Adrenal Crisis in Emergency Medicine

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.[8]

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.[9]

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,[10] 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.

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.[11]

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.[12]

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.[13]

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.[14]

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.

The following are important elements in the history of patients with adrenal crisis or adrenal insufficiency[5, 6] :

• Weakness (99%)

• Pigmentation of skin (98%)

• Weight loss (97%)

• Abdominal pain (34%)

• Salt craving (22%)

• Diarrhea (20%)

• Constipation (19%)

• Syncope (16%)

• Vitiligo (9%)

A cross-sectional study by Kawahara et al found that in adult patients presenting to a Japanese hospital’s emergency department with hypoglycemia, adrenal insufficiency was the cause in 6.1% of them. Adrenal insufficiency was the third most prominent etiology for hypoglycemia among hypoglycemic people aged 18 years or older who visited the emergency department, with antidiabetes medications (73.7%) and alcohol abuse (6.6%) being the first and second most frequent causes, respectively. The investigators also reported that hyponatremia, hypotension, and eosinophilia were found more often in association with adrenal insufficiency than with other causes of hypoglycemia. They recommended that in patients with protracted hypoglycemia of unknown etiology who also have hyponatremia, hypotension, and/or eosinophilia, a rapid adrenocorticotropic hormone (ACTH) loading test be used to evaluate adrenal function.[15]

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

• Patients with mineralocorticoid insufficiency may show signs of sodium and volume depletion (eg, orthostatic hypotension, tachycardia).

• Evidence of hyperpigmentation is observed, particularly in areas exposed to the sun or areas subject to friction or pressure.

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[11]

• Hypoglycemia (more likely a consequence rather than cause)

• Pain (unmasks, but does not cause)

• Psychoses or depression (associated with, but not causative)

• Exogenous steroid withdrawal

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

• Complete blood count (CBC)

• Electrolyte levels

• BUN level

• Creatinine level

• Cortisol level[7] /ACTH

• Serum calcium level

• Thyroid function (possibly performed in ED but unlikely to influence immediate management)

Chest radiograph

CT scan

• 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.

Emergency department care includes the following:

• 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[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

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.[18]

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[18] :

• 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 (PaO ₂/FiO ₂< 200 and within 14 days of onset)

A 2020 guidance by Simpson et al on the prevention and emergency management of adult adrenal insufficiency indicated that patients at risk for adrenal crisis include the following[19] :

• Patients in whom the presence of primary adrenal insufficiency has been established or is suspected; eg, those with Addison disease, congenital adrenal hyperplasia (CAH), bilateral adrenalectomy, or adrenal hemorrhage
• Patients with an established or suspected diagnosis of adrenal insufficiency arising from hypopituitarism that has itself resulted from hypothalamo-pituitary disease, who are either undergoing permanent glucocorticoid replacement or in whom glucocorticoid replacement is required owing to illness or stress (such as a surgical procedure)
• Patients undergoing exogenous glucocorticoid treatment—through an oral, a topical, an inhaled, an intranasal, or an intra-articular route—that equals or exceeds a dose of prednisolone 5 mg/day for 4 weeks or longer; this is because such patients are likely to have suppressed hypothalamic-pituitary-adrenal axis (HPA) function (ie, tertiary adrenal insufficiency)
• Patients undergoing a course of oral glucocorticoid within 12 months of long-term therapy cessation

One of the goals in treating adrenal insufficiency is glucocorticoid replacement.[20] Electrolyte and metabolic abnormalities, as well as hypovolemia, must also be corrected. In addition, address the event precipitating abrupt decompensation.

Class Summary

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

Hydrocortisone (Cortef, Solu-Cortef)

DOC because of mineralocorticoid activity and glucocorticoid effects.

Cortisone (Cortone Acetate)

Considered the DOC by some practitioners.

Prednisone (Deltasone, Liquid Pred)

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)

Alternative to hydrocortisone to avoid interference with testing of cortisol levels.

Fludrocortisone acetate (Florinef Acetate)

Partial replacement therapy for primary and secondary adrenocortical insufficiency.