 patients
• Same authors and same conventional and
intensive parameters as the first study
• Primary outcome was death in hospital
which was 37.3% in the intensive group
versus 40% in the conventional group
which was statistically insignificant.

6. Wiener et al
• Meta analysis of 34 randomized trials totaling
8432 patients.
• Hospital mortality did not differ between tight vs.
conventional glucose control.
• Tight glucose control was not associated with a
decreased risk for new dialysis, but was a
associated with a decreased risk of septicemia.
• Tight glucose control was associated with an
increased risk of hypoglycemia.

7. VISEP
• Multi-center, two by two factorial trial.
• Patients with severe sepsis were assigned to one
of 2 groups either intensive insulin therapy, or
conventional insulin therapy. And either starch
based colloid or LR for fluid resuscitation.
• The trial was stopped early for safety reasons.
The use of the more intensive insulin had a
higher rate of adverse events and patients were
at increased risk of hypoglycemia.

8. GLUCONTROL
• Prospective randomized control trial stopped
early due to adverse events in the tight BG
control group.
• Tight (80-110 mg/dL) vs Conventional(140-180
mg/dL) glucose control.
• Incidence of severe hypoglycemia (BG<40
mg/dL) was significantly more frequent in
patients assigned to tighter control group. Risk of
death was not increased by hypoglycemia.
• No difference in mortality 17% vs. 15% and the
conclusion of the authors was that there are no
apparent benefits of tight glucose control.

9. NICE-SUGAR
Intensive versus Conventional Glucose Control in Critically
Ill Patients

10. Methods
• Randomized, prospective un-blinded clinical
controlled trial of 6104 patients.
• Patients were randomized into one of 2 groups
within 24 hours of admission to the ICU if they
were expected to be in the ICU for more than 3
days.
• The 2 groups were intensive glucose control
target (80-108 mg/dL) or the conventional control
target (180mg/dL or less).

11. Figure 1

12. Methods
• Patients were admitted to surgical and
medical intensive care units at 42
hospitals internationally.
• In the intensive control group, control of
blood glucose was achieved with an
insulin infusion.
• In the conventional group, insulin was
administered if the blood glucose level
exceeded 180mgdL.

14. Methods
• Patients were followed for 90 days from the time
of randomization, or till their death whichever
came first.
• Death was the primary end-point
• Secondary outcomes included survival time
within the first 90 days, Cause-specific death,
duration of mechanical ventilation and RRT, and
stays in the ICU and hospital.
• Tertiary outcomes included death within 28 days
of randomization, incidence of new organ failure,
positive blood culture, RBC transfusion, and
volume of transfusion.

15. Methods
• A blood glucose less than 40 mg/dL was
considered a serious adverse event.

18. Results
• 3054 patients were assigned to the intensive
control group and 3050 to the conventional
control group.
• 829 patients(27.5%) died in the intensive control
group and 751(24.9%) in the conventional-
control group which is a difference of 2.6%.
• There was no statistical difference between
surgical vs. medical ICU patients.
• Severe hypoglycemia(<40mg/dL) was recorded
in 6.8% of patients in the intensive control group,
vs. 0.5% in the conventional group.

20. Results
• No difference between the two groups in
median length of ICU or hospital stay.
• No difference between number of days of
mechanical ventilation, RRT, positive
blood cultures, or RBC transfusions.

21. Discussion
Positves:
• Large multi-center study
• Robust statistical analysis
• Use of a uniform insulin protocol between sites.
• The primary outcome in this study is unbiased.
• Good representation of critically ill patients
• This study enrolled more patients than trials that
preceded it.

22. Discussion
Limitations:
– More patients in the IIT group received corticosteroids
which could affect the variable were studying
– 10% of the IIT discontinued prematurely.
– No significant difference in secondary or tertiary
outcomes, despite the difference in the primary
outcome, death.
– Inclusion criteria, i.e. length of stay is a subjective
parameter.
5. The study was not blinded to the treating personnel.

23. Questions?
• 1. What is the optimal target for glucose
therapy.
• 2. Does a particular sub-set of patients
benefit from tight glucose control
• 3. What about hypoglycemia?
• 4. Strategies for future management of
blood glucose in the ICU.

24. Bibliography
• Wiener RS. Wiener DC. Larson RJ. Benefits and risks of
tight glucose control in critically ill adults: a meta-
analysis.[see comment]. [Journal Article. Meta-Analysis.
Research Support, Non-U.S. Gov't. Research Support,
U.S. Gov't, Non-P.H.S.] JAMA. 300(8):933-44, 2008 Aug
27.
• Preiser JC. Current controversies around tight glucose
control in critically ill patients. [Review] [31 refs] [Journal
Article. Review] Current Opinion in Clinical Nutrition &
Metabolic Care. 10(2):206-9, 2007 Mar.