Chest
Volume 122, Issue 5, November 2002, Pages 1784-1796
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Critical Care Reviews
Adrenal Insufficiency in the Critically Ill: A New Look at an Old Problem

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Stress from many sources, including pain, fever, and hypotension, activates the hypothalamic-pituitary-adrenal (HPA) axis with the sustained secretion of corticotropin and cortisol. Increased glucocorticoid action is an essential component of the stress response, and even minor degrees of adrenal insufficiency can be fatal in the stressed host. HPA dysfunction is a common and underdiagnosed disorder in the critically ill. We review the risk factors, pathophysiology, diagnostic approach, and management of HPA dysfunction in the critically ill.

Section snippets

Molecular Actions of Glucocorticoids

Glucocorticoids exert their effects by binding to and activating a 90-kd intracellular glucocorticoid receptor (GR) protein.8 All cells appear to have appreciable levels of GR. The GR is localized in the cytoplasm of the cell and translocates into the nucleus on ligand binding. In the absence of hormone, cytoplasmic GR is associated with a large protein complex that includes heat shock protein-90 and heat shock protein-56.9 This protein complex functions to maintain the GR in an inactive

Major Physiologic Actions of Glucocorticoids

Glucocorticoids regulate gene transcription in every cell in the body. For the purposes of this review, we highlight some of the important actions of glucocorticoids during the stress response.

Regulation of Cortisol Secretion

Cortisol secretion by the adrenal cortex is under control of the HPA axis. Signals from the body (ie, cytokine release, tissue injury, pain, hypotension, hypoglycemia, hypoxemia) are sensed by the CNS and transmitted to the hypothalamus. The hypothalamus integrates these signals and increases or decreases the release of corticotropin-releasing hormone (CRH). CRH circulates to the anterior pituitary gland where it stimulates the release of ACTH, which in turn circulates to the adrenal cortex

Cytokines and the HPA Axis

The HPA axis and the immune response are linked in a negative feedback loop in which activated immune cells produce cytokines that signal the brain. Activation of the HPA axis by specific cytokines increases the release of cortisol that in turn feeds back and suppresses the immune reaction (and further cytokine release).28 IL-1α, IL-1β, and IL-6 administered peripherally increase HPA activity, increasing levels of CRH, ACTH, and glucocorticoids.29,30 Cytokines also affect the pituitary and

Cortisol Response to Stress

Stress from many sources, including cold, fever, infection, trauma, emotional distress, burns, inflammatory agents, pain, hypotension, exercise, hemorrhage, and other challenges to homeostasis, stimulates the HPA axis, increasing secretion of cortisol. There is much controversy regarding levels of circulating cortisol that are considered to be an adequate response to stress.50 Many textbooks and published articles state that the normal circulating cortisol response to stress is a level > 18 to

Diagnosis of HPA Failure

As there are no clinically useful tests to assess the cellular actions of cortisol (ie, end-organ effects), the diagnosis of adrenal insufficiency is based on the measurement of serum cortisol levels; this has resulted in much confusion and misunderstanding.35,50,67,71,72,73,74,75,76,77,78,79 Traditionally the “integrity” of the HPA axis has been assessed by the short corticotropin stimulation test (also known as the cosyntropin stimulation test). This test is usually performed by administering

Incidence of Adrenal Insufficiency

The incidence of adrenal insufficiency in critically ill patients is variable and depends on the underlying disease and severity of the illness. The reported incidence varies widely (0 to 77%) depending on the population of patients studied and the diagnostic criteria used to diagnose adrenal insufficiency.35,47,66,67,70,74,75,76,80,89,90,91 However, the overall incidence of adrenal insufficiency in critically ill patients approximates 30%, with an incidence as high as 50 to 60% in patients

Clinical Features of Acute HPA Failure

Patients with chronic adrenal insufficiency usually present with a history of weakness, weight loss, anorexia, and lethargy, with some patients complaining of nausea, vomiting, abdominal pain, and diarrhea. Clinical signs include orthostatic hypotension and hyperpigmentation (primary adrenal insufficiency). Laboratory testing may demonstrate hyponatremia, hyperkalemia, hypoglycemia, and a normocytic anemia.94 This presentation contrasts with the features of acute adrenal insufficiency (Table 1

Causes of Acute Adrenal Insufficiency in the Critically Ill

Acute adrenal insufficiency occurs in patients who are unable to increase their production of cortisol during acute stress. This includes patients with hypothalamic and pituitary disorders (secondary adrenal insufficiency) and patients with destructive diseases of the adrenal glands (primary adrenal insufficiency) [Table 2]. Secondary adrenal insufficiency is common in patients who have been treated with exogenous corticosteroids. However, the most common cause of acute adrenal insufficiency is

Prognosis

We believe that there is a bimodal distribution of mortality in relationship to the random cortisol level during sepsis. Patients with low cortisol levels (ie, < 25 μg/dL) who are not treated with corticosteroids and patients with very high levels (ie, > 45 μg/dL) have the highest mortality. This hypothesis may explain the apparent contradictory reports in the literature. Annane et al71 reported a mean random cortisol level of 34 μg/dL in 189 patients with septic shock, with the nonsurvivors

Perioperative Steroid Coverage

The stress of major surgery may precipitate acute adrenal insufficiency in patients with inadequate adrenal reserve (ie, adrenal crisis). This is especially true in patients with secondary adrenal insufficiency maintained on exogenous glucocorticoids. Prospective randomized trials have failed to adequately evaluate the dose of glucocorticoid required in various perioperative settings. Thus, recommendations for glucocorticoid coverage are based on a risk/benefit evaluation, published studies in

Therapeutic Approach to Patients With Presumed Adrenal Insufficiency

In patients with severe stress (ie, hypotension, hypoxemia, pain), a random (stress) serum cortisol level should be obtained. Hypotensive patients and patients at high risk of adrenal insufficiency should be started empirically on hydrocortisone (100 mg IV q8h) pending results of testing. If the serum cortisol level returns to < 25 μg/dL, the hydrocortisone should be continued. In addition, if the patient has improved clinically with hydrocortisone and the cortisol level is > 25 μg/dL, we favor

Conclusion

HPA dysfunction is common in severely ill patients. Even slight impairment of the adrenal response to severe illness can increase morbidity and mortality, and we believe that low serum cortisol levels may be the cause, rather than the consequence, of poor outcome in these patients. Therefore, a high index of suspicion for adrenal insufficiency is required in all critically ill patients, particularly those with refractory hypotension. All patients with suspected HPA dysfunction should be treated

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