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:
1. History
- 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]
2. Alarm Features
- 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
3. Medications
- 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]
4. Diet
- 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]
5. Review of Systems
- 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)
6. Collateral History and Family History
- 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
7. Risk Factors
- 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)
8. Differential Diagnosis
- 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]
9. Past Medical History
- 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]
10. Physical Exam
- 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]
11. Lab Studies
- 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]
12. Imaging
- 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
13. Special Tests
- 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
14. ECG
- 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]
15. Assessment
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]
16. Treatment Plan
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
17. Disposition
- 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]
18. Follow Up / Return Precautions
- 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]
References
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.