ACTH Stimulation Test (Cosyntropin Test)
The high-dose ACTH stimulation test (cosyntropin 250 mcg IV or IM) is the most appropriate confirmatory test for adrenal insufficiency when morning cortisol is low but not definitively diagnostic. 1, 2
Why the ACTH Stimulation Test is the Gold Standard
The cosyntropin stimulation test is the definitive confirmatory test when initial cortisol measurements are indeterminate, with a sensitivity of 95% and specificity of 90% for diagnosing adrenal insufficiency 1
The FDA-approved protocol involves administering 0.25 mg (250 mcg) cosyntropin IV or IM, with cortisol measurements at baseline, 30 minutes, and 60 minutes post-administration 2
**A peak cortisol <18 mcg/dL (500-550 nmol/L) at 30 or 60 minutes is diagnostic of adrenal insufficiency**, while values >18-20 mcg/dL are considered normal 1, 2, 3
Test Protocol and Administration
Obtain baseline serum cortisol and ACTH levels before administering cosyntropin to help differentiate primary from secondary adrenal insufficiency 1, 2
Administer 0.25 mg cosyntropin by IV or IM injection, then measure cortisol at exactly 30 and 60 minutes post-administration 2
Morning testing is preferred but not strictly required for the ACTH stimulation test 1
A single 60-minute cortisol measurement is 99.7% concordant with the traditional full protocol and may be sufficient in many cases, though the FDA label recommends both 30 and 60-minute measurements 4, 2
Critical Pre-Test Considerations
Stop glucocorticoids and spironolactone on the day of testing, as these medications can falsely elevate cortisol levels and produce inaccurate results 2
Discontinue estrogen-containing medications 4-6 weeks before testing, as estrogens increase cortisol-binding globulin and artificially elevate total cortisol levels 2
Long-acting glucocorticoids may need to be stopped for longer periods before accurate testing can be performed 2
Interpreting Results to Distinguish Primary vs Secondary Adrenal Insufficiency
In primary adrenal insufficiency, expect low/absent cortisol response with elevated baseline ACTH levels (typically >2-fold upper limit of normal), often accompanied by hyponatremia and hyperkalemia 1, 5, 3
In secondary adrenal insufficiency, expect blunted cortisol response with low or inappropriately normal baseline ACTH levels 5, 3
The combination of baseline ACTH and the stimulated cortisol response allows definitive categorization of the type of adrenal insufficiency present 1, 5
High-Dose vs Low-Dose Testing
The high-dose (250 mcg) test is recommended over the low-dose (1 mcg) test due to easier practical administration, comparable diagnostic accuracy, and FDA approval 6, 2
Both high- and low-dose ACTH tests have similar diagnostic accuracy for secondary adrenal insufficiency, with likelihood ratios of 9.1 and 5.9 respectively in adults 6
The low-dose test requires dilution of the commercial preparation at bedside, making it less practical for routine clinical use 6
Critical Pitfall to Avoid
Never delay treatment of suspected acute adrenal crisis to perform diagnostic testing—if the patient is clinically unstable with hypotension, altered mental status, or severe symptoms, immediately administer IV hydrocortisone 100 mg and 0.9% saline resuscitation 1, 3
Draw blood for baseline cortisol and ACTH before giving hydrocortisone if possible, but do not delay treatment if the patient is critically ill 1
The absence of hyperkalemia does not rule out adrenal insufficiency, as it is present in only ~50% of cases 1
When Morning Cortisol Alone is Sufficient
Morning cortisol >13 mcg/dL reliably rules out adrenal insufficiency and no further testing is needed 7
Morning cortisol <5 mcg/dL with elevated ACTH in the setting of acute illness is diagnostic of primary adrenal insufficiency without need for stimulation testing 1, 3
Morning cortisol between 5-13 mcg/dL requires ACTH stimulation testing for definitive diagnosis 3, 7