What is the appropriate work‑up for a patient with hypothermia, bradycardia, altered mental status, hypotension, hyponatremia and hyperkalemia to evaluate for adrenal insufficiency?

Work-up for Adrenal Insufficiency in a Patient with Hypothermia, Bradycardia, Altered Mental Status, Hypotension, Hyponatremia and Hyperkalemia

Immediate Action: Do Not Delay Treatment for Testing

If this patient is clinically unstable with suspected adrenal crisis, administer 100 mg IV hydrocortisone immediately and infuse 0.9% saline at 1 L/hour—do NOT wait for diagnostic test results, as mortality is high if untreated. 1, 2, 3

• Draw blood for baseline serum cortisol and plasma ACTH before giving hydrocortisone if possible, but never delay treatment to obtain these samples 1, 2
• If you must treat before confirming the diagnosis and still want diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays 4

Clinical Presentation Strongly Suggests Adrenal Insufficiency

This constellation of findings is highly suspicious for primary adrenal insufficiency (Addison's disease):

• Hypotension with altered mental status and hypothermia indicate severe adrenal crisis 1, 2
• Hyponatremia is present in 90% of newly diagnosed adrenal insufficiency cases 1, 2
• Hyperkalemia occurs in only ~50% of cases, so its presence strengthens the diagnosis but its absence does not rule it out 1, 4
• The combination of hyponatremia and hyperkalemia suggests primary adrenal insufficiency with both glucocorticoid and mineralocorticoid deficiency 1

Important Caveat About Electrolytes

• Do not rely solely on electrolyte abnormalities to make or exclude the diagnosis—serum sodium may be only marginally reduced and potassium is elevated in only about half of patients 1
• If severe vomiting is present, the patient may have hypokalemia and alkalosis instead of hyperkalemia, as gastrointestinal losses mask aldosterone deficiency 1, 3

Diagnostic Testing Protocol (If Patient is Stable Enough)

Step 1: Obtain Morning Cortisol and ACTH

Measure early morning (8 AM) serum cortisol and plasma ACTH as the first-line diagnostic tests: 1, 4, 5

• Serum cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency 1, 2
• Serum cortisol <400 nmol/L (<14 μg/dL) with elevated ACTH raises strong suspicion of primary adrenal insufficiency 1
• Primary adrenal insufficiency: low cortisol with high ACTH 4, 5
• Secondary adrenal insufficiency: low cortisol with low or inappropriately normal ACTH 4, 5

Step 2: Cosyntropin Stimulation Test (If Initial Results Indeterminate)

The cosyntropin (Synacthen) stimulation test is the gold standard for confirming adrenal insufficiency when baseline cortisol is neither clearly normal nor clearly diagnostic: 1, 4, 2, 6, 5

Test Protocol: 1, 2, 6

• Administer 0.25 mg (250 mcg) cosyntropin intramuscularly or intravenously
• Obtain baseline serum cortisol before administration
• Measure serum cortisol at exactly 30 minutes and 60 minutes after administration

Interpretation: 1, 4, 2, 6, 5

• Peak cortisol <500 nmol/L (<18 μg/dL) at either 30 or 60 minutes is diagnostic of adrenal insufficiency
• Peak cortisol >550 nmol/L (>18-20 μg/dL) is considered normal and excludes adrenal insufficiency

Critical Testing Considerations

Stop these medications before testing to avoid false results: 1, 4, 6

• Glucocorticoids (hydrocortisone, prednisone, prednisolone) should be stopped on the day of testing
• Long-acting glucocorticoids may need longer washout periods
• Estrogen-containing drugs should be stopped 4-6 weeks before testing, as they increase cortisol-binding globulin and falsely elevate total cortisol levels
• Spironolactone should be stopped on the day of testing

Do not attempt diagnostic testing in patients actively taking corticosteroids—the results will be falsely positive for adrenal insufficiency due to expected HPA axis suppression. 4

Step 3: Determine the Etiology of Adrenal Insufficiency

Once adrenal insufficiency is confirmed, establish the underlying cause:

For Primary Adrenal Insufficiency:

Measure 21-hydroxylase (anti-adrenal) autoantibodies first, as autoimmunity accounts for ~85% of primary adrenal insufficiency cases in Western populations: 1, 4, 2

If autoantibodies are negative, obtain CT imaging of the adrenals to evaluate for: 1, 4, 2

• Adrenal hemorrhage
• Metastatic disease or tumors
• Tuberculosis or fungal infections
• Other structural abnormalities

In male patients with negative antibodies, assay very long-chain fatty acids (VLCFA) to check for adrenoleukodystrophy 1, 4

For Secondary Adrenal Insufficiency:

• Evaluate the pituitary gland with MRI imaging to assess for tumors, hemorrhage, or infiltrative conditions 5
• Assess other pituitary hormone deficiencies (TSH, LH, FSH, prolactin, growth hormone) 4
• Review medication history for opioids or other drugs that suppress ACTH production 5

Additional Laboratory Tests to Obtain

Basic metabolic panel: 4

• Sodium (expect hyponatremia in 90% of cases)
• Potassium (expect hyperkalemia in ~50% of primary adrenal insufficiency cases)
• Glucose (may show hypoglycemia, especially in children)
• Creatinine (may be elevated due to prerenal renal failure)

Other supportive findings: 1

• Mild hypercalcemia (occurs in 10-20% of patients)
• Anemia, mild eosinophilia, lymphocytosis
• Elevated liver transaminases
• Low DHEAS levels (in primary adrenal insufficiency)
• Elevated plasma renin activity (in primary adrenal insufficiency)

TSH levels may be mildly elevated (4-10 IU/L) due to lack of cortisol's inhibitory effect on TSH production 1

Critical Pitfall: Adrenal Insufficiency Can Mimic SIADH

Adrenal insufficiency must be excluded before diagnosing SIADH, as both conditions present with euvolemic hypo-osmolar hyponatremia and similar laboratory findings: 4

• Both show serum sodium <134 mEq/L, plasma osmolality <275 mOsm/kg, inappropriately high urine osmolality, and elevated urinary sodium
• The cosyntropin stimulation test is medically necessary to rule out adrenal insufficiency in patients with hypo-osmolality and hyponatremia
• Correct diagnosis is crucial because treatment approaches differ significantly: adrenal insufficiency requires glucocorticoid replacement, while SIADH requires fluid restriction

Summary of Diagnostic Algorithm

1. If unstable: Give hydrocortisone 100 mg IV + saline immediately, draw cortisol/ACTH if possible but don't delay treatment 1, 2, 3

2. If stable: Measure morning cortisol and ACTH 1, 4, 5

   • Cortisol <250 nmol/L with high ACTH = primary adrenal insufficiency diagnosed
   • Cortisol 250-550 nmol/L = proceed to cosyntropin stimulation test

3. Cosyntropin test: 0.25 mg IV/IM, measure cortisol at 0,30, and 60 minutes 1, 2, 6

   • Peak <500 nmol/L = adrenal insufficiency confirmed
   • Peak >550 nmol/L = adrenal insufficiency excluded

4. Determine etiology: 1, 4, 2

   • Check 21-hydroxylase antibodies
   • If negative, obtain adrenal CT
   • In males, check VLCFA for adrenoleukodystrophy