Adrenal Crisis in Emergency Medicine

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Background

Adrenal crisis and severe acute adrenocortical insufficiency are often elusive diagnoses that may result in severe morbidity and mortality when undiagnosed or ineffectively treated.[1, 2]

Although it is thought by experts that more than 50 steroids are produced within the adrenal cortex,[3] cortisol and aldosterone are by far the most abundant and physiologically active. Regulation of the adrenal cortex is illustrated in the image below.



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Regulation of the adrenal cortex.

In primary adrenocortical insufficiency, glucocorticoid and mineralocorticoid properties are lost; however, in secondary adrenocortical insufficiency (ie, secondary to disease or suppression of the hypothalamic-pituitary axis), mineralocorticoid function is preserved.

Although suppression of the hypothalamic-pituitary axis from chronic exogenous steroid use is the most common cause of secondary adrenal insufficiency, the possibility of hypopituitarism due to hypothalamic-pituitary disease must be considered. With acute hypopituitarism, other hormone deficiencies must be identified and treated in addition to treating adrenal insufficiency with corticosteroids. For instance, if a patient with panhypopituitarism due to Sheehan syndrome (postpartum pituitary infarction) is only treated for adrenal crisis, severe cardiovascular compromise from the untreated associated hypothyroidism likely occurs. Death can result if the hypothyroid state is not diagnosed.

Every emergency physician should be familiar with adrenocortical insufficiency, which is a potentially life-threatening entity. The initial diagnosis and decision to treat are presumptive and are based on history, physical examination, and, occasionally, laboratory findings. Delay in treatment while attempting to confirm this diagnosis can result in poor patient outcomes.

Pathophysiology

Adrenal medullae normally secrete 80% epinephrine and 20% norepinephrine. Sympathetic stimulation results in secretion.

The adrenal cortex produces cortisol, aldosterone, and androgens. Cortisol is produced from 2 hydroxylations of 17alpha-hydroxyprogesterone. Cortisol, also known as hydrocortisone, is 90-93% protein bound (primarily by corticosteroid-binding globulin).

Physiologic effects of glucocorticoids

Glucocorticoids are nonspecific cardiac stimulants that activate release of vasoactive substances. In the absence of corticosteroids, stress results in hypotension, shock, and death. Glucocorticoids act as follows to:

Physiologic effects of aldosterone

Aldosterone is produced by multiple hydroxylations of deoxycorticosterone and is normally 60% protein bound. The renin-angiotensin system stimulates aldosterone release. Increased potassium stimulates aldosterone production, and decreased potassium inhibits production. Chronic adrenocorticotropic hormone (ACTH) deficiency may inhibit production.

The primary actions of aldosterone cause the kidneys, gut, and salivary/sweat glands to affect electrolyte balance. The primary targets are the kidneys; where it stimulates reabsorption of sodium and secretion of potassium and hydrogen ions. The kidneys' effect on sodium and potassium depend on the intake of these cations (ie, increased sodium intake = increased potassium secretion). The effects on hydrogen probably can occur independently.

Persistent aldosterone excess results in atrial natriuretic factor release and renal hemodynamic changes for compensation. Congestive heart failure (CHF) and cirrhosis with ascites are exceptions that cause progressive sodium retention. Excess aldosterone results in sodium retention, hypokalemia, and alkalosis. Aldosterone deficiency results in sodium loss, hyperkalemia, and acidosis. Hyperkalemia stimulates aldosterone release to improve potassium excretion. Aldosterone is the first-line defense against hyperkalemia.

Primary adrenal insufficiency

Primary adrenal insufficiency, which can be acute or chronic, may be caused by the anatomic destruction of the gland. This destruction can have various causes, including tuberculosis or fungal infection, other diseases infiltrating the adrenal glands, and hemorrhage. However, the most frequent cause is idiopathic atrophy, which is probably autoimmune in origin.

Primary adrenal insufficiency also may be caused by metabolic failure (eg, insufficient hormone production). This failure may be a result of congenital adrenal hyperplasia (CAH), enzyme inhibitors (eg, metyrapone), or cytotoxic agents (eg, mitotane).

Primary adrenocortical insufficiency is rare and occurs at any age. The male-to-female ratio is 1:1.

A retrospective study by Rushworth et al indicated that in pediatric patients with CAH, adrenal crises occur mostly in younger children. The study, which evaluated 573 admissions for medical problems in youngsters 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.[4]

A Japanese study reported that in children under age 7 years with 21-hydroxylase deficiency, a cause of CAH, the incidence of adrenal crisis was 10.9 cases per 100 person-years.[5]

Secondary adrenal insufficiency

Secondary adrenal insufficiency may be caused by hypopituitarism due to hypothalamic-pituitary disease or may result from suppression of the hypothalamic-pituitary axis by exogenous steroids or endogenous steroids (ie, tumor).

Secondary adrenocortical insufficiency is relatively common. Extensive therapeutic use of steroids has greatly contributed to increased incidence.

Acute adrenocortical insufficiency

Adrenal crisis may result from an acute exacerbation of chronic insufficiency,[6] usually caused by sepsis or surgical stress. Acute adrenal insufficiency also can be caused by adrenal hemorrhage (eg, usually septicemia-induced Waterhouse-Friderichsen syndrome [fulminant meningococcemia]) and anticoagulation complications. Steroid withdrawal is the most common cause of acute adrenocortical insufficiency and almost exclusively causes a glucocorticoid deficiency.

Epidemiology

Frequency

United States

Primary adrenocortical insufficiency is an uncommon disorder with an incidence in Western populations near 50 cases per 1,000,000 persons. With the advent of widespread corticosteroid use, however, secondary adrenocortical insufficiency due to steroid withdrawal is much more common. Approximately 6,000,000 persons in the United States are considered to have undiagnosed adrenal insufficiency, which is clinically significant only during times of physiologic stress.

Primary adrenocortical insufficiency has multiple etiologies; however, 80% of cases in the United States are caused by autoimmune adrenal destruction. Glandular infiltration by tuberculosis is the second most frequent etiology.

In patients with primary adrenocortical insufficiency due to idiopathic autoimmune lymphocytic infiltration, the presence of other associated endocrine disorders must be entertained. Consider polyglandular autoimmune disorders (PGAs) such as Schmidt syndrome.

Schmidt syndrome (PGA type II) includes adrenal insufficiency, autoimmune thyroid disease, and, occasionally, insulin-dependent diabetes mellitus. Adrenal insufficiency usually occurs in these patients when they are older than 20 years. In approximately 40-50% of patients with PGA II, the first manifestation of the syndrome is adrenal insufficiency.

PGA type I includes hypoparathyroidism and mucocutaneous candidiasis in conjunction with adrenal insufficiency. The full triad may manifest in approximately 30% of patients with PGA type I.

International

In a study from the Netherlands, Smans et al found evidence that in primary and secondary adrenal insufficiency, the incidence rate of adrenal crisis per 100 person-years is 5.2 and 3.6, respectively.[7]

A study by Notter et al found that among Swiss patients with primary or secondary adrenal insufficiency, 4.4 adrenal crises per 100 disease-years occurred.[8]

Mortality/Morbidity

Acute adrenocortical insufficiency is a difficult diagnosis to make. The disorder rarely occurs without concomitant injury or illness. Many of the presenting signs and symptoms are nonspecific. For instance, a postoperative fever may presumptively be treated as infection or systemic inflammatory response syndrome when it may be a subtle indicator of adrenal insufficiency.

Left untreated, a patient with acute adrenal insufficiency has a dismal prognosis for survival. Therefore, treatment upon clinical suspicion is mandatory. Any delay in management while waiting for diagnostic confirmation cannot be justified.[9]

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.[10]

Sex

Although primary adrenocortical insufficiency affects men and women equally, women are affected 2-3 times more often by the idiopathic autoimmune form of adrenal insufficiency.

Age

In idiopathic autoimmune adrenal insufficiency, the diagnosis is most often discovered in the third to fifth decades of life; however, it is particularly important to recognize that adrenocortical insufficiency is not limited to any specific age group.

History

The following are important elements in the history of patients with adrenal crisis or adrenal insufficiency[11, 12] :

Physical

Physical findings in patients with adrenal insufficiency are subtle and nonspecific.

Causes

Causes and related conditions include the following:

Laboratory Studies

The following should be assessed in patients with suspected adrenal crisis or adrenal insufficiency:

Imaging Studies

Chest radiograph

CT scan

Other Tests

Adrenocorticotropic hormone (ACTH) stimulation test

Electrocardiograph (ECG): Elevated peaked T waves may indicate hyperkalemia.

24-hour urinary cortisol: Use only in nonemergent situations.

Emergency Department Care

Emergency department care includes the following:

Consultations

Endocrine consultation following admission is beneficial. If no endocrinologist is available, a general internist can manage the process. Emergency management should be implemented in the ED prior to consultation when sufficient clinical suspicion for this diagnosis is present.

ICU admission is necessary for most patients with acute adrenal insufficiency and adrenal crisis.

Long-Term Monitoring

Maintenance of cortisol levels may be achieved by administering hydrocortisone 15-20 mg PO every morning and 5-10 mg PO between 4:00-6:00 PM every afternoon. A morning dose of 10-15 mg of hydrocortisone is believed to be potentially sufficient. Avoid giving hydrocortisone dose in the evening or at bedtime since it may cause insomnia. Mid to late afternoon is best suited for second dose.

Maintenance mineralocorticoid levels may be achieved by administering 9 alpha-fluorocortisol 0.05-0.1 mg every morning. (This treatment is necessary only for primary adrenocortical insufficiency.)

Periodically assess blood pressure, body weight, and electrolytes.

Advise patients to increase their cortisol dosage during times of physical stress.

Guidelines Summary

Guidelines from Britain’s Society for Endocrinology on the emergency management of adrenal crisis, published in 2016, include the following diagnostic recommendations[15] :

The guidelines include the following recommendations for emergency treatment[15] :

Guidelines on critical illness–related corticosteroid insufficiency (CIRCI) were published in 2017 by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine.[16]

The task force was unable to reach agreement on a single test that can reliably diagnose CIRCI, although delta cortisol (change in baseline cortisol of < 9 μg/dL at 60 min) after cosyntropin (250 μg) administration and a random plasma cortisol of >10 μg/dL may be used by clinicians. The guidelines also state the following[16] :

Medication Summary

One of the goals in treating adrenal insufficiency is glucocorticoid replacement.[17] Electrolyte and metabolic abnormalities, as well as hypovolemia, must also be corrected. In addition, address the event precipitating abrupt decompensation.

Hydrocortisone (Cortef, Solu-Cortef)

Clinical Context:  DOC because of mineralocorticoid activity and glucocorticoid effects.

Cortisone (Cortone Acetate)

Clinical Context:  Considered the DOC by some practitioners.

Prednisone (Deltasone, Liquid Pred)

Clinical Context:  Treats various diseases including adrenocortical insufficiency. Agent is inactive and must be metabolized to active metabolite prednisolone. Conversion may be impaired in patients with liver disease.

Dexamethasone (Decadron, AK-Dex, Alba-Dex, Dexone)

Clinical Context:  Alternative to hydrocortisone to avoid interference with testing of cortisol levels.

Fludrocortisone acetate (Florinef Acetate)

Clinical Context:  Partial replacement therapy for primary and secondary adrenocortical insufficiency.

Class Summary

These agents are primarily used to correct glucocorticoid deficiencies. The drugs of choice are hydrocortisone, cortisone, and prednisone.

What is an adrenal crisis?What is the difference between primary and secondary adrenocortical insufficiency in adrenal crisis?How does hypopituitarism contribute to adrenal crisis?What is the importance of early and accurate diagnosis of adrenal crisis?What is the normal function of the adrenal medullae and adrenal cortex?What are the physiologic effects of glucocorticoids relative to adrenal crisis?What are the physiologic effects of aldosterone and how does dysfunction contribute to adrenal crisis?What causes primary adrenal insufficiency?What causes secondary adrenal insufficiency?What causes acute adrenal insufficiency?How common is adrenocortical insufficiency in the US?What is the international incidence of adrenal crisis?What is the mortality of acute adrenocortical insufficiency?Is idiopathic autoimmune adrenal insufficiency more common in men or women?At what age is idiopathic autoimmune adrenal insufficiency most commonly diagnosed?What are the notable features in the history of patients with adrenal crisis?What are the physical findings in patients with adrenal insufficiency or crisis?What are the causes and related conditions associated with adrenal crisis?What is the relationship between etomidate and adrenal crisis?What are the differential diagnoses for Adrenal Crisis in Emergency Medicine?Which lab studies are indicated in suspected adrenal crisis?Which imaging studies are indicated in suspected adrenal crisis?Which additional tests are indicated in the workup of adrenal crisis?What is the emergency department treatment of adrenal crisis?Which specialist consultations are indicated in suspected adrenal crisis?What are the monitoring procedures for patients with adrenal crisis?What are the Society for Endocrinology’s diagnostic recommendations for adrenal crisis?What are the Society for Endocrinology’s recommendations for emergency treatment of adrenal crisis?What are the guidelines on the workup and treatment for critical illness–related corticosteroid insufficiency (CIRCI)?What are the goals of treating adrenal insufficiency and crisis?Which medications in the drug class Corticosteroids are used in the treatment of Adrenal Crisis in Emergency Medicine?

Author

Kevin M Klauer, DO, EJD, FACEP, Assistant Clinical Professor, Michigan State University College of Osteopathic Medicine; Chief Medical Officer, Emergency Medicine Physicians, Ltd; Director, Center for Emergency Medical Education; Medical Editor-in-Chief, ACEP Now; Former Editor-in-Chief, Emergency Physicians Monthly

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Howard A Bessen, MD, Professor of Medicine, Department of Emergency Medicine, University of California, Los Angeles, David Geffen School of Medicine; Program Director, Harbor-UCLA Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Romesh Khardori, MD, PhD, FACP, Professor of Endocrinology, Director of Training Program, Division of Endocrinology, Diabetes and Metabolism, Strelitz Diabetes and Endocrine Disorders Institute, Department of Internal Medicine, Eastern Virginia Medical School

Disclosure: Nothing to disclose.

Additional Contributors

Erik D Schraga, MD, Staff Physician, Department of Emergency Medicine, Mills-Peninsula Emergency Medical Associates

Disclosure: Nothing to disclose.

References

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Regulation of the adrenal cortex.

Regulation of the adrenal cortex.