What are the preparation and procedure guidelines for a patient undergoing an Adrenocorticotropic Hormone (ACTH) stimulation test, particularly for those with a history of pituitary or adrenal disorders?

ACTH Stimulation Test Preparation and Procedure

Pre-Test Medication Management

Stop glucocorticoids and spironolactone on the day of testing, but discontinue estrogen-containing medications 4-6 weeks before the test, as these drugs interfere with cortisol measurements and diagnostic accuracy. 1

• Glucocorticoids: Hold hydrocortisone for 24 hours before testing; long-acting glucocorticoids (prednisone, prednisolone) require longer washout periods and should be stopped on the day of testing at minimum 2, 1
• Spironolactone: Stop on the day of testing as it falsely elevates plasma cortisol levels 1
• Estrogen-containing drugs: Must be discontinued 4-6 weeks prior to testing because they elevate cortisol-binding globulin and falsely increase total cortisol levels 1
• Inhaled steroids: Fluticasone and other inhaled corticosteroids can suppress the HPA axis and should be considered when interpreting results 2

Critical Exception: Dexamethasone

• Dexamethasone does not interfere with cortisol immunoassays and the ACTH stimulation test remains fully interpretable in patients taking dexamethasone 3
• If you need to treat suspected adrenal crisis but want to preserve diagnostic testing options, use dexamethasone 4 mg IV instead of hydrocortisone 2, 3
• However, dexamethasone suppresses the HPA axis, so the test only evaluates adrenal responsiveness, not HPA axis integrity 3

Test Protocol and Administration

Administer 0.25 mg (250 mcg) cosyntropin by intravenous or intramuscular injection, with cortisol measurements at baseline, 30 minutes, and 60 minutes post-administration. 4, 1

Standard Dosing

• Adults: 0.25 mg (250 mcg) cosyntropin IV or IM 4, 1
• Pediatric patients (birth to <2 years): 0.125 mg (0.5 mL of reconstituted solution) 1
• Pediatric patients (2-17 years): 0.25 mg (1 mL of reconstituted solution) 1

Timing Considerations

• Perform the test in the morning (8:00-9:00 AM) when possible to capture the physiologic peak of cortisol secretion 4
• Afternoon testing significantly increases false-positive rates (odds ratio 6.98) and should be avoided 5
• The test can be performed at any time if the patient is clinically unstable, but morning testing improves diagnostic accuracy 4

Blood Sample Collection

• Obtain baseline serum cortisol and ACTH simultaneously before cosyntropin administration 2, 4, 1
• Measure serum cortisol at exactly 30 minutes and 60 minutes post-administration 4, 1
• Use minimal tubing during administration, as ACTH can adhere to tubing and reduce the delivered dose to 0.5-0.8 mcg 5

Interpretation of Results

Peak cortisol <500 nmol/L (<18 mcg/dL) at either 30 or 60 minutes is diagnostic of adrenal insufficiency, while peak cortisol >550 nmol/L (>18-20 mcg/dL) excludes the diagnosis. 4, 3, 1

Diagnostic Thresholds

• Peak cortisol <18 mcg/dL: Diagnostic of adrenal insufficiency 4, 1
• Peak cortisol >18-20 mcg/dL: Excludes adrenal insufficiency 4, 3
• Baseline cortisol <9 mcg/dL with elevated ACTH: Diagnostic of primary adrenal insufficiency without need for stimulation testing 4
• Baseline cortisol >18-20 mcg/dL: Reliably excludes adrenal insufficiency 4

Distinguishing Primary from Secondary Adrenal Insufficiency

• Primary adrenal insufficiency: Low cortisol with high ACTH (>5 ng/L or >1.1 pmol/L) 6, 2
• Secondary adrenal insufficiency: Low cortisol with low or inappropriately normal ACTH 6, 2
• Measure baseline ACTH simultaneously with baseline cortisol to distinguish these patterns 2, 4

Special Considerations for Patients with Pituitary or Adrenal Disorders

Pituitary Disease (Hypophysitis, Pituitary Adenomas)

• Evaluate morning ACTH and cortisol together, as pituitary lesions cause secondary adrenal insufficiency with low-normal cortisol and low-normal ACTH 6, 2
• Consider MRI brain with pituitary cuts in all patients with new hormonal deficiencies, particularly those with multiple endocrine abnormalities, severe headaches, or vision changes 6
• If secondary adrenal insufficiency is confirmed, initiate other hormone replacement only after adrenal replacement to avoid precipitating adrenal crisis 6

Primary Adrenal Disorders

• Measure 21-hydroxylase autoantibodies to identify autoimmune etiology, which accounts for ~85% of primary adrenal insufficiency cases in Western populations 2
• If autoantibodies are negative, obtain CT imaging of the adrenals to evaluate for hemorrhage, tumor, tuberculosis, or other structural causes 2
• Hyponatremia is present in 90% of newly diagnosed cases, but hyperkalemia occurs in only ~50% of cases, so its absence does not rule out the diagnosis 2, 4

Patients on Chronic Glucocorticoid Therapy

• Do not attempt diagnostic testing in patients actively taking glucocorticoids (except dexamethasone), as morning cortisol measurements will reflect iatrogenic secondary adrenal insufficiency 2
• Wait until the patient has been weaned off corticosteroids before performing definitive HPA axis testing 2
• For patients on long-term steroid exposure, consult endocrinology for a recovery and weaning protocol using hydrocortisone rather than attempting abrupt discontinuation 2

Critical Pitfalls to Avoid

Never delay treatment of suspected acute adrenal crisis for diagnostic procedures—immediately administer IV hydrocortisone 100 mg plus 0.9% saline infusion at 1 L/hour if the patient is clinically unstable. 6, 2, 4

• Do not rely on electrolyte abnormalities alone to make or exclude the diagnosis, as 10-20% of patients have normal electrolytes at presentation 2
• Do not assume a normal ACTH stimulation test excludes secondary adrenal insufficiency in patients on chronic dexamethasone—the test only confirms adrenal responsiveness, not HPA axis integrity 3
• Avoid testing patients on other glucocorticoids (prednisone, hydrocortisone) as these interfere with cortisol assays 2, 3
• Do not use the 30-minute cortisol value alone in patients on dexamethasone, as it may be inadequate; always wait for the 60-minute value 7

Post-Test Management

If Adrenal Insufficiency is Confirmed

• Initiate lifelong glucocorticoid replacement with hydrocortisone 15-25 mg daily in divided doses (typically 10 mg at 7:00 AM, 5 mg at 12:00 PM, 2.5-5 mg at 4:00 PM) 2, 4
• For primary adrenal insufficiency, add fludrocortisone 0.05-0.1 mg daily for mineralocorticoid replacement 6, 2, 4
• Provide mandatory patient education on stress dosing, emergency injectable hydrocortisone kit with self-injection training, and medical alert bracelet 6, 2, 4
• Arrange early endocrinology consultation for ongoing management and screening for associated autoimmune conditions 6, 2