Hypoadrenal Crisis and the Stress Management of the Patient on Chronic Steroid Therapy

Neil Aronin

The adrenal glands secrete five types of hormone, but two are critical in the intensive care unit (ICU) setting. Mineralocorticoids (primarily aldosterone) regulate electrolyte balance. Glucocorticoids (primarily cortisol) promote gluconeogenesis and have many other actions. Aldosterone and cortisol are life sustaining; deficiency of either can result in hypoadrenal crisis. The other three types of adrenal hormones (dehydroepiandrosterone and its sulfate, estrone, and catecholamines) do not play a major role in acute care settings.

Hypoadrenal crisis can occur as an acute event in individuals lacking a prior history of adrenal disorders. A high index of suspicion arises in patients who have inadequate responses to initial therapies. Patients treated with glucocorticoids have a heightened risk for inadequate cortisol response to stress. Diagnosis of cortisol deficiency can be elusive; conditions that contribute to ICU admission (e.g., sepsis, acute respiratory failure) might interfere with traditional tests of adrenal function.

The sometime uncertainty in biochemical diagnosis of adrenal hypofunction invokes the use of clinical judgment in starting therapy. Recent studies indicate that varied disease in ICU patients do not allow a unified algorithm of treatment. Because excess cortisol is beset with side effects and exacerbation of illness, it is prudent to have mastery of the normal regulation and actions of aldosterone and cortisol; the strengths and foibles of diagnostic tests of adrenal insufficiency; and the evidence for appropriate, effective, and safe use of glucocorticoids in ICU patients.

Etiology

The most common cause of primary adrenal failure is Addison’s disease, an autoimmune disease that is frequently known before the ICU admission. Addison’s disease often coexists with additional autoimmune endocrinopathies, especially Hashimoto’s thyroiditis. Other causes of adrenal failure present a difficult diagnosis in the ICU: overwhelming sepsis, hemorrhage secondary to trauma, circulating anticoagulants or anticoagulant therapy, tuberculosis, fungal disease, amyloidosis, acquired immune deficiency syndrome, antiphospholipid syndrome, infarction, irradiation, metastatic disease, and drugs [1,2,3,4,5]. Critical illness can cause or unmask adrenal insufficiency.

The most common cause of secondary adrenal insufficiency is suppression of corticotrophin (adrenocorticotrophic hormone [ACTH]) release by prior glucocorticoid therapy. ACTH regulates the maintenance of cells in the zona fasciculata and the synthesis and release of cortisol from these cells. Glucocorticoid therapy suppresses ACTH, thereby causing involution of the cortisol-producing cells. The anterior pituitary regains its ability to respond to stress before normal adrenal function is restored. There are no cutoffs on duration of glucocorticoid therapy, its route of administration, and its dosage that can cause adrenal cortical atrophy (zona fasciculata) and inadequate cortisol reserve. Adrenal suppression may occur in patients without obvious clinical signs of Cushing’s syndrome. Symptoms of withdrawal mimic those of Addison’s disease, such as weakness, lethargy, abdominal discomfort, arthralgias, myalgias, and weight loss. After short-term glucocorticoid treatment, symptoms may arise despite an intact hypothalamic-pituitary-adrenal axis by standard tests of adrenal reserve. These findings underscore the widespread and differential action of glucocorticoids in selected patients.

Pituitary dysfunction can also result in cortisol insufficiency, but not aldosterone lack. Noteworthy causes of impaired pituitary function are tumors in the region of the sella turcica and irradiation of the pituitary or hypothalamus.

Actions of Aldosterone and Cortisol

The adrenal cortex secretes aldosterone from the zona glomerulosa and cortisol from the zona fasciculata. Aldosterone promotes the reabsorption of sodium and the secretion of potassium and hydrogen in the renal tubule [6]. This mineralocorticoid is controlled mainly by the renin-angiotensin system; regulation of blood pressure is coordinated in the short term (angiotensin action on a membrane-bound receptor) and in the longer term (aldosterone, nuclear action on gene expression). Glucocorticoid suppression of ACTH, or primary ACTH loss, does not suppress aldosterone in the zona glomerulosa. Glucocorticoids promote gluconeogenesis and protein wasting and increase the secretion of free water by the kidney [7,8]. In large doses, cortisol binds to aldosterone receptors in the kidney, thereby increasing sodium reabsorption and potassium and hydrogen ion excretion. Glucocorticoids act on numerous tissues, including the central nervous system, and affect the sense of well-being, appetite, and mood. They inhibit ACTH release through hypothalamic and pituitary actions. Glucocorticoids have direct effects on the cardiovascular system and maintain blood pressure, although mechanisms are not established. Critical illness and glucocorticoid deficiency affect physiological systems in common.

Excess glucocorticoid therapy causes lymphopenia, leukocytosis, and eosinopenia [9], can lead to osteoporosis and reduction of hypercalcemia [10], and can impair host defenses to infectious diseases. These properties should be considered in the decision to treat ICU patients with glucocorticoids; the decision is not risk free.

Aldosterone deficiency results in sodium wasting, with concomitant loss of water and an increase in renal reabsorption of potassium. A decrease in plasma volume and dehydration occurs, with subsequent increases in blood urea nitrogen and plasma renin activity.

Reduction in circulating levels of cortisol causes a marked increase in circulating levels of ACTH and a corresponding increase in β-lipotropin, from which melanocyte-stimulating hormone activity increases; in longstanding adrenal insufficiency, the skin (especially creases and scars) develops hyperpigmentation [11]. Orthostatic hypotension can progress to frank shock in a crisis. Hypoglycemia and an increase in sensitivity to insulin are commonplace. Hyponatremia is a hallmark of aldosterone deficiency, but may also be found in cortisol deficiency. The mechanism for the latter may invoke increased sensitivity to vasopressin [12,13,14]; serum potassium levels would be normal.

Diagnosis

Clinical manifestations that suggest adrenal insufficiency include a nonspecific history of progressive weakness, lassitude, fatigue, anorexia, vomiting, and constipation. Patients in adrenal crisis are volume depleted and hypotensive or in frank shock [15,16,17,18]. They often have fever and stupor or coma. As a precipitous event (adrenal hemorrhage, overwhelming infection, anticoagulant therapy, trauma, surgery), adrenal crisis lacks hyperpigmentation. Flank pain may be present in adrenal hemorrhage or infection. Severely ill patients are suspected of developing adrenal hypofunction, but actual incidence is not established, a conundrum in making the diagnosis of adrenal crisis. To further complicate recognition of adrenal dysfunction, glucocorticoid resistance has been postulated in critical illness.

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