What is the recommended glucocorticoid and mineralocorticoid replacement regimen for adrenal insufficiency, including stress dosing and emergency management?

Management of Adrenal Insufficiency

For chronic maintenance therapy, prescribe hydrocortisone 15-25 mg daily in 2-3 divided doses (typically 10 mg morning, 5 mg noon, 2.5-5 mg afternoon) plus fludrocortisone 0.05-0.2 mg once daily for primary adrenal insufficiency; for acute adrenal crisis, immediately administer hydrocortisone 100 mg IV bolus with 1 liter 0.9% saline over the first hour without waiting for diagnostic confirmation. 1, 2, 3, 4

Chronic Maintenance Replacement Regimen

Glucocorticoid Replacement

• Hydrocortisone 15-25 mg daily is the preferred glucocorticoid, divided into 2-3 doses to mimic physiologic cortisol secretion (e.g., 10 mg upon waking, 5 mg at noon, 2.5-5 mg in late afternoon). 2, 4, 5

• Cortisone acetate 20-35 mg daily in divided doses is an acceptable alternative if hydrocortisone is unavailable. 4

• In children, use hydrocortisone approximately 8 mg/m² body surface area per day in divided doses. 4

• Short-acting hydrocortisone is strongly preferred over longer-acting agents like prednisone or dexamethasone for maintenance therapy. 2

Mineralocorticoid Replacement (Primary Adrenal Insufficiency Only)

• Fludrocortisone 0.05-0.2 mg once daily (median dose 0.1 mg) is required for all patients with primary adrenal insufficiency. 1, 2, 4

• Secondary adrenal insufficiency does NOT require fludrocortisone because aldosterone production remains intact. 2, 3

• Titrate fludrocortisone to achieve normotension, normokalemia, and plasma renin activity in the upper half of the reference range. 6, 7

• Patients must maintain unrestricted sodium intake to support mineralocorticoid replacement. 3

Monitoring for Appropriate Dosing

• Under-replacement manifests as persistent fatigue, lethargy, nausea, weight loss, postural hypotension, and hyponatremia. 2

• Over-replacement presents with weight gain, insomnia, peripheral edema, hypertension, and cushingoid features. 2

• Monitor blood pressure (both supine and standing to detect orthostatic changes), weight, and serum electrolytes at every follow-up visit. 6, 3

• Annual minimum monitoring should include weight, blood pressure, and serum electrolytes; consider bone densitometry every 3-5 years to assess glucocorticoid-related complications. 6

Stress Dosing During Illness

Minor to Moderate Illness

• Patients must double or triple their usual hydrocortisone dose immediately at the onset of fever, infection, gastroenteritis, or any acute illness, continuing for 48 hours to one week until symptoms resolve. 2, 3, 4

• This stress-dosing rule applies to all forms of adrenal insufficiency and is critical for preventing adrenal crisis. 2, 3

Severe Illness or Inability to Take Oral Medication

• If the patient cannot take oral medication due to vomiting, or develops severe weakness, confusion, or hypotension, administer hydrocortisone 100 mg IV or IM immediately. 2, 3

• Patients and family members should be trained in self-administration of emergency intramuscular hydrocortisone 100 mg. 2, 3

Perioperative Stress Dosing

Major Surgery in Adults

• Administer hydrocortisone 100 mg IV at induction of anesthesia, followed immediately by continuous IV infusion of 200 mg over 24 hours. 1, 2

• Alternative regimen: hydrocortisone 50 mg IV or IM every 6 hours (total 200 mg/24 hours) if continuous infusion is not feasible. 1

• Continue hydrocortisone 200 mg/24 hours by IV infusion while the patient is nil-by-mouth or has postoperative vomiting. 1

• Once oral intake resumes, transition to double the usual oral hydrocortisone dose for 48 hours after uncomplicated surgery, then return to maintenance dosing. 1, 6

• For major surgery with complications, continue doubled oral doses for up to one week. 1

Intermediate or Body Surface Surgery in Adults

• Hydrocortisone 100 mg IV at induction, followed by continuous infusion of 200 mg/24 hours. 1

• Double the regular glucocorticoid dose for 48 hours postoperatively if recovery is uncomplicated. 1

Major Surgery in Children

• Hydrocortisone 2 mg/kg IV at induction, followed by continuous IV infusion based on weight: up to 10 kg receive 25 mg/24 hours; 11-20 kg receive 50 mg/24 hours; over 20 kg prepubertal receive 100 mg/24 hours; pubertal receive 150 mg/24 hours. 1

• Alternatively, hydrocortisone 2 mg/kg every 4 hours IV or IM postoperatively. 1

• Once stable, double usual oral hydrocortisone doses for 48 hours, then taper to normal doses over up to one week. 1

Labor and Vaginal Delivery

• Hydrocortisone 100 mg IV at onset of labor, followed immediately by continuous infusion of 200 mg/24 hours. 1

• Alternative: hydrocortisone 100 mg IM followed by 50 mg IM every 6 hours. 1

• With rapid recovery, resume oral hydrocortisone at double the usual dose for 24 hours. 1

Cesarean Section

• Manage as major surgery (see above). 1

Patients on Chronic Glucocorticoid Therapy (≥5 mg Prednisolone Equivalent for ≥4 Weeks)

• These patients are at risk for hypothalamic-pituitary-adrenal axis suppression and require perioperative stress dosing identical to patients with established adrenal insufficiency. 1, 2

• For major surgery: hydrocortisone 100 mg IV at induction, then 200 mg/24 hours continuous infusion. 1

• Dexamethasone 6-8 mg IV at induction provides 24-hour coverage if used. 1

Emergency Management of Adrenal Crisis

Immediate First-Hour Management

• Administer hydrocortisone 100 mg IV bolus immediately upon clinical suspicion—do NOT delay for diagnostic confirmation, as mortality increases with treatment delay. 1, 2, 3, 4

• Simultaneously begin rapid volume expansion with 1 liter 0.9% isotonic saline IV over the first hour. 1, 2, 3

• If IV access cannot be rapidly established, give hydrocortisone 100 mg IM as backup. 3

• Draw blood for serum cortisol, ACTH, electrolytes (sodium, potassium), creatinine, BUN, and glucose before treatment if feasible, but never postpone therapy while awaiting results. 2, 3, 4

Clinical Recognition of Adrenal Crisis

• Suspect adrenal crisis in any patient with hypotension (often <90/60 mmHg), severe dehydration, persistent nausea/vomiting, abdominal pain, confusion or altered mental status, muscle pain/cramps, and unexplained collapse. 2, 3, 5

• Orthostatic hypotension appears early, before supine hypotension develops—monitor blood pressure in both supine and standing positions. 6, 3

• Laboratory findings typically include hyponatremia (present in ~90% of cases), hyperkalemia (in ~50% of primary adrenal insufficiency cases only), increased creatinine/BUN from prerenal azotemia, and hypoglycemia (especially in children). 3, 4

• The absence of hyperkalemia does NOT exclude adrenal crisis, particularly in secondary adrenal insufficiency where aldosterone production is preserved. 3

Ongoing Management (First 24-48 Hours)

• Continue hydrocortisone as continuous IV infusion of 200 mg per 24 hours (preferred) or alternatively 50 mg IV/IM every 6 hours. 2, 3

• Provide a total of 3-4 liters of 0.9% saline or 5% dextrose-in-saline over 24-48 hours, with frequent hemodynamic monitoring to avoid fluid overload. 2, 3

• Monitor serum electrolytes frequently to guide fluid management. 1, 3

• Do NOT add separate mineralocorticoid (fludrocortisone) during acute crisis management—high-dose hydrocortisone (≥50 mg/day) provides adequate mineralocorticoid activity by saturating 11β-hydroxysteroid dehydrogenase type 2. 6, 2, 3

• Admit patients with persistent hypotension or severe presentation to ICU or high-dependency unit. 3

• Provide gastric stress-ulcer prophylaxis and low-dose heparin for DVT prophylaxis. 3

• Treat precipitating infections promptly with appropriate antimicrobial therapy. 3

• Perform frequent blood glucose monitoring, especially in children who are more vulnerable to hypoglycemia. 3

Transition from Crisis to Maintenance Therapy

• Taper parenteral glucocorticoids over 1-3 days once the precipitating illness permits and oral intake is tolerated. 2, 3

• Resume oral hydrocortisone at double the usual maintenance dose for 48 hours after uncomplicated recovery, then return to standard dosing. 6, 2

• Restart fludrocortisone only when the hydrocortisone dose falls below 50 mg per day, as higher doses provide sufficient mineralocorticoid effect. 3

Common Precipitating Factors to Investigate

• Gastrointestinal illness with vomiting/diarrhea is the most common trigger. 3

• Any type of infection, surgical procedures without adequate steroid coverage, physical trauma, myocardial infarction, severe allergic reactions, and medication non-compliance are frequent precipitants. 3

• Evaluate patients with recurrent crises for chronic under-replacement with fludrocortisone, low salt intake, poor medication adherence, and underlying psychiatric disorders. 3

Essential Patient Education and Safety Measures

Emergency Preparedness

• Every patient with adrenal insufficiency must receive four critical safety interventions: (1) emergency hydrocortisone injection kit (100 mg IM) with training in self-administration, (2) medical alert bracelet or steroid emergency card, (3) written sick-day protocol, and (4) education on adrenal crisis symptoms. 2, 3

• The incidence of adrenal crisis remains 6-8 cases per 100 patient-years even under established replacement therapy, emphasizing the critical importance of patient education. 2

Stress-Dosing Education

• Patients must understand to double their dose immediately when illness begins—do NOT wait to see if symptoms improve. 6, 2

• Even mild gastrointestinal upset may precipitate crisis because patients cannot absorb oral medication when they need it most. 3

• Patients should carry an emergency hydrocortisone injection kit at all times and know how to self-administer 100 mg IM. 2, 3

Critical Pitfalls to Avoid

• Never delay glucocorticoid therapy for diagnostic confirmation in suspected adrenal crisis—mortality increases with treatment postponement. 2, 3

• Never confuse maintenance dosing with stress dosing: hydrocortisone 10 mg morning + 5 mg noon is maintenance, NOT a stress dose. 2

• Never start thyroid hormone replacement before adequate glucocorticoid replacement in patients with multiple pituitary hormone deficiencies—this can precipitate adrenal crisis. 6, 3

• Never taper glucocorticoids too quickly: within the supraphysiological range, tapering can be more rapid, but once at physiological dosing (hydrocortisone 15-25 mg/day), taper slowly. 6, 8

• Never abruptly discontinue steroids—always taper gradually. 6

• Do not assume patients are adequately educated about sick-day rules; documented instances exist where patients are discharged with little or no education. 3

• Recognize that patients taking prednisolone ≥5 mg daily (adults) or hydrocortisone-equivalent ≥10-15 mg/m² daily (children) for ≥1 month via ANY route (oral, inhaled, topical, intranasal, intra-articular) are at risk for hypothalamic-pituitary-adrenal axis suppression and require perioperative stress dosing. 1, 2

• Do not attribute persistent fever solely to infection in postoperative patients—it may be due to adrenal insufficiency itself, and steroid supplementation should not be reduced while the patient is febrile. 3