Update on Glycemic
Control in the ICU
Nicholas Sadovnikoff, MD, FCCM
Assistant Professor, Harvard Medical School
Co-Director, Surgical ICU
Brigham and Women’s Hospital
Kuwait City, Kuwait
November 24, 2011
What is the right target?

What is your target glucose level for the critically
ill patients in your ICU (choose the closest to
your practice)?

1.)
2.)
3.)
4.)



80 - 109 mg/dl
100 - 140 mg/dl
140 - 180 mg/dl
180 - 220 mg/dl
Hyperglycemia


common in critically ill patients
associated with adverse outcomes
Mortality
 Morbidity
 Rate of infections
 Length of stay (LOS)

Intensive Insulin Therapy in
Critically Ill Patients

For decades, hyperglycemia in the critically ill
population was accepted as the “price of doing
business”
Intensive Insulin Therapy in
Critically Ill Patients


For decades, hyperglycemia in the critically ill
population was accepted as the “price of doing
business”
It was considered an adaptive response, and
intervention was only undertaken if DKA or
severe hyperosmolar states developed
Intensive Insulin Therapy in
Critically Ill Patients

In the 1990s, Furnari et al published studies
showing lower sternal wound infection rates in
cardiac surgical patients with control of glucose
(180-220 mg/dl)
Intensive Insulin Therapy in
Critically Ill Patients


In the 1990s, Furnari et al published studies
showing lower sternal wound infection rates in
cardiac surgical patients with control of glucose
(180-220 mg/dl)
This led to the dissemination of the “Portland
Protocol”, but it was not widely accepted
Intensive Insulin Therapy in
Critically Ill Patients

In 2001, glucose management would change
drastically
Van den Berghe G, et al. N Engl J Med. 2001
Intensive Insulin Therapy in
Critically Ill Patients


In 2001, glucose management would change
drastically
Van Den Berghe et al, NEJM

Mortality can be decreased with tight glucose
control
Van den Berghe G, et al. N Engl J Med. 2001
Intensive Insulin Therapy in
Critically Ill Patients


In 2001, glucose management would change
drastically
Van Den Berghe et al, NEJM
Mortality can be decreased with tight glucose
control
 As well as a number of other outcomes!

Van den Berghe G, et al. N Engl J Med. 2001
Van den Berghe Study







Single center
Prospective, randomized controlled trial
University hospital in Belgium
1548 adults admitted to the surgical ICU
All mechanically ventilated
Randomized on admission
Primary outcome: Death from any cause in ICU
Study design

Conventional Group



insulin infusion started if blood glucose > 215 mg/dL
Whole blood glucose levels maintained between 180-200
Intensive Treatment


insulin infusion started if blood glucose > 110 mg/dL
Whole blood glucose levels maintained between 80-110
Study design

Given IV glucose 200-300gm over first 24h,
then parental/enteral/combined feeding

Undiluted arterial blood was used to check
whole blood glucose - admission & Q4h

Insulin adjusted by a team of RNs + a study
MD not involved in clinical care
Outcome Measures






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
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Death from any cause in ICU
Death during hospital stay
Length of ICU stay, need for readmission
Vent support
Renal replacement
Pressor support
Critical-illness polyneuropathy
C-reactive protein, WBC, body temperature
Bloodstream infection
Use of antibiotics for more than 10 days
Hyperbilirubinemia
Results

The results were nothing short of SHOCKING
Results
100
100
Survival in ICU, %
92
Conventional treatment
88
Mortality
 42%,
P<.04
84
80
0
0
20 40 60 80 100 120 140 160
Days After Admission
In-Hospital Survival, %
Intensive treatment
96
96
Intensive treatment
92
Conventional treatment
88
Mortality
 34%,
P<.01
84
80
0
0
50
100
150
200
Days After Admission
250
Results
Mortality
Sepsis
Dialysis
Blood
Transfusion Polyneuropathy
0
-10
N = 1,548
-20
-30
Reduction -40
(%)
-50
-60
-34%
-41%
-46%
-44%
-50%
Results


The results were nothing short of SHOCKING
We felt we had been committing
MALPRACTICE on a daily basis!
Results



The results were nothing short of SHOCKING
We felt we had been committing
MALPRACTICE on a daily basis!
Every critical care and endocrinologic society
jumped on board recommending intensive
insulin therapy
Results



The results were nothing short of SHOCKING
We felt we had been committing
MALPRACTICE on a daily basis!
Every critical care and endocrinologic society
jumped on board recommending intensive
insulin therapy… in spite of the fact that this
was a single-center study whose external validity
was unclear at best
Then the doubts began to emerge
Van den Berghe et al
Intensive Insulin Therapy in the Medical ICU



Prospective, randomized, controlled study
Insulin infusion to goal of 80-110 mg/dL vs.
usual therapy (180-200 mg/dL)
1,200 patients
Van den Berghe, et al, N Engl J Med, 2006, 354;5:449-461
Van den Berghe et al
Intensive Insulin Therapy in the Medical ICU

Primary outcome: death in hospital
 37.3% - intensive group vs. 40% conventional group
 statistically insignificant
Van den Berghe, et al, N Engl J Med, 2006, 354;5:449-461
VISEP
Brunkhorst et al, N Engl J Med 358:125-39, 2008
VISEP Trial




Randomized control trial, Multi-center, 2x2 design
600 patients
Conventional: Insulin started at > 200 mg/dl,
adjusted to maintain 180 - 200
Intensive: Insulin started at > 110 mg/dl, adjusted
to maintain BG 80 -110
VISEP

Primary Outcomes:
Mortality (28 days) and morbidity (sequential organ
failure dysfunction, SOFA)
 Safety end-point: hypoglycemia (BG<40 mg/dl)


Stopped early for safety reasons

Pts getting intensive insulin therapy had
no difference in mortality (24.7 vs. 26%) but
 increased risk of hypoglycemia (17 vs. 4%)

VISEP

Stopped early for safety reasons

Pts getting intensive insulin therapy had
no difference in mortality (24.7 vs. 26%) but
 increased risk of hypoglycemia (17 vs. 4%)

GLUCONTROL

Prospective randomized control trial

Tight (80-110) vs. Conventional (140-180 mg/dL)

Stopped early due to adverse events in tight control group

Severe hypoglycemia (BG<40 mg/dL)


more frequent in tight group (8.6 vs. 4%)
No difference in mortality

17% vs. 15%
Intensive Care Med 2009 Oct;35(10):1738-48
Wiener, R. S. et al. JAMA 2008;300:933-944.
Wiener et al




Meta analysis of 29 randomized trials
8432 patients
No difference in hospital mortality
Tight glucose control
associated with a decreased risk of septicemia
 associated with an increased risk of hypoglycemia

NICE-SUGAR
Intensive versus Conventional
Glucose Control
in
Critically Ill Patients
N Engl J Med. 2009
Hypothesis
Intensive glucose control
reduces mortality
at 90 days
Methods



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RCT
Medical and surgical ICUs
42 hospitals in New Zealand, Australia, North America
Patients expected to be in ICU for > 3 days
Randomized within 24h
Blood sugar controlled with IV insulin infusion
Intensive glucose target (80-108 mg/dL), conventional
target (180mg/dL or less)
Methods



Patients were followed for 90 days, or until their death
Death was the primary end-point
Secondary outcomes:


survival time within the first 90 days, cause-specific death,
duration of mechanical ventilation, RRT, and ICU and
hospital LOS
Tertiary outcomes:

death within 28 days, incidence of new organ failure, positive
blood culture, RBC transfusion, and volume of transfusion
Methods

The intervention discontinued when patient was eating
or discharged from ICU

resumed if the patient was readmitted within 90 d

Arterial samples preferred, use of capillary samples
discouraged

Blood glucose measured with point of care or arterial
blood gas analyzer or laboratory analyzer in routine use
at each center

Blood glucose < 40 mg/dL = serious adverse event
NICE-SUGAR Study: Design
6104 ICU patients
Conventional: 3050
IV insulin if BG >180 mg/dL
Target: 140-180 mg/dL
Intensive: 3054
IV insulin if BG >108 mg/dL
Target: 81-108 mg/dL
One third were surgical patients and two thirds were medical
patients; 20% had diabetes.
Primary Outcomes
90-day mortality
Results

Mortality: 27.5% vs. 24.9% - intensive vs.
conventional

Severe hypoglycemia(<40) in:
 6.8%

vs. 0.5 % - intensive vs. conventional
Both statistically significant
The NICE-SUGAR Study
Odds ratio for death with IIT was 1.14 (95% CI, 1.02 to 1.28; p = 0.02)
Results

No difference between surgical vs. medical ICU
patients

No difference in median length of ICU or
hospital stay, number of days of mechanical
ventilation, RRT, positive blood cultures, or
RBC transfusions
Griesdale DE, et al.
Intensive Insulin Therapy & Mortality in ICU





Systematic review and meta-analysis of 26
randomized trials
Effect of intensive insulin therapy in ICU
patients on risk of hypoglycemia, death
Systematic search
Rigorous statistical analysis to create pooled RRs
Primary outcome: 90d mortality
Griesdale DE, et al. CMAJ. 2009
Results
Intensive therapy had:

No effect on overall risk of death

May benefit patients in SICU

Had a 6-fold increased risk of severe hypoglycemia
 Risk
did not differ by type of ICU
Final analysis

Intensive insulin therapy seems to save lives in
Leuven
Final analysis


Intensive insulin therapy seems to save lives in
Leuven
This has yet to be replicated, particularly in any
multicenter trial
Final analysis



Intensive insulin therapy seems to save lives in
Leuven
This has yet to be replicated, particularly in any
multicenter trial
Hypoglycemia is a vexing problem, reassurances
from Leuven nonwithstanding
Final analysis




Intensive insulin therapy seems to save lives in
Leuven
This has yet to be replicated, particularly in any
multicenter trial
Hypoglycemia is a vexing problem, reassurances
from Leuven nonwithstanding
Protocols perform differently in different
cultures
Final analysis

Critical care and endocrinologic societies have
backed away from recommending intensive
insulin therapy
ADA/AACE Target Glucose
Levels in ICU Patients





Insulin infusion should be used to control
hyperglycemia
Starting threshold ~180 mg/dl
Once IV insulin is started, the maintain glucose
between 140 and 180 mg/dl
Lower glucose targets (110-140 mg/dl) may be
appropriate in selected patients
Targets <110 mg/dL are not recommended
Not recommended
< 110
Acceptable
110-140
Recommended
140-180
Not recommended
>180
ADA/AACE Inpatient Task Force
Endocrine Practice 2009;15;1-17
Where are we now?

Intensive insulin therapy is no longer widely
recommended (8 years after it was declared
mandatory)
Where are we now?

Intensive insulin therapy is no longer widely
recommended (8 years after it was declared
mandatory), BUT…
Where are we now?


Intensive insulin therapy is no longer widely
recommended (8 years after it was declared
mandatory), BUT…
I would submit that we have not “returned to
square one”
Where are we now?



Intensive insulin therapy is no longer widely
recommended (8 years after it was declared
mandatory), BUT…
I would submit that we have not “returned to
square one”
We are no longer tolerant of high glucose levels
(>200 mg/dl), and
Where are we now?




Intensive insulin therapy is no longer widely
recommended (8 years after it was declared
mandatory), BUT…
I would submit that we have not “returned to
square one”
We are no longer tolerant of high glucose levels
(>200 mg/dl), and
We have gained a lot of experience!
Thank you for your
attention!