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 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?

The ITT Bandwagon! Tipping pointsTipping points are "the levels at which the momentum for change becomes unstoppable.” Gladwell defines a tipping point as a sociological term: "the moment of critical mass, the threshold, the boiling point.” sociological

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.

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.

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 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 ” 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: mg/dl ITT Group: mg/dl Predominantly PN fed

Intensive Insulin Therapy and Pentastarch Resuscitation in Severe Sepsis Hypoglycemia rates higher in ITT: 12.1% vs 2.1% Mortality Brunkhorst NEJM 2008;358: ICUs in Germany (SepNet) Control: <180 mg/dl ITT Group: 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< ICUs across Europe Control: mmol/L ITT group: 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 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) Patients 206/ % 15/ % 14.7 (9.0 – 25.9) P <0.001 All reported and investigated as SAEs No 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 days 670/ % 627/ % 1.09 ( ) P = 0.17 Dead at 90 days 829/ % 751/ % 1.14 ( ) P = 0.02 Adjusted mortality at 90 days Adjusted for operative admission, geographic region, age, admission source, APACHE II score, mechanical ventilation 1.14 ( ) 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 Employed Case-control matching Krinsley CCM 2007;35:2262

Van den Berghe, 2001 Van den Berghe (ITT), 2006 VISEP, 2008NICE-SUGAR, 2009 Conventional Intensive p< p< p<0.001 % Intensive Insulin Therapy - Rate of Hypoglycemia (<40 mg/dl) p<0.001 GluControl, 2006

Kosiborad JAMA 2009:301:1556

Consider Glucose Variability? Ali CCM 2008;36:2316

Intensive Insulin Therapy Risks Benefits Workload

Intensive Insulin Therapy Bandwagon

Why it happened? (reached the Tipping Point!) Positive trial published in widely read, high ranking journal Articulate, intelligent spokesperson Simple, cheap, non-commercial intervention Community hungry for positive large scale trial Bandwagon for quality improvement Failure to consider generalizability of results from a single-center

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). Updated May 2009

Avoid Excessive Parenteral Glucose Loading