Endocrine

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Endocrine

  1. 1. Endocrine Issues in Critical Illness Paul Marik, MD, FCCM, FCCP Professor of Medicine Chief, Div. Pulmonary & CCM Thomas Jefferson University Philadelphia PA
  2. 2. Objectives <ul><li>Be able to identify the following: </li></ul><ul><li>Stress response </li></ul><ul><li>Pathophysiology of stress hyperglycemia </li></ul><ul><li>Immunomodulating properties of glucose and insulin </li></ul><ul><li>Benefits of tight glycemic control </li></ul><ul><li>Cortisol physiology and biosynthesis </li></ul><ul><li>HPA and the stress response </li></ul><ul><li>Evaluation of HPA in the critically ill </li></ul><ul><li>Adrenal physiology in sepsis </li></ul><ul><li>Steroid replacement in sepsis </li></ul>
  3. 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.
  4. 4. The Stress Response <ul><li>Activation of the hypothalamic-pituitary (HPA) axis </li></ul><ul><li>Activation of the sympatho-adrenal system </li></ul><ul><li>Activation of subset of vagal and sacral parasympathetic efferents to GUT </li></ul>
  5. 5. The Stress Response <ul><li>Activation of HPA axis </li></ul><ul><ul><li>Cortisol </li></ul></ul><ul><li>Epinephrine </li></ul><ul><li>Norepinephrine </li></ul><ul><li>Glucagon </li></ul><ul><li>Growth hormone </li></ul><ul><li>Prolactin </li></ul>
  6. 6. The Stress Response <ul><li>Cardiac output increases </li></ul><ul><li>Respiration increases </li></ul><ul><li>Blood flow directed to brain and skeletal muscle </li></ul><ul><li>Gluconeogenesis and catabolism </li></ul><ul><ul><li>fuel for brain, heart, muscles </li></ul></ul><ul><li>Endocrine programs of pleasure, growth, and reproduction shut down </li></ul>
  7. 7. Glucocorticoids and the Stress Response <ul><li>Increase blood glucose </li></ul><ul><ul><li>hepatic gluconeogenesis </li></ul></ul><ul><ul><li>adipose tissue glucose uptake </li></ul></ul><ul><li>Lipolysis - FFA release </li></ul><ul><li>Prototeolysis - AA release </li></ul><ul><li>Synthesis of catecholamines </li></ul><ul><li>Synthesis of adrenergic and angiotensin II receptors </li></ul><ul><li>Cardiac contractility </li></ul><ul><li>Vascular tone </li></ul>
  8. 8. Glucagon and Epinephrine Mediated - Gluconeogenesis
  9. 9. Glucagon and Epinephrine Mediated - Gylcolysis
  10. 10. Metabolic Consequence of the Stress Response <ul><li>Gluconeogenesis </li></ul><ul><li>Gylogenolysis </li></ul><ul><li>Proteolysis </li></ul><ul><li>Lipolysis </li></ul>HYPERGLYCEMIA
  11. 11. Critical illness-state characterized by a pathologically prolonged stress response
  12. 12. Acute Stress-Open Cholecystectomy
  13. 13. The Neuro-endocrine Response to Prolonged Critical Illness Van den Berghe G. J Clin End Metab. 1998;83:1827.
  14. 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.
  15. 15. Changes in the GH Axis During Critical Illness <ul><li>Loss of pulsatile GH secretion </li></ul><ul><li>Low IGF-1, IGFBP-3 </li></ul><ul><li>Inc GHBP </li></ul><ul><ul><li>recovery of GH resistance </li></ul></ul><ul><li>Inc. pulsatile GH secretion </li></ul><ul><ul><li>Mobilization fuel </li></ul></ul><ul><li>Low IGF-1, IGFBP-3 </li></ul><ul><ul><li>Dec anabolism </li></ul></ul><ul><li>Dec. GHBP </li></ul><ul><ul><li>GH resistance </li></ul></ul><ul><ul><li>Cytokine mediated </li></ul></ul><ul><ul><li>? Post-receptor JAK2 kinases </li></ul></ul>Acute Chronic
  16. 16. Stress Hyperglycemia <ul><li>Definition </li></ul><ul><ul><li>Blood glucose > 200 mg/dl (15 - 20%) </li></ul></ul><ul><ul><li>Blood glucose > 110mg/dl (75 - 97%) </li></ul></ul><ul><li>Etiology </li></ul><ul><ul><li>Increased release of counter-regulatory hormones </li></ul></ul><ul><ul><ul><li>- increased hepatic gluconeogenesis </li></ul></ul></ul><ul><ul><li>Decreased insulin release </li></ul></ul><ul><ul><li>Insulin resistance </li></ul></ul>
  17. 17. Insulin Mediated Glucose Uptake
  18. 18. Postulated Mechanism of Insulin Resistance in Sepsis
  19. 19. Hyperglycemia and Insulin <ul><li> ROS, NADPH oxidase </li></ul><ul><ul><li>Oxidative injury </li></ul></ul><ul><li> TNF, IL-8,IL-6 </li></ul><ul><li> TF, PAI-1 </li></ul><ul><li>CATABOLIC </li></ul><ul><li> ROS, NADPH oxidase </li></ul><ul><li> ICAM-1, MCP-1 </li></ul><ul><li> TNF, IL-6 </li></ul><ul><li> TF, PAI-1 </li></ul><ul><li> NO synthase </li></ul><ul><li>ANABOLIC </li></ul>Pro-inflammatory Anti-inflammatory Glucose Insulin
  20. 21. Glucose Toxicity
  21. 22. Conventional - 78% abnormal Intensive - 1% abnormal Hepatocyte
  22. 23. Conventional Intensive Conventional Intensive
  23. 24. <ul><li> ROS </li></ul><ul><li> ICAM-1 </li></ul><ul><li> MCP-1 </li></ul><ul><li> PAI-1 </li></ul>
  24. 26. < 110 mg/dl 110 -150 mg/dl >150 mg/dl
  25. 27. Intensive Insulin Therapy in Critically Ill Patients
  26. 28. Intensive Insulin Therapy in Critically Ill Patients 200g Dextrose
  27. 29. Intensive Insulin Therapy in Critically Ill Patients
  28. 30. Intensive Insulin Therapy in Critically Ill Patients Van den Berghe G. J Clin End Metab. 2004;89:219.
  29. 31. Intensive Insulin Therapy in Critically Ill Patients Van den Berghe G. J Clin End Metab. 2004;89:219.
  30. 32. Intensive Insulin Therapy in Critically Ill Patients Van den Berghe G. J Clin End Metab. 2004;89:219.
  31. 33. <ul><li>Regimen 1: 1L 30% sorbital and 1L 5% glucose </li></ul><ul><li>Regimen 2: 1L 50% and 1L 5% glucose insulin only BG > 270 mg/dl </li></ul><ul><li>Regimen 3: 1L 50% and 1L 5% glucose insulin to keep BG 72 - 144 mg/dl </li></ul>
  32. 34. JPEN. 2002;26:271.
  33. 35. Nitrogen grams JPEN. 1994;18:214.
  34. 36. <ul><li>Trauma meta-analysis </li></ul><ul><li>TEN (n = 92) versus TPN (n = 102) </li></ul><ul><li>Similar ATI, ISS, BEE, organ injuries </li></ul><ul><li>Goal: 0.2 - 0.25 g N/kg/d </li></ul>Hyperglycemia: TEN versus TPN Glucose mg/dl Moore FA, et al. Ann Surg. 1992;216:172.
  35. 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.
  36. 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
  37. 39. Glucose Control in the ICU <ul><li>Tight glycemic control </li></ul><ul><ul><li>insulin </li></ul></ul><ul><li>Early enteral nutrition </li></ul><ul><li>Slowly absorbed CHO </li></ul><ul><li>Permissive underfeeding </li></ul><ul><li>Omega 3 FA </li></ul><ul><li>High glucose load </li></ul><ul><li>High caloric intake </li></ul><ul><li>Poor glycemic control </li></ul><ul><li>Rapidly absorbed CHO </li></ul><ul><li>GH </li></ul><ul><li>TPN </li></ul><ul><li>Low omega 3FA </li></ul>THE GOOD THE BAD
  38. 40. Adrenal Insufficiency in the Critically Ill
  39. 41. Cortisol
  40. 42. The Hypothalamic-Pituitary-Adrenal Axis
  41. 43. GRE GRE
  42. 44. Steroid Hormone Receptor Trafficking Through the Nuclear Compartment HSP90 FKBP51 FKBP52 Dynein
  43. 46. 845 genes 1125 genes
  44. 47. Synthesis of Cortisol 80% exogenous 20% endogenous
  45. 48. HDL as Substrate Cholesterol for Steroidogenesis by Bovine Adrenal Cells Life Sciences. 1998;62:1387.
  46. 49. Scavenger Receptor, Type B, Class 1
  47. 50. Cortisol Synthesis
  48. 51. The Neuro-endocrine Response to Prolonged Critical Illness J Clin End Met. 1995;80:1238.
  49. 52. Decreased Cortisol Binding Globulin in “Acute” Illness
  50. 53. Free Serum Cortisol During the Post-op Period Determined by Mass Spectrometry Clin Chem Lab Med. 2003;41:146.
  51. 54. Hamrahian AH, et al. N Engl J Med. 2004;350:1629.
  52. 55. Baseline Serum-free Cortisol and Cosyntropin-Stimulated Serum-free Cortisol Concentrations in Two Groups of Critically Ill Patients and in Healthy Volunteers
  53. 56. “ Normal” Stress Response <ul><li>ACTH > 40 pg/dl </li></ul><ul><li>Cortisol level > 20 ug/dl </li></ul><ul><li>CBG  </li></ul><ul><li>Free cortisol  </li></ul><ul><li>Glucocorticoid receptor  </li></ul><ul><li>Androgen synthesis  </li></ul><ul><li>Aldosterone synthesis  </li></ul>
  54. 57. Cortisol and the Stress Response <ul><li>Fight and flight response </li></ul><ul><ul><li>Glucose – fuel </li></ul></ul><ul><ul><li>Hemodynamic reserve </li></ul></ul><ul><li>Suppress activated defense mechanisms </li></ul><ul><ul><li>Prevent tissue damage </li></ul></ul><ul><ul><li>Prevent excessive inflammation </li></ul></ul>
  55. 58. Adrenalectomy and Survival Following Hemorrhage Endocrinology. 1990;127:766.
  56. 59. Evaluation of Adrenal Function <ul><li>“ Gold Standard” - Stress Cortisol </li></ul><ul><li>When stress is not adequate: </li></ul><ul><ul><li>Provocative testing </li></ul></ul><ul><ul><ul><li>- Insulin hypoglycemia, metyrapone test </li></ul></ul></ul><ul><ul><li>CRH stimulation test </li></ul></ul><ul><ul><li>ACTH (corticotropin) stimulation test </li></ul></ul><ul><ul><ul><li>- Standard - 250 ug </li></ul></ul></ul><ul><ul><ul><li>- Low dose - 1 ug </li></ul></ul></ul>
  57. 60. Standard ACTH Test <ul><ul><li>Baseline cortisol </li></ul></ul><ul><ul><li>250 ug cosyntropin </li></ul></ul><ul><ul><li>1 hour level </li></ul></ul><ul><ul><ul><li>1 hour < 18 ug/dl (AI) </li></ul></ul></ul><ul><ul><ul><li> < 9 ug/dl - “Occult AI” </li></ul></ul></ul><ul><ul><ul><li>Annane - “Non responder” </li></ul></ul></ul>
  58. 61. Problems with Classic ACTH Test <ul><li>Bypasses the hypothalamus and pituitary </li></ul><ul><ul><li>unphysiological compared to endogenous stressor </li></ul></ul><ul><li>Produces supra-physiologic levels of ACTH </li></ul><ul><ul><li>serum levels 1000 x maximal normal stress levels </li></ul></ul><ul><li>Cutoff of 18 mcg/dl based on response to ACTH in nonstressed patients </li></ul><ul><li>Severely stressed patients may not increase levels further. </li></ul>
  59. 62. ~ 50% of healthy volunteers and stressed patients without evidence of HPA disease will have a  cortisol < 9ug/dl. Problems with Classic ACTH Test
  60. 64. 4 hour 12 hour Acad Emerg Med. 2001;8:1.
  61. 65. Low-dose Corticotropin Test J Clin End Metab. 1999;84:3648. ACTH
  62. 66. LD HD 18 ug/dl J Clin End Metab. 1995;80:1243.
  63. 67. Diagnosis of HPA Failure <ul><li>Clinical </li></ul><ul><li>High-dose (250 ug) cosyntropin stimulation test </li></ul><ul><li>Low-dose (1ug) cosyntropin stimulation test </li></ul><ul><li>Urinary cortisol (free) </li></ul><ul><li>Random “stress” cortisol (total s-cortisol) </li></ul><ul><li>Salivary cortisol (free) </li></ul><ul><li>Free cortisol index </li></ul><ul><li>Free cortisol </li></ul><ul><li>Intra-nuclear cortisol </li></ul><ul><li>Gene product </li></ul>
  64. 68. Adrenal Insufficiency in the Critically Ill – Clinical Presentation Adrenergic receptors Catecholamine NF-  B Hypotension Increased Proinflammatory Mediators Confusion Fever
  65. 69. Clinical Diagnosis of HPA Failure <ul><li>Hypotension </li></ul><ul><li>Hemodynamic instability </li></ul><ul><li>Fever </li></ul><ul><li>Unexplained confusion </li></ul><ul><li>Eosinophilia </li></ul><ul><li>Hypoglycemia </li></ul>
  66. 70. Reversible Adrenal Insufficiency of Sepsis
  67. 71. Sepsis and the HPA Axis Decreased glucocorticoid receptor synthesis and affinity
  68. 72. TNF and Cortisol Production Cortisol nmol/l Endocrinology. 1991;128:623.
  69. 74. T.Chol HDL LDL
  70. 76. Arterioscler Thromb. 1994;14:8.
  71. 78. Cortisol Synthesis in Sepsis TNF Endotoxin TNF
  72. 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.
  73. 80. Paul Marik & GaryZaloga 61% patients HPA failure
  74. 82. Study Description <ul><li>Design </li></ul><ul><ul><ul><li>Randomized, double-blind, placebo-controlled trial </li></ul></ul></ul><ul><ul><ul><li>19 ICUs France, 1995 - 1999 </li></ul></ul></ul><ul><li>Population – Septic Shock </li></ul><ul><ul><ul><li>Focus of infection + HR >90/min + fever/hypothermia </li></ul></ul></ul><ul><ul><ul><li>SBP < 90 mm Hg for 1 hour despite fluid /pressors </li></ul></ul></ul><ul><ul><ul><li>Randomization within 8 hours shock </li></ul></ul></ul><ul><li>Treatment Arms </li></ul><ul><ul><ul><li>Randomization to hydrocortisone 50mg IV q 6 + 50 ug fludrocortisone PO qd or matching placebo </li></ul></ul></ul>
  75. 83. Study Description <ul><li>Adrenal assessment </li></ul><ul><ul><ul><li>250 ug corticotropin test </li></ul></ul></ul><ul><ul><ul><li>Responders </li></ul></ul></ul><ul><ul><ul><ul><li> cortisol > 9 ug/dl </li></ul></ul></ul></ul><ul><ul><ul><li>Non-responders (occult adrenal insufficiency) </li></ul></ul></ul><ul><ul><ul><ul><li> cortisol  9 ug/dl </li></ul></ul></ul></ul><ul><li>End-points </li></ul><ul><ul><ul><li>28-day mortality </li></ul></ul></ul><ul><ul><ul><li>Time to vasopressor withdrawal </li></ul></ul></ul>
  76. 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
  77. 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
  78. 86. AJRCCM. 2003;167:512.
  79. 88. Conclusions <ul><li>Adrenal insufficiency (AI) common in ICU patients, especially those with sepsis. </li></ul><ul><li>Decreased synthesis of cortisol and release of ATCH mediated by cytokines, endotoxin, low HDL, etc. </li></ul><ul><li>Diagnosis of AI controversial - stress cortisol useful dx test in ICU </li></ul><ul><li>Treatment with replacement doses of hydrocortisone (50 - 100 mg q8) improves outcome. </li></ul>

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