2. ICU Endocrine Issue CIRCI and Glycemic Control Paul Marik, MD, FCCM, FCCP Division of Pulmonary and CCM Thomas Jefferson University Philadelphia, PA

3. Slide 3 Learning Objectives To understand the physiology of cortisol production in stress and critical illness. To review the recommendations for the diagnosis and management of corticosteroid insufficiency in the ICU. To understand the role of insulin and glucose regulation in stress hyperglycemia. To appreciate the effects of intensive insulin therapy.

4. Slide 4 The Stress Response Biologic, physical, or psychologic stressors generally precipitate similar response – “general adaptation syndrome” Selye H. A syndrome produced by diverse nocuous agents. Nature 1936;138:32

5. Slide 5 The HPA Axis

6. Slide 6 Cortisol & the Stress Response Fight & flight response –Glucose – fuel –Hemodynamic reserve Suppress activated defense mechanisms –Prevent tissue damage –Prevent excessive inflammation

7. Slide 7 Glucocorticoids Regulate gene transcription in every cell CHO-lipid-protein metabolism Immune function Cytokine synthesis and action Synthesis of catecholamines Synthesis of adrenergic receptors Cardiac contractility Vascular tone Membrane permeability Many other functions…..

8. Slide 8 Cortisol Synthesis in Sepsis TNFTNF Endotoxin TNFTNF

9. Slide 9 Corticosteroid Insufficiency - CIRCI Severe sepsis, septic shock, and ARDS are characterized by relative corticosteroid insufficiency with an exaggerated pro-inflammatory response. Pro-inflammatory mediators Anti-inflammatory mediators Homeostasis Cortisol NF-kB Immune dysregulation

10. Slide 10 CIRCI Adrenal insufficiency in critical illness is best described by the term critical illness-related corticosteroid insufficiency (CIRCI). The terms absolute or relative adrenal insufficiency are best avoided in the context of critical illness and should be replaced by the term CIRCI. CIRCI is a dynamic process, i.e., patients may not have CIRCI on admission to the hospital/ICU but may develop CIRCI during the course of the illness.

11. Slide 11 CIRCI CIRCI is defined as inappropriate corticosteroid activity for the severity of the patient’s illness. Relative cortisol insufficiency –Suppression at any point in the HPA axis with inadequate corticosteroid release –Drugs or destruction of components of the HPA axis by hemorrhage or necrosis Tissue resistance Analogous to Type II Diabetes

12. Slide 12 Adrenergic receptors Catecholamine NF- κ B Increased pro-inflammatory mediators CIRCI – Clinical Manifestations

13. Slide 13 Who to Treat? RCT demonstrating benefit from “moderate-dose” steroids –General ICU patients (n=1) –Septic shock (n=6) –Severe sepsis (n=2) –ALI/ARDS (n=5) –Ventilator weaning (n=1) –AF prophylaxis post-cardiac surgery (n=7) Cohort studies suggesting benefit from “moderate-dose” steroids –Liver failure (n=2) –Pancreatitis (n=1) RCT demonstrating NO benefit from “moderate-dose” steroids –CORTICUS (n=1)

14. Slide 14 Indications for steroids ?? ARDS –Progressive disease after 48 hours management –PaO2/FiO2 < 150 Septic shock: – Norepi > 0.05 -0.1 ug/kg/min within 12 hours of onset Cirrhosis/liver failure Prevent post-extubation stridor –-ve cuff leak test CABG Failure to wean? Pancreatitis? Head injury/SAH?

15. Slide 15 The clinical benefit of corticosteroids depends upon the dose, the duration of therapy, and weaning strategy* *Old Chinese proverb

16. Slide 16 Dosing Strategy The dose of glucocorticoid should be sufficient to down-regulate the pro-inflammatory response without causing immune-paresis and interfering with wound healing. The duration of glucocorticoid therapy should be guided by the duration of CIRCI and the associated duration of systemic inflammation. Myopathy and an increased risk of superinfections are more common in patients receiving in excess of 350 mg hydrocortisone equivalents per day. While suppressing an exaggerated pro-inflammatory response, a dose of 200-350 mg hydrocortisone/day maintains helper T-cell responsiveness and innate immunity.

17. Slide 17 Crit Care Med. 2008;36:1937-1949.

18. Slide 18 Recommendations Dysfunction of the HPA axis in critical illness is best described by the term critical illness-related corticosteroid insufficiency (CIRCI). The terms absolute and relative adrenal insufficiency are best avoided in the context of critical illness. At this time, adrenal insufficiency in critical illness is best diagnosed by a delta cortisol (after 250 ug cosyntropin) of <9 ug/dL or a random total cortisol of <10 ug/dL. (2B) The use of free cortisol measurements cannot be recommended for routine use at this time. Although the free cortisol assay has advantages over the total serum cortisol, this test is not readily available. Furthermore, the normal range of the free cortisol in critically ill patients is currently unclear. (2B)

19. Slide 19 Recommendations The ACTH stimulation test should not be used to identify those patients with septic shock or ARDS who should receive GCs. (2B) Hydrocortisone should be considered in the management strategy of patients with septic shock, particularly those patients who have responded poorly to fluid resuscitation and vasopressor agents. (2B) Moderate-dose GC should be considered in the management strategy of patients with early severe ARDS (PaO2/FiO2 <200) and before day 14 in patients with unresolving ARDS. The role of GC in acute lung injury and less severe ARDS is less clear. (2B)

20. Slide 20 Recommendations In patients with septic shock, intravenous hydrocortisone should be given in a dose of 200 mg/day in four divided doses or as a continuous infusion at 10 mg/hour (240 mg/day). The optimal dosing regimen in patients with early severe ARDS is 1 mg/kg/day methylprednisolone as a continuous infusion. (1B) The optimal duration of GC treatment in patients with septic and early ARDS is unclear. However, based on published studies and pathological data, patients with septic shock should be treated for ≥7days before tapering, assuming there is no recurrence or signs of sepsis or shock. Patients with early ARDS should be treated for ≥14 days before tapering. (2B)

21. Slide 21 Recommendations GC treatment should be tapered slowly and not stopped abruptly. (2B) Treatment with fludrocortisone (50 ug orally once daily) is considered optional. (2B) Dexamethasone is not recommended for treatment of septic shock or ARDS.

22. Stress Hyperglycemia Role of Intensive Insulin Therapy

23. Slide 23 The Stress Response Cortisol Epinephrine Norepinephrine Glucagon Growth Hormone Prolactin Gluconeogenesis + Glycolysis = Stress Hyperglycemia

24. Slide 24 Stress Hyperglycemia Definition –Blood glucose >200 mg/dL (15%-20%) –Blood glucose >110 mg/dL (75%-97%) Etiology –Increased release of counter-regulatory hormones –Increased hepatic gluconeogenesis –Decreased insulin release –Insulin resistance

25. Slide 25 Hyperglycemia and Insulin  ROS, NADPH oxidase  TNF, IL-8,IL-6  TF, PAI-1 CATABOLIC  ROS, NADPH oxidase  TNF, IL-6  TF, PAI-1  NO synthase ANABOLIC Glucose Pro-inflammatory Insulin Anti-inflammatory

26. Slide 26 Insulin-Mediated Glucose Uptake: Muscle and Adipose Tissue

27. Slide 27 Once Upon a Time… by Greet Van den Berghe

28. Slide 28 Intensive Insulin Therapy Prospective unblinded RCT of 1,538 adult SICU patients –70% cardiothoracic Conventional –titrate glucose to 180-200 mg/dL Intensive – titrate glucose to 80-110 mg/dL Primary outcome –in-hospital mortality Secondary outcome –ICU mortality, days to weaning from MV, ICU and hospital LOS, new kidney injury, incidence of bacteremia Van den Berghe G et al. N Engl J Med. 2001;345:1359-1367.

29. Slide 29 Intensive Insulin Therapy Van den Berghe G et al. N Engl J Med. 2001;345:1359-1367.

30. Slide 30 Intensive Insulin Therapy in Critically Ill Patients ↓ Bloodstream infections by 46% ↓ ARF requiring dialysis or CRRT by 41% ↓ Critical illness polyneuropathy by 44% ↓ RBC transfusions by 50% Greater number of ventilator-free days Shorter ICU LOS Episodes of hypoglycemia (<40 mg/dL) –5.1% (IIT) vs. 0.8% (conventional) p <0.001 –No adverse consequences Van den Berghe G et al. N Engl J Med. 2001;345:1359-1367.

31. Slide 31 Van den Berghe G et al. Crit Care Med. 2003;31:359-366. ▲ BG > 150 mg/dL ● BG 110-150 mg/dL ■ BG < 110 mg/dL Outcome of Intensive Insulin Therapy

32. Slide 32 Mechanisms of Reduced Morbidity and Mortality with Insulin Lower glucose –Improved macrophage/monocyte function –Decreased superoxide function and improved mitochondrial function (liver, neurons) Higher insulin –Anti-inflammatory effects –Anabolic effects –Improved lipid levels –Improved endothelial function Van den Berghe G. J Clin Invest. 2004;114:1187-1195.

33. Slide 33 Insulin Improves Dyslipidemia Abnormal serum lipid profiles in critically ill –↑ triglyceride levels, ↓↓ HDL and LDL. IIT results in almost complete reversal of hypertriglyceridemia, ↑ HDL and LDL. Lipid effects may explain beneficial effect on mortality and organ failure in prolonged critical illness. Mesotten D et al. J Clin Endocrinol Metab. 2004;89:219-226.

34. Slide 34 Intensive Insulin Therapy and Outcome in ICU Practice 1,600 mixed ICU patients at Stamford Hospital, CT, “before and after” design –800 on conventional therapy –800 IIT (BG <140 mg/dL) Less strict glucose control employed to avoid inadvertent hypoglycemia ~ BG 131 mg/dL in IIT vs. 152 mg/dL in conventional Krinsley JS. Mayo Clin Proc. 2004;79:992-1000.

35. Slide 35 The Fairy Tale Continues…..

36. Slide 36 Intensive Insulin Therapy Prospective unblinded RCT of 1,200 adult MICU patients staying >3 days Conventional –titrate glucose to 180-200 mg/dL Intensive –titrate glucose to 80-110 mg/dL Primary outcome –in-hospital mortality Secondary outcome –ICU mortality, days to weaning from MV, ICU and Hospital LOS, new kidney injury, incidence of bacteremia Van den Berghe G et al. N Engl J Med. 2006;354:449-461.

37. Slide 37 Intensive Insulin Therapy Van den Berghe G et al. N Engl J Med. 2006;354:449-461.

38. Slide 38 Intensive Insulin Therapy Van den Berghe G et al. N Engl J Med. 2006;354:449-461. 80% calories by parenteral nutrition

39. Slide 39 Intensive Insulin Therapy IIT – 18.7% hypoglycemia Van den Berghe G et al. N Engl J Med. 2006;354:449-461.

40. Slide 40 Intensive Insulin Therapy ConventionalIntensive Hospital Mortality - ITT40%37.3% Hypoglycemia - ITT3.1%18.7% Hospital Mortality - hypoglycemia 73.3%61.9% Mortality at day 32.8%3.9% Van den Berghe G et al. N Engl J Med. 2006;354:449-461. Hypoglycemia increases risk of DEATH

41. Intensive Insulin Therapy Clinical Trials: Update

42. Slide 42 German Competence Network Sepsis (SepNet) Prospective, randomized, multicenter study of intensive vs. conventional insulin therapy on outcome in patients with severe sepsis/septic shock April 2003 - December 2005 488 patients (planned 600): –247 intensive insulin (80­110 mg/dL) –241 conventional (180­200 mg/dL) N Engl J Med. 2008;358:125-139.

43. Slide 43 VISEP Trial: Stopped in Late 2005 Conventional n= 241 Intensive Insulin n=247 Male61.9%49.8% Mean age, year64.9%63.8% Hypoglycemia4.1%17* Serious adverse events5.2%10.9%# 28-day mortality26%24.7% 90-day mortality35.4%39.7% * p=<0.001; # p<0.01

44. Slide 44 GLUCONTROL Prospective, multicenter RCT of adult patients 7 countries, 21 ICUs in 19 centers Intervention: –Intensive: titrate glucose to 80-110 mg/dL –Conventional: titrate glucose to 140-180 mg/dL Planning: –3,500 patients required to detect 4% ↓ in mortality –Interim analysis each 100 ICU deaths Study stopped on May 29, 2006 –Safety concern http://clinicaltrials.gov

45. Slide 45 GLUCONTROL Group A n=538 (IIT) Group B n=553 (CV) p value Mortality rate12.27%9.76%0.186 Death among patients with hypoglycemia (<40 mg/dL) 18.3%11.6%0.0002

46. Slide 46 Ann Intern Med. 2007;146:233-243.

47. Slide 47 Intensive Intraoperative Insulin Rx Ann Intern Med. 2007; 146:233-243.

48. Slide 48 Tight Glycemic Control – Unanswered Questions Ideal goal? –80 -110 mg/dL –100 -140 mg/dL –110 -150 mg/dL Elective surgical (cardiac) vs. medical Only in patients on TPN? Less tight first 3 days? How to measure blood glucose? –Accuracy of “Accuchecks” –Q12 simultaneous lab glucose measurements

49. Case Studies with Questions The following are case studies that can be used for review of this presentation. Review Cases Skip Case Studies

50. Slide 50 Case Presentation A 56-year-old gentleman status post-coronary artery bypass surgery develops a ventilator-associated pneumonia with bacteremia. Despite fluid resuscitation, he remains hemodynamically unstable. His urine output has decreased. He is currently receiving 20 μg/min of norepinephrine, 2.4 units/hour of vasopressin, and 5 μg/min of dobutamine.

51. Slide 51 Case Presentation His vital signs are notable for: –A CVP of 12 –BP of 90/30 mm Hg –SpO2 of 91% on an FIO2 of 80% –Temperature of 40 degrees Celsius His laboratory data are notable for: –WBC: 17,000/mm3 –Random cortisol: 9 μg/dL –Glucose: 217 mg/dL

53. Slide 53 Conclusion This concludes this presentation.