1. Endocrine Issues in Critical Illness Paul Marik, MD, FCCM, FCCP Professor of Medicine Chief, Div. Pulmonary & CCM Thomas Jefferson University Philadelphia PA

3. 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.

8. Glucagon and Epinephrine Mediated - Gluconeogenesis

9. Glucagon and Epinephrine Mediated - Gylcolysis

11. Critical illness-state characterized by a pathologically prolonged stress response

12. Acute Stress-Open Cholecystectomy

13. The Neuro-endocrine Response to Prolonged Critical Illness Van den Berghe G. J Clin End Metab. 1998;83:1827.

14. The Neuro-endocrine Response to Prolonged Critical Illness Nocturnal profile Normal Acute illness Chronic critical illness Van den Berghe G. J Clin End Metab. 1998;83:1827.

17. Insulin Mediated Glucose Uptake

18. Postulated Mechanism of Insulin Resistance in Sepsis

21. Glucose Toxicity

22. Conventional - 78% abnormal Intensive - 1% abnormal Hepatocyte

23. Conventional Intensive Conventional Intensive

26. < 110 mg/dl 110 -150 mg/dl >150 mg/dl

27. Intensive Insulin Therapy in Critically Ill Patients

28. Intensive Insulin Therapy in Critically Ill Patients 200g Dextrose

29. Intensive Insulin Therapy in Critically Ill Patients

30. Intensive Insulin Therapy in Critically Ill Patients Van den Berghe G. J Clin End Metab. 2004;89:219.

31. Intensive Insulin Therapy in Critically Ill Patients Van den Berghe G. J Clin End Metab. 2004;89:219.

32. Intensive Insulin Therapy in Critically Ill Patients Van den Berghe G. J Clin End Metab. 2004;89:219.

34. JPEN. 2002;26:271.

35. Nitrogen grams JPEN. 1994;18:214.

37. Physiologic Effects of Enteral and Parenteral Feeding on Pancreaticobiliary Secretion in Humans Glucose Insulin O’Keefe SJ, et al. Am J Physiol. 2003;284:G27.

38. Glucose greater in GH group, p < 0.001 Nitrogen retention greater in GH group, p = 0.002 Multi-national study (n = 280) Finnsh Study (n = 242) < 0.001 44% 18% < 0.001 39% 20% p GH Placebo

40. Adrenal Insufficiency in the Critically Ill

41. Cortisol

42. The Hypothalamic-Pituitary-Adrenal Axis

43. GRE GRE

44. Steroid Hormone Receptor Trafficking Through the Nuclear Compartment HSP90 FKBP51 FKBP52 Dynein

46. 845 genes 1125 genes

47. Synthesis of Cortisol 80% exogenous 20% endogenous

48. HDL as Substrate Cholesterol for Steroidogenesis by Bovine Adrenal Cells Life Sciences. 1998;62:1387.

49. Scavenger Receptor, Type B, Class 1

50. Cortisol Synthesis

51. The Neuro-endocrine Response to Prolonged Critical Illness J Clin End Met. 1995;80:1238.

52. Decreased Cortisol Binding Globulin in “Acute” Illness

53. Free Serum Cortisol During the Post-op Period Determined by Mass Spectrometry Clin Chem Lab Med. 2003;41:146.

54. Hamrahian AH, et al. N Engl J Med. 2004;350:1629.

55. Baseline Serum-free Cortisol and Cosyntropin-Stimulated Serum-free Cortisol Concentrations in Two Groups of Critically Ill Patients and in Healthy Volunteers

58. Adrenalectomy and Survival Following Hemorrhage Endocrinology. 1990;127:766.

62. ~ 50% of healthy volunteers and stressed patients without evidence of HPA disease will have a  cortisol < 9ug/dl. Problems with Classic ACTH Test

64. 4 hour 12 hour Acad Emerg Med. 2001;8:1.

65. Low-dose Corticotropin Test J Clin End Metab. 1999;84:3648. ACTH

66. LD HD 18 ug/dl J Clin End Metab. 1995;80:1243.

68. Adrenal Insufficiency in the Critically Ill – Clinical Presentation Adrenergic receptors Catecholamine NF-  B Hypotension Increased Proinflammatory Mediators Confusion Fever

70. Reversible Adrenal Insufficiency of Sepsis

71. Sepsis and the HPA Axis Decreased glucocorticoid receptor synthesis and affinity

72. TNF and Cortisol Production Cortisol nmol/l Endocrinology. 1991;128:623.

74. T.Chol HDL LDL

76. Arterioscler Thromb. 1994;14:8.

78. Cortisol Synthesis in Sepsis TNF Endotoxin TNF

79. ACTH Response During Septic Shock and after Recovery (in patients with HPA failure) 13 of 20 patients BL < 25 mg/dl Intensive Care Med. 1996;22:894.

80. Paul Marik & GaryZaloga 61% patients HPA failure

84. Hydrocortisone Increases Survival in Septic Shock 30% RRR of death Time (days) Survival (%) 0 7 14 21 28 0 20 40 60 80 100 Placebo Treatment p = 0.0096 n = 299

85. Hydrocortisone Infusion in Patients with Severe CAP: A RCT AJRCCM. 2005;171:242. 0.007 4 10 Duration ventilation 0.009 0 7 (30%) Hosp Mortality 0.03 13 21 Hosp LOS 0.04 8 (35%) 16 (70%) Dev. MODS P value Hydro-cortisone Placebo n = 46

86. AJRCCM. 2003;167:512.