Diagnosis and Treatment of Adrenal Insufficiency in the Critically Ill Patient

Kwame Asare, Pharm.D.


Pharmacotherapy. 2007;27(11):1512-1528. 

In This Article

Adrenal Insufficiency

Adrenal insufficiency can be categorized into two types: primary and secondary. Primary adrenal insufficiency, or Addison's disease, is caused by the inability of the adrenal gland to produce cortisol, aldosterone, or both, with the rest of the HPA axis remaining intact. It is associated with a deficiency of glucocorticoid, mineralocorticoid, sex hormones, and cathecholamines (cortisol is required for synthesis of cathecholamines). Primary adrenal insufficiency is characterized by low cortisol production and high plasma ACTH concentration because of the lack of normal ACTH feedback inhibition. The secretion of high levels of ACTH results in the secretion of other hormones with similar chemical structure. One such hormone is melanocyte-stimulating hormone. This hormone causes melanocytes to form a black pigment, melanin, in the epidermis of the skin, leading to hyperpigmentation of the skin and mucous membranes. The effect of this hyperpigmentation is much greater in people with dark skin than in those with light skin. Primary adrenal insufficiency is characterized by orthostatic hypotension, hyponatremia, hyperkalemia, mild metabolic acidosis, and as just described, hyperpigmentation of the skin. Primary adrenal insufficiency becomes clinically evident when about 90% of the adrenal cortex has been destroyed.[9]

Secondary adrenal insufficiency is caused by dysfunction of the hypothalamus, pituitary gland, or both (with a normal adrenal gland) and is characterized by low cortisol production and low or normal plasma ACTH concentration. The glucocorticoid deficiency and low ACTH concentration may result in hypotension and hyponatremia, with normal potassium and hydrogen ion concentrations. The ACTH-induced hyperpigmentation is absent in secondary adrenal insufficiency, and the release of aldosterone, sex hormones, and cathecholamines is usually normal.

Primary and secondary adrenal insufficiency may be categorized as acute or chronic. The most common cause of acute adrenal insufficiency is functional (referred to as relative adrenal insufficiency), from exogenous glucocorticoid administration suppressing the HPA axis. The degree of suppression depends on the pharmacokinetics, dose, and duration of the steroid administered,[20] with larger doses of agents with longer half-lives and an extended course of therapy prolonging the suppression of the HPA axis. Adrenal insufficiency has been reported to occur in patients receiving prednisone 25 mg twice/day for as short a period as 5 days.[20] It should be anticipated in any patient receiving more than 30 mg/day of hydrocortisone or its equivalent for more than 3 weeks. In addition to oral and parenteral routes, glucocorticoids can produce HPA-axis suppression when administered intranasally or by inhalation at high doses.[21,22,23] The time to recovery of the HPA axis after the discontinuation of exogenous glucocorticoids is variable and may be as short as 2-5 days or as long as 9 months-1 year.[20,24]

In functional or relative adrenal insufficiency, there is either insufficient cortisol or a cortisol level that may be high in absolute terms but insufficient to respond to the degree of stress. Thus, serum cortisol concentrations that are normal in well patients may be inappropriately low in severely sick patients. This inability to mount the appropriate response increases the risk of death during severe illness.[7] Although absolute adrenal insufficiency is quite rare in critically ill patients, relative adrenal insufficiency is considerably more common.[25] In chronic critical illness, adrenal insufficiency may also result from catecholamine receptor desensitization or downregulation and/or chronic secretion of cytokines and other substances that suppress the HPA axis. This latter mechanism is sometimes called adrenal exhaustion syndrome.[26]

Although the causes of primary and secondary adrenal insufficiency are numerous, it has been postulated that the most common causes in the critically ill patient are sepsis and systemic inflammatory response syndrome. The most likely mechanisms are decreased synthesis and/or decreased release of ACTH, corticotropinreleasing hormone (CRH), and cortisol by cytokines and other inflammatory mediators released during sepsis.[27] In vitro, different cytokines reversibly impair glucocorticoid receptor affinity to cortisol or glucocorticoid response elements.[28] This hypothesis was supported in another study that reported decreased responses to corticotropin in patients with septic shock compared with responses in patients without septic shock, despite similar basal cortisol levels.[29]

In the ambulatory patient, tuberculosis remains the most common cause of primary adrenal insufficiency worldwide, with human immunodeficiency virus and other infections in immunosuppressed patients being a close second. In the West, however, the most common cause is idiopathic adrenal insufficiency, also known as autoimmune adrenal insufficiency.[30] Table 3 lists some of the diseases and conditions that can possibly cause adrenal insufficiency. As stated earlier, the most common cause of secondary adrenal insufficiency is the abrupt discontinuation of glucocorticoids.[31]

Several drugs have been implicated in adrenal insufficiency. Glucocorticoid production is impaired by ketoconazole,[32] megestrol (doses > 160 mg/day),[33,34] medroxyprogesterone,[35] aminoglutethimide, mitotane, metyrapone, etomidate,[36,37] and high-dose fluconazole (doses ≥ 400 mg).[38] In a descriptive case report, a possible temporal association of reversible adrenal insufficiency with the institution and withdrawal of fluconazole in two critically ill patients was reported.[38] The authors recommended that in critically ill patients who are not routinely receiving glucocorticoids and who require fluconazole, corticosteroid responsiveness should be monitored with the ACTH stimulation test. Although a pilot study, their data suggest a need for further investigation of the association between high-dose fluconazole and adrenal insufficiency in critically ill patients.

The use of the intravenous anesthetic, etomidate, has also been associated with adrenal insufficiency and increased mortality. It is a selective inhibitor of adrenal 11β-hydroxylase, the enzyme that converts deoxycortisol to cortisol.[37] One group measured the cortisol and aldosterone responses to ACTH stimulation in five patients receiving etomidate.[37] All five patients were found to have adrenal suppression. One patient received a 20-hour infusion and developed marked adrenocortical suppression that was still evident 4 days after discontinuation of the drug. The authors cautioned clinicians that etomidate inhibits adrenal steroidogenesis and suggested coadministration of corticosteroids in selected patients.

The clinical manifestations, as described by Addison, remain as accurate today as they were in 1855.[1] They are similar and nonspecific for both primary and secondary adrenal insufficiency ( Table 4 ). At presentation, patients may have fatigue, weakness, joint pain, dizziness, depression, and gastrointestinal symptoms such as nausea, vomiting, abdominal cramps, unintentional weight loss, and anorexia nervosa. Both primary and secondary adrenal insufficiency can cause hyponatremia, but the pathophysiology of the two disorders is completely different. In primary adrenal insufficiency, hyponatremia is mainly due to aldosterone deficiency and sodium wasting, whereas in secondary adrenal insufficiency it is due to low cortisol and free water retention mediated by secretion of vasopressin (antidiuretic hormone)[39] as a result of relative volume depletion.

For any given level of morning serum cortisol, patients with primary adrenal insufficiency present with more severe symptoms compared with those of patients with secondary adrenal insufficiency.[40] The most specific signs of primary adrenal insufficiency are hyperpigmentation of the skin, craving for salt, hyperkalemia, and acidosis. Specific signs of secondary adrenal insufficiency are pale skin, loss of axillary and pubic hair, decreased libido, and impotence. Because it remains difficult to recognize adrenal insufficiency in the intensive care unit (ICU), clinicians are encouraged to have a high index of suspicion. They should watch for important diagnostic clues like the presence of hyponatremia, hyperkalemia, hypoglycemia (rare), and hemodynamic instability despite adequate fluid and vasopressor therapy (the most common feature). Bear in mind that hyperkalemia may be absent in patients with secondary adrenal insufficiency because of the intact secretion of mineralocorticoid, but it is usually present in primary adrenal insufficiency.


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