1. Bruce W. Bode, MD FACE Susan S. Braithwaite, MD FACE R. Dennis Steed, MD Paul C. Davidson, MD FACE December 15, 2003 IV Insulin Infusion Therapy: Indications, Thresholds and Target Range Glucose, Protocols and Methodology Transition to Subcutaneous Insulin,

2. l Diabetic ketoacidosis l Non-ketotic hyperosmolar state l Critical care illness (surgical) l Myocardial infarction or cardiogenic shock l Post-operative period following heart surgery Indications for IV Insulin Infusion

3. l Critical care illness (medical) l NPO status in type 1 diabetes l General pre-, intra- and post- operative care l Organ transplantation l TPN l Exacerbated hyperglycemia during high dose glucocorticoid therapy Indications for IV Insulin Infusion

4. l Stroke l Dose finding strategy, anticipatory to initiation or re-initiation of SC insulin in type 1 or type 2 diabetes l Labor and delivery l Other acute illness requiring prompt glycemic control Indications for IV Insulin Infusion

5. Thresholds for Initiation and Targets of IV Insulin Infusion Therapy

6. Mortality of DM Patients Undergoing CABG Furnary et al J Thorac Cardiovasc Surg 2003;123:1007-21

7. Glycemic Threshold in CABG Portland data suggest BG: < 150 mg/dl for mortality < 175 mg/dl for infection < 125 mg/dl for atrial fibrillation Furnary et al J Thorac Cardiovasc Surg 2003;123:1007-21

8. P=0.000 9 P=0.026 BG<110 110<BG<150 BG>150 Surgical ICU Mortality Effect of Average BG Van den Berghe et al (Crit Care Med 2003; 31:359-366)

9. In this observational study of 531 ICU patients, glucose results were time- weighted for analysis. Shown as proportions of the whole admission, are percentages of admissions spent in bands of glucose. Survivors Nonsurvivors 111-144 200 Reduction of mortality below threshold glucose of 144- 200 mg/dL, with speculative upper limit of target range at about 145 mg/dL Finney SJ et al JAMA 2003;290(15):2041-47

10. Glycemic threshold in Surgical ICU l BG < 110 mg/dl or < 145 mg/dl Van den Berghe et al Crit Care Med 2003; 31(2):359-66 Finney SJ et al JAMA 2003;290(15):2041-47

11. What About Medical Patients?

12. Glycemic Threshold in Acute MI and Intervention (PTCA) l DIGAMI supports BG < 180 mg/dl l Minimal other data: - PTCA reflow better with BG 159 than 209 mg/dl Iwakura K: JACC 2003; 41:1-7 Malmberg BMJ 1997;314:1512

13. Other Medical Conditions l Infection data supports BG < 130 mg/dl Hartford ICU study 125 mg/dl vs 179 mg/dl 10X decrease in infections l Stroke data supports BG < 140 mg/dl l Pregnancy data supports BG < 100 mg/dl

14. Stamford CT ICU Study (Retrospective): Description of Patient Subgroups (N = 1826) l Cardiac (medical): 28.6% (540) l Pulmonary: 15.8% (289) l Septic Shock: 5.0% (92) l Other Medical: 14.9% (272) l Neurological: 13.2% (241) l Surgical: 7.1% (313) l Trauma: 4.3% (79) Krinsley JS: Mayo Clin Proc 2003; 78: 1471-1478

15. Hyperglycemia and Hospital Mortality 1826 consecutive ICU patients 10/99 thru 4/02, Stamford CT Krinsley JS: Mayo Clin Proc 78: 1471-1478, 2003

16. Glycemic Threshold for Medical Patients l < 140 mg/dl if IV Insulin is mandated by condition Acute MI, NPO, Gastroparesis, etc l < 180 mg/dl for patients failing SC therapy

17. Threshold blood glucose in mg/dL for starting IV insulin infusion l Peri-operative care:> 140 l Surgical ICU care:> 110 - 140 * l Non-surgical illness:> 140 - 180 * * l Pregnancy> 100 * Van den Berghes study supports 110; Finneys study supports 145 * * If drip indication is failure of SQ therapy, use 180 ; if indication is specific condition ( DM 1/ NPO, MI, etc ), use 140

18. Target blood glucose in mg/dL during IV insulin infusion l 80 – 110 in Surgical ICU patients l 90 – 140 in other Surgical and Medical Patients l 70 – 100 in Pregnancy

19. Methods For Managing Hospitalized Persons with Diabetes Take Diabetes out of the equation. Control glucose!!!

20. 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 staffs casual approach to BGs >150

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

22. The Ideal IV Insulin Protocol l Easily ordered (signature only) l Effective (Gets to goal quickly) l Safe (Minimal risk of hypoglycemia) l Easily implemented l Able to be used hospital wide

23. Components of IV Insulin Therapy l IV line with minimal flow (> 40 ml/l) l Glucose inflow kept constant l Potassium must be given l Regular insulin in a 1 U/ml or 0.5 U/ml concentration l Infusion controller adjustable in 0.1 U doses l Accurate bedside BG monitoring done hourly (and if stable, every 2 hours)

24. Essentials of a good IV Insulin Algorithm l Easily implemented by nursing staff l Able to seek BG range via: - Hourly BG monitoring - Adjusts to the insulin sensitivity of the patient

25. All three have IV insulin protocols Complex Require ICU housing (exception Furnary) Specially trained nurses Dedicated supervision Consequently not widely accepted IV Insulin Based Studies DIGAMI, Portland, Leuven

26. Protocol of Van den Berghe and colleagues Van den Berghe et al, NEJM 2001;345(19):1359

27. ICU Survival Blood glucose control in Intensive Group: Mean AM 103 mg/dl BG < 40 mg/dl 5.2% (39) Van den Berghe et al, NEJM 2001;345(19):1359 In no instance was hypoglycemia considered to be a serious event

28. 1. Start Portland protocol during surgery and continue through 7 AM of the third POD. Patients who are not receiving enteral nutrition on the third POD should remain on this protocol until receiving at least 50% of a full liquid or soft American Diabetes Association diet. 2. For patients with previously undiagnosed DM who have hyperglycemia, start Portland protocol if blood glucose is greater than 200 mg/dL. Consult endocrinologist on POD 2 for DM workup and follow-up orders. 3. Start infusion by pump piggyback to maintenance intravenous line as shown in Appendix Table 1. 4. Test blood glucose level by finger stick method or arterial line drop sample. Frequency of blood glucose testing is as follows: a. When blood glucose level greater than 200 mg/dL, check every 30 minutes. b. When blood glucose level is less than 200 mg/dL, check every hour. c. When titrating vasopressors, (eg, epinephrine) check every 30 minutes. d. When blood glucose level is 100 to 150 mg/dL with less than 15 mg/dL change and insulin rate remains unchanged for 4 hours (stable infusion rate), then you may test every 2 hours. e. You may stop testing every 2 hours on POD 3 (see items 1 and 8). f. At night on telemetry unit, test every 2 hours if blood glucose level is 150 to 200 mg/dL; test every 4 hours if blood glucose level is less than 150 mg/dL and stable infusion rate exists. 5. Insulin titration according to blood glucose level is performed as follows a. When blood glucose level is less than 50 mg/dL, stop insulin and give 25 mL 50% dextrose in water. Recheck blood glucose level in 30 minutes. When blood glucose level is greater than 75 mg/dL, restart with rate 50% of previous rate. b. When blood glucose level is 50 to 75 mg/dL, stop insulin. Recheck blood glucose level in 30 minutes; if previous blood glucose level was greater than 100 then give 25 mL 50% dextrose in water. When blood glucose level is greater than 75 mg/dL, restart with rate 50% of previous rate. c. When blood glucose level is 75 to 100 mg/dL and less than 10 mg/dL lower than last test, decrease rate by 0.5 U/h. If blood glucose level is more than 10 mg/Dl lower than last test, decrease rate by 50%. If blood glucose level is the same or greater than last test, maintain same rate. d. When blood glucose level is 101 to 150 mg/dL, maintain rate. e. When blood glucose level is 151 to 200 mg/dL and 20 mg/dL lower than last test, maintain rate. Otherwise increase rate by 0.5 U/h. f. When blood glucose level is greater than 200 mg/dL and at least 30 mg/dL lower than last test, maintain rate. If blood glucose level is less than 30 mg/dL lower than last test (or is higher than last test), increase rate by 1 U/h and, if greater than 240 mg/dL, administer intravenous bolus of regular insulin per initial intravenous insulin bolus dosage scale (see item 3). Recheck blood glucose level in 30 minutes. g. If blood glucose level is greater than 200 mg/dL and has not decreased after three consecutive increases in insulin, then double insulin rate. h. If blood glucose level is greater than 300 mg/dL for four consecutive readings, call physician for additional intravenous bolus orders. 6. American Diabetes Association 1800-kcal diabetic diet starts with any intake by mouth. 7. Postmeal subcutaneous Humalog insulin supplement is given in addition to insulin infusion when oral intake has advanced beyond clear liquids. a. If patient eats 50% or less of servings on breakfast, lunch, or dinner tray, then give 3 units of Humalog insulin subcutaneously immediately after that meal. b. If patient eats more than 50% of servings on breakfast, lunch, or supper tray, then give 6 units of Humalog insulin subcutaneously immediately after that meal. 8. On third POD, restart preadmission glycemic control medication unless patient is not tolerating enteral nutrition and is still receiving an insulin drip. Portland Protocol Furnary et al J Thorac Cardiovasc Surg 2003;123:1007-21

29. Two Specific IV Insulin Infusion Algorithms Markovitz, Braithwaite and colleagues - Tabular form Davidson, Steed and Bode - Computerized system called Glucommander

30. Protocol of Markovitz and colleagues, as modified Markovitz LJ et al Endocrine Practice 2002; 8(1):10-18

31. Formula for Markovitz Protocol Hourly insulin rate = hourly maintenance rate + ( BG – 150 ) / ISF

32. Formula for Markovitz Protocol Hourly insulin rate = hourly maintenance rate + ( BG – 150 ) / ISF To create a table, the upper target of 150 can be replaced with any upper target, and the insulin sensitivity factor ( ISF ) may be calculated by a rule of 1500 or 1700. The hourly maintenance rate for target range control for a given patient is discovered during treatment by response to column assignments.

33. The tabular insulin drip protocol now has been adapted to achieve glycemic targets lower than initially published The glycemic management protocol damped the variability of glycemic control Markovitz. 2002 any glucose < 70 percent of patient days mean > 250 mean > 200 before and with protocol

34. < 100 off 100-109 0.5 110-129 1.0 130-149 1.5 150-169 2.0 170-189 2.5 190-209 3.0 210-254 4.0 255-299 5.0 etc. Check BG every 1 hr and adjust rate The default insulin drip column

35. < 100 off 100-109 0.5 110-129 1.0 130-149 1.5 150-169 2.0 170-189 2.5 190-209 3.0 210-254 4.0 255-299 5.0 etc. Suppose the patient starts with CBG = 254 mg/dL but after 2 hours the CBG remains about the same The default insulin drip column

36. 80- 89 off < 100 off 90- 99 0.5 100-109 0.5100-109 1.0 110-129 1.0110-129 1.5 130-149 1.5130-149 2.0 150-169 2.0150-179 3.0 170-189 2.5180-209 4.0 190-209 3.0 210-239 5.0 210-254 4.0240-269 6.0 255-299 5.0270-299 7.0 The next column The default column Shifting between several algorithms allows the nurse to discover the insulin requirement that maintains normoglycemia

37. Instructions about modified Markovitz protocol Default: start with column 2; use priming bolus Switch to next higher column if: l BG 200 x 1h, falling < 30 mg/dL over the past 1h l BG 150 x 2h, falling < 60 mg/dL over the past 2h Test BG q 1h if drip turned off by protocol After drip interruption for low BG, resume when BG > 109 Switch to next lower column if: l interrupted for low BG, but now resuming l on column 4, 5 or 6 for past 8 hr and within target

38. A System for the Maintenance of Overnight Euglycemia and the Calculation of Basal Insulin Requirements in Insulin-Dependent Diabetics Practical Closed Loop Insulin Delivery 1/slope = Multiplier = 0.02 0 1 2 3 4 5 6 0100200300400 Glucose (mg/dl) Insulin Rate (U/hr) NEIL H. WHITE, M.D., DONALD SKOR, M.D., JULIO V. SANTIAGO, M.D.; Saint Louis, Missouri Ann Int Med 1982 ;97:210-214

39. Historical Perspective l IV Insulin Algorithm –Insulin (u/h) = (BG-60) x Multiplier l Whites Multiplier Not Applicable for Majority –Based on Type 1 Pediatric Pump Patients –IV Insulin Used Frequently in Stressed Type 2 Only 14% Stabilized at 0.02 Glucommander Multipliers N=2364 Runs White = 0.02

40. Continuous Variable Rate IV Insulin Drip (Davidson 1982) l Mix Drip with 125 units Regular Insulin into 250 cc NS l Starting Rate Units / hour = (BG – 60) x 0.02 where 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)

41. Continuous Variable Rate IV Insulin Drip (Davidson 1982) l Adjust Multiplier (initially 0.02) to obtain glucose in target range If BG > 140 mg/dL and not falling by 50mg/dl, increase by 0.01 If BG < 100 mg/dL, decrease by 0.01 If BG 100 to 140 mg/dL, no change in current multiplier l If BG is < 80 mg/dL, Give IV D50 cc = (100 – BG) x 0.3 l Give continuous rate of Glucose in IVFs l Once eating, continue drip till 2 hour post SQ insulin

42. Glucommander AN ADAPTIVE, COMPUTER-DIRECTED SYSTEM FOR IV INSULIN, SHOWN TO BE SAFE, SIMPLE, AND EFFECTIVE IN 120,618 HOURS OF OPERATION l Invented in 1984 Davidson and Steed l 19 Years Experience with this Computer Based Algorithm for the Administration of IV Insulin l Currently used as a software program housed in lap top computer in over 60 U.S. hospitals

43. Glucommander

44. Glucommander Orders

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

46. Glucommander 5802 Runs and 120,618 BGs 1985-1998

47. Glucose Management System (GMS) l In 1997, MiniMed and Roche purchased the marketing rights to the Glucommander l Changed the name to GMS l Multicenter U.S. trials done for FDA approval l Useful and Safe for Any Application of IV Insulin l Shelved Pending FDA Approval of IV Use of Insulin

48. Glucose Management System

49. Glucommander. Complete Data Set 1985 to 1998 Beyond Data Analyzed by Boehringer Manheim/MiniMed in 1995 13 years of data from Glucommander. 5802 Runs over 120,618 hours. Correction of hyperglycemia: Mean starting BG=259 mg/dL (SD 127). Mean stable <150 after three hours. Subsequent stability in target range for 60 hrs. Hypoglycemia: BGs <50 were 0.6% of total BGs. 2.6% all runs had one BG <40. All were immediately corrected to 100 with IV glucose No severe hypoglycemia.

50. Glucommander Average and Standard Deviation of of All Runs 1985 to 1998; 5808 runs, 120,618 BGs

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

52. Conformity of Blood Glucose to Glucommander Target

53. Hours Glucose Multiplier Insulin Glucose Typical Glucommander Run Hi Low

54. Leuven <40 mg/dl 5.2% Hypoglycemia on Glucommander 5772 Runs

55. 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 treat with oral CHO l Do Not Hold Insulin When BG Normal

56. Correction of Hypoglycemia with Glucose 100-BG X 0.2 Grams BeforeAfter Richardson Diabetes 1999 50:A200 100-BG X 0.15 Grams N = 827

57. Insulin Units / Hour Glucose mgm / dl Glucommander 33 u ADA 38 u IV DRIP 38 u MARKOVITZ 33 u Glucommander Similar Systems Features in Common Early high dose Decrease in parallel with BG End up at common dose Similar total dose

58. Glucommander. Surgical Series Compared to Watts Algorithm Watts Glucommander Watts et al Diab Care 1987 10:722-728

59. Glucommander. Surgical Series Compared to Watts Algorithm Glucommander Watts

60. How has the Glucommander been used? l Treatment of ketoacidosis l Hyperosmolar non-ketotic state l Perioperative glucose management l Labor and delivery l Myocardial infarction l Critically ill patients in ICU l Hyperalimentation l Gastroparesis with intractable nausea and vomiting l Estimating a patients insulin sensitivity –A guide for dosing insulin Estimating total insulin dose, correction factor, CHO/Ins

61. Clinical Experience with Glucommander l Simple, safe, and effective method for maintaining glycemic control thru out the hospital l Extensively studied l Standardized treatment method applicable in a wide variety of conditions l Available for review, www.glucommander.com

62. Transitioning off IV Insulin Infusion Therapy

63. Converting to SC insulin l If More than 0.5 u/hr IV insulin required with normal BG, start long-acting insulin (glargine) l Must start SC insulin at least 2 hours before stopping IV insulin l Some centers start long-acting insulin on initiation of IV insulin or the night before stopping the drip

64. Intravenous insulin infusion under basal conditions correlates well with subsequent subcutaneous insulin requirement. Units SQ Units IV Overwrite Hawkins et al Endocrine Practice: 1995; 1(6) 385-389

65. A nurse-managed overnight insulin infusion predicts insulin dose requirement in a wide range of otherwise well patients having poorly controlled diabetes insulin dose predicted actual Pre and post blood glucose Mao et al. JCEM 1997;82:2466-70

66. Converting to SC insulin l Establish 24 hr Insulin Requirement –Extrapolate from average over last 6-8 hours if stable l Give One-Half Amount As Basal l Give p.c. Boluses Based on CHO Intake –Start at CHO/Ins 1 CHO = 1.5 units Rapid-acting l Monitor a.c. tid, hs, and 3 am l Supplement All BG >140 mg/dl –(BG-100)/(1700/Daily Insulin Requirement)

67. Prescription for insulin therapy includes: Basal Insulin (BI) Carbohydrate-to-Insulin Ratio (CIR) Correction Factor (CF) 1801 Records from Pump Patients Studied Data from best-controlled of 591 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 Davidson PC et al Diabetes Tech & Ther 2003; 5:327

68. The Accurate Insulin Management (AIM) Formulae Davidson PC et al Diabetes Tech & Ther 2003; 5:327

69. Questions that need further study l What is the glucose threshold and target glucose for IV insulin in acute MI, pre-CABG, other states, etc? <110 mg/dl or <140 mg/dl ? l What is the best IV insulin infusion protocol? l What is the best way to transition to SC?

70. Conclusion All hospital patients should have normal glucose

71. The Paradigm for the Millenium Hyperglycemia: A Mortal Sin A blood glucose over 110 in a hospitalized patient causes increased morbidity and mortality. In the 21st Century Neglecting BG >200 Is Malpractice

72. l For a copy or viewing of these slides –Contact www.adaendo.com l How can I get use of Glucommander? – Available for review on internet, www.glucommander.com – Contact us: Glucommander@adaendo.com