Hyperglycemia in Hospitalized Patients

1. Robert J. Rushakoff, MD Professor of Medicine University of California, San Francisco robert.rushakoff@ucsf.edu Hyperglycemia in Hospitalized Patients • Strategies For Implementing Change • Nuts and bolts of management

2. Strategies For Implementing Inpatient Glycemic Control www.rushakoff.com www.endotext.com ucsfinpatientdiabetes.pbworks.com

3. Diabetes as a Secondary Diagnosis What is inpatient diabetes care?

4. Inpatient Diabetes Goals Appropriate Glucose Control Based on physiology and outcome studies Inpatient Diabetes Goals Normal glucoses for everyone A high glucose means failure Sliding Scales are banned Some hypoglycemia is acceptable Inpatient Diabetes Goals Who Cares Just get patient home Sliding Scales are fine Avoid that scary hypoglycemia

5. Goals for Inpatient management Evidence, if any, for stated goals Methods to Achieve Glucose Goals Insulin order forms NPO patients Patients eating TPN and hyperalimentation Special Situations Glucocorticoids Implementation Cases Care of the Hospitalized Diabetic Patient

6. Target Glucose Levels Alive

7. Target Glucose Levels No DKA or Hyperosmolar Coma

8. Quantifying the Impact of a Short-Interval Interruption of Insulin-Pump Infusion Sets on Glycemic Excursions Diabetes Care 31:238–239, 2008

9. Target Glucose Levels Occasional hypo- and hyperglycemia

10. Target Glucose Levels No hypo- or hyperglycemia • Prevent fluid and electrolyte abnormalities secondary to osmotic diuresis • Improve WBC function • Improve gastric emptying • Decrease surgical complications • Earlier hospital dischange • Decreased post-MI mortality • Decreased post-CABG morbidity and mortality

11. Target Glucose Levels Normal Glucoses Decreased Morbidity and Mortality

12. Problems With High Glucoses

13. Increased Infections Early postoperative glucose control predicts nosocomial infections rate in diabetic patients Pomposelli et al: J Parenteral Ent Nut. 1998; 22:77-81 • Relative risk for “serious” postop infections increased to 5.7 when glucose >220 mg/dl

14. Increased Infections Relative Odds of Wound Infections 121-206 -------207-229 1.17230-252 1.86 253-3531.78 (p<0.05 for upward trend) Perioperative Glycemic Control and the Risk of Infectious Complications in a Cohort of Adults with Diabetes Golden et al: Diabetes Care, 22:1408, 1999 411 diabetics who underwent CABGLeg and chest wounds, pneumonia and UTI

15. Glucose and post-CABG morbidity and mortality Diabetes and Coronary Artery Bypass Surgery. An examination of perioperative glycemic control and outcomes Diabetes Care 2003; 26:1518-1524 • Retrospective Review of 291 patients surviving 24 h post op • 40% with retinopathy, nephropathy or neuropathy Inpatient Complications For each 1 mmol/l (18 mg/dl) increase in postop day 1 over 6.1 mmol/l (110 mg/dl), a 17% increase risk of complications

16. HIGH BLOOD GLUCOSE LEVELS ASSOCIATED WITH INCREASED MORTALITY IN ICU • Retrospective Review of 216,000 critically ill patients conducted by the Veterans Affairs Inpatient Evaluation Center based in Cincinnati • Hyperglycemia was an independent predictor of mortality starting at 111 mg/dl. • Effect was greatest with acute myocardial infarction, unstable angina, and stroke • heart attack - 1.6-5 time • a stroke it raised risk from 3.4 to 15.1 times • unstable angina it raised risk from 1.7 to 6.2 times Falciglia et al: ADA Scientific Meetings, 2006, late breaking abstracts

17. HIGH BLOOD GLUCOSE LEVELS ASSOCIATED WITH INCREASED MORTALITY IN ICU • Retrospective Review of 216,000 critically ill patients conducted by the Veterans Affairs Inpatient Evaluation Center based in Cincinnati • A significant but weaker effect was seen in patients with sepsis, pneumonia, and pulmonary embolism. Hyperglycemia was not found to be associated with mortality in diseases such as COPD and hepatic failure. • In diabetes patients, the increase in mortality risk was not seen until mean glucose was >146 mg/dl Falciglia et al: ADA Scientific Meetings, 2006, late breaking abstracts

18. Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes • Retrospective Review • Hyperglycemia in 38% • 26% known diabetes • 12% no known diabetes • Mortality New hyperglycemia 16% Known Diabetes 3% Nondiabetics 1.7% J. Clin Endocrinol. 2002;87:978-982.

19. TPN: Adverse Outcomes Hyperglycemia Is Associated With Adverse Outcomes in Patients Receiving Total Parenteral Nutrition Cheung et al: Diabetes Care, 28:2367-2371, 2005 Risk of complications in relation to mean daily blood glucose level

20. Risk of Complications by glucose level quartile after adjusting for age, sex and presence of preexisting diabetes Cheung et al: Diabetes Care, 28:2367-2371, 2005

21. Intervention Studies

22. Decreased post-CABG morbidity and mortality Intensive Intervention by a Diabetes Team Diminishes Excess Hospital Mortality in Patients with diabetes who undergo CABG Kalin et al. Diabetes Suppl. 47:A87 1998 Diabetes team followed patientPerioperative IV insulin infusionAlgorithm based SQ premeal insulin Mortality during CABG 1993-96 Relative risk National 1.46Beth Israel 1.02

23. Decreased post-MI mortality Effects of insulin treatment on cause-specific one year mortality and morbidity in diabetic patients with acute myocardial infarction. DIGAMI Study Group. Malmberg et al. Eur Heart J 1996 PeriMI IV insulin infusionAlgorithm based SQ premeal insulin for 1 year Mortality (%) 1 year3.4 years Control 26 44 Insulin 19 33

24. DIGAMI Design • 620 patients • MI within 24 hours • Previous known DM with glucose > 11 mmol/l (198 mg/dl) or glucose > 11 mmol/l without known DM • Exclusion: (50% of 1240 were excluded) • To sick for consent • Unable to manage multidose insulin • Usual acute CCU MI care • Treatment group • Infusion for >24 hours (until stable) , then 3 months multiple shots insulin J Am Coll Cardiol 1995;26:57-65

25. DIGAMI2 (European Heart J. Prepublication Feb 2005) • Group 1 – IV insulin then long term SQ insulin • Group 2 – IV insulin then standard treatment • Group 3 – Standard treatment Mortality

26. Decreased Infections Insulin infusion improves neutrophil function in diabetic cardiac surgery patients. Rassias AJ, Marrin CA, Arruda J, Whalen PK, Beach M, Yeager MP. Anesth Analg 1999; 88:1011-6. Perioperative IV insulin infusion Neutrophil phagocytic activity % baseline Control 47 Insulin 75

27. Decreased Infections Glucose control lowers the risk of wound infection in diabetics after open heart operations Zerr et al: Ann Thoracic Surgery, 1997, 63:356-61Furnary et al. Annals of Thoracic Surgery 1999, 67:352-60Furnary et al. J Thoracic Cardiovascular Surgery 2003, 125: 1007-1021 Perioperative IV insulin infusionProtocol to maintain glucoses <200 Incidence of Deep Wound Infections (%) 19971999 Routine Control 2.4 2.0“Tight” Control 1.5 0.8

28. Decreased Infections Glucose control decreases mortality in diabetics after open heart operations Furnary et al. J Thoracic Cardiovascular Surgery 2003, 125: 1007-1021 14.5% 6.0% 4.1% 2.3% 1.3% 0.9%

29. Decreased Morbidity and Mortality Intensive Insulin Therapy in Critically Ill Patients. Van den Berghe G, Wouters P, Weekers F, et al. N Engl J Med 2001; 345:1359-1367. Patients (all) on mechanical Ventilation in ICU Randomly assigned to IV insulin maintaining glucoses between 80-110 mg/dl or conventional treatment (iv insulin if glucose >215 mg/dl then maintain glucose between 180-200.) % given Insulin24 hour doseAM glucose Intensive 99 71U 103 Conventional 39 33U 153

30. Decreased Morbidity and Mortality 12 month mortality Intensive 4.6% Conventional 8.6% Main effect on patients in ICU >5 days Intensive Insulin Therapy in Critically Ill Patients. Van den Berghe G, Wouters P, Weekers F, et al. N Engl J Med 2001; 345:1359-1367. Patients (all) on mechanical Ventilation in ICU Randomly assigned to IV insulin maintaining glucoses between 80-110 mg/dl or conventional treatment (iv insulin if glucose >215 mg/dl then maintain glucose between 180-200.)

31. Decreased Morbidity and Mortality Intensive Insulin Therapy in Critically Ill Patients. Van den Berghe G, Wouters P, Weekers F, et al. N Engl J Med 2001; 345:1359-1367. Patients (all) on mechanical Ventilation in ICU Randomly assigned to IV insulin maintaining glucoses between 80-110 mg/dl or conventional treatment (iv insulin if glucose >215 mg/dl then maintain glucose between 180-200.) • Intensive Treatment reduced: • In hospital mortality 34% • Sepsis 46% • Need for dialysis 41% • Number of transfusions 44%

32. Decreased Morbidity and Mortality • Post-op received high dose glucose - 200-300 g in 24 hours • All adults receiving mechanical ventilation who were admitted to intensive care unit • 63% had cardiac surgery • 59 percent had undergone coronary bypass surgery, 27 percent valve replacement, and 14 percent a combined procedure • Randomly assigned to IV insulin maintaining glucoses between 80-110 mg/dl or conventional treatment (iv insulin if glucose >215 mg/dl then maintain glucose between 180-200.) • Whole glucose, so Plasma range would be: 90-123 mg/dl

33. Intensive Intraoperative Insulin Therapy versus Conventional Glucose Management during Cardiac Surgery • Patients: Adults with and without diabetes who were undergoing on-pump cardiac surgery. • Primary outcome: composite of death, sternal infections, prolonged ventilation, cardiac arrhythmias, stroke, and renal failure within 30 days after surgery. Secondary outcome measures were length of stay in the intensive care unit and hospital. • Intervention: • continuous insulin infusion to maintain intraoperative glucose levels between 4.4 (80 mg/dL) and 5.6 mmol/L (100 mg/dL) (n = 199) • not given insulin during surgery unless glucose levels were greater than 11.1 mmol/L (>200 mg/dL). • Both groups were treated with insulin infusion to maintain normoglycemia after surgery. Ann Int Med. 2007 146: 233-243

34. Intensive Intraoperative Insulin Therapy versus Conventional Glucose Management during Cardiac Surgery • The groups had the same risk for perioperative adverse events (risk ratio, 1.0 [95% CI, 0.8 to 1.2]). • The intensive treatment group had more strokes (8 vs. 1) and more deaths (4 vs. 0) than the conventional treatment group. Ann Int Med. 2007 146: 233-243

35. Kaplan-Meier Curves for In-Hospital Survival Van den Berghe, G. et al. N Engl J Med 2006;354:449-461

36. Intensive Insulin Therapy and Pentastarch Resuscitation in Severe Sepsis: VISEP trial • Multicenter, two-by-two factorial trial • 537 patients • 18 academic tertiary hospitalsin Germany • Patients with severe sepsis receive either intensiveinsulin therapy to maintain euglycemia or conventional insulintherapy and either 10% pentastarch, a low-molecular-weight hydroxyethylstarch (HES 200/0.5), or modified Ringer's lactate for fluidresuscitation. • The rate of death at 28 days and the mean scorefor organ failure were coprimary end points. • The trial was stopped early for safety reasons Brunkhorst F et al. N Engl J Med 2008;358:125-139

37. Intensive Insulin Therapy and Pentastarch Resuscitation in Severe Sepsis Blood Glucose According to the Type of Insulin Therapy Kaplan-Meier Curves for Overall Survival Brunkhorst F et al. N Engl J Med 2008;358:125-139

38. Intensive Insulin Therapy and Pentastarch Resuscitation in Severe Sepsis • Findings similar to second study by Vanden Berghe et al • Nonsignificant differencesin the rates of death at 28 days and at 90 days in the intensive-therapygroup and the conventional-therapy group • Increase in hypoglycemic episodes the same: • VB: 18.7% vs. 3.1% • VSEP: 17.0% vs. 4.1% • Hypoglycemia the same: • VB: (32 mg and 31 mg per deciliter, respectively; P=0.50 • VISEP: 31 mg and 28 mg per deciliter, respectively; P=0.30 • Glucose levels the same: • VB: 111±29 mg and 153±31mg per deciliter, respectively • VISEP: 112±18 mg and 151±33 mg per deciliter,respectively • Taken together, these studies establish that intensive insulin therapy has nomeasurable, consistent benefit in critically ill patients ina medical ICU, regardless of whether the patients have severesepsis, and that such therapy increases the risk of hypoglycemicepisodes. Brunkhorst F et al. N Engl J Med 2008;358:125-139

39. GluControl Study • Anticipated 3500 subjects to be randomized • 80-110 vs 140-180 mg/dl • Stopped because of safety concerns • 1082 subjects recruited.

40. Intensive versus Conventional Glucose Control in Critically Ill Patients The NICE-SUGAR Study Investigators N Engl J Med Volume 360(13):1283-1297 March 26, 2009

41. Study Overview • In this study, adults who were expected to require treatment in the intensive care unit on 3 or more consecutive days were randomly assigned to undergo intensive blood glucose control (target range, 81 to 108 mg per deciliter [4.5 to 6.0 mmol per liter]) or conventional blood glucose control (180 mg per deciliter [10.0 mmol per liter]) • The primary end point was death from any cause within 90 days after randomization • Intensive glucose control increased mortality among the patients

42. NICE- SUGAR: Data on Blood Glucose Level, According to Treatment Group The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297

43. NICE-SUGAR: Probability of Survival and Odds Ratios for Death, According to Treatment Group The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297

44. NICE-SUGAR: Probability of Survival and Odds Ratios for Death, According to Treatment Group The NICE-SUGAR Study Investigators. N Engl J Med 2009;360:1283-1297

45. AACE Position Statement: Hospital Glycemic Goals Intensive Care Units: 110 mg/dL Non-Critical Care Units: Pre-Prandial 110 mg/dL Max. Glucose 180 mg/dL

46. 2009 Inpatient Glucose Goals

47. How to Obtain “Tight” Control • Bedside glucose monitoring • IV insulin drips • Diabetic Flow sheets • Discourage the use of traditional Sliding Scale insulin

48. INSULIN SLIDING SCALE

49. INSULIN SLIDING SCALE

50. Roller Coaster Effect of Insulin Sliding Scale