For a patient with suspected adrenal insufficiency and a morning plasma cortisol of 3.2 µg/dL, should I order a rapid ACTH (cosyntropin) stimulation test?

Yes, order the ACTH stimulation test immediately—a morning cortisol of 3.2 µg/dL is highly suggestive of adrenal insufficiency and requires confirmatory testing.

With a morning plasma cortisol of 3.2 µg/dL (well below the 5 µg/dL threshold), you should proceed with a cosyntropin stimulation test to confirm the diagnosis of adrenal insufficiency, unless the patient is acutely ill, in which case you should treat first and test later. 1

Diagnostic Approach

Interpretation of the 3.2 µg/dL Morning Cortisol

A morning cortisol of 3.2 µg/dL falls into the diagnostic gray zone that mandates further testing:

• **Cortisol <5 µg/dL (140 nmol/L)** combined with elevated ACTH (>2-fold above upper limit) is highly suggestive of primary adrenal insufficiency 1
• This level is too low to rule out adrenal insufficiency but not definitively diagnostic on its own
• Values <1.5 µg/dL are almost always pathologic, while your patient's 3.2 µg/dL requires confirmation 2

Next Steps: Order Both ACTH and Cosyntropin Test

Simultaneously obtain:

1. Plasma ACTH level - Draw this before any treatment if possible. An ACTH >66 pmol/L with low cortisol confirms primary adrenal insufficiency 1
2. Cosyntropin stimulation test - This is the gold standard confirmatory test 1

Cosyntropin Stimulation Test Protocol

Standard Test Administration 3

• Dose: 250 µg IV or IM (standard high-dose)
• Timing: Obtain baseline cortisol (already done), then measure at 30 and 60 minutes post-injection
• Interpretation: Peak cortisol <18 µg/dL at either 30 or 60 minutes suggests adrenal insufficiency 3

Important caveat: Newer monoclonal antibody assays may have different thresholds (14.5-17.0 µg/dL depending on the assay), so know your laboratory's specific cutoff 4, 2, 5. The FDA label uses 18 µg/dL, but recent evidence suggests 15.6 µg/dL may be more appropriate for newer assays 2.

Pre-Test Medication Management 3

Stop these medications before testing:

• Glucocorticoids and spironolactone on the day of testing
• Long-acting glucocorticoids may need longer washout
• Estrogen-containing drugs should be stopped 4-6 weeks prior (they elevate cortisol-binding globulin, falsely elevating total cortisol)

Exception: If the patient is acutely ill with signs of adrenal crisis, do NOT delay treatment for testing.

Critical Clinical Decision Point: Is the Patient Acutely Ill?

If Patient Has Severe Symptoms (Adrenal Crisis)

Signs to look for 1:

• Volume depletion or hypotension
• Hyponatremia or hyperkalemia
• Unexplained fever or abdominal pain
• Hypoglycemia (especially in children)
• Hyperpigmentation

If present:

1. Draw blood for baseline cortisol and ACTH immediately
2. Start IV hydrocortisone at stress doses WITHOUT waiting for test results
3. Perform cosyntropin test later after stabilization (can be done after temporary cessation of hydrocortisone) 1

Rationale: Delayed treatment increases morbidity and mortality. The diagnosis can be confirmed later, but treatment cannot wait 1.

If Patient Is Stable

Proceed with outpatient cosyntropin stimulation test as described above. The test can be performed at any time of day (not affected by diurnal variation) 1.

Common Pitfalls to Avoid

1. Don't rely on morning cortisol alone: While 3.2 µg/dL is concerning, confirmatory testing is recommended unless results are "absolutely unequivocal" 1

2. Check for confounding factors 3:

   • Oral contraceptives/estrogen therapy (increases CBG, falsely elevates cortisol)
   • Hypoalbuminemic states (cirrhosis, nephrotic syndrome—decreases CBG, falsely lowers cortisol)
   • Recent glucocorticoid use

3. Know your assay: The traditional 18 µg/dL cutoff was established with older polyclonal antibody assays. Newer monoclonal assays may require lower thresholds (15.6-17.0 µg/dL) 4, 2, 5

4. Don't order the 1 µg low-dose test: It provides no better diagnostic accuracy than the standard 250 µg test and adds complexity 1. Use it only if cosyntropin is in short supply 1.

Practical Efficiency Note

Recent evidence suggests a single 60-minute cortisol measurement may be sufficient (99.7% concordant with full testing), potentially eliminating the need for the 30-minute draw 6. However, the standard remains baseline, 30-minute, and 60-minute measurements 3.