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Adrenal failure


1.1 Incidence, risk factors and pathophysiology


An acute adrenal crisis is a medical emergency due to the sudden lack of adrenal gland hormones.
Symptomatic adrenocortical insufficiency (Addison’s disease) in cancer patients may be due to inadequate adrenal gland function due to
•    Destruction of the adrenal gland function
o    Destruction of more than 90% of adrenal tissue by metastatic carcinoma (lung and breast cancer) or bleeding;
o    Iatrogenic adrenal insufficiency (secondary to surgical adrenalectomy, treatment with mitotane, inhibition of steroid synthesis by aminoglutethimide)
•    Interference with the hypothalamic-pituitary-adrenal gland axis
o    Exogenous corticosteroids suppress the hypothalamic-pituitary-adrenal axis. Prior corticosteroid use with 20 mg daily of prednisone or its equivalent for at least 5 days may lead to an acute adrenal crisis if suddenly discontinued.
•    Insufficient availability of corticosteroids due to severe physiologic stress (e.g. sepsis, trauma, burns, surgery), infections (e.g. Haemophilus influenzae, Staphylococcus aureus, Streptococcus pneumonia, tuberculosis, fungi or meningococcemia); septic shock, azotemia; anticoagulants, hemorrhagic diathesis; or AIDS.

The adrenal cortex produces three steroid hormones: glucocorticoids (cortisol), mineralocorticoids (aldosterone, 11-deoxycorticosterone), and androgens (dehydroepiandrosterone).

Cortisol is the most important hormone in acute adrenal crisis:
•    It enhances gluconeogenesis and provides substrate through proteolysis, protein synthesis inhibition, fatty acid mobilization, and enhanced hepatic amino acid uptake.
•    It indirectly induces insulin secretion to counterbalance hyperglycaemia but also decreases insulin sensitivity.
•    It has a significant anti-inflammatory effect through stabilizing lysosomes, reducing leukocytic responses and blocking cytokine production. Phagocytic activity is preserved, but cell-mediated immunity is diminished in cortisol deficiency.
•    It facilitates free water clearance.
•    It enhances appetite.
•    It suppresses adrenocorticotropic hormone (ACTH) synthesis.

In case of adrenal insufficiency, all these aspects are dysregulated.


 2.1 Clinical presentation

Symptoms of adrenal insufficiency may develop insidiously in 20-30% of patients with metastatic cancer and adrenal enlargement on computed tomography. Chronic corticosteroid therapy can partially mask adrenal failure or can precipitate it after withdrawal.
An acute adrenal crisis can manifest itself with nausea and vomiting, abdominal or flank pain, hyperthermia or hypothermia, and hypovolaemic shock refractory to fluid and pressor resuscitation.
Other symptoms of adrenal gland insufficiency are weakness, weight loss, anorexia, nausea and vomiting (90%), hyperpigmentation of skin and mucous membranes or postural hypotension (80%).

Laboratory examinations are abnormal in 56% of patients with hyponatraemia, hyperkalaemia, hypercalcaemia, hypoglycaemia and mild metabolic acidosis. If adrenal failure is sudden, serum electrolytes may be normal.
Electrocardiographic abnormalities are observed in 50% of patients.
Abdominal computed tomography is recommended in patients with metastatic disease to detect adrenal metastases. High resolution endosonography can offer additional information and is optional

2.2 Diagnosis

Serum cortisol less than 20 µg/dL in severe stress situations or after ACTH stimulation is indicative of adrenal insufficiency.
After ACTH-stimulation test (Cosyntropin 250 µg IV), an increase of cortisol less than 9 µg/dL (measured 30 and 60 min later) is considered diagnostic of adrenal insufficiency, as suitable for individual clinical use , on a type R basis. This test should not be performed in patients with shock.
A low-dose test (Cosyntropin 10 µg IV) may have a better sensitivity and it is considered suitable for individual clinical use, on a type R basis.


The survival of patients with acute adrenal crisis is dependent on prompt recognition and treatment. With adequate treatment the survival rate is 85%. However, because the true incidence of adrenal crisis is unknown, the mortality rate is unknown.


4.1 Treatment of adrenal failure

If acute adrenal failure is suspected clinically and if there is haemodynamic instability, corticosteroid replacement should be started promptly, before laboratory results are obtained, as astandard option, on a type C basis. Delaying glucocorticoid replacement therapy while awaiting the results of the ACTH stimulation test is inappropriate and dangerous.

o    Administration of glucocorticoids in supra-physiological doses is the recommended treatment in patients with acute adrenal falure.

•    Hydrocortisone (50-100 mg IV q 6 h for 7 d, then discontinue or reduce to 50 mg IV q 6h for 4 doses; then taper by one half q d until discontinued or until prior maintenance dose) is thestandard treatment option, on a type C basis.

o    Aggressive fluid replacement with 5 or 10% intravenous dextrose and saline solutions

o    Treatment of hyperkalaemia

•    Fludrocortisone (0.1-0.2 mg orally (PO) q d) should be given as maintenance treatment for its mineralocorticoid effect, as a standard option, on a type C basis.

•    Identification of a precipitating cause and administration of empiric antibiotics is indicated. Reversal of coagulopathy should be attempted with fresh frozen plasma. Pressors (e.g. dopamine, norepinephrine) may be necessary to treat hypotension, and it is the standard option, on a type C basis.

Patients with known adrenocortical insufficiency who undergo a surgical procedure do not routinely require stress doses of corticosteroids as long as they continue to receive their usual daily dose of corticosteroid.

Patients receiving physiologic replacement doses of corticosteroids owing to primary disease of the hypothalamic-pituitary-adrenal axis, however, require supplemental doses of corticosteroids in the stressful situations. This is a standard optio, on a type 1 level of evidence.

These patients may be treated as follows:

•    Acute illness: Hydrocortisone 100 mg IV every 6-8 hours for 4 doses, taper if patient stabilizes

•    Peri-operative steroid therapy:

Timing Hydrocortisone Fludrocortisone
Routine daily 20 mg PO at 8 am
10 mg PO at 4 pm
0.1 mg PO at 8 am
Day of operation 10 mg/h CIV
Postoperative day 1 5-7.5 mg/h CIV
Postoperative day 2 2.5-5 mg/h CIV
Postoperative day 3 2.5-5 mg/h CIV or
40 mg PO at 8 am
20 mg PO at 4 pm
0.1 mg PO at 8 am
Postoperative day 4 2.5-5 mg/h CIV or
40 mg PO at 8 am
20 mg PO at 4 pm
0.1 mg PO at 8 am
Postoperative day 5 40 mg PO at 8 am
20 mg PO at 4 pm
0.1 mg PO at 8 am
Postoperative day 6 20 mg PO at 8 am
20 mg PO at 4 pm
0.1 mg PO at 8 am
Postoperative day 7 20 mg PO at 8 am
10 mg PO at 4 pm
0.1 mg PO at 8 am


•    In patients with chronic adrenal insufficiency, physiological glucicirticoid replacement with cortisone acetate orally 25 mg in the morning and 12.5 mg in the afternoon is a standard option on a type C basic.


Marik PE, Varon J. Requirement of perioperative stress doses of corticosteroids: a systematic review of the literature. Arch Surg 2008; 143: 1222-6 [Medline]

Marik PE, Pastores SM, Annane D, Meduri GU, Sprung CL, Arlt W, et al; American College of Critical Care Medicine. 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: 1937-49 [Medline]

Jung C, Inder WJ. Management of adrenal insufficiency during the stress of medical illness and surgery. Med J Aust 2008; 188: 409-13 [Medline]

Dr. Dirk Schrijvers (Reviewer)
University Hospital Antwerp – Antwerp, Belgium

Dr. Silvia Spinazzé (Associate Editor)
START Programme