What to do if a patient with adrenal insufficiency remains hypotensive on chronic hydrocortisone (cortisol replacement therapy) tablets?

Management of Persistent Hypotension in Adrenal Insufficiency Despite Chronic Hydrocortisone

If a patient with adrenal insufficiency remains hypotensive on chronic hydrocortisone tablets, immediately assess for mineralocorticoid deficiency (primary adrenal insufficiency) and optimize fludrocortisone dosing, as mineralocorticoids are vital for maintaining blood pressure and water/electrolyte homeostasis. 1

Immediate Assessment and Action

Determine Type of Adrenal Insufficiency

• Primary adrenal insufficiency (Addison's disease) requires both glucocorticoid AND mineralocorticoid replacement, while secondary adrenal insufficiency only requires glucocorticoids since the renin-angiotensin-aldosterone system remains intact 1, 2

• Check if the patient is receiving fludrocortisone—if they have primary adrenal insufficiency and are not on mineralocorticoid replacement, this is the most likely cause of persistent hypotension 1

Optimize Mineralocorticoid Replacement (Primary AI Only)

• Start or increase fludrocortisone dosing: typical range is 50-200 µg daily, but doses up to 500 µg daily may be needed in younger adults 1

• Evaluate mineralocorticoid adequacy by:

  • Asking about salt cravings or lightheadedness (classic signs of under-replacement) 1, 3
  • Measuring blood pressure in supine and standing positions to assess for orthostatic hypotension 1
  • Checking for peripheral edema (suggests over-replacement) 1

• Advise unrestricted sodium salt intake and salty foods without restriction—this is an essential third component of substitution therapy alongside glucocorticoid and mineralocorticoid replacement 1

• Avoid potassium-containing salts marketed as "healthy" 1

Evaluate for Glucocorticoid Under-Replacement

Clinical Assessment

• Under-replacement manifests as lethargy, nausea, poor appetite, weight loss, and increased pigmentation with uneven distribution 3

• Morning nausea and lack of appetite are particularly common in under-replaced patients 3

Optimize Hydrocortisone Dosing

• Standard maintenance dosing is 15-25 mg daily in divided doses, typically given as 10 mg at 7:00 AM, 5 mg at 12:00 PM, and 2.5-5 mg at 4:00 PM to approximate physiological cortisol secretion 1, 2

• Alternative effective regimens include 15+5 mg, 10+10 mg, or 10+5+5 mg depending on individual response 1, 2

• Consider timing adjustments: having the patient wake earlier to take the first dose and return to sleep may relieve morning symptoms 1

• Use serum or salivary cortisol day curve monitoring with morning postdose peak levels and trough predose levels to guide dose timing and quantities 1

Check for Drug Interactions

Medications That Increase Hydrocortisone Requirements

• Anti-epileptics/barbiturates, antituberculosis drugs (especially rifampin), antifungal medications, etomidate, and topiramate all accelerate hydrocortisone metabolism and may necessitate dose increases 1, 2

Medications That Interfere with Fludrocortisone

• Avoid diuretics, acetazolamide, carbenoxolone, liquorice, and NSAIDs as these interact with fludrocortisone 1

• Drospirenone-containing contraceptives may require increased fludrocortisone dosing 1

Substances That Decrease Requirements

• Grapefruit juice and liquorice decrease hydrocortisone requirements and should be avoided 1, 2

Rule Out Adrenal Crisis or Acute Decompensation

High-Risk Scenarios Requiring Immediate Action

• Any patient with unexplained collapse, hypotension, and gastrointestinal symptoms (vomiting or diarrhea) should be presumed to have adrenal crisis until proven otherwise 3

• Treatment should NEVER be delayed for diagnostic procedures if adrenal crisis is suspected—give 100 mg IV hydrocortisone immediately plus 0.9% saline infusion at 1 L/hour 1, 3

Stress Dosing Education

• Ensure the patient understands they must double or triple their hydrocortisone dose during febrile illness, infection, or minor stress 3, 2

• All patients need a hydrocortisone 100 mg IM injection kit with self-injection training for emergencies 3

• Patients must wear a medical alert bracelet indicating adrenal insufficiency to trigger stress-dose corticosteroids by emergency personnel 1, 3

Consider Alternative Glucocorticoid Formulations

• Prednisolone 4-5 mg daily may be considered in select patients who experience marked fluctuations in energy or well-being over the course of the day, or when hydrocortisone is not tolerated 1, 2

• Typical prednisolone regimens are 4-5 mg on awakening, or 3 mg on awakening and 1-2 mg at 14:00 h 1

• Dexamethasone should be avoided for chronic replacement therapy 1

Critical Pitfall to Avoid

Do not rely on electrolyte abnormalities alone—hyponatremia is present in 90% of newly diagnosed adrenal insufficiency cases, but hyperkalemia occurs in only ~50% of primary adrenal insufficiency cases 3. The absence of hyperkalemia cannot rule out inadequate replacement 3. Between 10-20% of patients may have mild hypercalcemia or even normal electrolytes at presentation 3.

Mandatory Endocrine Consultation

Refer to endocrinology for any patient with persistent hypotension despite apparent adequate replacement, as this requires expert evaluation of cortisol day curves, dose optimization, and exclusion of other causes of hypotension 3, 2.