In a patient receiving chemo‑immunotherapy, when should the early‑morning cortisol result be reviewed according to guidelines?

When to Check Early Morning Cortisol Results in Chemo-Immunotherapy Patients

Early morning cortisol results should be reviewed immediately upon availability—ideally within the same day—because adrenal insufficiency in chemo-immunotherapy patients can rapidly progress to life-threatening adrenal crisis, and treatment must never be delayed for diagnostic procedures. 1

Immediate Review Protocol

• Check results as soon as they are available (typically within 2–4 hours of laboratory processing), because immune checkpoint inhibitor-related adrenal insufficiency can present with sudden hemodynamic collapse, unexplained hypotension, or gastrointestinal symptoms that require urgent intervention 1

• Morning cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in the presence of acute illness is diagnostic of primary adrenal insufficiency and mandates immediate treatment with IV hydrocortisone 100 mg plus 0.9% saline infusion at 1 L/hour 1

• Morning cortisol <400 nmol/L (<14.5 μg/dL) with elevated ACTH in acute illness generates strong suspicion of adrenal insufficiency and should prompt urgent clinical assessment and consideration of empiric treatment 1

Interpretation Framework by Cortisol Level

Cortisol >375–550 nmol/L (>14–20 μg/dL)

• This range effectively excludes adrenal insufficiency in most clinical contexts, with assay-specific thresholds varying: 358 nmol/L for Siemens, 336 nmol/L for Abbott, and 506 nmol/L for Roche immunoassays 2
• No further dynamic testing is required if clinical presentation is not highly suggestive 3, 2

Cortisol 275–375 nmol/L (10–14 μg/dL)

• This indeterminate range requires ACTH stimulation testing to definitively rule in or exclude adrenal insufficiency 1, 3
• A basal cortisol >236 nmol/L predicts adrenal sufficiency with 84% sensitivity and 71% specificity, but the 95% specificity threshold is 375 nmol/L 4
• Do not delay treatment if the patient is clinically unstable—treat empirically and perform confirmatory testing later 1

Cortisol <275 nmol/L (<10 μg/dL)

• Strongly suggestive of adrenal insufficiency and mandates urgent ACTH stimulation testing or empiric treatment depending on clinical stability 3, 4
• A mean morning cortisol <110 nmol/L is highly likely to have subnormal cortisol response to ACTH stimulation 5

Critical Timing Considerations

• The 30-minute cortisol response to ACTH is constant and unrelated to time of day, so morning cortisol can be drawn at the patient's convenience, though 0800h is standard 6
• Results must be acted upon the same day because immune-related adrenal insufficiency can deteriorate rapidly, with mortality risk if untreated 1

Common Pitfalls to Avoid

• Never wait for ACTH stimulation test results to treat suspected adrenal crisis—give IV hydrocortisone 100 mg immediately if the patient has unexplained hypotension, collapse, severe vomiting, or altered mental status 1

• Do not rely on electrolyte abnormalities alone—hyperkalemia is present in only ~50% of adrenal insufficiency cases, and hyponatremia can be mild or absent 1

• Exogenous steroids (including inhaled fluticasone or recent dexamethasone premedication) suppress endogenous cortisol and make morning cortisol uninterpretable—document all steroid exposures before testing 1, 3

• If the patient is already on corticosteroid replacement therapy, there is no reason to check cortisol levels—the diagnosis is already established 1

Actionable Algorithm for Chemo-Immunotherapy Patients

1. Draw early morning (0800h) cortisol and ACTH simultaneously at first clinical suspicion (fatigue, nausea, hypotension, hyponatremia) 1

2. Review results within 2–4 hours of availability:

   • <250 nmol/L with high ACTH → Treat immediately with IV hydrocortisone 100 mg + saline 1
   • 250–375 nmol/L → Proceed urgently to ACTH stimulation test (0.25 mg cosyntropin IV/IM, measure cortisol at 30 and 60 minutes) 1
   • >375 nmol/L → Adrenal insufficiency excluded; consider alternative diagnoses 2

3. If clinically unstable at any cortisol level → Give IV hydrocortisone 100 mg immediately without waiting for confirmatory testing 1

4. For confirmed adrenal insufficiency → Initiate lifelong glucocorticoid replacement (hydrocortisone 15–25 mg daily in divided doses), provide stress-dosing education, and prescribe emergency injectable hydrocortisone kit 1