Adrenal Crisis 

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 with 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 exercises a significant anti-inflammatory effect by 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.

Hahner et al investigated the frequency and causes of, as well as the risk factors for, adrenal crisis in patients with chronic adrenal insufficiency. Using a disease-specific questionnaire, the authors analyzed data from 444 patients, including 254 with primary adrenal insufficiency and 190 with secondary adrenal insufficiency. At least one adrenal crisis was reported by 42% of patients, including 47% of those with primary adrenal insufficiency and 35% of patients with the secondary condition. GI infection and fever were the most common precipitating causes of crisis. Identified risk factors for adrenal crisis were, for patients with primary adrenal insufficiency, concomitant nonendocrine disease, and for patients with secondary adrenal insufficiency, female sex and diabetes insipidus.[7]

A study from the Netherlands, by Smans et al, of patients with adrenal insufficiency, found the existence of comorbidity to be the most important risk factor for adrenal crisis, with infections being the most common precipitating factors.[8]

A Japanese study, by Iwasaku et al, found that of 504 patients with adrenal crisis, only about one third had preexisting primary or central adrenal insufficiency. In the rest of the patients, comorbidities included cardiovascular disease (31.6%), infection (18.8%), diabetes (16.5%), cancer (19.1%), hypothyroidism (7.0%), autoimmune disease (9.3%), peptic ulcer (6.1%), chronic obstructive pulmonary disease or asthma (6.1%), and renal failure (6.1%).[9]

Frequency

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 et al'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.[10] 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.

The aforementioned study from the Netherlands, by Smans et al, found the incidence of adrenal crisis among persons with primary adrenal insufficiency to be 5.2 cases per 100 person-years, while in secondary adrenal insufficiency, the incidence was reported as 3.6 cases per 100 person-years.[8]

In a study of Swiss patients with either primary or secondary adrenal insufficiency, Notter et al found the prevalence of adrenal crisis to be 4.4 per 100 disease-years.[11]

According to a report by Chabre et al, the annual incidence of adrenal crisis in Europe is estimated to be 6-8 cases per 100 adrenal insufficiency patients.[12]

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 computed tomography (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.

A Japanese study, by Ono et al, indicated that among patients with adrenal crisis, the risk of death is relatively high in those who are older and have impaired consciousness and diabetes mellitus. In the study, of 799 patients with adrenal crisis and concomitant primary or secondary adrenal insufficiency at hospital admission, 2.4% (19) suffered in-hospital mortality, including 15 who were older than 60 years, 12 who had impaired consciousness at admission, and 13 who received insulin therapy.[13]

History can include the following:

• 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.

• Organisms associated with adrenal crisis (eg, Haemophilus influenzae, Staphylococcus aureus, Streptococcus pneumonia, fungi)

• Meningococcemia

• Severe physiologic stress[14] (eg, sepsis, trauma, burns, surgery): In a retrospective review of patients from a level 1 trauma center, Guillamondegui et al found that trauma patients with acute adrenal insufficiency who were treated for the condition had shorter hospital stays and required fewer days in the intensive care unit and on a ventilator than did untreated patients.[15] In addition, the authors concluded that recognition and treatment of the condition can reduce trauma patient mortality by almost 50%.

• 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.

• Congenital adrenal hyperplasia (CAH): A retrospective study by Rushworth et al indicated that in pediatric patients with CAH, adrenal crises occur mostly in the younger ones. The study, which evaluated 573 admissions for medical problems in children with CAH, found that 21 of 37 adrenal crises occurred in patients aged 1-5 years, with another six in children aged up to 1 year.[16]

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• Unexplained shock, usually refractory to fluid and pressor resuscitation

• Nausea, vomiting, abdominal or flank pain

• Hyperthermia or hypothermia

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• Rapid withdrawal of long-term steroid therapy

• Ketoconazole

• Phenytoin

• Rifampin

• Mitotane

• Septic shock

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• 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. However, the absence of laboratory abnormalities does not exclude the diagnosis of adrenal crisis.

• 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.

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• Chest radiography: Assess for tuberculosis, histoplasmosis, malignant disease, sarcoid, and lymphoma.

• Abdominal CT scanning: Visualize adrenal glands for hemorrhage (as in the image below), atrophy, infiltrative disorders, and metastatic disease. Adrenal hemorrhage appears as hyperdense, bilaterally enlarged adrenal glands.

  Computed tomographic (CT) scans of the abdomen show normal adrenal glands several months before the onset of hemorrhage (upper panel) and enlarged adrenals 2 weeks after an acute episode of bilateral adrenal hemorrhage (lower panel). The attenuation of the adrenal glands, indicated by arrows, is increased after the acute event. Reproduced from Rao RH, Vagnucci AH, Amico JA: Bilateral massive adrenal hemorrhage: early recognition and treatment. Ann Intern Med. Feb 1 1989;110(3):227-35 with permission from the journal.

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• Electrocardiography

  • Prolongation of the QT interval can induce ventricular arrhythmias.

  • Deep negative T waves have been described in acute adrenal crisis.

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.

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• Administration of glucocorticoids in supraphysiologic or stress doses is the only definitive therapy.[3, 4]

  • 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 are indicated. Reversal of coagulopathy should be attempted with fresh frozen plasma.

• Pressors (eg, dopamine, norepinephrine) may be necessary to combat hypotension.

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• Endocrinologist

• Infectious disease specialist

• Critical care physician

• Cardiologist

• Surgeon

• Other consultations as clinically indicated

Society for Endocrinology

Guidelines from Britain’s Society for Endocrinology on the emergency management of adrenal crisis, published in 2016, include the following diagnostic recommendations[17] :

• Adrenal insufficiency should be ruled out in any acutely ill patient with signs or symptoms potentially suggestive of acute adrenal insufficiency
• Assess blood pressure and fluid balance status; if clinically feasible, measure blood pressure from supine to standing to check for postural drop
• Assess patient drug history; determine whether there has been glucocorticoid use
• Perform appropriate blood tests: Sodium, potassium, urea, and creatinine; full blood counts; thyroid-stimulating hormone and free thyroxine; paired serum cortisol and plasma ACTH
• If the patient is hemodynamically stable, consider performing a short Synacthen test (serum cortisol at baseline and 30 min after intravenous injection of 250 μg ACTH _1–24)
• Serum/plasma aldosterone and plasma renin
• Diagnostic measures should never delay prompt treatment of a suspected adrenal crisis

The guidelines include the following recommendations for emergency treatment[17] :

• Administer hydrocortisone: Immediate bolus injection of 100 mg hydrocortisone intravenously or intramuscularly followed by continuous intravenous infusion of 200 mg hydrocortisone per 24 hours (alternatively, 50 mg hydrocortisone per intravenous or intramuscular injection every 6 h)
• Rehydrate with rapid intravenous infusion of 1000 mL of isotonic saline infusion within the first hour, followed by further intravenous rehydration as required (usually 4-6 L in 24 h; monitor for fluid overload in case of renal impairment and in elderly patients)
• Contact an endocrinologist for urgent review of the patient, advice on further tapering of hydrocortisone, and investigation of the underlying cause of the disease, including the diagnosis of primary versus secondary adrenal insufficiency
• Tapering of hydrocortisone can be started after clinical recovery guided by an endocrinologist; in patients with primary adrenal insufficiency, mineralocorticoid replacement must be initiated (starting dose 100 μg fludrocortisone once daily) as soon as the daily glucocorticoid dose is below 50 mg of hydrocortisone every 24 hours

Association of Anaesthetists, the Royal College of Physicians, and the Society for Endocrinology

Guidelines released in 2020 by the Association of Anaesthetists, the Royal College of Physicians, and the Society for Endocrinology examined perioperative glucocorticoid management in patients with adrenal insufficiency. With regard to adrenal crisis, the guidelines state that surgical stress or illness places all glucocorticoid-dependent patients at risk for this condition, the recognition and diagnosis of which are essential. If doubt exists as to the need for glucocorticoids in patients with adrenal crisis, these agents should be provided, since short-term glucocorticoid administration produces no long-term adverse consequences.[18]

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

Class Summary

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

Dexamethasone (Decadron, Baldex, Dexone)

Used as empiric treatment of shock in suspected adrenal crisis or insufficiency until serum cortisol levels are drawn.

Hydrocortisone (Hydrocortone, Hydrocort)

DOC because of mineralocorticoid activity and glucocorticoid effects.

Cortisone (Cortone)

Oral DOC for patients with adrenocortical insufficiency.

Use in patients undergoing moderate stress surgery (eg, vascular bypass, total joint replacement) who can take PO postoperatively.

Fludrocortisone (Florinef)

Acts on renal distal tubules to enhance reabsorption of sodium. Increases urinary excretion of both potassium and hydrogen ions. The consequence of these 3 primary effects, together with similar actions on cation transport in other tissues, appears to account for the spectrum of physiological activities characteristic of mineralocorticoids. Used in adrenal insufficiency. Produces marked sodium retention and increased urinary potassium excretion.

Methylprednisolone (Medrol, Solu-Medrol, Depo-Medrol)

Usually third-line DOC for adrenal crisis because of lack of mineralocorticoid activity.

Consider use in patients with fluid overload, edema, or hypokalemia.

Class Summary

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

Norepinephrine (Levophed)

For protracted hypotension following adequate fluid-volume replacement. Stimulates beta1- and alpha-adrenergic receptors, which in turn, increases cardiac muscle contractility and heart rate, as well as vasoconstriction. As a result, systemic blood pressure and coronary blood flow increase. After obtaining a response, the rate of flow should be adjusted and maintained at a low-normal blood pressure, such as 80-100 mm Hg systolic, sufficient to perfuse vital organs.

Dopamine (Intropin)

Stimulates both adrenergic and dopaminergic receptors. Hemodynamic effect is dependent on the dose.

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• 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.

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• 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).

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

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• Immunosuppression

• Hypertension

• Salt retention

• Hypokalemia

• Weight gain

• Delayed wound healing

• Hyperglycemia

• Metabolic alkalosis

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

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• 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 eMedicineHealth's Thyroid & Metabolism Center and patient education article Anatomy of the Endocrine System.