1. Glycemic Control in Acutely Ill Patients Martin J. Abrahamson, MD FACP Associate Professor of Medicine, Harvard Medical School Senior Vice President for Medical Affairs, Joslin Diabetes Center

2. Questions to Ask Is hyperglycemia associated with increased morbidity/mortality in acutely ill patients? Will lowering glucose improve outcomes for acutely ill patients? What glucose levels should be attained in the acutely ill patient? How do we best do this?

3. Mortality Increases with Increases in Average ICU BG Krinsley JS: Mayo Clin Proc. 2003;78:1471-1478. (1826 consecutive ICU patients 10/99 thru 4/02)

4. Intensive Insulin Therapy and Mortality in Patients Admitted to SICU 1548 consecutive admissions to SICU Randomly assigned (with stratification based on type of critical illness) to conventional vs intensive insulin treatment Van de Berghe G, et al. NEJM 2001;345:1359-1367

5. Conventional treatment –Standardized nutritional therapy and intravenous insulin therapy if BG >215 mg/dl to maintain blood glucose <200 mg/dl. Intensive therapy –Standardized nutritional therapy and intravenous insulin therapy if BG>110 mg/dl to maintain glucose 80 - 110 mg/dl. Intensive Insulin Therapy and Mortality in Patients Admitted to SICU

6. Intensive Insulin Therapy in Critically Ill Surgical Patients Conventional Treatment Intensive Treatment Trigger for starting iv insulin > 215> 100 Glucose achieved 153 + 33103 + 19 % with glucose < 40 mg/dL 0.75 Glucose in mg/dL Van den Berghe et al. NEJM 2001; 345:1359-1367

7. Intensive Insulin Therapy in Surgical ICU Patients Reduces Mortality Conventional :insulin when blood glucose > 215 mg/dL mean BG = 153 mg/dL Intensive : insulin when glucose > 110 mg/dL and maintained at 80-110 mg/dL mean BG = 103 mg/dL Conventional :insulin when blood glucose > 215 mg/dL mean BG = 153 mg/dL Intensive : insulin when glucose > 110 mg/dL and maintained at 80-110 mg/dL mean BG = 103 mg/dL Survival in ICU (%) 100 96 92 88 80 0 0 84 0 0 20 40 60 80 100 120 140 160 Intensive treatment Conventional treatment Days after Admission 4.6% mortality 8% mortality Van den Berghe, G. NEJM. 2001;345:1359–1367.

8. Intensive Insulin Therapy in Surgical ICU Patients Reduces Morbidity and Mortality Percent Reduction MortalitySepsisDialysisPolyneuropathy Blood Transfusio n 34% 46% 41% 44% 50% Van den Berghe, G. NEJM. 2001;345:1359–1367.

9. What about Intensive Therapy in the MICU? ♦1,200 patients who “were considered to need intensive care for at least 3 days” ♦Randomized to two groups: ♦IV insulin to achieve glucose 80-110 mg/dl ♦Conventional therapy using insulin for blood glucose > 215 mg/dl and tapered when < 180 mg/dl ♦16.9% of these patients had diabetes NEJM 354:449, 2006

10. Intensive Insulin Therapy in Critically Ill Medical Patients Conventional Treatment Intensive Treatment Trigger for starting iv insulin > 215> 100 Glucose achieved 153111 % with glucose < 40 mg/dL 3.118.7 Glucose in mg/dL Van den Berghe et al. NEJM 2006; 354:449-460

11. Intensive Insulin in the MICU Does Not Decrease Mortality In-hospital deaths –Conventional Therapy: 40% –Intensive Insulin Therapy: 37.3% NEJM 354:449, 2006 P = 0.33 100 80 60 40 20 A. Intention-to-Treat Group (n = 1,200) Intensive treatment Conventional treatment 0 0100200300400500 Days First 30 days 100 80 60 40 0 0102030 In-Hospital Survival (%)

12. Subgroup in ICU ≥ 3 days (n = 767) P = 0.009 NEJM 354:449, 2006 100 80 60 40 20 B. Subgroup in ICU ≥3 Days (n = 767) Intensive treatment Conventional treatment 0 050150200250350 Days First 30 days 100 80 60 40 0 0102030 In-Hospital Survival (%) 100300500 In-hospital deaths –Conventional Therapy: 52.5% –Intensive Insulin Therapy: 43.0%

13. Effect of Intensive Insulin Therapy on Morbidity NEJM 354:449, 2006

14. Conclusions Intensive insulin therapy significantly reduced morbidity but not mortality among all patients in the MICU. Although the risk of subsequent death and disease was reduced in patients treated for ≥3 days, these patients could not be identified before therapy. NEJM 354:449, 2006

15. Diabetes Care in the Hospital: NICE-SUGAR Study (1) Largest randomized controlled trial to date Tested effect of tight glycemic control (target 81–108 mg/dL) on outcomes among 6,104 critically ill participants Majority (>95%) required mechanical ventilation ADA. IX. Diabetes Care in Specific Settings. Diabetes Care. 2013;36(suppl 1):S46.

16. Diabetes Care in the Hospital: NICE-SUGAR Study (2) In both surgical/medical patients, 90-day mortality significantly higher in intensively treated vs conventional group (target 144–180 mg/dL) –Severe hypoglycemia more common (6.8% vs 0.5%; P<0.001) –Findings strongly suggest may not be necessary to target blood glucose levels <140 mg/dL; highly stringent target of <110 mg/dL may be dangerous ADA. IX. Diabetes Care in Specific Settings. Diabetes Care. 2013;36(suppl 1):S46.

17. So what glycemic target should be attempted for acutely ill patients admitted with diabetes?

18. ADA Recommendations Critically ill patients: 140 – 180 mg/dL Start iv insulin when glucose exceeds 180 mg/dL Goal of 110 – 140 mg/dL may be appropriate for some patients if there is no risk of hypoglycemia Non-critically ill Premeal < 140 mg/dL mg/dL Random <180 mg/dL

19. What Does Insulin Do to Improve Outcomes? With near normoglycemia insulin –Stimulates endothelial NO production –Inhibits FFA synthesis –Suppresses production of proinflammatory cytokines and acute phase proteins –Suppresses inflammatory growth factors This probably leads to improved outcomes in critically ill patients

20. So how do we manage someone who requires insulin and is NPO or too ill to eat?

21. Using Sliding Scale SC Insulin is Like Being on a Roller Coaster! IT IS A RELIC FROM THE PAST AND SHOULD BE AVOIDED WHEREVER AND WHENEVER POSSIBLE!!

22. IV Insulin Infusion Gets BG to Goal Quicker than SC Goldberg, PA et al. Diabetes Care 2004; 27:461-467

23. Estimating Insulin Dose for Infusion Infusion of 1.0 - 2.0 units/hr usually maintains blood glucose in 120 - 180mg/dL range Insulin requirements depend on –Previous therapy –Degree of control –Use of steroids –Presence of sepsis –Type of surgery Increased insulin requirements for renal transplant and open heart surgery

24. Guidelines for Insulin Infusion Decreased insulin needs –Patients requiring diet and/or oral agents –Patients taking less than 50 U of insulin per day Increased insulin needs –Obesity, hepatic disease (x 1.5) –Steroid therapy (x2) –Sepsis (x2) –Renal transplant (x 2) –Open heart surgery (x 3-5)

25. Insulin Infusion Algorithm Decision to initiate iv insulin If BG < 200 mg/dL start with D5 ½ N Saline at 60 – 100 cc/hr If BG > 300 mg/dL give iv regular insulin 0.1U/kg stat Initiate at an hourly rate of total daily dose of insulin / 24 For patients not usually on insulin start at 0.02 U/kg/hr Check BG hourly

26. Adjustment of Insulin is dependent on current glucose, previous glucose and rate of change of glucose

27. Transitioning to SC Insulin Do not stop iv insulin before giving some short acting insulin sc Usually continue iv infusion by about 1 hour after administration of short acting sc insulin Plan to stop iv after a meal – preferably during the day Ensure that there is always intermediate or long acting insulin given to cover basal requirements

28. Remember – Insulin Requirements.. Basal Prandial/Nutritional Correction or Supplemental

29. Summary Hyperglycemia is associated with increased morbidity and mortality in acutely ill patients Maintaining glucose levels between 140 and 180 mg/dL in acutely ill patients is associated with the least morbidity and optimal outcomes Using iv insulin infusion to achieve this in the ICU is the preferred modality of administering insulin