ACTH Stimulation Test: Purpose and Procedure
The ACTH stimulation test (cosyntropin test) is the recommended diagnostic test for evaluating adrenal insufficiency, with the high-dose (250-μg) protocol being preferred over the low-dose (1-μg) test due to comparable diagnostic accuracy, easier administration, and more standardized reference ranges. 1, 2
Purpose of the Test
- The ACTH stimulation test is used to diagnose adrenal insufficiency by evaluating the adrenal cortex's ability to respond to stimulation with synthetic ACTH (cosyntropin) 3
- It helps differentiate between primary adrenal insufficiency (adrenal gland dysfunction) and secondary adrenal insufficiency (pituitary dysfunction) 2
- The test is indicated for screening adrenocortical insufficiency in adults and pediatric patients, in combination with other diagnostic tests 3
- It is particularly valuable in evaluating patients with suspected Critical Illness-Related Corticosteroid Insufficiency (CIRCI) 1
Test Procedure
Preparation
- Discontinue glucocorticoids and spironolactone on the day of testing 3
- For long-acting glucocorticoids, discontinuation should occur for a longer period before testing 3
- Estrogen-containing medications should be stopped 4-6 weeks before testing as they may elevate plasma total cortisol levels 3
Administration Protocol
- High-dose protocol (recommended): 250 μg of cosyntropin administered intravenously or intramuscularly 1, 2
- For pediatric patients: 0.125 mg for patients under 2 years; 0.25 mg for patients 2-17 years 3
- Blood samples are collected for serum cortisol measurement at baseline (0 minutes) and at 30 and 60 minutes after cosyntropin administration 3, 4
Interpretation
- In primary adrenal insufficiency: A peak cortisol level below 18 μg/dL (500 nmol/L) at 30 or 60 minutes indicates adrenal insufficiency 1, 2
- For newer specific cortisol assays: Updated cutoff values of 14-15 μg/dL are recommended instead of the historical 18 μg/dL threshold 5
- In equivocal cases: A delta cortisol (change from baseline) of <9 μg/dL after cosyntropin administration may indicate CIRCI 1
- A baseline cortisol <2 μg/dL is highly predictive of subnormal stimulated cortisol values 5
Clinical Applications
- Primary Adrenal Insufficiency: The test shows low cortisol and elevated ACTH levels 1
- Secondary Adrenal Insufficiency: Shows low cortisol with low or normal ACTH levels 1, 2
- Critical Illness-Related Corticosteroid Insufficiency (CIRCI): The test helps identify patients who may benefit from corticosteroid therapy 1
- Immune-Related Adverse Events: Used to diagnose adrenal insufficiency in patients receiving immune checkpoint inhibitor therapy 1
Advantages of High-Dose vs. Low-Dose Protocol
- The Society of Critical Care Medicine and European Society of Intensive Care Medicine recommend the high-dose (250-μg) ACTH test over the low-dose (1-μg) test 1, 2
- Advantages of high-dose protocol:
Potential Pitfalls and Limitations
- Cortisol binding globulin levels can affect total cortisol measurements, potentially leading to diagnostic inaccuracies 3, 7
- Recent pituitary injury cases may show false-negative results with the ACTH stimulation test 6
- The test should be performed within the first 3 days after initiation of empiric glucocorticoid therapy for reliable results 8
- Medications affecting cortisol or cortisol binding globulin levels can interfere with test interpretation 3, 7
- The time of day when the test is performed may affect results, though the high-dose test is less affected by this variable 7
Special Considerations
- In critically ill patients, a random plasma cortisol <10 μg/dL may be diagnostic of CIRCI without requiring an ACTH stimulation test 1
- Treatment of suspected acute adrenal insufficiency should never be delayed for diagnostic procedures 1
- All patients diagnosed with adrenal insufficiency should receive education on stress dosing and carry emergency identification 1