Adrenal Insufficiency (AI) in the Septic Patient Fady Youssef, MD PGY-2 2014

Objectives Define adrenal insufficiency Understand who gets Relative adrenal insufficiency Review the current evidence Understand how to manage “Relative adrenal insufficiency” in the setting of sepsis.

Case Problem 68 yo male with PMH of HTN, HL and COPD presents to ER with AMS and cough with productive sputum for 1 day. T 39 degrees C, BP 70/35, HR 121, RR 21. He has been given 4L of NS and has been started on norepinephrine, with no improvement in his vitals. Which of the following next steps is most appropriate? A: Draw a random cortisol level B: Perform a high dose ACTH stimulation test C: Administer hydrocortisone D: Administer hydrocortisone with fludrocortisone E: None of the above Presenter to ask the audience for an answer and differ discussion till the end of the lecture

Definition Acute reversible dysfunction of the HPA axis in the setting of physiologic stress (e.g. sepsis, intra/post operative state) It is estimated that ___ % of critically ill patients suffer from HPA axis dysfunction 30% Symptoms of AI shock, abdominal pain, fever, nausea and vomiting, electrolyte disturbances and, occasionally, hypoglycemia

Who gets AI? Any patient in the setting of physiologic stress Etiology: Adrenal ACTH resistance Decreased responsiveness of the target tissue to glucocorticoids (GC) Secondary AI: 2/2 chronic steroid therapy (dose dependent) Certain meds: Etomidate, Phenytoin, Ketoconazole High suspicion for patients with PMH of transplant or rheumatologic d/o as they will be at a much higher risk for AI. Patients on > 20 mg of pred daily, for ex, will have a suppressed adrenal response to steroids. Less than 5 mg daily, their adrenals should be able to handle the stress. 5-15 mg daily could go either way Highlight Etomidate as some of our patients will be intubated in the ED for severe sepsis and will receive Etomidate and will go into shock subsequently

HPA Axis 2ry AI Where is the dysfunction occurring in secondary AI? Secondary AI: Impairment of the pituitary e.g. use of exogenous steroids, pituitary adenoma Primary AI: Impairment of the adrenal glands e.g. Addison disease Tertiary AI: Hypothalamic impairment 2ry AI Where is the dysfunction occurring in secondary AI?

Diagnosing Relative Adrenal Insufficiency Diurnal variation is LOST during physiological stress Lab assays of plasma cortisol concentration and ACTH stimulation test are unreliable in critically ill patients Random serum cortisol: Varies widely in critically ill patients. Increased mortality with both very low and very high cortisol levels There is are no reliable tests for diagnosing relative adrenal insufficiency.

So when to start steroid therapy? Low MAP or SBP: requiring vasopressors Response to vasopressors is irrelevant to whether steroids should be started or not All meta-analyses confirmed improved shock reversal with low-dose corticosteroid use (trials listed below for further reference) Responsiveness is defined as: maintaining MAP > 65 mmHg without vasopressor use within 1 day of starting hydrocortisone Don’t delay treatment for ACTH stim test Meta Anlayses: Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review. JAMA 2009 The effects of steroids during sepsis depend on dose and severity of illness: an updated meta-analysis. Clinical Micro Biol Corticosteroid therapy for severe sepsis and septic shock. JAMA 2009 Safety and efficacy of corticosteroids for the treatment of septic shock: A systematic review and meta-analysis. Clin Infectious Disease 2009

Treatment in sepsis Hydrocortisone: total of 200 – 300 mg over 24 hrs 50 – 100 mg q6-8h for 5-7 days with taper Patients receiving higher doses of steroids had worse outcomes (citation below) Fludrocortisone (a mineralocorticoid) has not been shown to help in relative adrenal insufficiency. Hydrocortisone seems to have sufficient mineralocorticoid activity COIITSS trial Minneci PC, Deans KJ, Banks SM, et al: Meta-analysis: The effect of steroids on survival and shock during sepsis depends on the dose.  Ann Intern Med  2004; 141:47-56. COIITSS (the Corticosteroids and Intensive Insulin Therapy for Septic Shock) trial: randomly assigned 509 patients with septic shock to receive either hydrocortisone plus fludrocortisone or hydrocortisone alone. There was no difference in any of the clinical outcomes.

Case Problem 68 yo male with pmxh of HTN, HL and COPD presents to ER with AMS and cough with productive sputum for 1 day. T 39 degrees C, BP 70/35, HR 121, RR 21. He has been given 4L of NS and has been started on norepinephrine, with no improvement in his vitals. Which of the following next steps is most appropriate? A: Draw a random cortisol level B: Perform a high dose ACTH stimulation test C: Administer hydrocortisone D: Administer hydrocortisone with fludrocortisone E: None of the above C A random cortisol level will not change your management but it could shed some light re: mortality ACTH test is unreliable in septic patients and should not be a reason to delay starting steroid therapy Fludrocortisone has not been shown to improve outcomes

Summary No diagnostic test is reliable for relative adrenal insufficiency. Low threshold to treat relative adrenal insufficiency in patients with septic shock Use low dose hydrocortisone/physiologic dosing for a limited time Fludrocortisone has not been shown to help in relative AI

Interested? Here is more … HPA axis – Normal response Physiological stress activates the HPA axis which in turn increases serum cortisol levels Serum Cortisol levels remain elevated during stress due to several factors: Reduced activity of cortisol metabolizing enzymes Renal dysfunction prolonging the half life Decrease in cortisol-binding globulin and albumin which brings > 90% of cortisol Inflammatory cytokines: Increase GC receptor affinity and increase the peripheral conversion of precursors to cortisol