What is the most appropriate confirmatory test for adrenal insufficiency in a patient with hypocortisolism?

ACTH Stimulation Test (Cosyntropin/Synacthen Test)

The cosyntropin stimulation test is the most appropriate confirmatory test for adrenal insufficiency in a patient with low cortisol levels. 1, 2, 3

Test Protocol

Administer 0.25 mg (250 mcg) cosyntropin intramuscularly or intravenously 1, 3

• Obtain baseline serum cortisol and ACTH before administration 1, 3
• Measure serum cortisol at exactly 30 minutes and 60 minutes post-administration 1, 3
• The test is preferably performed in the morning, though not strictly required 1

Interpretation of Results

A peak cortisol level <500-550 nmol/L (<18-20 mcg/dL) at 30 or 60 minutes is diagnostic of adrenal insufficiency 1, 3

• Peak cortisol >550 nmol/L (>18-20 mcg/dL) is considered normal and excludes adrenal insufficiency 1
• The FDA-approved cutoff is <18 mcg/dL as suggestive of adrenocortical insufficiency 3
• Measure cortisol at both 30 AND 60 minutes - approximately 54% of patients peak at 60 minutes, and some patients who fail at 30 minutes will pass at 60 minutes 4

Critical Pre-Test Considerations

Stop interfering medications before testing to avoid false results: 1, 3

• Glucocorticoids and spironolactone: Stop on the day of testing 3
• Long-acting glucocorticoids: May require longer washout period 3
• Estrogen-containing drugs: Stop 4-6 weeks before testing, as they elevate cortisol-binding globulin and falsely increase total cortisol levels 3
• Exogenous steroids (prednisolone, inhaled fluticasone): Can suppress the HPA axis and cause false results 1

Exception for dexamethasone: If you must treat suspected adrenal crisis but still need diagnostic testing, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays 1

When NOT to Perform Testing

Never delay treatment for diagnostic testing if adrenal crisis is suspected 1, 2, 5

• If the patient is clinically unstable with suspected adrenal crisis, immediately give IV hydrocortisone 100 mg plus 0.9% saline infusion at 1 L/hour 1, 2
• Draw blood for cortisol and ACTH before treatment if possible, but do not delay treatment 1, 2
• Clinical features warranting immediate treatment include: unexplained collapse, hypotension refractory to fluids/vasopressors, vomiting, diarrhea, or acute illness with suspected adrenal insufficiency 1, 2

Distinguishing Primary vs. Secondary Adrenal Insufficiency

Measure baseline ACTH alongside cortisol to differentiate: 1, 2

• Primary adrenal insufficiency: Low cortisol with HIGH ACTH 1, 2
• Secondary adrenal insufficiency: Low cortisol with LOW or inappropriately normal ACTH 1, 2

Additional diagnostic clues: 1, 2

• Hyponatremia + hyperkalemia suggests primary adrenal insufficiency 1
• Hyponatremia without hyperkalemia suggests secondary adrenal insufficiency 1
• However, hyperkalemia is present in only ~50% of primary adrenal insufficiency cases, so its absence does not rule out the diagnosis 1

High-Dose vs. Low-Dose Testing

The high-dose (250 mcg) test is recommended over the low-dose (1 mcg) test 1

• Easier practical administration - the low-dose test requires dilution of commercial preparation at bedside 1
• FDA-approved dosing 3
• Comparable diagnostic accuracy to low-dose testing 1
• The low-dose test may be more sensitive for secondary adrenal insufficiency, but is not validated or standardized 6, 7

Common Pitfalls to Avoid

• Do not rely solely on a 30-minute cortisol level - always measure at 60 minutes as well to avoid overdiagnosing adrenal insufficiency 4
• Do not rely on electrolyte abnormalities alone - hyponatremia is present in 90% of cases, but hyperkalemia occurs in only 50% 1
• Do not test patients currently on glucocorticoids - wait until they have been weaned off, or use empiric replacement and retest at 3 months 1
• Measure cortisol-binding globulin if necessary - conditions like cirrhosis or nephrotic syndrome lower CBG and can falsely lower total cortisol levels 3