What is the recommended approach to cortisol replacement therapy in adults, particularly those with a history of adrenal insufficiency?

Cortisol Replacement Therapy in Adults with Adrenal Insufficiency

Standard Maintenance Replacement Regimen

Adults with adrenal insufficiency should receive hydrocortisone 15-25 mg daily divided into 2-3 doses, with the majority given in the morning to mimic physiologic cortisol rhythm. 1, 2

• Hydrocortisone is the preferred glucocorticoid because it is structurally identical to cortisol and provides the most physiologic replacement 3
• Alternative option: prednisone 3-5 mg daily (using 5:1 equivalency ratio where 10 mg hydrocortisone = 2 mg prednisone) 4, 5, 2
• A modified-release hydrocortisone formulation (Plenadren) allowing once-daily dosing is available in Europe, though its role is still being evaluated 1

Mineralocorticoid Replacement (Primary Adrenal Insufficiency Only)

Patients with primary adrenal insufficiency require fludrocortisone 50-200 µg daily, taken as a single morning dose. 1, 2

• Higher doses (up to 500 µg daily) may be needed in children, younger adults, or during the third trimester of pregnancy when progesterone counteracts mineralocorticoids 1
• Patients should be instructed to consume sodium salt and salty foods without restriction and avoid potassium-containing salts 1
• Unrestricted sodium intake is the critical third component of replacement therapy to prevent salt craving and adrenal crisis 1
• Monitor clinically by assessing salt cravings, orthostatic blood pressure changes, and peripheral edema 1

Critical Drug Interactions Requiring Dose Adjustments

Multiple medications accelerate hydrocortisone metabolism and necessitate dose increases:

• Anti-epileptic drugs/barbiturates, antituberculosis medications, topiramate, and etomidate all increase hydrocortisone requirements 1
• Antifungal drugs may require dose changes 1
• Grapefruit juice and liquorice potentiate both glucocorticoid and mineralocorticoid effects—patients must avoid these completely 1

For fludrocortisone, avoid concurrent use of:

• Diuretics, acetazolamide, carbenoxolone, liquorice, and NSAIDs 1
• Drospirenone-containing contraceptives may require increased fludrocortisone dosing 1

Stress Dosing During Illness

Patients must double or triple their oral glucocorticoid dose during minor illnesses (fever, vomiting, diarrhea, infections). 6, 3, 2

• All patients should be prescribed injectable hydrocortisone 100 mg for intramuscular self-administration during severe illness when oral intake is impossible 1, 6, 2
• Even mild gastrointestinal upset can precipitate adrenal crisis because patients cannot absorb oral medication when they need it most 6
• Patients should wear medical alert jewelry and carry an emergency steroid card 6, 2

Perioperative Management

For major surgery, administer hydrocortisone 100 mg IV at induction, followed by continuous infusion of 200 mg over 24 hours until the patient can take oral medications. 1, 4

• Continue stress-dose hydrocortisone throughout any surgical intervention without reduction 6
• Once oral intake resumes, double the usual oral dose for 48 hours after uncomplicated surgery, or up to one week for major/complicated procedures 1, 4
• If there is any doubt about the need for glucocorticoids perioperatively, give them—short-term administration has no long-term adverse consequences 1, 4

Adrenal Crisis Recognition and Emergency Treatment

Adrenal crisis presents with hypotension (often severe), dehydration, nausea/vomiting, abdominal pain, altered mental status, hyponatremia (90% of cases), and hyperkalemia (50% of cases). 6

Immediate treatment protocol:

1. Administer hydrocortisone 100 mg IV bolus immediately without waiting for diagnostic confirmation 1, 6, 3
2. Start aggressive fluid resuscitation with 1 liter isotonic saline over the first hour 6, 3
3. Draw blood for cortisol, ACTH, and electrolytes before treatment, but never delay therapy waiting for results 6, 3
4. Continue hydrocortisone 200 mg per 24 hours as continuous IV infusion (or 50 mg IV/IM every 6 hours) 6, 3, 7
5. Administer 3-4 liters total isotonic saline over 24 hours with frequent hemodynamic monitoring 6, 3

Critical pitfalls to avoid:

• Never use dexamethasone alone in primary adrenal insufficiency—it lacks mineralocorticoid activity 1, 6, 3
• Do not add separate fludrocortisone during acute crisis; high-dose hydrocortisone provides adequate mineralocorticoid effect 6, 3
• Never assume normal cortisol levels exclude adrenal crisis—relative adrenal insufficiency can occur with normal or elevated cortisol during physiologic stress 6, 4

Special Populations

Pregnancy:

• Increase hydrocortisone by 2.5-10 mg daily during the third trimester due to rising free cortisol levels 1
• Fludrocortisone dose often requires increase in late pregnancy due to progesterone's anti-mineralocorticoid effects 1
• During labor, give hydrocortisone 100 mg IV bolus, followed by 200 mg per 24 hours as continuous infusion or 50 mg IM every 6 hours until after delivery 6, 3

Glucocorticoid-induced adrenal insufficiency:

• Suspect in any patient taking prednisolone ≥5 mg daily (or hydrocortisone-equivalent ≥10-15 mg/m² in children) for ≥1 month via any route (oral, inhaled, topical, intranasal, intra-articular) 1, 2
• These patients require the same stress-dose coverage during illness and surgery 1

Monitoring and Optimization

Under-replacement with fludrocortisone is common and predisposes to recurrent adrenal crises. 1, 6

• Assess for salt cravings, orthostatic hypotension, and review sodium intake patterns 1
• Essential hypertension in a patient with primary adrenal insufficiency should be treated by adding a vasodilator, not by stopping mineralocorticoid replacement (though dose reduction should be considered) 1
• Salivary cortisol measurements show promise for monitoring daily cortisol exposure and optimizing glucocorticoid dosing 8

Patient Education Priorities

Patient education is paramount to preventing recurrent crises and unnecessary deaths. 6

• Teach patients to recognize early warning signs: fatigue, nausea, lightheadedness, salt cravings 6, 2
• Ensure patients understand when and how to increase oral doses during illness 6, 3, 2
• Train patients in self-administration of emergency intramuscular hydrocortisone 6, 2
• Never assume patients are adequately educated—documented instances exist where patients are discharged with little or no education 6
• Collaborate with the patient's endocrinologist when planning scheduled surgery or managing postoperative care 1