Adrenal Insufficiency (Addisonian Crisis)

Adrenal crisis is a life-threatening endocrine emergency defined by hemodynamic instability (hypotension/shock) due to cortisol deficiency, requiring immediate parenteral hydrocortisone and aggressive fluid resuscitation — treatment must never be delayed for diagnostic workup. [1-3] Up to 50% of patients with primary adrenal insufficiency present with adrenal crisis as their first manifestation. [3]

The following diagnostic algorithm from a 2025 JAMA review outlines the approach to suspected adrenal insufficiency based on hemodynamic stability and biochemical testing:

• Key HPI questions: Ask about chronic fatigue, anorexia, weight loss, nausea/vomiting, abdominal pain, salt cravings, dizziness/syncope, and skin darkening [1-2]
• Timing/triggers: Identify precipitating events — recent infection (especially GI illness), surgery, trauma, emotional stress, dental procedures, strenuous exercise, or recent steroid taper/discontinuation [2][4]
• Medication history is critical: Any current or recent glucocorticoid use (oral, inhaled, topical, intra-articular), opioids, immune checkpoint inhibitors, ketoconazole, etomidate, mitotane, or CYP3A4 inducers (rifampin, phenytoin, carbamazepine) [1][4]
• Symptom characterization: Fatigue (50%–95%), nausea/vomiting (20%–62%), anorexia/weight loss (43%–73%), orthostatic hypotension (68% in primary AI), hyperpigmentation (74% in primary AI), muscle/joint pain (40%) [1]
• Important negatives: Absence of hyperpigmentation suggests secondary or glucocorticoid-induced AI rather than primary; absence of hyperkalemia also favors secondary AI [1-2]

• Hypotension/shock refractory to fluids and vasopressors — hallmark of adrenal crisis [4-5]
• Altered mental status: confusion, delirium, obtundation, seizures, coma [2]
• Severe hyponatremia, hyperkalemia, or hypoglycemia
• Abdominal pain mimicking acute abdomen (peritoneal irritation can occur) [6]
• Fever without clear infectious source
• Acute reversible heart failure (decreased myocardial contractility from cortisol deficiency) [5]
• Circulatory collapse or syncope

• Causative/contributing medications:
  • Exogenous glucocorticoids (most common cause of AI overall) — abrupt withdrawal or taper below physiological doses [1][7]
  • Opioids (suppress ACTH) [1]
  • Immune checkpoint inhibitors (hypophysitis/adrenalitis, risk <1%) [2]
  • Adrenal enzyme inhibitors: ketoconazole, metyrapone, etomidate, mitotane [8]
  • CYP3A4 inducers accelerating glucocorticoid metabolism: rifampin, phenytoin, carbamazepine, phenobarbital, apalutamide, enzalutamide [4]
• Treatment medications: Hydrocortisone (preferred), prednisolone, dexamethasone (least preferred); fludrocortisone for primary AI maintenance [2][8]
• Caution: Initiating levothyroxine in undiagnosed AI can precipitate crisis by increasing cortisol clearance [2-3]

• Patients with primary AI may have salt cravings due to aldosterone deficiency — liberal salt intake is recommended during maintenance [1]
• During acute illness: electrolyte-containing fluids as tolerated when managing at home [8]
• Hydration is critical — dehydration from vomiting/diarrhea is a common crisis precipitant and impairs oral medication absorption [2]

• Constitutional: Fatigue, malaise, weight loss, anorexia, fever
• GI: Nausea, vomiting, abdominal pain, diarrhea
• Cardiovascular: Orthostatic dizziness, syncope, palpitations
• Neuropsychiatric: Confusion, mood changes, depression, anxiety, cognitive deficits [3][6]
• Musculoskeletal: Myalgias, arthralgias, muscle cramps
• Dermatologic: Hyperpigmentation (buccal mucosa, palmar creases, scars — primary AI only)
• Endocrine: Amenorrhea, decreased libido (DHEAS deficiency)

• Confirm medication compliance — nonadherence to glucocorticoid replacement is a common crisis precipitant [2][6]
• Check for medical alert identification (bracelet, necklace, steroid emergency card) [8]
• Ask about prior adrenal crises (strongest risk factor for future crises) [4]
• Family history: Autoimmune conditions (type 1 diabetes, autoimmune thyroid disease, vitiligo, pernicious anemia) — autoimmune polyendocrine syndromes [8]
• Social context: Ability to self-inject hydrocortisone, access to emergency care, caregiver availability

• History of prior adrenal crisis (single strongest predictor) [4]
• Current or recent glucocorticoid use (any route — oral, inhaled, topical, intra-articular) [1][4]
• Age >65 years or adolescence/transition of care [4]
• Higher comorbidity burden [4]
• Autoimmune adrenalitis (Addison disease) — most common cause of primary AI in developed countries [1]
• Coexisting autoimmune conditions: type 1 diabetes, autoimmune thyroid disease, vitiligo, celiac disease [8]
• Infections: tuberculosis (leading cause in developing countries), HIV, fungal infections [1]
• Pituitary pathology: tumors, surgery, radiation, hemorrhage (Sheehan syndrome), hypophysitis [1]
• Bilateral adrenalectomy, adrenal metastases, adrenal hemorrhage (Waterhouse-Friderichsen syndrome)

• Septic shock — most important mimic; adrenal crisis may coexist with sepsis
• Hypovolemic shock from GI losses, hemorrhage
• Cardiogenic shock / acute heart failure — adrenal crisis itself can cause reversible cardiomyopathy [5]
• Anaphylaxis — hypotension, GI symptoms overlap
• Diabetic ketoacidosis — nausea, vomiting, abdominal pain, dehydration
• Acute abdomen (appendicitis, perforation) — abdominal pain with guarding can mimic surgical pathology [6]
• Myxedema coma — hypothyroidism with altered mental status and hypotension
• Hypoglycemia from other causes (insulinoma, liver failure)
• Distinguishing feature: Shock disproportionate to the severity of the trigger and refractory to fluids/vasopressors should raise suspicion for adrenal crisis [4-5]

• Known adrenal insufficiency (primary, secondary, or glucocorticoid-induced)
• Previous adrenal crises and precipitants
• Autoimmune conditions (polyendocrine syndromes)
• Pituitary surgery, radiation, or known pituitary pathology
• History of chronic glucocorticoid use for any indication (asthma, COPD, rheumatologic disease, transplant)
• Bilateral adrenalectomy
• Congenital adrenal hyperplasia
• Cancer with adrenal metastases or checkpoint inhibitor therapy [2]

• Vital signs: Hypotension (SBP <100 mmHg or ≥20 mmHg below baseline), tachycardia, orthostatic changes, fever [2]
• Skin: Hyperpigmentation of palmar creases, buccal mucosa, scars, areolae, axillae (primary AI only — due to elevated ACTH/MSH) [2-3]
• Abdomen: Tenderness, guarding (can mimic acute abdomen) [6]
• Neurologic: Altered mental status ranging from lethargy to coma [2]
• General: Cachexia, dehydration, poor skin turgor
• Absence of hyperpigmentation does not rule out AI — secondary and glucocorticoid-induced AI will not have this finding [1]

• Draw before treatment if possible, but never delay treatment: [6][8]
  • Serum cortisol (random in crisis; morning 6–10 AM in stable patients) — <5 µg/dL strongly suggests AI [1][5]
  • Plasma ACTH — elevated (>2× upper limit) in primary AI; low/low-normal in secondary/tertiary [1][5]
  • DHEAS — low in all forms of AI [1]
• BMP: Hyponatremia (84% of undiagnosed AI), hyperkalemia (34%, primary AI only), elevated creatinine/BUN (prerenal), hypoglycemia [4][6]
• CBC: Eosinophilia, lymphocytosis, mild normocytic anemia [2]
• Additional: Aldosterone/renin (low aldosterone, high renin in primary AI), calcium (mild hypercalcemia possible), TSH (may be elevated) [6][8]
• Etiologic workup (once stable): 21-hydroxylase antibodies (autoimmune), very long-chain fatty acids (adrenoleukodystrophy in males), 17-hydroxyprogesterone (CAH) [1]

• Not required for acute diagnosis — adrenal crisis is a clinical diagnosis [4]
• CT abdomen: Consider if etiology unclear after labs — may show adrenal enlargement (infection, hemorrhage, metastases) or calcification (TB, prior hemorrhage) [1]
• Pituitary MRI: Indicated for suspected secondary AI (pituitary tumor, hemorrhage, hypophysitis, infiltrative disease) [1]
• Chest X-ray: May show small heart size (chronic volume depletion); rule out infectious precipitant

• Cosyntropin (ACTH) stimulation test — gold standard for confirming AI in stable patients: [8]
  • Administer 250 µg cosyntropin IV/IM → measure cortisol at 0 and 60 min
  • Peak cortisol <18 µg/dL confirms AI (assay-dependent; newer assays may use lower thresholds ~15–17 µg/dL) [1][3]
  • Sensitivity 64%, specificity 93% for secondary AI — a normal result does not fully exclude recent-onset secondary AI [1]
• Not needed if baseline cortisol is unequivocally low with elevated ACTH (primary AI) [8]
• Point-of-care glucose: Check immediately — hypoglycemia common, especially in children [8]
• VBG/ABG: Assess acid-base status in shock

• Hyperkalemia findings: Peaked T waves, widened QRS, prolonged PR, sine wave pattern — particularly in primary AI with mineralocorticoid deficiency [2]
• Sinus tachycardia from hypovolemia/shock
• Low voltage QRS (chronic volume depletion)
• Cardiac monitoring recommended during acute crisis management [8]
• Rule out acute MI as a precipitant of crisis [6]

Adrenal crisis is defined as hypotension or hypovolemic shock plus at least one of: nausea/vomiting, severe fatigue, fever, or impaired consciousness. [4] The shock is characteristically out of proportion to the severity of the trigger and resistant to conventional vasopressors and fluids until glucocorticoids are administered. [4-5]

Key distinctions:

• Primary AI (Addison disease): Deficiency of cortisol + aldosterone + androgens → hyperpigmentation, hyperkalemia, salt wasting [1]
• Secondary AI: Cortisol deficiency only (aldosterone preserved) → no hyperpigmentation, no hyperkalemia [1]
• Glucocorticoid-induced AI: Most common form overall; crisis may be the first manifestation [4]

Immediate stabilization (do not delay for labs): [2-3][8]

• Hydrocortisone 100 mg IV bolus immediately (IM if no IV access)
• IV fluids: 1 L of 0.9% normal saline in the first hour
• D50 or D10 for hypoglycemia (dextrose 0.5–1 g/kg)

Ongoing management

• Hydrocortisone 200 mg/24 hours — preferably as continuous IV infusion, or 50 mg IV q6h [2-3][8]
• Continue IV crystalloid resuscitation guided by hemodynamics and electrolytes [6]
• After 24 hours: reduce to hydrocortisone 100 mg/day [3]
• Once clinically stable and tolerating PO: transition to oral hydrocortisone at 2–3× usual dose, taper to maintenance over 2–3 days [2]

If hydrocortisone unavailable: Prednisolone 25 mg bolus then 50 mg/day, or dexamethasone 4 mg/day (least preferred) [2][8]

Additional mineralocorticoid (fludrocortisone) is not needed during crisis — high-dose hydrocortisone provides sufficient mineralocorticoid activity. Resume fludrocortisone (0.05–0.3 mg daily) once on maintenance hydrocortisone for primary AI [2-3]

Treat the precipitant: Antibiotics for infection, surgical management if indicated [2]

Sick-day rules for known AI patients: [1][8]

• Fever >38°C: double oral hydrocortisone dose
• Fever >39°C: triple oral hydrocortisone dose
• Vomiting/unable to take PO: IM hydrocortisone 100 mg and present to ED

• Admit all patients with adrenal crisis — ICU or high-dependency unit for hemodynamic monitoring [6]
• Consider ICU for: persistent hypotension despite initial treatment, altered mental status, severe electrolyte derangements, or significant comorbidities
• Observation may be appropriate for incipient crisis (symptomatic AI without frank hypotension) that responds rapidly to stress-dose steroids [2]
• Endocrinology consultation for all new diagnoses, recurrent crises, or patients with HPA axis recovery not achieved within 1 year [4]
• Persistent shock despite adequate hydrocortisone and fluids should prompt investigation for alternative causes of hypotension [2]

• Before discharge: Ensure patient has emergency hydrocortisone injection kit (100 mg vial + syringes), steroid emergency card, and medical alert identification [6][8]
• Education: Teach sick-day rules, self-injection technique, and ensure a caregiver can also administer IM hydrocortisone [6][8]
• Follow-up: Endocrinology within 1–2 weeks of discharge; reinforce education at every visit [8]
• Vaccinations: Annual influenza; pneumococcal vaccine if >60 years [6]
• Return immediately for: Persistent vomiting/diarrhea preventing oral medication, fever not responding to stress dosing, dizziness/near-syncope, confusion, or any symptoms resembling prior crisis
• Expected recovery: With prompt treatment, hemodynamic improvement typically occurs within hours; oral transition usually feasible within 24–48 hours; full taper to maintenance over 2–3 days [2]
• Monitor for glucocorticoid-induced AI recovery: Periodic morning cortisol measurement (after holding glucocorticoids for 24 hours) to assess HPA axis recovery [1]

1. Adrenal Insufficiency in Adults. — Vaidya A, Findling J, Bancos I. The Journal of the American Medical Association. 2025.

2. Adrenal Crisis. — Rushworth RL, Torpy DJ, Falhammar H. The New England Journal of Medicine. 2019.

3. Clinical Features, Investigation, and Management of Addison's Disease. — Dong J, Hahner S, Bancos I, Tomlinson JW. The Lancet. Diabetes & Endocrinology. 2026.

4. European Society of Endocrinology and Endocrine Society Joint Clinical Guideline: Diagnosis and Therapy of Glucocorticoid-Induced Adrenal Insufficiency. — Beuschlein F, Else T, Bancos I, et al. The Journal of Clinical Endocrinology and Metabolism. 2024.

5. An Unexpected Cause of Hypotension. — Heath JR, Chang A, Finkbeiner M. JAMA Internal Medicine. 2025.

6. Adrenal Insufficiency. — Husebye ES, Pearce SH, Krone NP, Kämpe O. Lancet. 2021.

7. What Is Adrenal Insufficiency?. — Voelker R. The Journal of the American Medical Association. 2026.

8. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. — Bornstein SR, Allolio B, Arlt W, et al. The Journal of Clinical Endocrinology and Metabolism. 2016.