1. Sugar control in Critical care unit Senior clinical pharmacist : Lihua Fang Koo Foundation Cancer Center

2. Glycemic Control in the ICU A 42-year-old man is admitted to (ICU) with an acute exacerbation of asthma associated with community- acquired pneumonia. cefotaxime and azithromycin, nebulized albuterol, and intravenous hydrocortisone No known history of diabetes mellitus Glucose 105 mg/dl-> 195 mg/dl, HbA1c : 5.3% Should this elevated glucose level be treated?

3. Causes and Effects of Stress Hyperglycemia. Kavanagh BP, McCowen KC. N Engl J Med 2010;363:2540-2546.

4. STRATEGIES AND EVIDENCE Evaluation Acute hyperglycemia : > 200 mg/dl In 2010 the American Diabetes Association : > 140 mg/dl HbA1c > 6.5% Management Studies of Intensive Insulin Therapy Before 2001, little attention was paid to control of hyperglycemia in the ICU Targeted is 80 to 110 mg/dl

5. A single-center trial in Leuven, Belgium 1548 pts, cardiac surgery not blinded The first evidence of a benefit of tight glucose control in the ICU Intensive insulin therapy (target glucose 80-110 mg/dl) vs standard care (180-200 mg/dl ) Reduced mortality in ICU (4.6% vs. 8%) Serious hypoglycemia ( <40 mg/dl, 5% ) cause for concern The mortality in the control group was high relative to that in other cardiac surgical centers. NEJM 2001;345:1359-1367

6. A single-center, nonblinded trial from the same group 1200 medical ICU pts :> 3 days Intensive insulin therapy (target glucose 80-110 mg/dl) vs standard care (180-200 mg/dl ) Not reduce overall mortality, serious hypoglycemia (18.7%) lower rate of acquired renal impairment (5.9% vs. 8.9%) shorter duration of mechanical ventilation shorter stays in the ICU NEJM 2006;354:449-461

7. Four additional studies (two multicenter trials and two single-center trials) 2600 pts at 41 centers (medical and surgical) Target glucose levels vs intensive-therapy Intensive insulin therapy : significant effect on mortality and resulted in a high incidence of hypoglycemia (8 to 28%) No benefits of secondary outcomes Renal impairment, duration of mechanical ventilation, length of stay

8. The largest trial–Survival Using Glucose Algorithm Regulation (NICE-SUGAR) 6104 pts (42 centers) The intensive-therapy group : an absolute  in mortality of 2.6% points (P=0.02) and hypoglycemia (6.8% vs. 0.5%). Intensive therapy 118±25 mg/dl, the control group : <180 mg/dl. The mortality rate in the control group :24.9% was lower than that predicted by the APACHE II score (39%) The nutrition regimen : less aggressive Intensive insulin therapy with glucocorticoids for septic shock: no reduction in mortality and also a higher hypoglycemia (16.4% vs. 7.8 ) NEJM 2009;360:1283-1297

9. 5.1% 0.8% 18.7% 3.1% 17% 4.1% 8.7% 2.7% 16.4% 7.8% 6.8% 0.5% Severe Hypoglycemia ≤40mg/dL (2.2 mmol/L) Treatment vs control P<0.001

10. A meta-analysis of 26 randomized trial >13,500 pts Intensive insulin therapy No overall effect on mortality Hypoglycemia that was 6 times higher A more recent meta-analysis restricted to the seven largest randomized trials ( > 11,000 pts) Target glucose : 80 to 110 mg/dl no survival benefit and increased morbidity CMAJ 2009;180:821-827

11. Glucose Monitoring By intra-arterial, venous catheters or a fingerstick Point-of-care bedside glucometers (inaccurate, by > 20%) Laboratory analysis of plasma (slow for use in the ICU) Blood gas analyzers (highly accurate) : practical New technologies : Subcutaneous glucose sensors ( every 5 minutes) glucose levels in interstitial fluid, lag behind blood levels. Continuous intravascular glucose sensors in development, real-time monitoring

14. Insulin-infusion An insulin-infusion protocol validated and Algorithm for Monitoring Glucose Levels and Managing Insulin Therapy in the ICU Computer-directed algorithms Target glucose level : < 180 mg/dl The risk of hypoglycemia with insulin therapy Subcutaneous insulin

15. Algorithm for Monitoring Glucose Levels and Managing Insulin Therapy in the ICU. NEJM 2010;363:2540-2546.

16. Calculating 24-hour insulin needs Physical Activity Level Normal WeightObese High0.3 U/kg0.5 U/kg Moderate0.4 U/kg0.6 U/kg Low0.5 U/kg0.8 U/kg Coexisting Illness (CKD) Subtract 0.2 U/kg “Big eater” eating habits Add 0.1 U/kg

18. Insulins and Duration of Action

19. By Sliding scale

21. Basal and bolus insulin dosing Based on IV insulin infusion Several models :a threecomponent basal insulin, nutritional insulin, Basal insulin : Long acting (glargine) or intermediate- acting insulin every 6–12 hrs ( NPH) At least 2–4 hrs before stopping the insulin infusion rapid-acting insulin ( 10% of the basal dose) may be given with the basal insulin injection Initial basal dose to 80% of the estimated TDD Changes in other drug therapy or nutritional regimens

22. Hypoglycemia An increase in mortality Severe hypoglycemia ( <40 mg/dl) 28% of intensive insulin therapy The neurologic consequences of hypoglycemia difficult to detect in critically ill patients At 4 years of follow-up, intensive insulin therapy was found to have impairments in quality of life and social functioning vs conventional treatment. The long-term sequelae of iatrogenic hypoglycemia in the ICU difficult to measure

23. Hypoglycemia BG < 70 mg/dL (<100mg/dL in neurologic injury patients) Stopping the insulin infusion and administering 10– 20g of hypertonic (50%) dextrose The BG repeated in 15 mins to achieve BG > 70mg/dL 20-50% dextrose dose in grams = [100 − BG] × 0.2g), 10–20g of IV dextrose Target range in 98% within 30 mins Crit Care Med 2012 Vol. 40, No. 12

24. Nutrition A recent meta-analysis in Intensive insulin therapy with a reduction in mortality only High calories was provided parenterally, to avoid hypoglycemic complications of intensive insulin therapy and lower the risk of death only when administered in the context of intensive nutritional support Enteral feeding and parenteral nutrition More beneficial in intensive insulin infusion

25. Guidelines from Professional Organizations on the Management of Glucose Levels in the ICU. Kavanagh BP, McCowen KC. N Engl J Med 2010;363:2540-2546.

26. Glycemic Control in the ICU A 42-year-old man is admitted to (ICU) with an acute exacerbation of asthma associated with community- acquired pneumonia. cefotaxime and azithromycin, nebulized albuterol, and intravenous hydrocortisone No known history of diabetes mellitus Glucose 105 mg/dl-> 195 mg/dl, HbA1c : 5.3% Should this elevated glucose level be treated?

27. CONCLUSIONS AND RECOMMENDATIONS With ongoing use of glucocorticoids and the institution of nutritional support Follow plasma glucose HbA1c : 5.3%, No preexisting diabetes Target : 140 -180 mg/dl Computerized insulin-infusion algorithm and close monitoring of glucose levels Nutritional support : enteral feeding

28. Reference Guidelines for the use of an insulin infusion for the management of hyperglycemia in critically ill patients Crit Care Med 2012 Vol. 40, No. 12