1. Adrenal Insufficiency (AI) in the Septic Patient
Fady Youssef, MD PGY

2. 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.

3. 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

4. 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

5. 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 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

6. 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?

7. 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.

8. 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

9. 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.

10. 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

11. 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

12. 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