How to interpret an adrenocorticotropic hormone (ACTH) stimulation test in a critically ill patient with end-stage renal disease (ESRD), severe hypoglycemia, and hypoalbuminemia, who has a baseline morning serum cortisol level of 17 and no response to ACTH stimulation?

Interpretation of ACTH Stimulation Test in This Critically Ill Patient

Direct Answer

This patient has Critical Illness-Related Corticosteroid Insufficiency (CIRCI) based on the flat cortisol response (delta cortisol = 0 μg/dL) to ACTH stimulation, and should receive stress-dose hydrocortisone 200-300 mg/day immediately, regardless of the baseline cortisol level of 17 μg/dL. 1

Key Diagnostic Interpretation

The Flat Response Indicates CIRCI

• A delta cortisol of <9 μg/dL after ACTH stimulation defines CIRCI in critically ill patients 1, 2
• Your patient has a delta of 0 μg/dL (17 → 17 → 17), which is profoundly abnormal and diagnostic 1
• The baseline cortisol of 17 μg/dL is misleading and should not reassure you—this is the critical pitfall 3

Why the Baseline Cortisol is Misleading

The measured total cortisol of 17 μg/dL significantly overestimates actual cortisol activity in this patient due to severe hypoalbuminemia (albumin 2.2). 1

• Over 90% of circulating cortisol is bound to cortisol-binding globulin (CBG) and albumin 1
• With albumin of 2.2 and ESRD, the free (biologically active) cortisol is likely much lower than the total cortisol suggests 1, 3
• Free cortisol <50 nmol/L (~1.8 μg/dL) at baseline or <86 nmol/L after ACTH indicates adrenal insufficiency in critically ill patients 1
• Standard immunoassays measuring total cortisol will overestimate adrenal function in hypoalbuminemic patients 1

The Complete Lack of Response is the Critical Finding

• The adrenal glands failed to respond at all to maximal ACTH stimulation—this is pathologic regardless of baseline level 1, 2
• Normal adrenal glands should increase cortisol production by at least 9 μg/dL, typically reaching >18-20 μg/dL post-stimulation 2, 4
• A flat response indicates the adrenals cannot mount an appropriate stress response 1, 5

Clinical Context Supporting CIRCI Diagnosis

Multiple Risk Factors Present

• Severe illness with hypoglycemia, poor oral intake, and ESRD creates maximal physiological stress 6
• Hypoglycemia itself can be a presenting manifestation of adrenal insufficiency 6
• ESRD patients can have atypical presentations of adrenal failure—hypertension and normal electrolytes do not exclude the diagnosis 6
• Malnutrition and critical illness suppress the hypothalamic-pituitary-adrenal axis 5, 3

Why Electrolytes May Be Normal

• ESRD and dialysis mask the typical hyperkalemia and hyponatremia of adrenal insufficiency 6
• Do not rely on electrolyte abnormalities to diagnose adrenal insufficiency in dialysis patients 6

Immediate Management Recommendations

Start Hydrocortisone Now

Administer hydrocortisone 200-300 mg/day (50 mg IV every 6 hours or continuous infusion) immediately without waiting for further testing. 1, 4

• The 2017 SCCM/ESICM guidelines recommend the 250-μg ACTH stimulation test for CIRCI diagnosis, and your patient meets diagnostic criteria 1
• Treatment should never be delayed for diagnostic procedures when adrenal crisis is suspected 2
• Continue hydrocortisone until the acute illness resolves and vasopressors (if being used) are no longer required 1

Taper When Stable

• Taper steroids gradually over several days once the patient is clinically stable and off vasopressors 1
• Abrupt cessation can cause hemodynamic and immunologic rebound 1
• No fixed duration is superior, but 3-7 days is typical 1

Important Caveats and Pitfalls

Do Not Repeat the ACTH Stimulation Test

• ACTH stimulation test results are poorly reproducible in critically ill patients, particularly those in shock 7
• A single test showing no response is sufficient for diagnosis and treatment decisions 7
• Repeating the test within 24 hours shows poor correlation and adds no useful information 7

The Concept of "Relative" vs "Absolute" Insufficiency is Outdated

• Modern understanding shows that decreased cortisol breakdown (not increased production) elevates cortisol levels in critical illness 5, 3
• Sustained feedback inhibition of ACTH from elevated total cortisol impairs adrenocortical function over time 5
• The flat ACTH response indicates true adrenal dysfunction, not just "relative" insufficiency 5, 3

Monitor for Hyperglycemia

• Hydrocortisone will worsen hyperglycemia 1
• Use continuous infusion rather than bolus dosing to minimize glucose fluctuations 1
• Adjust insulin accordingly but do not withhold necessary corticosteroid therapy 1

Address the Hypoglycemia Simultaneously

• The hypoglycemia may improve with hydrocortisone, but also requires nutritional support 6
• Cortisol is essential for gluconeogenesis and maintaining blood glucose during fasting 6
• Consider enteral or parenteral nutrition if oral intake remains poor 6