• 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 20 15 10 5 0 Tight Control 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 206/3016 6.8% Conventional Glucose Control 15/3014 0.5% Odds ratio (95% CI) 14.7

(9.0 – 25.9) All reported and investigated as SAEs No long term sequelae reported P <0.001

© The NICE SUGAR Study Investigators 2009

Outcomes: Mortality

Intensive Glucose Control Conventional Glucose Control Dead at 28 days Dead at 90 days Adjusted mortality at 90 days 670/3010 22.3% 627/3012 20.8% 829/3010 27.5% 751/3012 24.9% Adjusted for operative admission, geographic region, age, admission source, APACHE II score, mechanical ventilation Odds ratio (95% CI) 1.09

(0.96 - 1.23) 1.14

(1.02 - 1.28) 1.14

(1.01 - 1.29) P = 0.17

P = 0.02

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

© 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 30 SH Control 20 10 0 ICU

Employed Case-control matching Krinsley CCM 2007;35:2262

Intensive Insulin Therapy

- Rate of Hypoglycemia (<40 mg/dl) -

30 25 Conventional Intensive 20 % 15 p<0.001

18.7

10 5 0 p<0.001

5.1

3.1

0.8

Van den Berghe, 2001 Van den Berghe (ITT), 2006 p<0.001

17.6

4.5

VISEP, 2008 p<0.001

14.5

p<0.001

6.8

3.9

0.5

NICE-SUGAR, 2009 GluControl, 2006

Kosiborad JAMA 2009:301:1556

Consider Glucose Variability?

Ali CCM 2008;36:2316

Intensive Insulin Therapy

Risks Workload Benefits

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