• 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

• 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

What happened?

• Clearly a difference in outcome

• High mortality rate in control group?

• Repeatability?

• Interpretation of findings?

• Generalizability of findings?

TIGHT GLYCEMIC CONTROL

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

• 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

Supplemental PN

• 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).

PN vs Standard Care

TIGHT GLYCEMIC CONTROL

Van den Berge NEJM 2001;345:1359

Harmed by glucose?

Rescued by Insulin?

• “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.”

Reproducibility of the Original Protocol?

GENERALIZABILITY OF VAN DEN BERGHE’S INITIAL

STUDY?

• Hypoglycemia rates higher in ITT: 18.7% vs 3.1%Mortality

• Single center• 1200 MICU patients• Same protocol• Control: 180-215 mg/dl• ITT Group: 80-110 mg/dl• Predominantly PN fed

Intensive Insulin Therapy and Pentastarch Resuscitation in Severe

Sepsis

• Hypoglycemia rates higher in ITT: 12.1% vs 2.1%

0

5

10

15

20

25

30

35

40

28 day 90 day

TightControl

Mortality

Brunkhorst NEJM 2008;358:125

• 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

A prospective multi-centre controlled trial on tight glucose control by intensive insulin therapy in adult intensive care units:

The GLUCONTROL study

Preiser JC Intensive Care Med 2009

Mortality

• Hypoglycemia rates higher in ITT: 8.7% vs 2.7%, p<0.001

• 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

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

© The NICE SUGAR Study Investigators 2009

Severe hypoglycaemia(≤2.2mmol/L: ≤40mg/dL)

Intensive Glucose Control

Conventional Glucose Control

Odds ratio

(95% CI)

Patients206/3016

6.8%

15/3014

0.5%

14.7

(9.0 – 25.9)P <0.001

All reported and investigated as SAEsNo long term sequelae reported

© The NICE SUGAR Study Investigators 2009

Outcomes: Mortality

Intensive Glucose Control

Conventional Glucose Control

Odds ratio

(95% CI)

Dead at 28 days670/3010

22.3%

627/3012

20.8%

1.09

(0.96 - 1.23)P = 0.17

Dead at 90 days829/3010

27.5%

751/3012

24.9%

1.14

(1.02 - 1.28)P = 0.02

Adjusted mortality at 90 days

Adjusted for operative admission, geographic region, age, admission source, APACHE II score, mechanical ventilation

1.14

(1.01 - 1.29)P = 0.04

© 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

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

0

10

20

30

40

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60

ICU

SHControl

Employed Case-control matching

Krinsley CCM 2007;35:2262

0.8

5.1

0

5

10

15

20

25

30

Van den Berghe,2001

Van den Berghe(ITT), 2006

VISEP, 2008 NICE-SUGAR,2009

Conventional

Intensive

3.1

18.7

p<0.001

0.5

6.8

p<0.001

4.5

17.6

p<0.001

p<0.001

%

Intensive Insulin Therapy - Rate of Hypoglycemia (<40 mg/dl) -

3.9

14.5

p<0.001

GluControl, 2006

Kosiborad JAMA 2009:301:1556

Consider Glucose Variability?

Ali CCM 2008;36:2316

Intensive Insulin Therapy

RisksRisks

BenefitsBenefits

WorkloadWorkload

Intensive Insulin Therapy Bandwagon

Canadian RecommendationsIntensive 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

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