What is the optimal approach for physiologic dosing of steroids (corticosteroids), such as hydrocortisone, in patients requiring replacement therapy, considering factors like age, weight, and underlying medical conditions?

Physiologic Dosing of Steroids for Replacement Therapy

Standard Maintenance Dosing

For adults with adrenal insufficiency requiring physiologic replacement, hydrocortisone 15-20 mg daily in divided doses is the preferred regimen, typically administered as 10 mg upon waking, 5 mg at midday, and 2.5-5 mg in early afternoon to approximate the normal cortisol circadian rhythm. 1

Hydrocortisone Dosing Strategy

• Administer hydrocortisone in 2-3 divided doses per day, with the largest dose (typically 10 mg) given immediately upon waking to replicate the physiologic cortisol peak 1, 2
• A typical regimen is 10 mg morning, 5 mg midday, and 2.5-5 mg early afternoon (total 15-20 mg/day) 1
• Weight-based dosing can be considered: approximately 0.2-0.3 mg/kg/day of hydrocortisone, divided into 2-3 doses 2
• Avoid dosing after 4-5 PM to prevent insomnia and disruption of the natural cortisol nadir 3

Alternative Glucocorticoid Options

• Prednisone 5 mg daily can substitute for hydrocortisone 20 mg daily (4:1 equivalency ratio) 1, 4, 5
• If using prednisone, administer as a single morning dose or split into 2.5 mg twice daily 1
• Dexamethasone is NOT recommended for routine physiologic replacement due to its long half-life (25x more potent than hydrocortisone), which makes dose titration difficult and increases risk of over-replacement 5

Mineralocorticoid Replacement (Primary Adrenal Insufficiency Only)

• Fludrocortisone 0.05-0.2 mg daily (typically 0.1 mg) is required for patients with primary adrenal insufficiency 1
• Secondary adrenal insufficiency does NOT require mineralocorticoid replacement, as aldosterone secretion remains intact 1
• Monitor adequacy by assessing blood pressure, serum electrolytes, and absence of salt cravings 1

Stress Dosing Protocols

Minor Illness (Fever, Gastroenteritis, Minor Infections)

• Double or triple the usual daily hydrocortisone dose during illness 1, 6
• Continue increased dosing until recovery (typically 2-3 days) 1
• If unable to tolerate oral intake due to vomiting, administer hydrocortisone 100 mg IM and seek emergency care 1

Major Surgery

• Hydrocortisone 100 mg IV at induction, followed by continuous infusion of 200 mg over 24 hours 1, 7
• Alternative: Hydrocortisone 50 mg IV/IM every 6 hours 1, 7
• Once tolerating oral intake, resume oral hydrocortisone at double the usual dose for 48 hours, then taper to maintenance over 5-7 days if recovery is uncomplicated 1, 7

Intermediate/Minor Surgery

• Hydrocortisone 100 mg IV at induction, followed by 200 mg/24h infusion 1
• Resume double oral dose for 24-48 hours postoperatively 1

Labor and Delivery

• Hydrocortisone 100 mg IV at onset of labor, followed by 200 mg/24h continuous infusion 1
• Alternative: Hydrocortisone 100 mg IM, then 50 mg IM every 6 hours 1

Special Populations

Pregnancy

• Increase hydrocortisone by 2.5-10 mg daily during the third trimester due to rising cortisol-binding globulin and increased free cortisol requirements 1
• Fludrocortisone dose often needs to be increased in late pregnancy due to progesterone's anti-mineralocorticoid effects 1
• During delivery, administer hydrocortisone 100 mg IV bolus, repeated every 6 hours as needed 1
• Double oral dose for 24-48 hours postpartum 1

Children

• Hydrocortisone 10-15 mg/m² body surface area per day in divided doses 1
• For major surgery: Hydrocortisone 2 mg/kg IV at induction, followed by continuous infusion based on weight 1:
  • Up to 10 kg: 25 mg/24h
  • 11-20 kg: 50 mg/24h
  • Over 20 kg (prepubertal): 100 mg/24h
  • Pubertal: 150 mg/24h

Patients on Chronic Glucocorticoid Therapy

• Any patient taking prednisone ≥5 mg daily (or hydrocortisone equivalent ≥20 mg daily) for ≥1 month is at risk for HPA axis suppression and requires stress-dose coverage for surgery 1, 6
• This applies to ALL routes of administration: oral, inhaled, topical, intranasal, and intra-articular 1

Monitoring and Dose Adjustment

Clinical Monitoring

• Assess for signs of under-replacement: fatigue, weight loss, hypotension, salt craving, hypoglycemia, hyponatremia 1
• Assess for signs of over-replacement: weight gain, hypertension, hyperglycemia, insomnia, mood changes 1, 8
• Morning cortisol levels and ACTH stimulation tests are NOT reliable for monitoring adequacy of replacement 1

Dose Titration

• Adjust based on clinical symptoms, blood pressure, weight, and electrolytes rather than cortisol levels 1, 2
• The FDA label emphasizes that dosage requirements are highly variable and must be individualized based on disease and patient response 4
• Aim for the lowest dose that maintains adequate clinical response 4

Critical Safety Considerations

Patient Education Requirements

• All patients must receive education on stress dosing, emergency injectable hydrocortisone use, and when to seek medical attention 1
• Provide a medical alert bracelet or necklace identifying adrenal insufficiency 1
• Teach patients to double or triple doses during illness and to administer emergency IM hydrocortisone if vomiting 1

Common Pitfalls to Avoid

• Never start thyroid hormone replacement before or simultaneously with glucocorticoid replacement in patients with multiple pituitary hormone deficiencies, as this can precipitate adrenal crisis 1
• Do not withhold stress-dose steroids based solely on preoperative cortisol levels; err on the side of supplementation 7, 6
• Do not use dexamethasone for routine physiologic replacement or in patients with primary adrenal insufficiency (lacks mineralocorticoid activity) 1, 7
• Do not abruptly discontinue steroids after stress dosing; taper gradually over 48 hours to one week 1, 7
• Avoid liquorice and grapefruit juice, which potentiate mineralocorticoid effects 1

Adrenal Crisis Recognition

• Adrenal crisis occurs at a rate of 6-8 per 100 patient-years and carries significant mortality risk 7, 6
• Even mild gastrointestinal upset can precipitate crisis due to malabsorption of oral medication 1
• Mortality risk is elevated 2.19-fold in men and 2.86-fold in women with adrenal insufficiency 7