Glycemic Control In The Hospital Setting

1. Glycemic Control In The Hospital Setting

2. LOYOLA UNIVERSITY MEDICAL CENTER Total Number of Beds 580 LOCATION: ICU # OF BEDS� MICU 15 CCU 10 Heart Transplant Unit 10 CV Surgery ICU 21 Trauma Units 20 Surgical ICU 18 Neuro ICU 15 Burn ICU 15 Neonatal ICU 50 Pediatric ICU 14

3. Loyola Medical Center LOCATION: Non-ICU # OF BEDS� IMC Cardiac & Angioplasty 28 Telemetry Unit 67 Bone Marrow 15 Pediatrics 32 Post partum 30 Labor and Delivery 15 Nursery 25 Rehab Unit 24 General Medicine 60 Hematology/Oncology 30 Orthopedic 19 Neurology, Neurosurgery and ENT 40 Surgery 32 Burn and Surgical Unit 21

4. Glycemic Control In The Hospital Setting The Evidence For Tight Glycemic Control The Achievement of Better Control: Strategies and Protocols

5. Insulin In The Hospital Setting Retrospective Studies

7. Effect of Continuous Insulin Infusion on Mortality Following CABG 3554 DM Patients Undergoing CABG From Jan. 1987 to Dec. 2001 Treated With: Subcutaneous Injection Group (SQI) (n=942) Received Insulin Q4h to Maintain BG <250 mg/dl Continuous Infusion Group (n=2612) 1987 to 1991 Target BG of 220 mg/dl 1991 to 1998 Target BG of 150-200 mg/dl In 1999, Target Lowered to 125-175 mg/dl In 2001, Target Lowered to 100-125 mg/dl This study was done at the St. Vincent Medical Center in Portland Oregon over a 15 year period. Patients with DM undergoing only CABG (eg � no valve replacement) were included. Patients were randomized to receive either subcutaneous insulin or a continuous insulin infusion, although the CII protocol changed as the program evolved. In the CII group, all patients with DM undergoing CABG operated on between October 1991 and December 2001 received an insulin infusion titrated per protocol in the perioperative period (Portland protocol). The protocol prescribes insulin initiation, infusion and titration rates, and glucose testing frequency requirements to safely maintain a patient�s blood glucose within target levels. Between 1991 and 1998, the target glucose range was 150 to 200 mg/dL; in 1999 it was dropped to 125 to 175 mg/dL and in 2001 was again lowered to 100 to 150 mg/dL. From 1991 to 1995, the Portland protocol was used post-operatively only in the intensive care unit (ICU) and was stopped when the patient was transferred to the telemetry unit. In January 1996, the protocol was expanded with initiation in the operating room (before sternotomy and after induction of anesthesia, with continuation during cardiopulmonary bypass) and uniform continuation until 7 AM of the third POD, even for patients who had transferred out of the ICU.This study was done at the St. Vincent Medical Center in Portland Oregon over a 15 year period. Patients with DM undergoing only CABG (eg � no valve replacement) were included. Patients were randomized to receive either subcutaneous insulin or a continuous insulin infusion, although the CII protocol changed as the program evolved. In the CII group, all patients with DM undergoing CABG operated on between October 1991 and December 2001 received an insulin infusion titrated per protocol in the perioperative period (Portland protocol). The protocol prescribes insulin initiation, infusion and titration rates, and glucose testing frequency requirements to safely maintain a patient�s blood glucose within target levels. Between 1991 and 1998, the target glucose range was 150 to 200 mg/dL; in 1999 it was dropped to 125 to 175 mg/dL and in 2001 was again lowered to 100 to 150 mg/dL. From 1991 to 1995, the Portland protocol was used post-operatively only in the intensive care unit (ICU) and was stopped when the patient was transferred to the telemetry unit. In January 1996, the protocol was expanded with initiation in the operating room (before sternotomy and after induction of anesthesia, with continuation during cardiopulmonary bypass) and uniform continuation until 7 AM of the third POD, even for patients who had transferred out of the ICU.

8. Post-CABG Mortality by Diabetic Status This figure depicts the annualized operative mortality for all patients undergoing CABG at St. Josephs. Mortality among patients with DM undergoing CABG fell significantly since CII implementation in 1992. Perioperative mortality among patients without DM undergoing CABG did not change during the same period (slope of 0.9, P = .4). As a result of the insulin protocol, there are now no significant differences in operative mortality between patients with and without DM undergoing CABG at this institution.This figure depicts the annualized operative mortality for all patients undergoing CABG at St. Josephs. Mortality among patients with DM undergoing CABG fell significantly since CII implementation in 1992. Perioperative mortality among patients without DM undergoing CABG did not change during the same period (slope of 0.9, P = .4). As a result of the insulin protocol, there are now no significant differences in operative mortality between patients with and without DM undergoing CABG at this institution.

9. Hyperglycemia in the Hospital Stroke Hyperglycemia ? Independent Determinent of Infarct Expansion Baird TA, et al. Stroke. 2003; 34: 2208-14 Hyperglycemia ? Hospital Mortality ? X 2 Weir CJ, et al. BMJ. 1997; 314:1303-1306 Hyperglycemia ? Hospital Mortality ? X 2 Jorgensen H, et al. Stroke. 1994; 25:1977-1984

10. Hyperglycemia In Critical IllnessTargeting Risk?From The VA Inpatient Evaluation Center From 177 ICUs In 73 VA Hospitals 216,000 Patients Glycemia Independent Predictor Of Mortality Starting At 1 mg% Above Normal (Normal = 70-110 mg%) True In Medical, Surgical & Cardiac ICUs

11. Hyperglycemia In Critical IllnessTargeting Risk?From The VA Inpatient Evaluation Center Different Disease States Variably Affected Condition Risk Of Death* Acute MI 1.6-5 Unstable Angina 1.7-6.2 Stroke 3.4-15.1 Outcomes Worse In �Non-Diabetics�

12. Insulin In The Hospital Setting Prospective Studies

13. DIGAMI Study 620 Randomized to 2 Groups At 19 Swedish Hospitals Control: Standard Coronary Care for Their Center Intensive: Insulin-Glucose Infusion for >24 Hrs Target Serum Glucose 126 � 180 mg/dl Multidose (4/day) Insulin for Minimum of 3 Months Following Discharge The DIGAMI study looked at all patients admitted to the CCUs of 19 Swedish hospitals between January 1990 and December 1993. Initially 1240 patients were eligible for the study but 620 were excluded for various reasons, primarily for health reasons or refusal to participate in the long term injection protocol. Patients in the infusion group received a combination of 5% glucose and insulin by infusion to achieve a target serum glucose between 126 and 180 mg/dL for at least 24 hours � until normoglycemia was attained. Insulin injections were begun as soon as the infusion was stopped to maintain normal glycemia. The regimen involved 3 shots before meals and one at bedtime. The DIGAMI study looked at all patients admitted to the CCUs of 19 Swedish hospitals between January 1990 and December 1993. Initially 1240 patients were eligible for the study but 620 were excluded for various reasons, primarily for health reasons or refusal to participate in the long term injection protocol. Patients in the infusion group received a combination of 5% glucose and insulin by infusion to achieve a target serum glucose between 126 and 180 mg/dL for at least 24 hours � until normoglycemia was attained. Insulin injections were begun as soon as the infusion was stopped to maintain normal glycemia. The regimen involved 3 shots before meals and one at bedtime.

14. Cardiovascular RiskMortality After MI Reduced by Insulin Therapy in the DIGAMI Study

15. Intensive Insulin Therapy in Critically Ill PatientsVan Den Berghe, G et al. NEJM 345: 1359-1367. 2001

16. Intensive Insulin Therapy in Critically Ill Patients 1548 Mechanically Ventilated Patients in SICU 2 Glycemic Treatment Groups: Insulin Infusion to Keep Blood Glucose 80-110 mg/dl Insulin Treatment Only If Blood Glucose >215 mg/dl to Maintain Glucose 180- 210 mg/dl

17. Intensive Insulin Therapy in Critically Ill Patients 87% Diagnosed With DM in the ICU 13% Had Previous Dx of Diabetes Mellitus 5% Had Previous Insulin Treatment

18. Intensive Insulin Therapy in Critically Ill Patients 34% Decrease in In-Hospital Mortality 46% Decrease in Sepsis 41% Decrease in Renal Replacement Therapy 50% Decrease in Median Number of RBC Transfusions 44% Decrease in Critical Illness Polyneuropathy

23. And Now Van den Berghe -2

24. Intensive Insulin Therapy in the Medical ICU Greet Van den Berghe, M.D., Ph.D., Alexander Wilmer, M.D., Ph.D., Greet Hermans, M.D., Wouter Meersseman, M.D., Pieter J. Wouters, M.Sc., Ilse Milants, R.N., Eric Van Wijngaerden, M.D., Ph.D., Herman Bobbaers, M.D., Ph.D., and Roger Bouillon, M.D., Ph.D.

25. Intensive Insulin Therapy in Critically Ill Patients: Van den Berghe 2 1200 Patients in MICU 2 Glycemic Treatment Groups: Insulin Infusion to Keep Blood Glucose 80-110 mg/dl Insulin Treatment Only If Blood Glucose >215 mg/dl to Maintain Glucose 180- 200 mg/dl

26. With Intensive Insulin Therapy Reduced Newly Acquired Kidney Disease Earlier Weaning From Ventilator Faster Discharge from ICU Shorter Hospital Length of Stay

27. The Two Van den Berghe Studies

29. New Trials On The Horizon� NICE (NormoGlycemia In Intensive Care Evaluation: 4,000 Patients in 20 ICU�s In Australia & New Zealand SUGAR (Survival Using Glucose Algorithm Regulation): Another 1,000 ICU Patients In Canada

31. Is It Less Serious If a Patient Has Not Had a Previous Diagnosis of Diabetes?

32. Hyperglycemia: An Independent Marker of In-Hospital Mortality in Patients with Undiagnosed Diabetes Question: Does Hyperglycemia, New or Established, Predict Mortality? 2030 Consecutive Records of Adults Admitted to Georgia Baptist Hospital Hyperglycemia: FBG = 126 mg/dl or Random Glucose = 200 mg/dl New Hyperglycemia 223 Pts. (12%)

33. Hyperglycemia: An Independent Marker of In-Hospital Mortality in Patients with Undiagnosed Diabetes

34. A Marker of In-Hospital Mortality in Patients with Undiagnosed Diabetes New Hyperglycemia Patients ~3 x�s As Likely to Be Admitted to ICU New Hyperglycemia Patients Had Twice the Length of Stay

35. There are other benefits�

37. Glycemic Management In The HospitalFinancial Aspects

38. Glycemic Management In The HospitalFinancial Aspects

39. Glycemic Management In The HospitalFinancial Aspects

40. Glycemic Control In The Hospital Setting The days of casual glycemic control for critically ill patients should be over!

41. Glycemic Control In The Hospital Setting The Evidence For Tight Glycemic Control The Achievement of Better Control: Strategies and Protocols

42. What Are The Treatment Goals?

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

44. Strategies and Protocols for Achieving Inpatient Glycemic Control Strategies and Protocols for Achieving Inpatient Glycemic ControlStrategies and Protocols for Achieving Inpatient Glycemic Control

45. IV Insulin Infusion Protocols

46. The Ideal IV Insulin Protocol Easily Ordered (Signature Only) Effective (Reach Goal Quickly) Safe (Minimal Risk Of Hypoglycemia) Easily Implemented The Ideal IV Insulin Protocol In addition to specifying insulin dose, protocols should include specific guidelines for identifying patients at risk for hypoglycemia and actions to be taken to prevent and treat hypoglycemia. The Ideal IV Insulin Protocol In addition to specifying insulin dose, protocols should include specific guidelines for identifying patients at risk for hypoglycemia and actions to be taken to prevent and treat hypoglycemia.

47. IV Insulin Protocol Based On Insulin Sensitivity

48. Intravenous Insulin Infusion Targeting BG 80�110 mg/dL Intravenous Insulin Infusion Targeting BG 80�110 mg/dL

49. < 70 Off 70-109 0.2 110-119 0.5 120-149 1.0 150-179 1.5 180-209 2.0 210-239 2.0 240-269 3.0 270-299 3.0 300-329 4.0 Etc.

50. Shifting Between Several Algorithms Makes It Possible To Discover The Insulin Requirement That Maintains Normoglycemia

51. Recommended IV FluidsTo Prevent Hypoglycemia, Hypokalemia & Ketosis: Glucose: 5-10 gms/hour Potassium: 20 meq/L The Primary Service Should Choose the Type and the Rate of the Fluid Depending on the Underlying Disease

52. Other Protocols Exist DIGAMI (Studied In Acute MI Setting) Van den Berghe (Critical Care Setting) Portland Protocol (Surgical Setting) Markovitz (Postoperative Heart Surgery) Yale Protocol (Medical Intensive Care Setting) Glucommander.com; Endotool.com; Medicaldecisions.com (Critical Care & Non- Critical Care) Various Protocols Exist A number of protocols have been published for the administration of continuous insulin infusion. The use of standardized protocols is associated with improved glycemic control and low rates of hypoglycemia. Various Protocols Exist A number of protocols have been published for the administration of continuous insulin infusion. The use of standardized protocols is associated with improved glycemic control and low rates of hypoglycemia.

53. Life After The Drip�.

54. Physiologic Insulin Secretion :Basal/Bolus Concept  When we consider glucose control, we need to focus on both postprandial and basal requirements. This slide illustrates the normal diurnal physiologic response, which highlights the need for both basal and meal insulin. Meal-insulin release occurs in response to nutrient ingestion. Basal insulin is continually secreted over a 24-hour period to maintain homeostasis in the body energy requirements and balance. The �normal� human adult secretes about 25-30 units of insulin a day. As you can see, about � of this is in �BASAL� insulin. You can also see that a �normal� patient would likely not exceed PG = 150 mg/dL, even after a meal. These ambient glucose levels (euglycemia) are reflected in a �normal� GHbA1c range of 4.5-6.5% in the USA. NOTE � if you take a random BG (about 15-20% less in value than PG) and it is >130mg/dL, it would be suspect. I will show you what I mean in later slides, but keep this in mind. - If the patient just ate, or it he/she ate 2-3 hours before, it would make a difference in how you may advise him/her concerning seeking medical advise. (Refer to OGTT � Oral Glucose Tolerance Test � data) In the past, we have had to make due with various insulin formulations that did not have adequate pharmacokinetics to duplicate these profiles. However, within the past few years, new insulin analogs have been developed, which provide more physiologic profiles. When we consider glucose control, we need to focus on both postprandial and basal requirements. This slide illustrates the normal diurnal physiologic response, which highlights the need for both basal and meal insulin. Meal-insulin release occurs in response to nutrient ingestion. Basal insulin is continually secreted over a 24-hour period to maintain homeostasis in the body energy requirements and balance. The �normal� human adult secretes about 25-30 units of insulin a day. As you can see, about � of this is in �BASAL� insulin. You can also see that a �normal� patient would likely not exceed PG = 150 mg/dL, even after a meal. These ambient glucose levels (euglycemia) are reflected in a �normal� GHbA1c range of 4.5-6.5% in the USA. NOTE � if you take a random BG (about 15-20% less in value than PG) and it is >130mg/dL, it would be suspect. I will show you what I mean in later slides, but keep this in mind. - If the patient just ate, or it he/she ate 2-3 hours before, it would make a difference in how you may advise him/her concerning seeking medical advise. (Refer to OGTT � Oral Glucose Tolerance Test � data) In the past, we have had to make due with various insulin formulations that did not have adequate pharmacokinetics to duplicate these profiles. However, within the past few years, new insulin analogs have been developed, which provide more physiologic profiles.

55. Transition From IV to SQ Insulin In The Adult Patient Basal Insulin Bolus Insulin Prandial Insulin Correction Factor Insulin

56. Effective Onset Peak Duration Lispro/Aspart/Glulisine <15 min 1 hr 3 hr Regular 1/2-1 hr 2-3 hr 3-6 hr NPH/Lente 2-4 hr 7-8 hr 10-12 hr Ultralente 4 hr Varies 18-20 hr Insulin Glargine 1-2 hr Flat/Predictable 24 hr Current Insulin Preparations

57. Onset Peak Effective Duration Lispro/Aspart/Glulisine <15 min 1 hr 3 hr Regular 1/2-1 hr 2-3 hr 3-6 hr NPH 2-4 hr 7-8 hr 10-12 hr Insulin Glargine 1-2 hr Flat 24 hr Insulin Detemir 0.8-2 hr * ~8-9 hr * Up to 24 hr * Current Insulin Preparations

58. Insulin DetemirPharmacokinetics

59. Transition to SQ: An Approach To Transition A Patient From An IV Insulin Infusion To SQ Insulin: Multiply Last Drip Dose By 20, And Give This Amount As Glargine Turn The IV Drip Off 2 Hours Later

60. Glucose Levels after Starting Lantus

61. Transition to SQ: An Approach To Transition A Patient From An IV Insulin Infusion To SQ Insulin: Multiply Last Drip Dose By 20, And Give This Amount As Glargine Turn The IV Drip Off 2 Hours Later

62. Transition to SQ: An Approach To Transition A Patient From An IV Insulin Infusion To SQ Insulin: Multiply Last Drip Dose By 20, And Give This Amount As Glargine Turn The IV Drip Off 2 Hours Later

63. Example: Last Drip Dose Is 1.5 Unit/Hour; Give 1.5 X 20 = 30 units Of Glargine SQ; Discontinue Drip Two Hours Later This Is Basal Insulin

64. Adjust Basal Insulin By FBS: Decrease 4 U if FBS are below 60 mg/dL Decrease 2 U if FBS Is 60-80 mg/dL If FBS Is 80-100mg/dL, At Goal-No Change is Needed Increase 2 U If FBS Is 100 to 120 mg/dL Increase 4 U If FBS Is 121 to 140 mg/dL Increase 6 U If FBS Is 141 to 160 mg/dL Increase 8 U If FBS Is 161 to 180 mg/dL Increase 10 U If FBS Is > 180 mg/dL

65. Transition From IV to SQ Insulin In The Adult Patient Basal Insulin Bolus Insulin Prandial Insulin Correction Factor Insulin

66. Onset Peak Effective Duration Lispro/Aspart/Glulisine <15 min 1 hr 3 hr Regular � -1 hr 2-3 hr 3-6 hr NPH 2- 4 hr 7-8 hr 10-12 hr Insulin Glargine 1-2 hr Flat 24 hr Insulin Detemir 0.8-2 hr * ~8-9 hr * Up to 24 hr * Current Insulin Preparations

67. When Patient Is Able To Eat,  Add Rapid Acting Insulin For Mealtime Coverage Rule Of Thumb: 50% Basal 50% Prandial, Divided Over 3 Meals

68. Example: Patient Is On 30 units Glargine Daily; Give 10 units With Each Meal Of Lispro (Humalog), Aspart (Novolog), Or Glulisine (Apidra) This Is Prandial Insulin

69. Basal-Bolus Insulin Therapy: Glargine and Mealtime Rapid Acting Slide 6-31 INSULIN TACTICS Multiple Daily Injections (MDI) The Quest for Basal Insulin Replacement An experimental intensive insulin regimen tested by Italian researchers in patients with type 1 diabetes illustrates the lack of adequate long-acting insulin preparations to provide a reliable and consistent basal insulin. The quest for basal insulin replacement has prompted the use of multiple daily injections of mealtime insulin lispro + NPH and NPH at bedtime. The combination of four doses of NPH with higher proportions of lispro provides a constant basal insulin, with the desired insulin peak effects after mealtimes, as well as maintenance of better glycemic control during the night and between meals. Bolli GB, Di Marchi RD, Park GD, Pramming S, Koivisto VA. Insulin analogues and their potential in the management of diabetes mellitus. Diabetologia. 1999;42:1151-1167.Slide 6-31 INSULIN TACTICS Multiple Daily Injections (MDI) The Quest for Basal Insulin Replacement An experimental intensive insulin regimen tested by Italian researchers in patients with type 1 diabetes illustrates the lack of adequate long-acting insulin preparations to provide a reliable and consistent basal insulin. The quest for basal insulin replacement has prompted the use of multiple daily injections of mealtime insulin lispro + NPH and NPH at bedtime. The combination of four doses of NPH with higher proportions of lispro provides a constant basal insulin, with the desired insulin peak effects after mealtimes, as well as maintenance of better glycemic control during the night and between meals. Bolli GB, Di Marchi RD, Park GD, Pramming S, Koivisto VA. Insulin analogues and their potential in the management of diabetes mellitus. Diabetologia. 1999;42:1151-1167.

70. Transition From IV to SQ Insulin In The Adult Patient Basal Insulin Bolus Insulin Prandial Insulin Correction Factor Insulin

71. Correction Factor Dose, Added To Prandial Dose

72. What About Patients Admitted With Hyperglycemia On The Floor?

73. Sliding Scale Episodic Bolus Insulin WITHOUT Basal Insulin

74. Pitfalls of Sliding Scale Common Problems With SS Only Is Reactive Rather Than Proactive Often Mismatched With Changes In Patient�s Insulin Sensitivity It Does Not Meet The Physiologic Needs Of The Patient Leads To Insulin Stacking

75. Calculate Starting Total Daily Dose (TDD) Previous Total Daily Insulin Units Used or 0.4 units/kg (Type 1 DM) 0.6 units/kg (New Onset Or Lean Type 2) 0.8 units/kg (Type 2 DM) This Is Very Conservative and Actual Needs May Turn Out to Be Substantially More

76. NPH or Combination Insulin Discontinue this while an inpatient Disadvantages Insulin peaks Less reliable timing Variation in food intake Often poorer control Conversion Add all doses of insulin total daily dose

77.

78. Hypoglycemia: Most Frequent Causes Not Lowering Insulin Dose For Decreased Caloric Intake Interrupted Tube Feeding Unrecognized Renal Insufficiency Sulfonylurea�s In Addition To Insulin Very Rare: Adrenal Insufficiency & Drugs

79. A Word About Oral Agents�.

80. Therapy of Type 2 Diabetes Mellitus:Hospital Use of Oral Agents

81. Common Errors in Glucose Management in Hospital Patients Discontinuing All Diabetes Medicines On Admission (Some Pills Must Be Stopped) Setting High Glycemic Targets (>200 mg/dL) Not Changing Therapy With The Situation Or The Glucose Profile Overutilization Of Sliding Scale Insulin Underutilization Of Insulin Infusions and Basal Insulin

82. Have A Discharge Plan

83. Admission HbA1C Very Helpful Can A Patient Go Back To Oral Agents At Discharge?

84. Admission HbA1C Very Helpful If Known Diabetic and Pre-Admission Control Acceptable ? YES!!! If > 7.5% on Maximum Oral Agents, Needs Basal Insulin Can A Patient Go Back To Oral Agents At Discharge?

85. Natural History of Type 2 Diabetes

88. Inpatient Diabetes Management: Is Cost a Barrier? Use of a Diabetes Management Team: Reduction in LOS Cost Reduction of $2353/ Patient MICU: Annual Savings $40,000/ ICU Bed SICU: Savings $3,000/Patient

89. Hospital Diabetic Management: Medical Benefits Unequivocal Few Studies Address Optimal Method Principles Borrowed From Outpatient Management Insulin Strategy Should Be Physiologic All Regimens Must Include Adequate Basal Insulin Prandial and Correction Factor Team Approach Essential Financial Incentives