• Mr PS
• 76 years old
• COPD, no DM
• Severe CAP
• Day 1- intubated, sedated, high o2
requirements, vasopressor dependent
• Starting early EN
• Glucose 11.1 mmol/L (200 mg/dl)
What would you do?
A. Start insulin infusion and
titrate glucose to 4.4- 6.1
mmol/l
B. Start insulin infusion and
titrate infusion to 7-9 mmol/l
C. Watchful waiting
D. Don’t Know
E. Don’t care
Intensive Insulin Therapy
Van den Berge NEJM 2001;345:1359
The Intensive Insulin Therapy
Bandwagon
What happened?
•
•
•
•
Endorsed by National and International societies
Recommend by clinical practice guidelines
Standards for hospital accreditation
Part of Institute for Healthcare Improvement and
other quality improvement campaign
TIGHT GLYCEMIC CONTROL
• Clearly a difference in
outcome
• High mortality rate in
control group?
• Repeatability?
• Interpretation of findings?
• Generalizability of
findings?
Van den Berge NEJM 2001;345:1359
Feeding
• All given IV glucose from day of admission
Nutritional Strategy:
Usual Practice?
Canadian Recommendations
Enteral vs. Parenteral Nutrition
• Based on one level 1 and 12 level 2 studies,
when considering nutrition support for critically ill
patients, we strongly recommend the use of
Enteral Nutrition over Parenteral Nutrition.
www.criticalcarenutrition.com
Canadian Recommendations
Combined EN and PN
• Based on 5 level 2 studies, for critically ill
patients starting on enteral nutrition we
recommend that parenteral nutrition not be
started at the same time as enteral nutrition.
www.criticalcarenutrition.com
ASPEN/SCCM ICU Nutrition CPGs
PN vs Standard Care
• In the patient who was previously healthy prior to critical
illness with no evidence of protein-calorie malnutrition,
use of PN should be reserved and initiated only after
the first 7 days of hospitalization (when EN is not
available).
Supplemental PN
• If unable to meet energy requirements after 7-10 days
by the enteral route, consider initiating PN.
• Initiating PN prior to this 7-10 day period does not
improve outcome and may be detrimental to the patient.
McClave JPEN 2009;33:277
TIGHT GLYCEMIC CONTROL
Harmed by glucose?
Rescued by Insulin?
Van den Berge NEJM 2001;345:1359
Reproducibility of the Original
Protocol?
• “If blood glucose is 40-60 mg/dl, stop the
insulin infusion, assure adequate baseline
glucose intake, and check the blood glucose
level within the next hour.”
• “If blood glucose approaches the normal
range, reduce insulin by 25-50.”
GENERALIZABILITY OF
VAN DEN BERGHE’S INITIAL STUDY?
•
•
•
•
•
•
Single center
1200 MICU patients
Same protocol
Control: 180-215 mg/dl
ITT Group: 80-110 mg/dl
Predominantly PN fed
Mortality
• Hypoglycemia rates higher in ITT: 18.7% vs 3.1%
Intensive Insulin Therapy and Pentastarch
Resuscitation in Severe Sepsis
• 18 ICUs in Germany
(SepNet)
• Control: <180 mg/dl
• ITT Group: 80-110 mg/dl
• Predominantly enteral fed
• 50% surgery
• Suspended prematurely
because of higher rate of
hypoglycemia
40
35
30
25
Tight
Control
20
15
10
5
0
28 day
90 day
Mortality
• Hypoglycemia rates higher in
ITT:
12.1% vs 2.1%
Brunkhorst NEJM 2008;358:125
A prospective multi-centre controlled trial on tight glucose control
by intensive insulin therapy in adult intensive care units:
The GLUCONTROL study
•
•
•
•
21 ICUs across Europe
Control: 7.8 -10.0 mmol/L
ITT group: 4.4-6.1 mmol/L
Trials suspended early
because of protocol
violations
• 1,101 patients randomized
• 60% surgical/40% medical
Mortality
• Hypoglycemia rates higher in ITT:
8.7% vs 2.7%, p<0.001
Preiser JC Intensive Care Med 2009
NICE – SUGAR Study
• Aim
– to compare the effects of the two blood glucose targets
on 90 day all-cause mortality
• Hypothesis
– The hypothesis is that there is no difference in the
relative risk of death between patients assigned a
glucose range of 4.5 - 6.0 mmol/L (81 – 108 mg/dl) and
those assigned a glucose range of 10.0 mmol/L or less
(180mg/dL or less)
Inclusion Criteria
•
ICU treatment that extends beyond the calendar
day after the day of admission (i.e. on three
consecutive days).
•
Arterial catheter in situ (or imminent)
•
Consent has been / will be obtained
Maximal Generalizability
Severe hypoglycaemia
(≤2.2mmol/L: ≤40mg/dL)
Patients
Intensive Glucose
Control
Conventional
Glucose Control
Odds ratio
(95% CI)
206/3016
6.8%
15/3014
0.5%
14.7
(9.0 – 25.9)
All reported and investigated as SAEs
No long term sequelae reported
© The NICE SUGAR Study
Investigators 2009
P <0.001
Outcomes: Mortality
Intensive Glucose
Control
Conventional
Glucose Control
Odds ratio
(95% CI)
Dead at 28 days
670/3010
22.3%
627/3012
20.8%
1.09
(0.96 - 1.23)
P = 0.17
Dead at 90 days
829/3010
27.5%
751/3012
24.9%
1.14
(1.02 - 1.28)
P = 0.02
1.14
(1.01 - 1.29)
P = 0.04
Adjusted mortality
at 90 days
Adjusted for operative admission,
geographic region, age, admission
source, APACHE II score, mechanical
ventilation
© The NICE SUGAR
Study Investigators 2009
Survival
Hazard ratio 1.11 (conventional vs. ITT, p=0.03)
© The NICE SUGAR Study
Investigators 2009
Pre-defined subgroup pairs
© The NICE SUGAR Study
Investigators 2009
Conclusions of the Trial
• A blood glucose target of 4.5 – 6.0 mmol/L resulted in
increased mortality compared to a target of <10.0mmol/L.
• In comparison with other trials, severe hypoglycaemia was
relatively uncommon but significantly more common in those
assigned to intensive glucose control.
• On the basis of these results we do not recommend targeting
normoglycaemia in critically ill adults.
CMAJ 2009;180:821
Severe Hypoglycemia (SH) in Critically Ill
Patients: Risk Factors and Outcomes
• Observational study of
>5000 ICU patients
• 102 had at least 1 episode
of glucose < 2.2 mmol (40
mg/dL)
• Risk Factors: diabetes,
septic shock, renal failure,
mechanical ventilation,
APACHE score and
treatment with ITT.
• SH independently
associated with increased
mortality
60
50
40
SH
Control
30
20
10
0
ICU
Employed Case-control matching
Krinsley CCM 2007;35:2262
Intensive Insulin Therapy
- Rate of Hypoglycemia (<40 mg/dl) 30
Conventional
Intensive
25
p<0.001
20
%
p<0.001
18.7
p<0.001
17.6
14.5
15
p<0.001
10
p<0.001
6.8
5.1
5
4.5
3.9
3.1
0.5
0.8
0
Van den Berghe,
2001
Van den Berghe
(ITT), 2006
VISEP, 2008
NICE-SUGAR,
2009
GluControl,
2006
Kosiborad JAMA 2009:301:1556
Consider Glucose Variability?
Ali CCM 2008;36:2316
Intensive Insulin Therapy
Benefits
Risks
Workload
Intensive Insulin Therapy Bandwagon
Canadian Recommendations
Intensive Insulin Therapy
We recommend that hyperglycemia (blood
sugars > 10 mmol/L) be avoided in all critically ill
patients. Based on the NICE-SUGAR study and
a recent meta-analysis, we recommend a blood
glucose target of around 8.0 mmol/L (or 7-9
mmol/L), rather than a more stringent target
range (4.4 to 6.1 mmol/L) or a more liberal target
range (10 to 11.1 mmol/L).
www.criticalcarenutrition.com
Updated May 2009
Avoid Excessive Parenteral
Glucose Loading