1. I need help! l l Searching for Diabetes Type 2 patients l l Drug Naïve l l New category of oral agent l l Clinical outpatient trial l l Email me: oatess@arnett.com oatess@arnett.com l l Call me 448-8007

2. Diabetes Management in the Hospital Shannon Oates Endocrinology Arnett Clinic

3. Today l Money l Mortality l Morbidity l Math (I love algebra)

4. Diabetes in Hospitalized Patients 1997 3.5 Million US Hospitalizations 15% of Admissions 14 Million Hospital Days 20% of All Hospital Days 36% First Diagnosed in Hospital 66% No Documentation by Physician 27% Labeled Hyperglycemia 2% Diagnosed on Chart

5. Diabetes in Hospitalized Patients 1997 Costs $ 23,500 Each Diabetes Patient vs.$ 23,500 Each Diabetes Patient vs. $12,200 for Non-Diabetes Patient $12,200 for Non-Diabetes Patient 60% of All Diabetes-Related Costs60% of All Diabetes-Related Costs Only 5% DKA, HHNKCOnly 5% DKA, HHNKC 48% Diabetes Complications48% Diabetes Complications 52% Other Conditions52% Other Conditions

6. Diabetes in Hospitalized Patients Reason for Higher Costs l Higher Rate of Hospitalization l Longer Stays l More Procedures, Medications l Chronic Complications l More Arteriosclerotic Disease l More Infections l Complicated Pregnancies

7. Diabetes in Hospitalized Patients High-risk for Bacterial Infection –Surgery –Catheters –Intravenous Access –Anesthesia Problems with wound healing Problems with tissue and organ perfusion

8. Infectionsin Diabetes Infections in Diabetes More Frequent l Bacteremia l Septic Shock l Pyelonephritis l Candida Unique l Necrotizing Fasciitis l Fournier’s Gangrene l Mucormycosis l Malignant External Otitis

9. Mucormycosis above Necrotising fasiitis right

10. Infections in Diabetes l One BG >220 mg/dl results in 5.8 times increase in nosocomial infection rate l Two hours hyperglycemia results in impaired WBC function for weeks Pomposelli, New England Deaconess, J Parenteral and Enteral Nutrition 22:77-81,1998

11. Side Effects of BG >200 mg/dl l Reduced Intravascular Volume l Dehydration l Electrolyte Fluxes l Impaired WBC Function l Immunoglobulin Inactivation l Complement Disabling l Increased Collagenase, Decreased Wound Collagen

12. Psychology of Diabetes in Hospital l Patients expect good glycemic control as part of hospital care l They strive for recommended goals at home l Difficult to understand staff’s casual approach to BG’s >200

13. Evidence for Immediate Benefit of Normoglycemia in Hospitalized Patients l Numerous Publications on in Vitro Evidence –Neutrophil Dysfunction –Complement Inhibition –Altered Redox State (Pseudohypoxia) l Six Recent Clinical Publications supporting good glucose control in the hospital setting

14. Open Heart Surgery in Diabetes Portland St. Vincent Medical Center Control Group l N=968 l 1987-1991 l SubQ Insulin q 4 h l Goal 200 mg/dl l Standard Deviation 36 l All Mean BG’s <200 47% Study Group l l N=1499 l l 1991-1997 l l IV Insulin l l Goal 150-200 mg/dl l l Standard Deviation 26 l l All Mean BG’s <200 84% Furnary et al, The 34th Meeting of The Society of Thoracic Surgeons New Orleans, LA January 26, 1998

15. Open Heart Surgery in Diabetes Portland CII Protocol Demographics l Total Open Heart Surgery Patients 14,468 l Diabetes at Admission 2467 (17%) l Age 65 SD 10 l Males 62% l Insulin Rx 36% l Oral diabetes agent 48%

16. Open Heart Surgery in Diabetes Portland St. Vincent Medical Center Perioperative Blood Glucose Furnary et al, The 34th Meeting of The Society of Thoracic Surgeons New Orleans, LA January 26, 1998

17. Incidence of DSWI: 1987-1997 CII Furnary, et al, The 34th Meeting of The Society of Thoracic Surgeons New Orleans, LA January 26, 1998

18. Open Heart Surgery in Diabetes Portland CII Protocol Infectious Complications Diabetes l 31/2467 (1.3%) Deep Sternal Wound Infection (DSWI) 23/31 Required Second Admission 22 Micrococcus 0 Anaerobes, fungal, yeast 0 Anaerobes, fungal, yeastNon-Diabetes l 40/12,005 (0.3%)

19. Open Heart Surgery in Diabetes Portland CII Protocol Mortality l All(99/2467) 4.0% l SQI 6.1% l CII 3.0% l DSWI 19.0% l No DSWI 3.8% Recent Experience l 1994-1997 DSWI as in non-diabetics l 1996-7 No DSWI in last 15 mo. SQI= subcutaneous insulin CII= continuous insulin infusion DSWI=deep sternal wound infection

20. Open Heart Surgery in Diabetes Portland CII Protocol Comparison of Groups Higher Risk Patients in CII Group

21. Open Heart Surgery in Diabetes Portland CII Protocol Univariate Analysis of DSWI

22. VariableSQICIISavings # DSWI2,96810091,959 Additional LOS47,48816,41631,342 Additional $$78.4M$26.6M$51.7M # Deaths564192372 Estimated USA Socioeconomic Savings Assumes 742K cases*, 20% prevalence of DM & 2% DSWI with SQI *1998 Heart & Stroke Statistical update, AHA

23. Open Heart Surgery in Diabetes Portland CII Protocol Weakness of Study l Not Randomized l Temporal Sequential Nature l Subtle Cumulative Improvements in Techniques

24. Open Heart Surgery in Diabetes Portland CII Protocol Conclusions l Magnitude and Strength of Study is Compelling l Ethics of Confirming Study Would be Questionable l Application of CII (continuous insulin infusion) is Simple and Safe l Hyperglycemia Predicts DSWI l CII Prevents DSWI

25. Open Heart Surgery in Diabetes John Hopkins l Prospective Cohort Study of 411 OHS pts with Diabetes 1990 – 1995 l Diabetes based on history (42% insulin treated, 45% oral agents) l SMBG 4x/day with sliding scale l Examined relationship between peri-operative glucose control and risk of all infections

26. Open Heart Surgery in Diabetes John Hopkins l 24.3% with infections l BG divided into quartiles Relative Odds Q1 121-206 20.1% Q2 207-229 21.6% 1.17 Q3 230-252 29.8% 1.86* Q4 252-352 25.7% 1.72* Golden SH Diabetes Care 22: 1408, 1999 * P < 0.01

27. DIGAMI Study Diabetes, Insulin Glucose Infusion in Acute Myocardial Infarction(1997) l Acute MI With BG > 200 mg/dl l Intensive Insulin Treatment l IV Insulin For > 24 Hours l Four Insulin Injections/Day For > 3 Months l Reduced Risk of Mortality By: 28% Over 3.4 Years 51% in Those Not Previous Diagnosed Malmberg BMJ 1997;314:1512

28. Cardiovascular Risk Mortality After MI Reduced by Insulin Therapy in the DIGAMI Study Malmberg, et al. BMJ. 1997;314:1512-1515. All Subjects (N = 620) Risk reduction (28%) P =.011 Standard treatment 0.3.2.4.7.1.5.6 01 Years of Follow-up 2345 Low-risk and Not Previously on Insulin (N = 272) Risk reduction (51%) P =.0004 IV Insulin 48 hours, then4 injections daily 0.3.2.4.7.1.5.6 01 Years of Follow-up 2345 6-11

29. ICU Survival l 1548 Patients (mostly OHS pts.) l All with BG >200 mg/dl l Randomized into two groups –All Maintained on IV insulin –Conventional group (BG 180-200) –Intensive group (BG 80-110) l Conventional Group had 1.74 X mortality Van den Berghe et al, NEJM 2001;345(19):1359

30. ICU IV Insulin Protocol (not DKA) l If > 100 mg/dl, 2 U/h If > 200 mg/dl, 4 U/h l If > 140 mg/dl, increase by 1 – 2 U/h l If 121 to 140 mg/dl, increase by 0.5 – 1 U/h l If 111 to 120 mg/dl, increase by 0.1 – 0.5 U/h l If 81 to 110 mg/dl, no change l If 61 to 80 mg/dl, change back to prior rate Van den Berghe et al, NEJM 2001;345(19):1359

31. ICU Survival Blood glucose control: Conventional Intensive Mean AM BG 153 103 % Receiving Insulin 39% 100% BG < 40 mg/dl 6 39 Van den Berghe et al, NEJM 2001;345(19):1359

32. ICU Survival Intensive Therapy (80 to 110 mg/dL) resulted in: l 34% reduction in mortality l 46% reduction in sepsis l 41% reduction in dialysis l 50% reduction in blood transfusion l 44% reduction in polyneuropathy Van den Berghe et al, NEJM 2001;345(19):1359

33. Conclusion All hospital patients should have normal glucose

34. Insulin The agent we have to control glucose most powerful

35. Methods For Managing Hospitalized Persons with Diabetes l Continuous Variable Rate IV Insulin Drip Major Surgery, NPO, Unstable, MI, DKA, Hyperglycemia, Steroids, Gastroparesis l Basal / Bolus Therapy when eating l Teach them insulin injections

36. IV insulin protocol l Not as intuitive as the Van den Berghe l More agile in response to rate of change of blood sugars l We do have a version of Van den Berghe available in the ICU

37. Continuous Variable Rate IV Insulin Drip l 25 units Regular Insulin into 250 cc NS –(0.1 unit/cc) l Starting Rate Units / hour = (BG – 60) x 0.02 –BG is current Blood Glucose and 0.02 is the multiplier l Check glucose every hour and adjust drip l Adjust Multiplier to keep in desired glucose target range (100 to 140 mg/dl)

38. Continuous Variable Rate IV Insulin Drip l Adjust Multiplier (initially 0.02) to obtain glucose in target range 100 to 140 mg/dL If BG > 140 mg/dL, increase by 0.01 If BG < 100 mg/dL, decrease by 0.01 If BG 100 to 140 mg/dL, no change in Multiplier l If BG is < 80 mg/dL, give D50 (one to three cc) l Once eating, continue drip till 1 hour post SQ insulin

39. Example l Initial glucose of 200: drip starts at 2 units per hour l Glucose drops to 90, decrease drip to 0.6 units per hour l If glucose instead rose to 210, the drip increases to 4.5 units per hour

40. 4:00 25 50 75 8:0012:0016:0020:0024:004:00 BreakfastLunchDinner Plasma insulin (U/ml) Plasma insulin ( µ U/ml) Time 8:00 Physiological Serum Insulin Secretion Profile

41. Comparison of Insulins Insulin Onset ofDuration of preparations action Peak action Regular30–60 min2–4 h6–10 h Lispro/aspart5–15 min1–2 h 4–6 h NPH 1–2 h4–8 h10–18 h Lente 1–2 h6–8 h12–20 h Ultralente2–4 hUnpredictable16–20 h Glargine1–2 hFlat~24 h

42. 4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Glargine or Detemir Lispro Lispro Lispro Aspart Aspart Aspart or Plasma insulin Basal/Bolus Treatment Program with Rapid-acting and Long-acting Analogs

43. Lepore, et al. Diabetes. 1999;48(suppl 1):A97. 6 5 4 3 2 1 0 010 Time (h) after SC injection End of observation period 2030 Glargine NPH Glucose utilization rate (mg/kg/h) Glargine vs NPH Insulin in Type 1 Diabetes Action Profiles by Glucose Clamp

44. Correction Bolus—Rule of 1500 l Must determine how much glucose is lowered by 1 unit of short- or rapid-acting insulin l This number is known as the correction factor (CF) l Use the 1500 rule to estimate the CF l CF = 1500 divided by the total daily dose (TDD) ex: if TDD = 30 units, then CF = 1500/30 = 50 meaning 1 unit will lower the BG ~50 mg/dl

45. Correction Bolus Formula Example: –Current BG:220 mg/dl –Ideal BG: 100 mg/dl –Glucose Correction Factor: 50 mg/dl Current BG - Ideal BG Glucose Correction factor 220 - 100 50 =2.4u

46. How to Initiate MDI l Starting dose = 0.4 to 0.5 x weight in kilograms l Bolus dose (aspart/lispro) = 20% of starting dose at each meal l Basal dose (glargine/NPH) = 40% of starting dose given at bedtime or anytime l Correction bolus = (BG - 100)/ Correction Factor (CF = 1500/total daily dose)

47. How to Initiate MDI-example l starting dose = 0.45 x wgt. in kg l Wt is 110 kg; 0.45 x 110 = 50 units l Basal dose (glargine) = 40% of starting dose at HS; 0.4 x 50 = 20 units at HS l Bolus dose (aspart / lispro) = 20% of starting dose at each meal; 0.2 x 50 = 10 units ac (t.i.d.) l Correction bolus = (BG - 100)/ CF, where CF = 1500/total daily dose; CF = 30

48. Correction Bolus Formula Example: –Current BG:250 mg/dl –Ideal BG: 100 mg/dl –Glucose Correction Factor: 30 mg/dl Current BG - Ideal BG Glucose Correction factor 250 - 100 30 =5.0u

49. Diabetes Plan What Can We Do For Patients Admitted To Hospital? Diabetes Plan What Can We Do For Patients Admitted To Hospital? Finger Stick BG ac q.i.d. on ALL Admissions l Do Not Use Sliding Scale As Only Diabetes Management l Check All Steroid Treated Patients l Diagnose Diabetes FBG >126 mg/dl Any BG >200 mg/dl

50. Diabetes Plan What Can We Do For Patients Admitted To Hospital? Diabetes Plan What Can We Do For Patients Admitted To Hospital? l Get Diabetes Education Consult 449-5180 l Do an A1C l Instruct Patient in Monitoring and Recording l See That Patient Has Meter on Discharge l Decide on Case Specific Program for Discharge l Arrange Early F/U with PCP l Do Not Use Sliding Scale As Only Diabetes Management

51. Diabetes at Hospital Conclusions l Any BG >200 mg/dl Is Diabetes (Fasting >126 mg/dl) l Most Diabetes Is Type 2 l All DM patients Must Self-Monitor BGs and Record l No BG >150 mg/dl Should Go Untreated l Most Hospitalized DM Patients Should Be on Insulin l IV Insulin is Most Effective, Efficient, Safest Rx in Acute Illness

52. Diabetes at Hospital Conclusions 2 l Type 2 Diabetes is Resistant to Insulin Reaction l Do Not Hold Insulin for Normal BG l A1C Values >7% Indicates Sub-optimal Care

53. Diabetes at Hospital Conclusions 3 l Discharge Plan For BG Control l You Are the Link Between the Best Diabetes Care and the Patient l Use Your Diabetes Resources Regional Diabetes Center 449-5180Endocrinologists

54. The Paradigm for the Millenium Hyperglycemia: A Mortal Sin A blood glucose over 200 in a hospitalized patient causes increased morbidity and mortality. In the 21st Century Neglecting a BG >200 May Be Malpractice

55. Conclusion Intensive therapy is the best way to treat patients with diabetes

56. QUESTIONS l Email oatess@arnett.co m oatess@arnett.co m l l Thanks to Dr. Bruce Bode

57. I need help! l l Searching for Diabetes Type 2 patients l l Drug Naïve l l New category of oral agent l l Clinical outpatient trial l l Email me: oatess@arnett.com

59. TPN In Diabetes VA Cooperative Trial l Benefit Negated l Increased Infections l Related to Hyperglycemia Buzby et al. NEJM 325:525-531, 1991

60. GlyThrGluPheTyrProLysThr GlyThrGluPheTyrProLysThr 23 24 25 26 27 28 29 30 Insulin Detemir (CH 2 ) 4 NH CO R Primary Structure of Lys(B29)-N-  - Tetradecanoyl, Des(B30)-Insulin

61. 61 Brunner GA, et al. Exp Clin Endocrinol Diabetes. 2000;108:100-105. Elapsed time (min) 0.0 0.5 1.0 1.5 2.0 -10010030050070090011001300 1500 Detemir-high Detemir-low Placebo Glucose infusion rate (mg/kg/min) Insulin Detemir in Nondiabetic Subjects— Pharmacokinetics by Glucose Clamp