Corticosteroid Replacement in Critically Ill Patients

1. Corticosteroid Replacement in Critically Ill Patients Deepika Nehra, MSIV Trauma Conference July 10th 2006

2. Steroid Physiology

3. Basal Cortisol Production = 8-25 mg in 24hrs Production can be increased 6-fold in stress Diurnal pattern of cortisol production lost in stress situations Cortisol T1/2 = 70-120 minutes Bound to circulating CBG, albumin, ?1-acid glycoprotein 10% free = biologically active CBG decreases rapidly in critically ill pts ? increased free cortisol

4. Adrenal Insufficiency (AI) 1. Primary Adrenal Insufficiency (Addison�s) >90% destruction of adrenal cortex Causes: thrombosis, hemorrhage (septic shock with DIC), necrosis from ischemia Sxs: truncal pain, fever, shaking chills, hypotension, shock, abdominal rigidity or rebound, dehydration, hyponatremia, hyperkalemia, elevated BUN Failure to recognize and tx severe adrenal insufficiency (addisonian crisis) can be fatal within 6-48 hours

5. Adrenal Insufficiency (AI) 2. Secondary Adrenal Insufficiency Pituitary or hypothalamic abnormalities Causes: empty sella syndrome, tumors, hypopituitarism, head trauma, postpartum pituitary necrosis, exogenous glucocorticoid use Sxs: similar to primary AI but with preserved aldosterone (no Na, K abnormalities)

6. Adrenal Insufficiency (AI) 3. Relative or Functional AI (1) Reported in critically ill pts Subnormal adrenal corticosteroid production Hypoadrenal state without clearly defined defects in hypothalamic-pituitary-adrenal axis Difficult to define based on serum cortisol concentrations as cortisol production may be inadequate to control inflammatory response or meet an elevated metabolic demand Characteristic rapid improvement on HC thx

7. Diagnosis of Adrenal Insufficiency High-dose corticotropin stimulation test Can be done at any time of day Baseline cortisol ? 250?g cosyntropin ? measure cortisol at 30 and 60 minutes Nonstressed pt: increase to ?18 ?g /dL r/o AI Hi sensitivity & specificity for primary AI using threshold value of 15 ?g /dL Less sensitive for secondary AI

8. Diagnostic Clues in Critically Ill Patients Persistent hypotension despite adequate volume resuscitation Hyperdynamic circulation and low SVR Ongoing e/o inflammation w/o obvious source that does not respond to empiric treatment

9. Lab test difficulties in critical illness Cortisol level interpretation complicated by: Hard to define �normal� ranges as expected levels vary based on disease & severity Reduced CBG Changes in tissue resistance to cortisol Local release of free cortisol Etomidate use for intubation

10. Random Cortisol Level Poor prognosis in septic shock patients: (4) extremely HIGH (>34?g/dL) total cortisol extremely LOW (<25?g/dL) total cortisol Interpretation of Baseline Cortisol = Controversial Cortisol level <15?g/dL suggested to ID pts with clinical features of AI or who would benefit from replacement (2) Others suggest that a pt w/ septic shock on vasopressors should have baseline cortisol of >25 ?g/dL if measured w/i 48 hrs of admit (3)

11. Cosyntropin Stimulation Advocated as standard of diagnosis of AI in critically ill pts (5) Failure to increase cortisol concentration at least 9 ?g/dL to value >20 ?g/dL associated w/ Increased mortality Lack response to catecholamines Disagreement on threshold of basal concentration and change in cortisol with stimulation necessary to diagnose relative AI

12. Outcome of steroid replacement Cochrane Database Meta-analysis in 2004 (6) 15 trials ? no significant reduction in all-cause mortality at 28 days w/ steroid replacement in septic shock 4 trials ? reduced mortality & increased shock reversal with long courses of low dose steroids Another Meta-analysis in 2004 (7) Short courses of high-dose steroids decreased survival during sepsis But a 5- to 7-day course of physiologic hydrocortisone doses with subsequent tapering increased survival rate and shock reversal in patients with vasopressor-dependent septic shock

13. Conclusion Patients with septic shock should have: Baseline cortisol measured Undergo corticotropin-stimulation testing Patients with inadequate cortisol response (baseline <15-25?g/dL and failure to increase by ?9?g/dL) benefit from glucocorticoid replacement HC at 200-300 mg/d recommended with intermittent or continuous IV infusion Steroids tx for 5-7days followed by taper (total treatment time of 10days)

14. References Bollaert PE. 2000. Stress doses of glucocorticoids in catecholamine dependency: a new therapy for a new syndrome?. Intensive care medicine 26 (1): 3-5. Cooper MS, Stewart PM. 2003. Corticosteroid insufficiency in acutely ill patients. The New England journal of medicine 348 (8): 727-734. Marik PE, Zaloga GP. 2003. Adrenal insufficiency during septic shock. Critical care medicine 31 (1): 141-145. Marik PE, Zaloga GP. 2002. Adrenal insufficiency in the critically ill: a new look at an old problem. Chest 122 (5): 1784-1796. Jacobi J. 2006. Corticosteroid replacement in critically ill patients. Critical care clinics 22 (2): 245-53, vi. Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y. 2004. Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis. BMJ 329 (7464): 480-480. Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C. 2004. Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose. Annals of internal medicine 141 (1): 47-56.