AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Do not confuse acute adrenal crisis with Addison disease. In 1855, Thomas Addison described a syndrome of long-term adrenal insufficiency that develops over months to years, with weakness, fatigue, anorexia, weight loss, and hyperpigmentation as the primary symptoms. In contrast, an acute adrenal crisis can manifest with vomiting, abdominal pain, and hypovolemic shock.

Pathophysiology

The adrenal cortex produces 3 steroid hormones: glucocorticoids (cortisol), mineralocorticoids (aldosterone, 11-deoxycorticosterone), and androgens (dehydroepiandrosterone). The androgens are relatively unimportant in adults, and 11-deoxycorticosterone is a fairly weak mineralocorticoid in comparison to aldosterone. The primary hormone of importance in acute adrenal crisis is cortisol; adrenal aldosterone production is relatively minor.

Cortisol enhances gluconeogenesis and provides substrate through proteolysis, protein synthesis inhibition, fatty acid mobilization, and enhanced hepatic amino acid uptake. Cortisol indirectly induces insulin secretion to counterbalance hyperglycemia but also decreases insulin sensitivity. Cortisol also 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 situations of cortisol deficiency. Finally, cortisol facilitates free water clearance, enhances appetite, and suppresses adrenocorticotropic hormone (ACTH) synthesis.

Aldosterone is released in response to angiotensin II stimulation via the renin-angiotensin-aldosterone system, hyperkalemia, hyponatremia, and dopamine antagonists. Its effect on its primary target organ, the kidney, is to promote reabsorption of sodium and secretion of potassium and hydrogen. The mechanism of action is unclear; an increase in the sodium- and potassium-activated adenosine triphosphatase (Na⁺/K⁺ ATPase) enzyme responsible for sodium transport, as well as increased carbonic anhydrase activity, has been suggested. The net effect is to increase intravascular volume. The renin-angiotensin-aldosterone system is unaffected by exogenous glucocorticoids, and ACTH deficiency has a relatively minor effect on aldosterone levels.

Adrenocortical hormone deficiency results in the reverse of these hormonal effects, producing the clinical findings of adrenal crisis.

Primary adrenocortical insufficiency occurs when the adrenal glands fail to release adequate amounts of these hormones to meet physiologic needs, despite release of ACTH from the pituitary. Infiltrative or autoimmune disorders are the most common cause, but adrenal exhaustion from severe chronic illness also may occur.

Secondary adrenocortical insufficiency occurs when exogenous steroids have suppressed the hypothalamic-pituitary-adrenal (HPA) axis. Too rapid withdrawal of exogenous steroid may precipitate adrenal crisis, or sudden stress may induce cortisol requirements in excess of the adrenal glands' ability to respond immediately. In acute illness, a normal cortisol level may actually reflect adrenal insufficiency because the cortisol level should be quite elevated.

Bilateral massive adrenal hemorrhage (BMAH) occurs under severe physiologic stress (eg, myocardial infarction, septic shock, complicated pregnancy) or with concomitant coagulopathy or thromboembolic disorders.

Frequency

United States

The incidence of primary adrenocortical insufficiency is variable and depends on the defining cortisol level and the method of testing (ie, ACTH stimulation versus single random cortisol level). The underlying disease also is a factor. Studies of critically ill patients with septic shock demonstrate a de novo (excluding patients with known adrenal insufficiency or patients on glucocorticoid therapy) incidence ranging from 19-54%. Secondary adrenal insufficiency has been demonstrated in 31% of patients admitted to a critical care unit.

Annane's landmark 2002 study found a very high rate, ie, 76% of all enrolled patients with septic shock. Of the general perioperative population, in 62,473 anesthetic administrations, only 419 (0.7%) patients required glucocorticoid supplementation and only 3 hypotensive events were thought to be attributable to glucocorticoid deficiency.¹ Studies of patients undergoing cardiac or urologic surgery reveal an incidence of 0.01-0.1%. In a study of 2000 consecutive general hospital autopsies, only 22 (1.1%) revealed bilateral adrenal hemorrhage; however, as many as 15% of patients dying in shock have been demonstrated to have BMAH.

No description regarding racial data, sexual predilection, or age is available in the literature.

Mortality/Morbidity

In the absence of bilateral adrenal hemorrhage, the survival rate of patients with acute adrenal crisis that is diagnosed promptly and treated appropriately approaches that of patients without acute adrenal crisis with similar severity of illness. Patients who developed BMAH before the availability of hormonal testing or CT scanning rarely survived. In one series, patients who were diagnosed using CT scanning had an 85% rate of survival. Because the true incidence of adrenal crisis and BMAH are unknown, the actual mortality rate also is unknown.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• Prior steroid use: Use involves at least 20 mg daily of prednisone or its equivalent for at least 5 days within the past 12 months. Patients receiving doses close to normal physiologic levels require only 1 month to recover normal adrenal function.
• Severe physiologic stress (eg, sepsis, trauma, burns, surgery), organisms associated with adrenal crisis (eg, Haemophilus influenzae, Staphylococcus aureus, Streptococcus pneumonia, fungi), meningococcemia
• Azotemia
• Anticoagulants, hemorrhagic diathesis
• Newborn, complicated pregnancy
• Adrenocorticotropin therapy, known primary or secondary adrenocortical insufficiency
• AIDS
• Invasive or infiltrative disorders
• Tuberculosis
• Topical steroids: Risk of adrenal crisis occurs when used over a large surface area for a prolonged duration, using occlusive dressings and a highly potent drug.
• Inhaled steroids
• • Use of a high dose (>0.8mg/d) over a prolonged duration increases risk.
  • Fluticasone may cause suppression at lower dose.

Physical

• Unexplained shock, usually refractory to fluid and pressor resuscitation
• Nausea, vomiting, abdominal or flank pain
• Hyperthermia or hypothermia

Causes

• Rapid withdrawal of long-term steroid therapy
• Ketoconazole
• Phenytoin
• Rifampin
• Mitotane
• Septic shock

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Acute abdomen

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Serum chemistry: Abnormalities are present in as many as 56% of patients. Hyponatremia is common (although not diagnostic); hyperkalemia, metabolic acidosis, and hypoglycemia also may be present.
• Serum cortisol: Less than 20 mcg/dL in severe stress or after ACTH stimulation is indicative of adrenal insufficiency.
• ACTH test (diagnostic): Determine baseline serum cortisol, then administer ACTH 250 mcg intravenous push (IVP), and then draw serum cortisol 30 and 60 minutes after ACTH administration. An increase of less than 9 mcg/dL is considered diagnostic of adrenal insufficiency.
• CBC: Anemia (mild and nonspecific), lymphocytosis, and eosinophilia (highly suggestive) may be present.
• Serum thyroid levels: Assess for autoimmune, infiltrative, or multiple endocrine disorders.
• Cultures: Perform blood and other cultures as clinically indicated. Infection is a common cause of acute adrenal crisis.

Imaging Studies

• Chest radiography: Assess for tuberculosis, histoplasmosis, malignant disease, sarcoid, and lymphoma.
• Abdominal CT scanning: Visualize adrenal glands for hemorrhage, atrophy, infiltrative disorders, and metastatic disease. Adrenal hemorrhage appears as hyperdense, bilaterally enlarged adrenal glands.

Other Tests

• Electrocardiography
• • Prolongation of the QT interval can induce ventricular arrhythmias.
  • Deep negative T waves have been described in acute adrenal crisis.

Histologic Findings

Histology depends on the cause of the adrenal failure. In primary adrenocortical failure, histologic evidence of infection, infiltrative disease, or other condition may be demonstrated. Secondary adrenocortical insufficiency may cause atrophy of the adrenals or no histologic evidence at all, especially if due to exogenous steroid ingestion. Appearance of bilateral adrenal hemorrhage may be striking, as if bags of blood are replacing the glands.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

• Administration of glucocorticoids in supraphysiologic or stress doses is the only definitive therapy.
• • Dexamethasone does not interfere with serum cortisol assay and, thus, may be the initial drug of choice. However, because dexamethasone has little mineralocorticoid activity, fluid and electrolyte replacement are essential.
  • A short ACTH stimulation test may be performed during resuscitation. Once complete, hydrocortisone 100 mg IV every 6 hours is the preferred treatment to provide mineralocorticoid support.
  • Delaying glucocorticoid replacement therapy while awaiting the results of the ACTH stimulation test is inappropriate and dangerous.
• In addition to corticosteroid replacement, aggressive fluid replacement with 5% or 10% intravenous dextrose and saline solutions and treatment of hyperkalemia is mandatory. Fludrocortisone, a mineralocorticoid, may also be given.
• A thorough search for a precipitating cause and administration of empiric antibiotics is indicated. Reversal of coagulopathy should be attempted with fresh frozen plasma.
• Pressors (eg, dopamine, norepinephrine) may be necessary to combat hypotension.

Consultations

• Endocrinologist
• Infectious disease specialist
• Critical care physician
• Cardiologist
• Surgeon
• Other consultations as clinically indicated

MEDICATION

Section 7 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Corticosteroids are the mainstays of treatment. Other medications, such as pressors (eg, dopamine, norepinephrine) or antibiotics, are administered as clinically indicated.

Drug Category: Corticosteroids

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.

Drug Category: Vasopressors

These agents are potent vasocontrictors, inotropes and chronotropes. They should be used with caution in conjunction with corticosteroids and intravenous fluid support.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Admit to ICU as clinically indicated.
• • Perform fluid resuscitation and hemodynamic monitoring as clinically indicated.
  • Monitor serum electrolytes, magnesium, and glucose every 4-6 hours until stable.
  • Search for precipitating cause of crisis (eg, infection, myocardial infarction, unreported exogenous steroid use within 12 mo, autoimmune disorder).

Further Outpatient Care

• Treat any underlying or precipitating disorder as clinically indicated.
• Carefully monitor growth and development in pediatric patients.
• Recommend medical tag or bracelet that alerts emergency personnel to adrenal gland insufficiency.
• If exposed to chickenpox, prophylaxis with varicella-zoster immune globulin is indicated.
• If exposed to measles, prophylaxis with immune globulin is indicated.
• Closely observe for reactivation of tuberculosis in patients with latent disease.

In/Out Patient Meds

• Taper steroid dose as outlined previously (see Medication).

Complications

• Immunosuppression
• Hypertension
• Salt retention
• Hypokalemia
• Weight gain
• Delayed wound healing
• Hyperglycemia
• Metabolic alkalosis

Prognosis

• Prognosis is the same as for patients without adrenal insufficiency if the condition is diagnosed and treated appropriately.

Patient Education

• Instruct patients regarding the importance of careful attention to health and fluid intake and to double maintenance doses when ill until medical attention is obtained.
• Avoid exposure to chickenpox or measles; if exposed, seek medical advice without delay.
• Notify physician or seek medical attention for persistent nausea and vomiting, fatigue, and abdominal pain.
• For excellent patient education materials, see eMedicine's Endocrine System Center and patient education article Anatomy of the Endocrine System.

MISCELLANEOUS

Section 9 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to obtain a comprehensive history, including medications, may lead to lack of recognition of potentially fatal, yet often preventable, secondary adrenocortical insufficiency.

Special Concerns

• Management of known or suspected primary or secondary adrenocortical insufficiency during stress includes the following:
• • Acute illness - Hydrocortisone 100 mg IV every 6-8 hours for 4 doses, taper if patient stabilizes
  • Perioperative - See the Table.

    Perioperative Steroid Therapy for Patients with Known Adrenal Insufficiency

    Timing	Hydrocortisone	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 continuous infusion	…	…
    Postoperative day 1	5-7.5 mg/h continuous infusion	…	…
    Postoperative day 2	2.5-5 mg/h continuous infusion	…	…
    Postoperative day 3	2.5-5 mg/h continuous infusion 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 continuous infusion 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 pregnancy, anticipated benefits must outweigh risks because no adequate human reproductive studies are available.
• Corticosteroids appear in breast milk.
• Corticosteroids can suppress growth and interfere with infant endogenous corticosteroid production.
• In primary adrenocortical insufficiency, glucocorticoid and mineralocorticoid replacement is required for life.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Enlarged, dense, suprarenal masses
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

1. Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. Aug 21 2002;288(7):862-71. [Medline].
2. Ahlawat SK, Jain S, Kumari S, Varma S, Sharma BK. Pheochromocytoma associated with pregnancy: case report and review of the literature. Obstet Gynecol Surv. Nov 1999;54(11):728-37. [Medline].
3. Aono J, Mamiya K, Ueda W. Abrupt onset of adrenal crisis during routine preoperative examination in a patient with unknown Addison's disease. Anesthesiology. Jan 1999;90(1):313-4. [Medline].
4. Arafah BM. Hypothalamic pituitary adrenal function during critical illness: limitations of current assessment methods. J Clin Endocrinol Metab. Oct 2006;91(10):3725-45. [Full Text].
5. Axelrod L. Perioperative management of patients treated with glucocorticoids. Endocrinol Metab Clin North Am. Jun 2003;32(2):367-83. [Medline].
6. Chin R. Adrenal crisis. Crit Care Clin. Jan 1991;7(1):23-42. [Medline].
7. Cronin CC, Callaghan N, Kearney PJ, et al. Addison disease in patients treated with glucocorticoid therapy. Arch Intern Med. Feb 24 1997;157(4):456-8. [Medline].
8. Iga K, Hori K, Gen H. Deep negative T waves associated with reversible left ventricular dysfunction in acute adrenal crisis. Heart Vessels. 1992;7(2):107-11. [Medline].
9. Koo DJ, Jackman D, Chaudry IH, Wang P. Adrenal insufficiency during the late stage of polymicrobial sepsis. Crit Care Med. Mar 2001;29(3):618-22. [Medline].
10. Nicholson G, Burrin JM, Hall GM. Peri-operative steroid supplementation. Anaesthesia. Nov 1998;53(11):1091-104. [Medline].
11. Obenour RA, Ross S. Adrenal Crisis. Hospital Formulary of the University of Tennessee Medical Center [serial online]. 1999;Available at http://www.cushings-help.com/adrenal-crisis.htm.
12. Passmore JM Jr. Adrenal Cortex. Clinics in Critical Care Medicine. 1985;97-134.
13. Rao RH. Bilateral massive adrenal hemorrhage. Med Clin North Am. Jan 1995;79(1):107-29. [Medline].
14. Schroeder S, Wichers M, Klingmuller D, et al. The hypothalamic-pituitary-adrenal axis of patients with severe sepsis: altered response to corticotropin-releasing hormone. Crit Care Med. Feb 2001;29(2):310-6. [Medline].
15. Vella A, Nippoldt TB, Morris JC 3rd. Adrenal hemorrhage: a 25-year experience at the Mayo Clinic. Mayo Clin Proc. Feb 2001;76(2):161-8. [Medline].
16. Williams GH, Dluhy RG. Disease of the Adrenal Cortex. In: Braunwald E, Fauci AS, Kasper DL, eds. Harrison's Principles of Internal Medicine. 13^th ed. New York, NY: McGraw-Hill; 1994:1953-76.
17. Xarli VP, Steele AA, Davis PJ, et al. Adrenal hemorrhage in the adult. Medicine (Baltimore). May 1978;57(3):211-21. [Medline].
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Article Last Updated: Dec 18, 2007