1. Diabetes Management in Hospital Orlando, May 31, 2003 Paul C. Davidson, MD, FACE Atlanta Diabetes Associates Atlanta, Georgia

2. Diabetes in Hospitalized Patients 6 Million US Hospitalizations 15% of Admissions 24 Million Hospital Days 20% of All Hospital Days 36% First Diagnosed in Hospital 66% No Documentation by Physician 27% Labeled Hyperglycemia 2% Diagnosis on Face Sheet

3. 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

4. Impairment of Phagocytic Function Bybee, 1964 Short, Transient Hyperglycemia Abnormalities in granulocyte adherence, chemotaxis, phagocytosis, bacterocidal function. Bybee, 1964; Hill, 1974; Chase, 1981; Rosenberg, 1990 Effects of Hyperglycemia Infectious Disease

5. Global Perspectives Effect of Underlying Diabetes Impact of Acute Diabetic State Stress Response Counter Regulatory Hormones Epinephrine, Glucagon, Cortisol, GH Glucose Toxicity Increased Glucose, FFA, Ketones Acidosis: Lactic or Ketosis Mechanism of Progressive Insulin Resistance Diabetes in Hospitalized Patients. Pathophysiology

6. Role of Insulin and Glucose in Acute MI Insulin l Anti-inflammatory –Acute Reduction CRP l Anti-thrombotic –Profibrinolytic Suppresses PAI-1 l Suppresses FFA –Preserve Endothlium l Suppresses MMPs –Prevents Rupture Glucose l l Pro-inflammatory l l Pro-thrombotic l l Induces MMPs (Matrix Matalloproteinases) –Mediates Plaque Rupture Dandona Diab Care 2003

7. Detriments: Decreased Appetite Meals Held or Delayed Decreased Activity Oral Agents Stopped Insulin Held Sliding Scale Insulin Only for Extreme BGs Benefit: Detecting Hyperglycemia Effects of Hospitalization on Diabetes Management

8. Missed Opportunities: To Reduce Hospital Morbidity and Mortality To Initiate Interventions to Delay Long-term Complications Diabetes in Hospitalized Patients. Diabetes in Hospitalized Patients. Failure to Treat Hyperglycemia

9. Diabetes in Hospitalized Patients. Psychology 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 >150

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

11. 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

12. 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

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) –Glucose Rich Edema as Culture Media l Recent Outcome Studies Supporting Good Glucose Control in Hospital Setting l Reduction in CRP

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 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

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

17. 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.

18. 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

19. Admission glucose values >108 mg/dl IV Insulin with Bypass Surgery Hospital mortality identical Diabetics and Non-diabetics (1.75% vs. 1.71%) Usual Diabetic Mortality 50% Higher CABG in Diabetes Kalin 1998

20. DIGAMI Study Diabetes, Insulin Glucose Infusion in Acute Myocardial Infarction 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

21. 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

22. 623 Hyperglycemic Patients Mortality and Stroke Severity Increase Linearly with BG BG >144 mg/dl in First 24 Hours Double Mortality Risk Stroke in Diabetes Weir

23. Diabetes with Steroid Therapy Piedmont Hospital 1998 l Problem Noted by DRC Case Managers –Frequency of Hyperglycemia in “Non- Diabetic” Patients –Prevalence Among Steroid Treated –No Systematic Plan of Response –Frequency of Discharge “Out-of-Control” The Dark Side of Corticosteroids

24. Diabetes with Steroid Therapy Piedmont Hospital 1998 Chart Review by Terry Kaplan RN

25. Diabetes with Steroid Therapy Piedmont Hospital 1998 Opportunity for Improvement 59%

26. Classical Diabetes Management Typical A1c 9% l The daily dosage of insulin is divided –2/3 in the morning and 1/3 in the evening. –Two thirds NPH and 1/3 Regular. l Results –70/30 Insulin (The insulin for the retarded) –No Patients to Goal!

27. Sliding Scale Insulin Five Units for Each Plus on bid Urine Testing Table of BG Ranges and R Doses Correction Bolus Formula – (BG-Target BG) / CF No Benefit When Used Without Basal Insulin Three Times More Hyperglycemia Compared to Standing Dose NPH Queale, 1997

28. ICU Survival l 1548 Patients (mostly OHS pts.) l All with BG >200 mg/dl l Randomized into two groups –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

29. ICU Survival 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 No serious hypoglycemic events

30. 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

31. ICU IV Insulin Protocol l Arterial BG q 1-2 hrs 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

32. Methods For Managing Hospitalized Persons with Diabetes l Continuous Variable Rate IV Insulin Drip Major Surgery, NPO, Unstable, MI, DKA, Hyperglycemia, Steroids, Gastroparesis, Delivery, etc l Basal / Bolus Therapy (MDI)

33. Continuous Variable Rate IV Insulin Davidson 1982 l Mix Drip with 125 units Regular Insulin in 250 cc NS l Starting Rate: Units / hour = (BG – 60) x 0.02 l Check glucose hourly and adjust l Change Multiplier to keep in desired range –100 to 140 mg/dl

34. Continuous Variable Rate IV Insulin l Adjust Multiplier to obtain glucose in target range If BG not decreasing > 50 mg/dL and > 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 cc = (100 – BG) x 0.4 l Give continuous rate of Glucose in IVF’s l Once eating, continue drip till 2 hour post SQ insulin

35. Glucommander l Invented in 1984 Davidson and Steed l Based on 17 Year Experience with a Computer Based Algorithm for the Administration of IV Insulin l Developed for Marketing by MiniMed and Roche l GMS System l Shelved Pending FDA Approval of IV Use of Insulin l Useful and Safe for Any Application of IV Insulin

36. Glucommander l Computer Based Algorithm for IV Insulin l Invented by Davidson and Steed in 1984 l 17 Year Experience l Developed for Marketing by MiniMed and Roche l GMS System l Shelved Pending FDA Approval of IV Insulin l Useful and Safe for Any Application of IV Insulin

37. Glucose Management System

38. Glucommander. Summary of Performance Glucose Averages for 3404 Patients Glucose mgm/dl Hours 50 Percentiles 90 10

39. Glucommander. Effectiveness l Initial blood glucose –Median 292 mg/dl –Range 181-1,568 l Time to achieve glucose < 180 mg/dl –Median 3 hours –Range 0.3 - 19.7 l Time to achieve first of three consecutive glucose results between 60 - 180 mg/dL –Median 3. 1 hours –Range 0.3 - 22.5

40. Glucommander Principles Insulin Units / Hour Glucose mgm / dl

41. Glucommander Comparsion to Other Systems Insulin Units / Hour Glucose mgm / dl Glucommander ADA MARKS FURNEY METCHICK VAN DEN BERGHE IV DRIP

42. Hospital Diabetes Plan l NPO Pathway For All Diabetes Patients l Finger Stick BG ac qid on ALL Admissions l Check All Steroid Treated Patients l Diagnose Diabetes FBG >126 mg/dl Any BG >200 mg/dl Paul Davidson MD Atlanta Diabetes Associates

43. Hospital Diabetes Plan l Document Diagnosis in Chart l Hyperglycemia Is Diabetes Until Proven Otherwise l Bring to All Physician’s Attention l Note on Problem List and Face Sheet l Check Hemoglobin A1C l Hold Metformin; Hold TZD with CHF, Liver Dysfunction l Use Insulin in All Hospitalized Persons with Diabetes l Use Insulin in All Hospitalized Persons with Diabetes Continue for Course of Hospitalization Paul Davidson MD Atlanta Diabetes Associates

44. Hospital Diabetes Plan l Get Diabetes Education Consult l Instruct Patient in Monitoring and Recording See That Patient Has Meter on Discharge l Decide on Case Specific Program for Discharge l Arrange Early F/U with PCP Paul Davidson MD Atlanta Diabetes Associates

45. Hospital Diabetes Plan l Follow National Guidelines For Endocrinology Consults –Any Type 1 –Any Hypoglycemia Requiring Intervention –DKA or HHNC –Patient on Insulin Pump –Pregnant Diabetic –Glucocorticoid Therapy in Diabetes –Progressive Diabetic Complications –HbA1c >8%, Microalbuminuria >30 mg,LDL >130, HDL 400 mg/dl

46. l Treat Any Patient With BG > 150 With Insulin –Treat Any BG >150 with Rapid-acting Insulin (BG-100) / (7000 / wt #) –Treat Any Recurrent BG >200 with IV Insulin l If More than 0.5 u/hr IV Insulin Required with Normal BG Start Long Acting Insulin Protocol for Insulin in Hospitalized Patient

47. Prescription for insulin therapy includes: Basal Insulin (BI) Carbohydrate-to-Insulin Ratio (CIR) Correction Factor (CF) 1600 Records from Pump Patients Studied Data from 182 best-controlled pump patients Analyzed for optimum parameters Resulting formulae used as model for others The Accurate Insulin Management (AIM) formulae The Accurate Insulin Management (AIM) Formulae

48. RESULTS

49. 125 100 75 50 25 Correction Factor 25 20 15 12 10 9 8 7 6 5 Carbohydrate to Insulin Ratio CF Curve AIM Nomogram Davidson et al Diab Tech Ther 2003 Vol 5 No 2 ( CIR = 2.8 Wt / TDD ) ( CF = 1700 / TDD ) Intial Dosing: Plot BW and 25 CIR for BI Plot BW and 12 CIR for TDD Plot BW and TDDfor CIR Plot TDD and CF curve for CF Follow-up Dosing: Change CF as above Change CIR by 20% toward CIR AIM 4 3 2

50. Protocol for Insulin in Hospitalized Patient l Daily Total: Pre-Admission or Weight (#) x 0.24 u –50 % as Glargine (Basal) Split as q 12 DosesSplit as q 12 Doses –50% as Rapid-acting Insulin (Bolus) Give in Proportion to CHO Eaten, CIR 12Give in Proportion to CHO Eaten, CIR 12 l BG >150: (BG-100) / CF –CF = 7000 / Wt(#) l Do Not Use Sliding Scale As Only Insulin l Do Not Hold Insulin When BG Normal

51. Protocol for Insulin in Hospitalized Patient Treatment of Hypoglycemia l Any BG <80 mg/dl: D50 = (100-BG) x 0.4 ml IV l Do Not Hold Insulin When BG Normal

52. Correction of Hypoglycemia with Glucose 100-BG X 0.2 Grams BeforeAfter Richardson Diabetes 1999 50:A200 100-BG X 0.15 Grams

53. Hospital Diabetes Plan 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 BG’s 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 (Glucommander)

54. Hospital Diabetes Plan Hospital Diabetes Plan Conclusions 2 l Switch to Basal Insulin Glargine –IV Hourly Dose X 24 / 2 l DC IV Glucose l Feed and Give Rapid Acting Insulin p.c. –One Unit Per 12 Grams CHO l BG ac tid, hs, 3 am –Correct with Rapid Insulin (BG - 100) / 7000 / BW# l Type 2 Diabetics Are Resistant to Insulin Reactions l Treat Insulin Reactions in Hospital With IV Glucose l Do Not Be Hold Insulin for Normal BG, i.e. 80-120 l HbA1c Values >7% Indicates Sub-optimal Care

55. Hospital Diabetes Plan Hospital Diabetes Plan Conclusions 3 l Discharge Plan For BG Control l The Physician of Record Is the Link Between the Best Diabetes Care and the Patient l Use Available Diabetes Resources Diabetes Educators Dietiticians Endocrinologists

56. 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 BG >200 Is Malpractice

57. Conclusion All hospital patients should have normal glucose

58. Insulin The agent we have to control glucose only most powerful

59. QUESTIONS l For a copy or viewing of these slides, contact l WWW.adaendo.com WWW.adaendo.com