Cosyntropin Stimulation Test
What It Is and Why It's Done
The cosyntropin stimulation test is the gold standard diagnostic test for evaluating adrenal insufficiency, involving administration of synthetic ACTH (cosyntropin) to assess whether the adrenal glands can produce adequate cortisol in response to stimulation. 1, 2
The test is indicated for screening suspected primary or secondary adrenal insufficiency in both adults and children 2. It's particularly valuable when:
- Morning cortisol levels are indeterminate (neither clearly normal nor clearly diagnostic) 1
- Distinguishing between primary adrenal insufficiency (adrenal gland failure with high ACTH) and secondary adrenal insufficiency (pituitary/hypothalamic failure with low ACTH) 3
- Evaluating hypo-osmolar hyponatremia where adrenal insufficiency can mimic SIADH 1, 3
- Assessing patients receiving immune checkpoint inhibitor therapy for possible hypophysitis 3
Test Protocol
Standard Dosing
The FDA-approved high-dose protocol uses 0.25 mg (250 mcg) cosyntropin administered intravenously or intramuscularly. 1, 2
For pediatric patients 2:
- 0.125 mg for patients birth to less than 2 years of age
- 0.25 mg for patients 2 to 17 years of age
Timing of Blood Samples
Obtain serum cortisol measurements at baseline (before injection) and at exactly 30 and 60 minutes after cosyntropin administration. 1, 2
The test can be performed at any time of day, though morning testing is preferred but not strictly necessary 1. Fasting is not required 1.
Pre-Test Medication Management
Critical medication adjustments before testing 1, 2:
- Stop glucocorticoids on the day of testing (hydrocortisone must be held for 24 hours; other steroids require longer washout periods) 1, 2
- Stop spironolactone on the day of testing 2
- Stop estrogen-containing drugs 4-6 weeks before testing (elevates cortisol-binding globulin and falsely elevates total cortisol) 2
- Long-acting glucocorticoids require extended discontinuation periods before testing 2
Exception: If adrenal crisis is suspected, use dexamethasone 4 mg IV instead of hydrocortisone for emergency treatment, as dexamethasone does not interfere with cortisol assays and allows subsequent diagnostic testing 1.
Interpretation of Results
Diagnostic Thresholds
Peak cortisol >500-550 nmol/L (>18-20 μg/dL) at either 30 or 60 minutes is normal and excludes adrenal insufficiency. 1, 4
Peak cortisol <500 nmol/L (<18 μg/dL) at 30 or 60 minutes is diagnostic of adrenal insufficiency. 1, 4
Distinguishing Primary from Secondary Adrenal Insufficiency
After confirming adrenal insufficiency with the stimulation test, measure baseline ACTH levels 1:
- Primary adrenal insufficiency: Low cortisol with elevated ACTH, often accompanied by hyponatremia and hyperkalemia (though hyperkalemia occurs in only ~50% of cases) 1, 3
- Secondary adrenal insufficiency: Low cortisol with low or inappropriately normal ACTH 1, 4
Test Performance Characteristics
The test performs excellently for primary adrenal insufficiency with 97% sensitivity at 95% specificity. 5
For secondary adrenal insufficiency, sensitivity is lower at 57% for the 250-mcg test, with a positive likelihood ratio of 11.5 and negative likelihood ratio of 0.45. 5 This means if clinical suspicion remains high despite a normal test, additional hypothalamic-pituitary axis testing may be needed 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. 1, 4 The low-dose test requires bedside dilution of the commercial preparation, making it less practical for routine use 1. Both tests have similar operating characteristics for secondary adrenal insufficiency 5.
Critical Pitfalls to Avoid
Never delay treatment of suspected acute adrenal crisis for diagnostic testing—mortality is high if untreated. 1, 3 If the patient is clinically unstable with unexplained hypotension, collapse, or gastrointestinal symptoms, immediately administer IV hydrocortisone 100 mg and 0.9% saline infusion at 1 L/hour 1.
Do not rely solely on electrolyte abnormalities for diagnosis. Hyponatremia is present in 90% of newly diagnosed adrenal insufficiency cases, but hyperkalemia occurs in only ~50% of cases 1, 3. The absence of hyperkalemia cannot rule out adrenal insufficiency 1, 3.
Do not attempt diagnostic testing in patients actively taking corticosteroids. Morning cortisol measurements will be falsely suppressed due to iatrogenic secondary adrenal insufficiency, and testing should wait until adequate washout time has elapsed after discontinuation 1.
Be aware of conditions affecting cortisol-binding globulin (CBG). Any condition that elevates or lowers CBG levels will increase or decrease plasma total cortisol levels respectively, potentially leading to diagnostic inaccuracies 2.
Special Considerations
In critically ill patients with treatment-refractory hypotension, a random plasma cortisol <10 μg/dL (276 nmol/L) or delta cortisol <9 μg/dL (248 nmol/L) after ACTH stimulation defines critical illness-related corticosteroid insufficiency (CIRCI) and is associated with poorer outcomes. 1, 4
Adrenal insufficiency must be excluded before diagnosing SIADH in patients with hypo-osmolar hyponatremia, as both conditions present with nearly identical laboratory findings including euvolemic hypo-osmolar hyponatremia, inappropriately high urine osmolality, and elevated urinary sodium. 1, 3
When treating concurrent secondary adrenal insufficiency and hypothyroidism, always start corticosteroids several days before initiating thyroid hormone replacement to prevent precipitating adrenal crisis. 1, 3