What is the treatment approach for suspected adrenal insufficiency if Adrenocorticotropic hormone (ACTH) levels cannot be obtained?

Treatment Approach When ACTH Cannot Be Obtained

If ACTH levels cannot be obtained, proceed directly with clinical assessment and morning cortisol measurement, then initiate empiric treatment based on clinical severity while arranging ACTH stimulation testing for definitive diagnosis. 1

Immediate Clinical Decision-Making Without ACTH

Step 1: Assess Clinical Severity First

The absence of ACTH testing should never delay treatment in suspected adrenal insufficiency. Your clinical assessment determines the urgency:

• Severe symptoms (hypotension, collapse, vomiting, confusion): Give IV hydrocortisone 100 mg immediately without waiting for any laboratory results, followed by 100 mg every 6-8 hours plus IV 0.9% saline 1, 2
• Moderate symptoms (significant fatigue, nausea, weight loss): Start outpatient treatment at 2-3 times maintenance dose (hydrocortisone 30-50 mg daily in divided doses), then taper over 5-10 days 3, 1
• Mild symptoms (subtle fatigue, mild nausea): Begin physiologic replacement with hydrocortisone 15-20 mg daily in divided doses 3, 1

Step 2: Obtain Morning Cortisol Before Treatment (If Stable)

If the patient is clinically stable enough to wait:

• Draw morning (8 AM) serum cortisol before starting any glucocorticoid therapy 1
• Cortisol <250 nmol/L (<9 μg/dL) in the context of acute illness is virtually diagnostic of adrenal insufficiency and warrants immediate treatment 1, 2
• Cortisol 140-275 nmol/L (5-10 μg/dL) requires confirmatory testing but suggests adrenal insufficiency 1
• Cortisol >550 nmol/L (>18-20 μg/dL) makes adrenal insufficiency unlikely 1

Step 3: Arrange ACTH Stimulation Test for Definitive Diagnosis

The ACTH stimulation test (cosyntropin test) is the gold standard when ACTH levels are unavailable and can definitively diagnose adrenal insufficiency without requiring baseline ACTH measurement. 1

Protocol:

• Administer 0.25 mg (250 mcg) cosyntropin (Synacthen/Cortrosyn) intramuscularly or intravenously 1
• Measure serum cortisol at baseline and 30 minutes (and optionally 60 minutes) post-administration 1
• Peak cortisol <500-550 nmol/L (<18-20 μg/dL) is diagnostic of adrenal insufficiency 1, 2
• Peak cortisol >550 nmol/L (>18-20 μg/dL) rules out adrenal insufficiency 1

Critical caveat: If you need to treat urgently but still want diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays 1. However, dexamethasone lacks mineralocorticoid activity and is inadequate for primary adrenal insufficiency long-term 1.

Distinguishing Primary vs. Secondary Adrenal Insufficiency Without ACTH

Without ACTH levels, use these clinical and laboratory clues:

Suggests Primary Adrenal Insufficiency:

• Hyponatremia (90% of cases) PLUS hyperkalemia (50% of cases) 1, 2
• Hyperpigmentation (increased melanocyte-stimulating hormone from elevated ACTH) 2
• Salt craving 4
• More severe volume depletion 1

Suggests Secondary Adrenal Insufficiency:

• Hyponatremia WITHOUT hyperkalemia (mineralocorticoid function preserved) 1, 5
• History of chronic steroid use (≥20 mg prednisone daily for ≥3 weeks) 1
• Other pituitary hormone deficiencies or pituitary pathology 1
• No hyperpigmentation 5

Important pitfall: Do not rely solely on electrolytes—10-20% of primary adrenal insufficiency patients have normal electrolytes at presentation 1. Hyperkalemia is absent in 50% of primary cases 1.

Treatment Algorithm Based on Presumed Type

If Primary Adrenal Insufficiency is Suspected:

Glucocorticoid replacement:

• Hydrocortisone 15-25 mg daily in divided doses (typically 10 mg upon awakening, 5 mg at noon, 2.5-5 mg at 4 PM) 4, 2, 6
• Alternative: Cortisone acetate 25-37.5 mg daily in divided doses 4

PLUS Mineralocorticoid replacement:

• Fludrocortisone 0.05-0.1 mg once daily in the morning 2, 7
• Titrate based on blood pressure, serum sodium, potassium, and plasma renin (target upper half of reference range) 2

If Secondary Adrenal Insufficiency is Suspected:

Glucocorticoid replacement ONLY:

• Hydrocortisone 10-20 mg in the morning and 5-10 mg in the afternoon 2
• Do NOT give fludrocortisone—mineralocorticoid function is preserved in secondary adrenal insufficiency 2, 5

Essential Patient Education and Safety Measures

Regardless of whether ACTH was obtained, all patients require:

• Medical alert bracelet or necklace indicating adrenal insufficiency 1, 2
• Stress dosing instructions: Double dose for minor illness, triple for moderate illness, IV hydrocortisone 100 mg for severe illness 2
• Emergency injectable hydrocortisone 100 mg IM kit with self-injection training 1, 2
• Recognition of adrenal crisis symptoms: severe weakness, confusion, abdominal pain, vomiting, hypotension 2

Critical Pitfalls to Avoid

• Never delay treatment of suspected acute adrenal insufficiency to obtain ACTH or perform diagnostic testing—mortality is high if untreated 1, 2
• Never start thyroid hormone replacement before glucocorticoids in patients with concurrent hypothyroidism and suspected adrenal insufficiency, as this can precipitate adrenal crisis 3, 1
• Never use dexamethasone for long-term replacement in primary adrenal insufficiency—it lacks mineralocorticoid activity 1, 2
• Do not assume normal electrolytes rule out adrenal insufficiency—some patients have completely normal labs at presentation 1

Follow-Up Testing to Determine Etiology

Once the patient is stable on replacement therapy, obtain:

• 21-hydroxylase (anti-adrenal) autoantibodies to identify autoimmune primary adrenal insufficiency (85% of cases in Western populations) 1
• Adrenal CT imaging if autoantibodies are negative, to evaluate for hemorrhage, tumor, tuberculosis, or other structural causes 1
• MRI of the sella turcica if secondary adrenal insufficiency is suspected, to evaluate for pituitary pathology 8
• Very long-chain fatty acids (VLCFA) in males with negative antibodies to screen for adrenoleukodystrophy 1