1. The Patient Undergoing Surgery: Proven Steps to Better Outcomes Ariel U. Spencer, MD Lafayette Surgical Clinic Lafayette, Indiana

2. Disclosures No conflicts of interest to disclose

3. Risk Factor Modification What specific steps have been proven to improve outcomes? What guidelines are supported by current literature?

4. Hyperglycemia Stress and fasting Relative insulin deficiency Increased insulin resistance Decreased insulin production Free fatty acids

5. Hyperglycemia Fluid shifts Increased inflammatory response Endothelial dysfunction Thrombotic complications

6. Effects of Hyperglycemia on Immune System Decreased granulocyte adhesion Impairment of chemotaxis Impaired intracellular killing Compromised phagocytosis Superoxide formation

7. At what blood sugar level do harmful effects of hyperglycemia begin to occur? Clinical signs appear after cellular and tissue damage has already happened

8. Conventional Therapy No perioperative insulin administration NPO status Postoperative management with sliding scale insulin; inclusion of oral hypoglycemic agents as diet is advanced No standardization for target blood glucose levels (?, 200 mg/dl, etc.)

9. Intensive Insulin Therapy (IIT) Very influential study in 2001 (large randomized controlled trial, > 1500 critically ill, intubated surgical ICU patients) Underlying concept: maintain total normoglycemia in the perioperative period Van den Berghe G, N Engl J Med 2001; 345:1359-1367)

10. Intensive Insulin Therapy Average blood glucose in study group of 101 mg/dl was achieved Control group (treatment threshold at glucose = 220 mg/dl) achieved an average blood glucose of 152 mg/dl 42% reduction in mortality risk

11. Intensive Insulin Therapy Serum insulin levels in patients receiving IIT were similar to levels in patients receiving conventional insulin therapy, despite much higher doses of insulin Conclusion that normoglycemia can be achieved without significantly elevating insulinemia Evidence for improved insulin sensitivity

12. Mode of Insulin Delivery Decreased sternal wound infections 69% reduction in death, myocardial infarction, and CHF (continuous IV insulin therapy; blood sugar maintained between 100 - 150) Subramaniam B, Anesthesiology 2009; 110:970-977

13. Tight glucose control AACE (2007) ADA (2008) Institute for Healthcare Improvement (2009) Protocols began to be instituted across the nation Some concerns expressed

14. Problems with IIT RCT testing IIT in the intra-operative setting (on-pump cardiac surgery, n= 201) with a very aggressive BG goal (80-100) This study found an increased risk of death and stroke in the IIT group Conclusion: IIT implemented during surgery may actually worsen outcomes Gandhi GY, et al., Ann Int Med 2007;146:233-43.

15. Hypoglycemia Dilemma Considerable variability between studies in the target blood glucose achieved With IIT-driven protocols, significantly increased rate of episodes of profound hypoglycemia (rates from 5 - 29%) Termination of two large European studies

16. NICE-SUGAR Normoglycemia in Intensive Care Evaluation - Survival Using Glucose Algorithm Regulation Largest trial of IIT thus far IIT group: target glucose 80-108 Control group: target glucose 144-180 N Engl J Med 2009; 360:1283-97

17. NICE-SUGAR INCREASED mortality in the group receiving tighter blood glucose control 3% higher absolute mortality rate Increased rate of cardiovascular death

18. Avoiding hypoglycemia Fluctuation in an individual’s blood glucose may be more critical than the average glucose level Using computer-driven models to predict an individual patient’s insulin resistance and requirements Careful monitoring