Adrenal Insufficiency



  • Inadequate glucocorticoid (cortisol) and/or mineralocorticoid (aldosterone) secretion to meet the body's stress requirement
  • Primary adrenal failure associated with impaired glucocorticoid and mineralocorticoid production
  • Secondary/tertiary adrenal insufficiency associated with only glucocorticoid deficiency
  • Adrenal deficiency:
    • Inadequate cortisol/aldosterone
    • Unresponsive to stimulation with adrenocorticotropic hormone (ACTH)
  • Adrenal crisis (Addisonian crisis):
    • Life-threatening emergency
    • Precipitated by:
      • Steroid-dependent patient under stress (pregnancy, surgery, trauma, infection, or dehydration)
      • Rapid steroid withdrawal
      • Acute adrenal hemorrhage
      • Recent pituitary/craniopharyngioma resection
      • Congenital adrenal hyperplasia
      • Postpartum pituitary gland necrosis (Sheehan syndrome)


Primary Adrenal Failure: Adrenal Gland Dysfunction
  • Adrenal dysgenesis/impaired steroidogenesis:
    • Congenital hypoplasia
    • Allgrove syndrome:
      • ACTH resistance
      • Achalasia
      • Alacrima
    • Glycerol kinase deficiency:
      • Psychomotor retardation
      • Hypogonadism
      • Muscular dystrophy
  • Congenital adrenal hyperplasia:
    • 21-hydroxylase deficiency accounts for 95% of cases
  • Aldosterone synthetase deficiency
  • Mitochondrial disease
  • Adrenal destruction:
    • Autoimmune:
      • Autoimmune polyglandular syndrome types 1 and 2 (alopecia universalis, chronic mucocutaneous candidiasis, hypoparathyroid, thyroid autoimmunity, diabetes, celiac disease, pernicious anemia)
      • Adrenoleukodystrophy
    • Infectious:
      • Granulomatous: TB
      • Protozoal and fungal: Histoplasmosis, coccidioidomycosis, and candidiasis
      • Viral: Cytomegalovirus, herpes simplex virus, and HIV
      • Bacterial
      • Fungal
    • Metastatic tumors
    • Infiltration:
      • Sarcoid
      • Hemochromatosis
      • Amyloidosis
      • Iron depletion
  • Bilateral adrenalectomy
  • Hemorrhage
    • Sepsis: Particularly meningococcemia (Waterhouse–Friderichsen syndrome), Pseudomonas infection
    • Birth trauma/anoxia
    • Pregnancy
    • Seizures
    • Anticoagulants
    • Rhabdomyolysis
  • Pharmacologic inhibition:
    • Etomidate
    • Phenobarbital
    • Ketoconazole/fluconazole
    • Phenytoin
    • Rifampicin

Secondary Adrenal Failure: Pituitary Dysfunction (Corticotropin Deficiency)
  • Pituitary insufficiency
  • Sepsis
  • Head trauma
  • Hemorrhage
  • Infarction (Sheehan syndrome)
  • Infiltration: Neoplasm, amyloid, sarcoid, and hemochromatosis
  • Prader–Willi syndrome

Tertiary Adrenal Failure: Hypothalamus Dysfunction (Corticotropin-Releasing Hormone Deficiency)
  • Pharmacologic inhibition:
    • Glucocorticoid therapy
    • Mifepristone
    • Chlorpromazine
    • Imipramine
  • Sepsis
  • Infiltrative: Neoplasm, amyloid, sarcoid, and hemochromatosis
  • Head trauma (skull base fractures most common)


Signs and Symptoms

  • Symptoms:
    • Depression
    • Weakness, tiredness, fatigue
    • Anorexia
    • Abdominal pain (can mimic acute abdomen)
    • Nausea or vomiting
    • Salt craving (primary only)
    • Postural dizziness
    • Muscle or joint pains
    • Dehydration (found in primary adrenal insufficiency only)
    • Dry/itchy skin (women)
    • Loss of libido (women)
  • Signs:
    • Fever or hypothermia
    • Mental status changes
    • Hypotension (<110 mm Hg systolic)
    • Tachycardia
    • Orthostatic BP changes or frank shock
    • Weight loss
    • Goiter
    • Hypogonadism
    • Hyperkalemia (primary)
    • Hypercalcemia (primary)
    • Sodium depletion
    • Azotemia
    • Eosinophilia
    • Hyperpigmentation (primary only)
    • Vitiligo
  • Addisonian crisis:
    • Hypotension and shock
    • Hyponatremia
    • Hyperkalemia
    • Hypoglycemia

Essential Workup

  • Lab confirmation of diagnosis may not be possible in ED
  • Adrenal crisis: Life-threatening condition:
    • High degree of suspicion should prompt initiation of therapy before definitive diagnosis
  • Plasma cortisol level
  • Thyroid levels
  • Chemistry panel
  • CBC with differential
  • Core temperature

Diagnostic Tests and Interpretation

  • CBC with differential:
    • Anemia
    • Eosinophilia
    • Lymphocytosis
  • Arterial blood gases/chemistry:
    • Hypoxemia
    • Acidosis
    • Hyperkalemia (primary insufficiency only)
    • Hyponatremia
    • Elevated creatinine (primary only)
    • Decreased glucose
    • Hypercalcemia (primary only)
  • Cortisol levels in critically ill patients:
    • Baseline AM cortisol <3 mcg/dL diagnostic for adrenal deficiency but impractical in the ED
    • Consensus critical care recommendation to diagnose acute adrenal deficiency:
      • Random serum cortisol <10 mcg/dL (while under physiologic stress)
      • A change in cortisol <9 mcg/dL after cosyntropin (250 mcg) administration at 60 min
  • Cosyntropin stim test also suggestive if cortisol level at 60 min <18 mcg/dL
  • Search for underlying infection

  • Look for infection or pulmonary edema

Diagnostic Procedures/Other
  • Evaluate for signs electrolyte disturbances

Differential Diagnosis

  • Sepsis
  • Shock
  • Hypoglycemia
  • Hypothermia
  • Acute abdominal process


Initial Stabilization/Therapy

  • Airway, breathing, and circulation management (ABCs)
  • Cardiac monitor
  • BP support for hypotension:
    • Normal saline (0.9%) IV fluids 500 mL–1 L (peds: 20 mL/kg) bolus
  • Supplemental oxygen to meet metabolic needs
  • Correct hyperthermia/hypothermia

Ed Treatment/Procedures

  • Glucocorticoid/mineralocorticoid replacement:
    • IV hydrocortisone or dexamethasone immediately
    • Use IM route if no IV access
    • Dexamethasone will not interfere with results of cosyntropin stimulation tests
    • Hydrocortisone at doses >50 mg provide adequate mineralocorticoid coverage, dexamethasone does not
    • Fludrocortisone (oral only) can be given for isolated mineralocorticoid deficiency
  • Volume expansion:
    • NS (0.9%) or D5NS at rate of 500–1,000 mL/hr for first 3–4 hr
    • Care should be taken to note patient's age, volume, and cardiac and renal function
  • For hypoglycemia:
    • D50W
  • Treat life-threatening dysrhythmias secondary to hyperkalemia with calcium, bicarbonate, and insulin/glucose
  • Identification and correction of underlying precipitant
  • Should see BP improvement within 4–6 hr of therapy


  • Dexamethasone: 6–10 mg (peds: 0.15 mg/kg per dose) q12h
  • Hydrocortisone: 50–100 mg (peds: 1–2 mg/kg per dose) IV q6h, doses >50 mg adequately treats mineralocorticoid deficiency
  • Fludrocortisone (50–100 mcg) oral formulation only in patients with isolated mineralocorticoid deficiency

Ongoing Care


Admission Criteria
  • All patients with acute adrenal insufficiency
  • ICU admission for patients with unstable or potentially unstable cases

Discharge Criteria
  • Normal lab evaluation with treated adrenal insufficiency
  • Should speak with endocrinologist before discharge in patients with chronic adrenal insufficiency

Follow-Up Recommendations

  • Should have primary care physician follow-up within a few weeks depending on symptoms
  • May benefit from endocrinology referral

Pearls and Pitfalls

  • Acute adrenal insufficiency is a life-threatening emergency, and treatment should not be delayed in the ED while waiting for definite lab diagnosis
  • Patients with primary adrenal insufficiency are lacking both glucocorticoids and mineralocorticoids
  • Patients with secondary and tertiary adrenal insufficiency are deficient only in glucocorticoids
  • Morning cortisol levels are not practical in the ED, but a random cortisol <10 mcg/dL in a patient under physiologic stress is suggestive of adrenal insufficiency
  • An increase of cortisol <9 mcg/dL 1 hr after cosyntropin administration or a cortisol level <18 mcg/dL 1 hr after cosyntropin administration is also suggestive of adrenal insufficiency
  • Hydrocortisone doses greater than 50 mg provide adequate mineralocorticoid coverage
  • Dexamethasone can be used to treat glucocorticoid deficiency and will not interfere with the cosyntropin stim test. Dexamethasone has minimal mineralocorticoid effects
  • Patients using chronic steroids may need increased doses during times of critical illness
  • Steroids in septic shock is controversial but still recommended in shock refractory to vasopressors or in patients using chronic corticosteroids
  • The clinical consequence of a single dose of etomidate for rapid sequence intubation is controversial. Studies do show biochemical adrenal suppression which must be weighed against agents with other undesirable properties while performing a critical, life-saving procedure

Additional Reading

  • Bancos I, Hahner S, Tomlinson JT, et al. Diagnosis and management of adrenal insufficiency. Lancet Diabetes and Endocrinol. 2015;3(3):216–226.
  • Bornstein SR, Allolio B, Arit W, et al. Diagnosis and treatment of primary adrenal insufficiency: An endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(2):364–389.
  • Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet. 2014;383:2152–2167.
  • Chou SH. Adrenal insufficiency. Hosp Med Clin. 2012;1(1):e97–e108.
  • Gibbison B, Lopez JA, Higgins JP, et al. Corticosteroids in septic shock: A systematic review and network meta-analysis. Crit Care. 2017;21:78.
  • Marik PE, Pastores SM, Annane D, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: Consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med. 2008;36:1937–1949.
  • UVar A, Baş F, Saka N. Diagnosis and management of pediatric adrenal insufficiency. World J Pediatr. 2016;12(3):261–274.

See Also

Cushing Syndrome
The authors gratefully acknowledge Rita K. Cydulka and Joseph P. Tagliaferro for their contribution to the previous edition of this chapter.


Terry Singhapricha
Todd A. Taylor

© Wolters Kluwer Health Lippincott Williams & Wilkins