In a patient on checkpoint‑inhibitor immunotherapy who now has severe hypoglycemia (blood glucose 22 mg/dL) and a low‑normal 9 am cortisol level (~8 µg/dL) without neurologic deficits, what is the next step in oncologic management?

Immediate Management of Suspected Checkpoint Inhibitor-Induced Adrenal Insufficiency

Hold immunotherapy immediately and initiate stress-dose IV hydrocortisone 100 mg bolus, followed by endocrine consultation to confirm adrenal insufficiency with ACTH level and establish maintenance glucocorticoid replacement. 1

Clinical Context and Severity Assessment

This patient presents with severe hypoglycemia (glucose 22 mg/dL) and an inappropriately low-normal 9 AM cortisol (~8 µg/dL) while on checkpoint inhibitor therapy, which strongly suggests immune-related adrenal insufficiency. The absence of neurologic symptoms after glucose correction does not rule out adrenal crisis—hypoglycemia itself is a manifestation of cortisol deficiency and indicates Grade 3-4 severity requiring immediate intervention. 1

• A morning cortisol of ~8 µg/dL in the setting of severe hypoglycemia is inadequate; normal stress response should produce cortisol >18-20 µg/dL 1
• The combination of hypoglycemia with low-normal cortisol meets criteria for severe (G3-4) adrenal insufficiency: "medically significant or life-threatening consequences" 1

Immediate Oncologic Management Steps

1. Hold Checkpoint Inhibitor Therapy

Permanently discontinue the checkpoint inhibitor until the patient is stabilized on replacement hormones. 1 For Grade 3-4 adrenal insufficiency, ASCO guidelines specify holding ICPi rather than permanent discontinuation, but resumption requires complete stabilization on maintenance therapy. 1

2. Initiate Stress-Dose Glucocorticoids Immediately

Administer IV hydrocortisone 100 mg bolus immediately, even before confirmatory testing. 1, 2

• If diagnostic uncertainty exists and you need to perform ACTH stimulation testing later, use dexamethasone 4 mg IV instead, as it does not interfere with cortisol assays 1
• However, since the clinical picture strongly suggests adrenal insufficiency, hydrocortisone 100 mg is preferred for immediate treatment 1, 2
• Continue stress-dose hydrocortisone at 100 mg IV every 6-8 hours or as continuous infusion 2

3. Obtain Diagnostic Testing

Draw ACTH and repeat cortisol levels immediately before or concurrent with first hydrocortisone dose (if possible), along with basic metabolic panel. 1

• Check sodium, potassium, and glucose to assess for hyponatremia and hyperkalemia (suggests primary adrenal insufficiency) 1
• Obtain ACTH level to distinguish primary (high ACTH, low cortisol) from secondary/central (low ACTH, low cortisol) adrenal insufficiency 1
• Most checkpoint inhibitor-induced adrenal insufficiency is secondary/central due to hypophysitis, presenting with low ACTH and low cortisol 1, 3, 4

4. Provide Supportive Care

Administer at least 2 liters of normal saline IV for volume resuscitation. 1

• Continue dextrose-containing IV fluids to maintain euglycemia while treating underlying adrenal insufficiency 1
• Monitor vital signs closely for orthostasis and hemodynamic instability 1

5. Urgent Endocrine Consultation

Obtain endocrine consultation within 24 hours for all Grade 3-4 cases. 1 The endocrinologist will:

• Confirm diagnosis and distinguish primary vs. secondary adrenal insufficiency 1
• Consider pituitary MRI if multiple hormone deficiencies suspected (hypophysitis) 1, 4
• Establish transition plan from stress-dose to maintenance glucocorticoids 1

Transition to Maintenance Therapy

After 7-14 days of stress-dose therapy, taper to maintenance glucocorticoid replacement. 1

Maintenance Regimen Options:

• Hydrocortisone 10-20 mg orally every morning, 5-10 mg orally in early afternoon (preferred for physiologic dosing) 1
• Prednisone 5-10 mg daily (alternative) 1
• Do NOT add fludrocortisone unless primary adrenal insufficiency is confirmed (secondary/central AI preserves aldosterone production) 1

Critical Patient Education and Safety Measures

All patients with confirmed adrenal insufficiency require comprehensive education before resuming outpatient care: 1

• Stress-dosing protocol: Double glucocorticoid dose during illness, injury, or procedures 1
• Medical alert bracelet indicating adrenal insufficiency 1
• Emergency injectable hydrocortisone kit for home use 1
• Written instructions for when to seek emergency care 1
• Endocrine consultation before any surgery or procedure for stress-dose planning 1

Checkpoint Inhibitor Resumption Considerations

Resumption of checkpoint inhibitor therapy may be considered only after: 1

• Patient is completely stabilized on maintenance hormone replacement 1
• Symptoms have resolved to Grade 1 or less 1
• Endocrine consultation confirms adequate replacement and patient safety 1
• Note: Adrenal insufficiency is typically permanent and requires lifelong replacement 1, 5

The decision to resume immunotherapy should balance cancer treatment efficacy against the risk of worsening endocrinopathy, with close monitoring if resumed. 1, 5

Common Pitfalls to Avoid

Do not wait for confirmatory testing to initiate treatment—empiric stress-dose glucocorticoids are both diagnostic and therapeutic in suspected adrenal crisis. 1

Do not use high-dose immunosuppressive glucocorticoids (e.g., methylprednisolone 1-2 mg/kg)—unlike other immune-related adverse events, endocrinopathies require only physiologic hormone replacement, not anti-inflammatory doses. 1, 5 High-dose steroids are reserved for other irAEs like colitis or pneumonitis, not adrenal insufficiency.

Do not attempt to interpret morning cortisol or ACTH levels while patient is on exogenous glucocorticoids—these values are not interpretable during treatment. 1, 6

Be aware that combination checkpoint inhibitor therapy (e.g., nivolumab + ipilimumab) causes secondary adrenal insufficiency in up to 29% of patients, with median onset at 8 weeks. 3 This patient's presentation is consistent with this high-risk scenario.