Debasish Sundi, MD
Misop Han, MD
BASICS
DESCRIPTION
• Acute adrenal insufficiency (Sometimes called Addisonian crisis) symptoms are attributable to mineralocorticoid deficiency—there are many etiologies (1)[A].
• Adrenal crisis is a subtype of acute adrenal insufficiency; it is a rapid and intensive process triggered by a stressor such as surgery or sepsis.
• Symptoms of the Addison disease (chronic adrenal insufficiency) are difficult to recognize; often the diagnosis of Addison disease is made when patients present with an acute crisis.
• Patient may present in hemodynamic compromise secondary to sodium and plasma volume depletion.
• Addisonian crisis should be treated immediately; treatment should not be delayed pending diagnostic test results.
• The disease usually results from bilateral adrenal cortex destruction: Destruction of the adrenal cortex causes a combined deficiency of glucocorticoids, mineralocorticoids, and adrenal androgens.
ALERT
Hypotension and shock refractory to resuscitation with fluids and vasopressors should be considered Addisonian crisis and treated with intravenous steroids.
EPIDEMIOLOGY
Incidence
• Addison disease incidence: 0.6/100,000 per year
• Up to 0.7% of patients undergoing major surgery may experience adrenal insufficiency
Prevalence
• Addison disease prevalence: 4–11/100,000
• >75% of patients with septic shock manifest adrenal insufficiency
RISK FACTORS
• Neonates: Bilateral adrenal hemorrhage from birth trauma
• Children: Pseudomonal or meningococcal septicemia leading to acute hemorrhagic destruction of both adrenal glands (Waterhouse–Friderichsen syndrome)
• Adults: Adrenal crisis after surgical or septic stress; bilateral adrenal hemorrhage from systemic anticoagulation or coagulation disorder
• Special at-risk populations: Pregnant women, patients with idiopathic adrenal vein thrombosis, patients who have undergone venography or vascular embolization of adrenal adenoma
• Most common cause: Rapid withdrawal of steroids from patients with adrenal atrophy secondary to chronic steroid use
• Medications: Ketoconazole, aminoglutethimide, dronabinol, mitotane, phenytoin, rifampin
Genetics
• Hereditary factors may influence development of autoimmune adrenal insufficiency.
• Familial glucocorticoid insufficiency may be associated with a recessive gene pattern.
• Addison disease has been associated with a variety of autoimmune diseases.
PATHOPHYSIOLOGY
• The adrenal cortex produces 3 classes of steroid hormones: Mineralocorticoids (aldosterone), glucocorticoids (cortisol), and androgens.
• Cortisol deficiency is primarily responsible for the manifestations of the crisis.
• Primary adrenal insufficiency is due to failure of the adrenal cortex.
• Secondary adrenal insufficiency is caused by failure of ACTH stimulation of the adrenal cortex.
• Chronic steroid administrations result in suppression of ACTH production via feedback inhibition
ASSOCIATED CONDITIONS
Nearly 50% of patients with adrenalitis have some form of autoimmune disease: Hypoparathyroidism, gonadal collapse, diabetes mellitus type I, hypothyroidism (Hashimoto thyroiditis), or hyperthyroidism (Grave disease).
GENERAL PREVENTION
• Perioperative stress dose steroid replacement when indicated (3)[B].
• Low threshold to intervene with IV glucocorticoid replacement at early signs of fluid refractory hypotension
DIAGNOSIS
HISTORY
• Prior steroid use:
– Risk increases with minimum 20 mg/d prednisone or equivalent for at least 5 days within the past 12 mo
– Patients receiving normal physiologic levels require about 1 mo to recover normal adrenal function.
– Extensive topical use of high-potency steroids or high-dose inhaled steroids over prolonged periods can also be a factor
• Lapse in steroid therapy in a patient on chronic therapy
• Severe physiologic stress such as burn, surgery, or severe bacterial infection
• Bleeding diathesis or anticoagulant use
• Worsening or possibly intractable nausea, vomiting, and abdominal pain
• Fever may be severe or completely absent
• Primary or secondary adrenal insufficiency usually present insidiously with nonspecific symptoms of chronic fatigue, weakness and lethargy, anorexia, weight loss, postural hypotension, and somnolence
• Acute adrenal crisis usually presents acutely with hypotension or hypotensive shock:
– Clinical picture is more complex as a result of a mixture of preceding slow-onset symptoms and signs including abdominal pain, sepsis, pituitary or adrenal hemorrhage, surgery, or trauma
– Acute adrenal insufficiency should be considered in patients presenting in the emergency room with abdominal pain, nausea, diarrhea, hypotension, and fever
– The etiology of hypotension is profound hypovolemia
– Hypotension may be one of the last signs (preterminal) because mineralocorticoid secretion is usually somewhat preserved in patients on chronic glucocorticoid replacement.
PHYSICAL EXAM
• Check blood pressure: Extreme hypotension and/or shock refractory to fluids and vasopressors suggests acute adrenal crisis.
• Vitiligo often coexists with Addison disease: Hyperpigmentation along palmar creases, buccal mucosa, pressure points, perianal mucosa, and nipple areolas.
• Check for signs of generalized weakness and specifically muscle weakness.
• Check for loss of axillary hair in females.
• In adrenal crisis, patients may be hyper- or hypothermic.
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Plasma cortisol: Early AM levels <3 μg/dL (80 nmol/L) suggests diagnosis
• Serum ACTH:
– If low in the setting of low cortisol, patient has pituitary/hypothalamic disease
– If high in the setting of low cortisol, primary adrenal insufficiency exists
• Electrolyte abnormalities: Decreased sodium and chloride levels, increased potassium levels and an increased BUN/Cr ratio (reflecting hypovolemia)
• Hypercalcemia may be seen during adrenal crisis
• Hypocalcemia may be seen with associated polyglandular failure and hypoparathyroidism
• Excess proopiomelanocortin and melanocyte-stimulating hormone levels may be found
ALERT
Labs are used only in the setting of nonemergent adrenal insufficiency and have no role in the acute management of adrenal crisis.
Imaging
• Abdominal x-rays may show adrenal calcifications if adrenocortical insufficiency is secondary to fungal or TB infection.
• Abdominal CT may show enlarged adrenal glands with TB infection or malignant mass.
• Adrenals may be small secondary to idiopathic atrophy, autoimmune adrenalitis, or advanced TB.
• Adrenal gland hemorrhage or thrombosis may be seen.
Diagnostic Procedures/Surgery
• Rapid ACTH stimulation (cosyntropin, a synthetic derivative of ACTH) test:
– Following collection of baseline serum cortisol, 250 μg of synthetic ACTH is administered IM or IV.
– Plasma cortisol response is reassessed at 60 min.
– Those with no response have primary adrenal failure; if the cortisol levels increase following synthetic ACTH injection, the adrenal insufficiency is secondary to pituitary dysfunction.
Pathologic Findings
• Autoimmune adrenal cortical infiltrate
• Adrenal cortical infarction/necrosis, with or without hemorrhage
• Metastatic carcinoma in adrenal gland
• Tuberculous granuloma of adrenal
• Radiation effect
DIFFERENTIAL DIAGNOSIS
• Acute insufficiency (addisonian crisis) (1)[A]
– Shock (septic, cardiogenic, or hemorrhagic)
– Acute abdomen
• Chronic insufficiency (Addison disease)
– Secondary adrenocortical insufficiency
– Celiac disease
– Syndrome of inappropriate ADH secretion
– Lead exposure
– Severe nutritional deficiencies
– Neurofibromatosis
– Peutz–Jeghers syndrome
– Porphyria cutanea tarda
– Salt-depletion nephritis
– Bronchogenic carcinoma
– Anorexia nervosa, depression
TREATMENT
GENERAL MEASURES
• In critically ill and decompensating patients, maintain airway, and ensure adequate ventilation.
• Treatment instituted with IV fluid and dexamethasone or hydrocortisone should not be delayed in suspected adrenal crisis. Start treatment and perform more extensive tests once patient is stabilized.
MEDICATION
First Line
• IV fluids: 0.9% NS or 5% dextrose in NS
• Hydrocortisone: 100 mg IV bolus immediately; followed by either 100 mg q6h or 10 mg/h continuous infusion for 2–3 days (2)[A].
• Dexamethasone: 2–8 mg as a single dose; this may be repeated as necessary
Second Line
• Pediatric considerations
– Hydrocortisone: 1–2 mg/kg/dose bolus immediately; followed by 25–150 mg/d given in divided doses q6–8h (infants and young children)
• Geriatric considerations
– Start dosage on the low end of the dosing range due to greater frequency of impaired cardiac and renal function
– Increased susceptibility to adverse effects such as glaucoma, diabetes, and osteoporosis with long-term therapy
• Pregnancy considerations
– During labor and delivery, IV normal saline 0.9% and 25 mg of IV hydrocortisone should be given q8h with quick tapering after delivery
– Considered compatible with lactation: Infant must be monitored for adverse effects including hypoadrenalism
SURGERY/OTHER PROCEDURES
• Perioperative management during routine urologic surgery
– Consultation with the preoperative physician for medical clearance and the procedural anesthesiologist is advised.
– Many patients taking low-dose prednisone (such as for autoimmune inflammatory disorder) are able to undergo major surgery without any endocrine morbidity even without administration of intraoperative stress-dose steroids (3)[B]. Incident fluid-refractory hypotension in this group should be promptly treated with IV hydrocortisone.
– Patients with chronic adrenal failure and complete physiologic steroid replacement do generally require procedural stress-dose steroids.
– Individualization of stress-doses and postoperative taper regimens is recommended.
ADDITIONAL TREATMENT
Radiation Therapy
N/A
Additional Therapies
• Maintenance doses of steroids:
– Hydrocortisone (oral): 15–20 mg qAM and 5–10 mg qPM
– Prednisone (oral): 5 mg AM and 2.5 mg PM
– Fludrocortisone (oral): 0.05–0.2 mg/d
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• There is a high risk of morbidity and mortality associated with unrecognized acute crisis. May result in cardiovascular collapse if not recognized.
• Excellent long-term prognosis following immediate management of acute crisis and long-term maintenance therapy.
COMPLICATIONS
• Abdominal distention, peptic ulcer
• Edema, glaucoma, increased intraocular pressure
• Hyperglycemia, hypertension
• Immunosuppression
• Mood changes, weight gain, hirsutism
FOLLOW-UP
Patient Monitoring
• Consider increase in steroid dosing when the patient has an episode of minor fever, infection, trauma, or physical stress.
• Monitor blood pressure, weight, serum electrolytes, and blood glucose levels.
• Monitor growth in pediatric patients.
• Bone density, ophthalmologic exams.
Patient Resources
National Library of Medicine: http://www.nlm.nih.gov/medlineplus/ency/article/000378.htm
REFERENCES
1. Oelkers W. Adrenal insufficiency. N Engl J Med. 1996;335:1206–1212.
2. Annane D, Sébille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288(7):862–871.
3. Marik PE, Varon J. Requirement of perioperative stress doses of corticosteroids. Arch Surg. 2008;143(12):1222–1226.
ADDITIONAL READING
Williams GH, Dluhy RG. Disorders of the Adrenal Cortex. In: Harrison’s Principles of Internal Medicine, 16th ed. New York, NY: McGraw-Hill, 2004.
See Also (Topic, Algorithm, Media)
• Adrenal Calcifications
• Addison Disease
• Addison Disease (Adrenocortical Insufficiency Algorithm 
)
• Adrenal Hemorrhage
• Adrenal Hypoplasia
CODES
ICD9
255.41 Glucocorticoid deficiency
ICD10
• E27.2 Addisonian crisis
• E27.40 Unspecified adrenocortical insufficiency
CLINICAL/SURGICAL PEARLS
Preoperative anesthesia consultation for perioperative stress dose steroid replacement is recommended for any patient on steroid therapy.