Review of the Data: State of the Art 2007

1. Review of the Data:State of the Art 2007 Stephen Clement, MD Andrew Ahmann, MD

2. Insulin in the Hospital:Who, why, how, where should we treat? Clinical Trial Data Insights from Mechanism of Injury

3. The Growing Number of Hospital Patients with Hyperglycemia

4. 20.8 Million in US with Diabetes > 50% increase over the last decade > Nearly 10% of the adult population 7% / year increase over the last 5 years Prevalence will double by 2024 Lifetime Risk for those born in 2000 33% for males; 38.5% for Females

5. The Increasing Rate of Diabetes Among Those Hospitalized

6. Distribution of First-Listed Diagnoses Among Hospital Discharges with Diabetes as Any Listed Diagnosis, Adults Age 18 and Older 2002

7. Hyperglycemia in the Hospital Diabetes: Previously diagnosed Previously undiagnosed HbA1c > 7.0% during admission Hyperglycemia without diabetes diagnosis Diabetes diagnosed later on follow-up Prediabetes with overt hyperglycemia during acute physiologic stress Hyperglycemia due to physiologic stress without underlying metabolic abnormality (normal f/u testing)

8. Prevalence of Hyperglycemia in 181 Cardiac Patients Without Known Diabetes Norhammar data demonstrates that 2/3rds of patients admitted to the hospital for an AMI are either hyperglycemic or have undiagnosed DM. Importantly, this does not appear to be stress hyperglycemia in most cases since there is very little change in the pravalence of these disorders when test are repeated 3 months after discharge Abstract BACKGROUND: Glycometabolic state at hospital admission is an important risk marker for long-term mortality in patients with acute myocardial infarction, whether or not they have known diabetes mellitus. Our aim was to ascertain the prevalence of impaired glucose metabolism in patients without diagnosed diabetes but with myocardial infarction, and to assess whether such abnormalities can be identified in the early course of a myocardial infarction. METHODS: We did a prospective study, in which we enrolled 181 consecutive patients admitted to the coronary care units of two hospitals in Sweden with acute myocardial infarction, no diagnosis of diabetes, and a blood glucose concentration of less than 11.1 mmol/L. We recorded glucose concentrations during the hospital stay, and did standardised oral glucose tolerance tests with 75 g of glucose at discharge and again 3 months later. FINDINGS: The mean age of our cohort was 63.5 years (SD 9) and the mean blood glucose concentration at admission was 6.5 mmol/L (1.4). The mean 2-h postload blood glucose concentration was 9.2 mmol/L (2.9) at hospital discharge, and 9.0 mmol/L (3.0) 3 months later. 58 of 164 (35%, 95% CI 28-43) and 58 of 144 (40%, 32-48) individuals had impaired glucose tolerance at discharge and after 3 months, respectively, and 51 of 164 (31%, 24-38) and 36 of 144 (25%, 18-32) had previously undiagnosed diabetes mellitus. Independent predictors of abnormal glucose tolerance at 3 months were concentrations of HbA(1c) at admission (p=0.024) and fasting blood glucose concentrations on day 4 (p=0.044). INTERPRETATION: Previously undiagnosed diabetes and impaired glucose tolerance are common in patients with an acute myocardial infarction. These abnormalities can be detected early in the postinfarction period. Our results suggest that fasting and postchallenge hyperglycaemia in the early phase of an acute myocardial infarction could be used as early markers of high-risk individuals. Norhammar data demonstrates that 2/3rds of patients admitted to the hospital for an AMI are either hyperglycemic or have undiagnosed DM. Importantly, this does not appear to be stress hyperglycemia in most cases since there is very little change in the pravalence of these disorders when test are repeated 3 months after discharge Abstract BACKGROUND: Glycometabolic state at hospital admission is an important risk marker for long-term mortality in patients with acute myocardial infarction, whether or not they have known diabetes mellitus. Our aim was to ascertain the prevalence of impaired glucose metabolism in patients without diagnosed diabetes but with myocardial infarction, and to assess whether such abnormalities can be identified in the early course of a myocardial infarction. METHODS: We did a prospective study, in which we enrolled 181 consecutive patients admitted to the coronary care units of two hospitals in Sweden with acute myocardial infarction, no diagnosis of diabetes, and a blood glucose concentration of less than 11.1 mmol/L. We recorded glucose concentrations during the hospital stay, and did standardised oral glucose tolerance tests with 75 g of glucose at discharge and again 3 months later. FINDINGS: The mean age of our cohort was 63.5 years (SD 9) and the mean blood glucose concentration at admission was 6.5 mmol/L (1.4). The mean 2-h postload blood glucose concentration was 9.2 mmol/L (2.9) at hospital discharge, and 9.0 mmol/L (3.0) 3 months later. 58 of 164 (35%, 95% CI 28-43) and 58 of 144 (40%, 32-48) individuals had impaired glucose tolerance at discharge and after 3 months, respectively, and 51 of 164 (31%, 24-38) and 36 of 144 (25%, 18-32) had previously undiagnosed diabetes mellitus. Independent predictors of abnormal glucose tolerance at 3 months were concentrations of HbA(1c) at admission (p=0.024) and fasting blood glucose concentrations on day 4 (p=0.044). INTERPRETATION: Previously undiagnosed diabetes and impaired glucose tolerance are common in patients with an acute myocardial infarction. These abnormalities can be detected early in the postinfarction period. Our results suggest that fasting and postchallenge hyperglycaemia in the early phase of an acute myocardial infarction could be used as early markers of high-risk individuals.

9. Hyperglycemia In The Hospital

10. Potential Consequences of Hyperglycemia in the Hospital Impaired leukocyte function Poor wound healing Increased infection rate with TPN Risk of ischemia Electrolyte fluxes Volume depletion Thrombosis Additional ?-cell impairment in type 2 Insulin resistance A signal to the patient that glucose control is unimportant

11. Proposed Associations Between Hyperglycemia and Inpatient Outcomes Hyperglycemia a risk factor for: Complications of strokes Complications of MI Complications of vascular and cardiac surgery Mortality in critically ill Mortality in trauma patients Complications of orthopedic surgery Aggressive insulin treatment improves: Cardiac surgery outcomes MI outcomes Intensive care unit outcomes

12. Nosocomial Infection Rates Within The First 14 Postoperative Days after Elective Surgery

14. Hyperglycemia Is A Risk Factor in Outcomes of Trauma Patients

15. Hospital mortality rate in critically ill patients vs mean BG Hospital Mortality Rate and Mean Glucose Levels in Critically Ill Patients Retrospective data were reviewed for 1,826 consecutive patients whose glucose values were obtained during their intensive care unit stay at The Stamford Hospital in Stamford, Connecticut, between October 1, 1999, and April 4, 2002. Mean glucose values were significantly higher among nonsurvivors than among survivors for the entire group (P < 0.001) and for each subgroup except for patients with septic shock. The lowest hospital mortality, 9.6%, occurred among patients with mean glucose values between 80 and 99 mg/dL. Hospital mortality increased progressively as glucose values increased, reaching 425% among patients with mean glucose values exceeding 300 mg/dL. Even a modest degree of hyperglycemia occurring after intensive care unit admission was associated with a substantial increase in hospital mortality in patients with a wide range of medical and surgical diagnoses. Krinsely JS. Association between hyperglycemia and increased hospital mortality in a heterogeneous population of critically ill patients. Mayo Clin Proc. 2003;78:1471–1478. Hospital Mortality Rate and Mean Glucose Levels in Critically Ill Patients Retrospective data were reviewed for 1,826 consecutive patients whose glucose values were obtained during their intensive care unit stay at The Stamford Hospital in Stamford, Connecticut, between October 1, 1999, and April 4, 2002. Mean glucose values were significantly higher among nonsurvivors than among survivors for the entire group (P < 0.001) and for each subgroup except for patients with septic shock. The lowest hospital mortality, 9.6%, occurred among patients with mean glucose values between 80 and 99 mg/dL. Hospital mortality increased progressively as glucose values increased, reaching 425% among patients with mean glucose values exceeding 300 mg/dL. Even a modest degree of hyperglycemia occurring after intensive care unit admission was associated with a substantial increase in hospital mortality in patients with a wide range of medical and surgical diagnoses. Krinsely JS. Association between hyperglycemia and increased hospital mortality in a heterogeneous population of critically ill patients. Mayo Clin Proc. 2003;78:1471–1478.

16. Effects of Hyperglycemia In Stroke Retrospective review of 656 cases of stroke over 5 years at one hospital Hyperglycemia = admitting BG >130 mg/dl 40% of patients; 43% not treated in hospital LOS higher with hyperglycemia 7.2 vs 6 days (p = 0.015) Hyperglycemic patients had higher charges $6,611 vs $5,262 Hyperglycemia was independently associated with increased mortality for up to 6 years

17. Association Between Hyperglycemia and LOS

18. Treating Hyperglycemia In Patients Presenting With Acute MI

19. Glucose Level and Treatment In Patients With Diabetes Mellitus and Acute MI Study of 620 diabetics Randomized to IV insulin or control at time of MI Predictors of mortality old age previous heart failure diabetes duration admission BG & HbA1c Intensive therapy ? mortality 29% at 1 year ? mortality 28% at 3.4 yrs

20. CVD Mortality After MI (DIGAMI Study) BARRIERS TO INSULIN THERAPY Cardiovascular Risk Mortality After MI Reduced by Insulin Therapy in the DIGAMI Study Patients at high risk of cardiovascular disease are often thought to be inappropriate candidates for treatment with insulin because of the belief that hypoglycemia, hyperinsulinemia, or other metabolic effects of insulin might provoke or worsen the outcome of major cardiovascular events. This figure shows data from the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) trial. This Swedish trial studied the short-term and long-term effects of intensive insulin treatment of patients with diabetes who were enrolled in the trial at the time of a myocardial infarction. The subjects were immediately randomized to continued management according to the judgment of their physicians, or to intravenous infusion of insulin and glucose for 48 hours followed by a four-injection regimen subsequently for as long as 5 years. Other aspects of management of the infarction included treatment with b-blockers, angiotensin-converting enzyme inhibitors, fibrinolytic agents, and aspirin in high proportions of both groups. The rationale underlying the study was the old observation that, in animal experiments and studies of small numbers of humans, infarct size and outcome are improved by insulin-glucose infusion, in part because of suppression of otherwise elevated free fatty acid levels in plasma. The figure shows the cumulative total mortality rates in the whole population of 620 subjects randomized to the two treatments, as well as the rates for a predefined subgroup of subjects who were judged likely to survive the initial hospitalization and were not previously using insulin. The whole population showed an 11% actual and a 28% relative risk reduction with intensive insulin treatment after 5 years, and the subgroup showed a 15% actual and a 51% relative risk reduction. Most of the benefit was apparent in the first month of treatment and presumably was partly due to immediate intravenous infusion of insulin; however, the survival curves tended to separate further over time, suggesting an ongoing benefit from intensive treatment. This study suggests that insulin is an entirely appropriate treatment for patients with type 2 diabetes and high cardiovascular risk, especially at the time of myocardial infarction. Malmberg K, Rydén L, Hamsten A, Herlitz J, Waldenström, Wedel H, and the DIGAMI study group. Effects of insulin treatment on cause-specific one-year mortality and morbidity in diabetic patients with acute myocardial infarction. Eur Heart J. 1996;17:1337-1344; Nattrass M. Managing diabetes after myocardial infarction: time for a more aggressive approach. BMJ. 1997;314:1497; Malmberg K, and the DIGAMI study group. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. BMJ. 1997;314:1512-1515.BARRIERS TO INSULIN THERAPY Cardiovascular Risk Mortality After MI Reduced by Insulin Therapy in the DIGAMI Study Patients at high risk of cardiovascular disease are often thought to be inappropriate candidates for treatment with insulin because of the belief that hypoglycemia, hyperinsulinemia, or other metabolic effects of insulin might provoke or worsen the outcome of major cardiovascular events. This figure shows data from the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) trial. This Swedish trial studied the short-term and long-term effects of intensive insulin treatment of patients with diabetes who were enrolled in the trial at the time of a myocardial infarction. The subjects were immediately randomized to continued management according to the judgment of their physicians, or to intravenous infusion of insulin and glucose for 48 hours followed by a four-injection regimen subsequently for as long as 5 years. Other aspects of management of the infarction included treatment with b-blockers, angiotensin-converting enzyme inhibitors, fibrinolytic agents, and aspirin in high proportions of both groups. The rationale underlying the study was the old observation that, in animal experiments and studies of small numbers of humans, infarct size and outcome are improved by insulin-glucose infusion, in part because of suppression of otherwise elevated free fatty acid levels in plasma. The figure shows the cumulative total mortality rates in the whole population of 620 subjects randomized to the two treatments, as well as the rates for a predefined subgroup of subjects who were judged likely to survive the initial hospitalization and were not previously using insulin. The whole population showed an 11% actual and a 28% relative risk reduction with intensive insulin treatment after 5 years, and the subgroup showed a 15% actual and a 51% relative risk reduction. Most of the benefit was apparent in the first month of treatment and presumably was partly due to immediate intravenous infusion of insulin; however, the survival curves tended to separate further over time, suggesting an ongoing benefit from intensive treatment. This study suggests that insulin is an entirely appropriate treatment for patients with type 2 diabetes and high cardiovascular risk, especially at the time of myocardial infarction. Malmberg K, Rydén L, Hamsten A, Herlitz J, Waldenström, Wedel H, and the DIGAMI study group. Effects of insulin treatment on cause-specific one-year mortality and morbidity in diabetic patients with acute myocardial infarction. Eur Heart J. 1996;17:1337-1344; Nattrass M. Managing diabetes after myocardial infarction: time for a more aggressive approach. BMJ. 1997;314:1497; Malmberg K, and the DIGAMI study group. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. BMJ. 1997;314:1512-1515.

21. Treating Hyperglycemia In Coronary Artery Surgery

22. Progressive Decline In Blood Glucose with Portland Protcol - - Furnary 2006

23. (CLICK) The Portland protocol was implemented in gradual steps designed to maintain patient safety, prevent hypoglycemia, and ensure nursing comfort and compliance. (CLICK) We started with a target range of 150 - 200 only in the ICU. (CLICK) In1996 the protocol was expanded…. with initiation in the OR and continuation on the telemetry floor until the 3rd postoperative day. (CLICK) (CLICK) Target levels were then dropped in 1999 and again in 2001. (CLICK) The Portland protocol was implemented in gradual steps designed to maintain patient safety, prevent hypoglycemia, and ensure nursing comfort and compliance. (CLICK) We started with a target range of 150 - 200 only in the ICU. (CLICK) In1996 the protocol was expanded…. with initiation in the OR and continuation on the telemetry floor until the 3rd postoperative day. (CLICK) (CLICK) Target levels were then dropped in 1999 and again in 2001.

24. Relationship Between Postoperative Glucose Level and DSWI Rates

25. Reduced Mortality in CABG Patients Treated with Insulin Infusion Compared 2612 patients treated aggressively with CII vs 942 treated with SC insulin Mortality with CII = 2.5%; with SCI = 5.3% P < .0001 BG mean = 177 for CII vs 213 for SC Multivariate analysis showed an independent protection from death with odds ratio of 0.5

26. Mortality Decrease with Portland Protocol – Furnary 2006

28. Outcomes and Perioperative Hyperglycemia After CABG Retrospective review of 1574 consecutive patients having CABG in 1998 & 1999 Perioperative glucose control was managed by individual physicians without a specific protocol 34.6% had prior diagnosis of diabetes Perioperative glucose = mean glucose from day of and day after surgery

29. Effect Of Hyperglycemia On LOS and Costs after CABG - Per 50mg/dl elevation -

31. Intensive Insulin Therapy in Critically Ill Patients 1548 patients enrolled in Surgical ICU study 62% CABG Randomized to iv insulin or control IV insulin started if blood glucose exceeded 110 mg/dl Goal of intensive therapy was to keep glucose 80-110. Control group started at 215 mg/dl & goal was 180-200 Intensive therapy (IT) reduced mortality, bacteremia, and dialysis Primary benefit was in those ? 5 days in the ICU Greatest benefit was in those with sepsis Only about 13% had previous diagnosis of diabetes.

34. Intensive Management Protocol Reduces Mortaility In A Medical-Surgical ICU Percent reductions were glucose > 200 mg/dL ? 56.3 % new renal insufficiency ? 75 % RBC transfusions ? 18.7 % mortality ? 29.3 % length of ICU stay ? 10.8 %

35. First AACE Consensus ConferenceOn Inpatient Diabetes and Metabolic Control December 14-15th, 2003 Attended by about 100 stakeholders Two days of presentations Presented a Position Statement at a press conference in DC on 12/16/2003 Co-sponsors: AADE ADA AHA ASA (anesthesiologists) SCCM (critical care) STS (thoracic surgery) Endocrine Society SHM (hospitalists) Participating Organiz.

36. Glycemic Targets in Hospitalized Patients ADA Targets Critically ill As close to 110 mg/dl as possible and usually under 180 mg/dl Noncritically ill Premeal glucose 90-130 mg/dl Postprandial glucose < 180 mg/dl AACE/ ACE Targets Intensive care unit 110 mg/dL Medical/surgical floors 110 mg/dL preprandial 180 mg/dL maximal glucose Glycemic Targets in Hospitalized Patients Depending on the indication and setting, different glycemic thresholds for the initiation of insulin are recommended Intensive care unit 110 mg/dL (6.1 mmol/L) Medical/surgical floors 110 mg/dL (6.1 mmol/L) preprandial 180 mg/dL (10.0 mmo/L) maximal glucose Values above 180 mg/dL (10 mmol/L) are an indication to monitor glucose levels more frequently to determine the direction of any glucose trend and the need for more intensive intervention. Achieving these targets may require consultation with an endocrinologist or diabetes specialist. 1. AACE/ACE. American College of Endocrinology consensus statement on guidelines for glycemic control. Endocr Pract. 2002;8(suppl 2):5–11. Glycemic Targets in Hospitalized Patients Depending on the indication and setting, different glycemic thresholds for the initiation of insulin are recommended Intensive care unit 110 mg/dL (6.1 mmol/L) Medical/surgical floors 110 mg/dL (6.1 mmol/L) preprandial 180 mg/dL (10.0 mmo/L) maximal glucose Values above 180 mg/dL (10 mmol/L) are an indication to monitor glucose levels more frequently to determine the direction of any glucose trend and the need for more intensive intervention. Achieving these targets may require consultation with an endocrinologist or diabetes specialist. 1. AACE/ACE. American College of Endocrinology consensus statement on guidelines for glycemic control. Endocr Pract. 2002;8(suppl 2):5–11.

37. A Meta-Analysis of Randomized Trials Treating Critically Ill Patients with Insulin

38. Things Get More Complicated

39. Van den Berghe Medical ICU Study N = 1200 Considered to need ICU care for > 3 days Randomized to strict BG control (80 – 110 mg/dl vs. conventional tx. Results: overall no survival benefit Modest mortality reduction in patients in ICU > 3 days (52% ?43%)

40. Conclusion of From the MICU Study “ A reasonable approach would be to provide adequate exogenous insulin to achieve target glucose values < 150 mg/dl at least during the first three days… a goal of normoglycemia (80 – 110 mg/dl) could then be considered.”

41. Intensive Intraoperative Insulin Therapy versus Conventional Glucose Management during Cardiac SurgeryA Randomized Trial Gunjan Y. Gandhi, MD, MSc; Gregory A. Nuttall, MD; Martin D. Abel, MD et al. Annals Int Med; 20 February 2007; 146:233-243

52. Efforts to Validate The Goals Coming from the Van den Berghe Trials Glucontrol VISEP NICE-SUGAR

53. Glucontrol Study Mixed population of ICU patients N = ~3500, multicenter, Europe Target glucose: 80 – 110 mg/dl vs. 140 – 180 mg/dl Endpoint: in-hospital and 28 day mortality Start: October 2004

57. REASONS FOR DISCONTINUATION GLUCONTROL and VISEP High rate of hypoglycemia No beneficial effect on mortality

58. Why the Discrepant Data? ? Unable to replicate the tight control done in Belgium ? Fear of hypoglycemia ? Patients in Belgium are different

59. Normoglycemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation (NICE-SUGAR) Study 6100 ICU patients (Medical/Surgical) Targets: 81-108 mg/dl (4.5-6.0 mmol/L) < 180 mg/dl (< 10 mmol/L) Outcome: 90 day mortality

60. NICE-SUGAR Study 40% Women 60% Medical ICU / 40% Post-Op Mean Age 60 years 3882 patients enrolled Anticipated Completion mid-2008 Report results end 2008

61. Hyperglycemia Causing Injury in Critical Illness Is the mechanism of injury relevant for critical illness? What is the glucose threshold and time of exposure for injury to occur? Is it reversible and over what frame? Which patient subgroups are most vulnerable?

62. Proposed role of hyperglycemia and hypoinsulininemia in poor hospital outcomes. The metabolic stress of illness causes elevations in counterregulatory hormones. Hormonal elevations accelerate catabolism, hepatic glyconeogenesis, and lipolysis. The rise in circulating substrates further fuels hyperglycemia and blunts islet cell insulin secretory response via the mechanism of glucose toxicity. Hyperglycemia and relative hypoinsulinemia in turn triggers immune dysfunction, further elevates FFA’s, ketones, lactic acid, and accelerates ROS generation. Tissue and organ injury occurs via the combined insults of infection, direct fuel-mediated injury, and via oxidative stress and downstream mediators. Proposed role of hyperglycemia and hypoinsulininemia in poor hospital outcomes. The metabolic stress of illness causes elevations in counterregulatory hormones. Hormonal elevations accelerate catabolism, hepatic glyconeogenesis, and lipolysis. The rise in circulating substrates further fuels hyperglycemia and blunts islet cell insulin secretory response via the mechanism of glucose toxicity. Hyperglycemia and relative hypoinsulinemia in turn triggers immune dysfunction, further elevates FFA’s, ketones, lactic acid, and accelerates ROS generation. Tissue and organ injury occurs via the combined insults of infection, direct fuel-mediated injury, and via oxidative stress and downstream mediators.

63. Plausible Targets for Glucose-Mediated Injury in ICU

64. Plausible Mechanisms for Glucose-Mediated Injury in the ICU Glucose Toxicity Alternate Fuels (FFA’s, Lactate, Ketones) Oxidative Stress

65. Glucotoxicity (Glucose Toxicity) B Cells normally function within a narrow range of plasma glucose Modestly higher glucose creates an unnatural environment Leads to alteration in function, the most notably the loss of acute glucose-stimulated insulin release

66. Five Stages of Progression of Diabetes

67. Effect of One Week of Hyperglycemia on Isolated Rat Islets

68. Effect of One Week of Hyperglycemia on Isolated Rat Islets

69. Mechanism of Glucose Toxicity of B Cell Depletion of Insulin Stores (Acute) Oxidative Stress ?Activation of Jun N-terminal Kinase (JNK) pathway Decreased PDX-1 expression and activity Down-regulation of genes: Insulin GLUT2 glucokinase

70. Evidence for Glucose Toxicity in Acute Illness DKA in Type 2 DM* 1st phase insulin response is restored after 20 hours of normoglycemia by intravenous insulin infusion**

71. Glucose Toxicity in Critically Ill Patient Is the mechanism of injury relevant for critical illness? What is the glucose threshold and exposure time necessary for injury to occur? Is it reversible? Over what time frame? Which patient subgroup(s) are more/less vulnerable?

72. Alternate Fuels (FFA’s, Ketones, Lactate) Production in ICU Patients FFA’s are toxic to ischemic myocardium Hypothesis:Suppression of FFA’s w/ insulin in a glucose/insulin/potassium (GIK) infusion will improve outcomes in patients with ST elevation myocardial infarction CREATE-ECLA study

73. CREATE ECLA Study Randomized 20,201 patients with ST-elevation AMI Intervention 24 hrs GIK infusion of: 25% Glucose/50 U/L insulin/80 mEq/L K Infused at rate of 1.5 cc/kg/hr Results: No benefit in 30 day mortality Caveat: Glucose levels at 6 hours 187 mg/dl w/GIK 148 mg/dl w/control

74. CREATE ECLA Study “Acute hyperglycemia negates the beneficial effects of insulin..”1 “Glycemia-independent actions of insulin evoked increased myocardial contractility occur only when normoglycemia was maintained”2

75. Oxidative Stress in ICU Patients Likely the most important mechanism for hyperglycemia-induced cellular injury

79. Oxidative Stress in Critically Ill Patient Is the mechanism of injury relevant for critical illness? What is the glucose threshold and exposure time necessary for injury to occur? Is it reversible? Over what time frame? Which patient subgroup(s) are more/less vulnerable?

80. Plausible Targets for Glucose-Mediated Injury in ICU

86. Insulin-glucose interactions Insulin makes glucose pro-thrombotic Hyperglycemia negates the anti-thrombotic effect of insulin Concentrated dextrose infusion activates coagulation cascade Lessons: When using insulin infusion, control the glucose Use the minimum required dextrose infusion

87. Hyperglycemia Causing Thrombosis Is the mechanism of injury relevant for critical illness? What is the glucose threshold? Is it reversible? Which patient subgroup(s) are most vulnerable?

88. Interpreting Experimental and Epidemiologic Data Mechanism Research and Epidemiology Helps Determine What to Test, not How to Treat Hypothesis-Generating, not Hypothesis-testing Need additional large clinical trials

89. Is Intensive Insulin Therapy Safe? Increased risk for severe hypoglycemia BG < 40 mg/dl predicts high mortality i.e. multi-organ failure, hypoglycemia, death ? Impaired counterregulatory response Can iatrogenic hypoglycemia cause harm? ? Via stress response ? Via hypoglycemia “unawareness” Single episode may blunt counterregulatory response to future events Not all insulin infusion protocols are the same Frequency of BG testing Incorporate rate of change of BG, change in nutrition, method for glucose testing

90. My Summary of the Data Hyperglycemia is a modifiable culprit Multiple organs/tissues/organelles at risk Best Subgroup: Too early to tell Use dextrose infusion that has least injury to the vascular endothelium Iatrogenic Hypoglycemia also harmful Until more clinical trials, treat all patients to a glucose level as close to normal as possible using a very good protocol If hypoglycemia occurs: R/O adrenal insufficiency ? relax BG target for 6-7 days

91. Future:Comprehensive Metabolic Support Insulin Infusion w/ continuous glucose sensor ? Incretin Mimetic Tx (to suppress HGP) ? Adrenergic Blockade for all patients ? Recombinant IGF-1 Rx to overcome elevated IGFBP-1