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.
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:
Stimulate gluconeogenesis and decrease cellular glucose use
Mobilize amino acids and fatty acids
Inhibit the effects of insulin
Give rise to ketone bodies in metabolism (ketogenesis)
Elevate RBC and platelet levels
Exhibit anti-inflammatory effects, including the following:
Maintenance of normal vascular response to vasoconstrictors
Opposition to increases in capillary permeability
Inhibition of interleukin-2 (IL-2) production by macrophages
Stimulation of polymorphonuclear neutrophil (PMN) leukocytosis
Reduction of adherence of macrophages to endothelium
Depletion of circulating eosinophils and lymphocytes
Reduction of circulating lymphocytes (primarily T cells)
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.
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.
Causes and related conditions include the following:
Surgery
Anesthesia (eg, etomidate)
Volume loss (unmasks, unless there is bleeding in the adrenals)
Trauma
Asthma (steroid withdrawal)
Hypothermia (a consequence, not cause)
Alcohol (not well substantiated)
Myocardial infarction (unmasks but does not cause)
Fever/infection: In the aforementioned study from the Netherlands, Smans et al found that among patients with adrenal insufficiency, the existence of comorbidity is the most important risk factor for adrenal crisis, with infections being the most common precipitating factors[7]
Hypoglycemia (more likely a consequence rather than cause)
Pain (unmasks, but does not cause)
Psychoses or depression (associated with, but not causative)
A CT scan of the abdomen may show hemorrhage in the adrenals, calcification of the adrenals (seen with tuberculosis), or metastasis.
In cases of secondary adrenal insufficiency, a head CT scan may show destruction of the pituitary (ie, empty sella syndrome) or a pituitary mass lesion.
Adrenocorticotropic hormone (ACTH) stimulation test
Note: In emergent situations, do not delay treatment of presumed adrenal insufficiency during diagnostic testing. Treatment with dexamethasone allows ACTH stimulation testing without affecting or interfering with the measurement of serum cortisol levels.
Obtain baseline serum cortisol and ACTH levels.
Administer 0.25 mg (250 mcg) of cosyntropin (synthetic ACTH) intravenously (IV) or intramuscularly (IM).
Repeat cortisol levels every 30 minutes (some authors recommend 60 min) and 6 hours after ACTH administration (generally not recommended).
Normal response is indicated when the cortisol peak exceeds 18 ug/dL in response to ACTH stimulation.
In adrenal insufficiency, serum cortisol levels fail to rise after ACTH administration.
Electrocardiograph (ECG): Elevated peaked T waves may indicate hyperkalemia.
24-hour urinary cortisol: Use only in nonemergent situations.
Maintain airway, breathing, and circulation in patients with adrenal crisis.
Use coma protocol (ie, glucose, thiamine, naloxone).
Use aggressive volume replacement therapy (dextrose 5% in normal saline solution [D5NS]).
Correct electrolyte abnormalities as follows:
Hypoglycemia (67%)
Hyponatremia (88%)
Hyperkalemia (64%, may be offset by concurrent vomiting/diarrhea and potassium loss)
Hypercalcemia (6-33%)
Use dextrose 50% as needed for hypoglycemia.
Administer hydrocortisone 100 mg intravenously (IV) every 6 hours. During adrenocorticotropic hormone (ACTH) stimulation testing, dexamethasone (4 mg IV) can be used instead of hydrocortisone to avoid interference with testing of cortisol levels.
Administer fludrocortisone acetate (mineralocorticoid) 0.1 mg every day as needed. Mineralocorticoid administration is usually not necessary for treatment of secondary adrenocortical insufficiency.
Once the patient stabilizes, usually by the second day, the corticosteroid dose may be reduced and then tapered. Oral maintenance can usually be achieved by the fourth or fifth day.
Always treat the underlying problem that precipitated the crisis. Infectious etiologies commonly precipitate adrenal crisis. Recognition and treatment of causative factors are crucial aspects of managing adrenal hypofunction.
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.
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 from Britain’s Society for Endocrinology on the emergency management of adrenal crisis, published in 2016, include the following diagnostic recommendations[15] :
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 ACTH1–24)
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[15] :
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
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] :
Suggest against using plasma-free cortisol or salivary cortisol level over plasma total cortisol
For treatment of specific conditions, suggest using IV hydrocortisone < 400 mg/day for ≥3 days at full dose in patients with septic shock that is not responsive to fluid and moderate- to high-dose vasopressor therapy
Suggest not using corticosteroids in adult patients with sepsis without shock
Suggest the use of IV methylprednisolone 1 mg/kg/day in patients with early moderate to severe acute respiratory distress syndrome (PaO2/FiO2< 200 and within 14 days of onset)
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.
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.
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?
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
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