When to order a cosyntropin (Adrenocorticotropic hormone stimulation) test versus morning adrenocorticotropic hormone (ACTH) and cortisol levels?

From the Guidelines

The cosyntropin stimulation test should be ordered when adrenal insufficiency is suspected but not definitively diagnosed by baseline testing, while morning (8 AM) ACTH and cortisol levels are appropriate for initial screening. For the cosyntropin test, administer 250 mcg of synthetic ACTH (cosyntropin) intravenously or intramuscularly and measure serum cortisol at baseline, 30 minutes, and 60 minutes post-administration. A normal response is a cortisol level >18-20 μg/dL at any time point, which effectively rules out adrenal insufficiency 1. Morning ACTH and cortisol should be drawn between 6-8 AM when levels are naturally highest; a morning cortisol >15 μg/dL generally excludes adrenal insufficiency, while values <5 μg/dL strongly suggest it.

Key Considerations

• The high-dose (250-μg) ACTH stimulation test is easy to perform and safe, and has comparable accuracy to the low-dose ACTH test for the diagnosis of critical illness-related corticosteroid insufficiency (CIRCI) 1.
• The cosyntropin test is more definitive and particularly useful for suspected secondary adrenal insufficiency, recent pituitary insults, or when baseline results are equivocal.
• Very recent onset secondary adrenal insufficiency (within 2-4 weeks) may show false-negative results with cosyntropin testing, as adrenal atrophy has not yet occurred.
• Both tests require careful timing and should be performed before initiating glucocorticoid therapy whenever possible, as exogenous steroids can suppress the hypothalamic-pituitary-adrenal axis and confound results.

Diagnostic Criteria

• A delta total serum cortisol of <9 μg/dl after i.v. cosyntropin (250 μg) administration or a random total cortisol of <10 μg/dl can be used to diagnose CIRCI 1.
• Peak cortisol levels below 18 μg/dl (assay dependent) at 30 or 60 min indicate adrenal insufficiency 1.

From the FDA Drug Label

Stop these drugs on the day of cosyntropin for injection testing. Long-acting glucocorticoids may need to be stopped for a longer period before cosyntropin for injection testing [see Dosage and Administration (2. 1) and Drug Interactions (7)]. Estrogen-containing drugs increase cortisol binding globulin levels which can increase plasma total cortisol levels To obtain accurate plasma total cortisol levels, stop estrogen containing drugs four to six weeks before cosyntropin for injection testing to allow cortisol binding globulin levels to return to levels within the reference range [see Dosage and Administration(2. 1)and Drug Interactions (7)].

The decision to order a cosyntropin test vs. an a.m. ACTH and cortisol test depends on the clinical scenario and the medications the patient is taking.

• If the patient is taking glucocorticoids or spironolactone, these medications should be stopped on the day of cosyntropin testing, and long-acting glucocorticoids may need to be stopped for a longer period.
• If the patient is taking estrogen-containing drugs, these should be stopped 4 to 6 weeks before cosyntropin testing to allow cortisol binding globulin levels to return to normal. The cosyntropin test is used to assess adrenocortical function, while a.m. ACTH and cortisol levels can provide information on the body's natural corticosteroid production. However, the choice between these tests should be based on the specific clinical question and the patient's medication regimen 2.

From the Research

Cosyntropin Test vs. a.m. ACTH and Cortisol

• The cosyntropin test is used to diagnose adrenal insufficiency, and its interpretation can be challenging due to various technical and clinical factors 3.
• The test is commonly performed when basal serum cortisol levels are inconclusive, and the choice between the cosyntropin test and a.m. ACTH and cortisol measurement depends on the clinical presentation and likelihood of adrenal insufficiency 3.

Diagnostic Criteria

• The 1-microg cosyntropin stimulation test is more sensitive than the 250-microg test for diagnosing secondary adrenal insufficiency in nonstressed patients 4.
• A cortisol level of 18-20 microg/dL at 30 minutes after stimulation is considered a cutoff value for nonstressed patients, while a level of less than 25 microg/dL or an increment of less than 9 microg/dL from baseline is used for critically ill patients 4.
• New diagnostic cutoffs for adrenal insufficiency after cosyntropin stimulation using the Abbott Architect cortisol immunoassay have been established, with a threshold of 14.6 microg/dL at 60 minutes after stimulation 5.

Test Interpretation

• The interpretation of the cosyntropin test requires consideration of the clinical presentation, likelihood of adrenal insufficiency, and technical factors that can affect cortisol values 3.
• The use of assay-specific cutoffs is essential for reducing misclassification and overtreatment in patients with suspected adrenal insufficiency 5.
• Liquid chromatography-tandem mass spectrometry (LC-MS/MS) provides more accurate measurements of cortisol and 17-hydroxyprogesterone levels, allowing for the establishment of new normal reference ranges 6.

Clinical Decision-Making

• In acutely ill patients, a low threshold for initiating glucocorticoid replacement is recommended, even in the presence of a normal cosyntropin response, if there are signs of adrenal insufficiency such as hypoglycemia and shock 7.
• The cosyntropin test may be redundant in the acutely ill patient suspected of adrenal insufficiency, and other criteria such as increment from basal serum cortisol should be considered 7.