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  • Activation of the hypothalamic-pituitary-adrenal (HPA) axis with increased glucocorticoid activity is an essential component of the general adaptation to stress.
  • Mediators released in patients with sepsis may either stimulate or impair the synthesis and action of cortisol via actions on the HPA axis and glucocorticoid receptor.
  • A random cortisol level in a highly stressed ICU patient is currently the most useful test to assess the integrity of the HPA axis.
  • A stress cortisol level of less than 25 μg/dL in a highly stressed patient (hypotensive, respiratory failure) is highly suggestive of adrenal failure.
  • The incidence of adrenal failure may be as high as 60% in patients with septic shock.
  • All patients with suspected HPA axis dysfunction should be treated with stress doses of hydrocortisone (100 mg q 8 IV) pending the results of diagnostic testing.
  • A random cortisol level of less than 15 μg/dL or a level of less than 20 μg/dL post low-dose corticotrophin stimulation testing (low-dose ACTH test) in a non-hypotensive patient with unexplained fever, eosinophilia or altered mental status warrants a trial of treatment with stress doses of hydrocortisone.

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The maintenance of life depends on the capacity of the organism to sustain its equilibrium via allostasis—the ability to achieve stability through change. Allostasis is critical to survival in stress situations.1 The three major regulatory systems of the body responsible for allostasis include the central nervous system (CNS), the endocrine system, and the immune system. These three regulatory systems are closely interrelated and orchestrate the stress response. Importantly, activation of the hypothalamic-pituitary-adrenal (HPA) axis with the release of cortisol is the cornerstone of the stress response.

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The qualitative and quantitative aspects of the stress response depend on the nature and severity of the stressor and are time-dependent. With mild to moderate short-term stress there is general activation of the CNS, the endocrine system, and the immune system in an attempt to restore homeostasis. However, with severe and/or prolonged stress, this coordinated allostatic response may fail with the ultimate demise of the organism. Teleologically, the latter may be viewed as a mechanism to spare society of those overwhelmed by disease. However, these are the very patients who are treated in ICUs and who are trying to “cheat death.”

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Cortisol, the primary glucocorticoid hormone in humans, is secreted by the adrenal glands. In healthy, unstressed persons, cortisol is secreted in a diurnal pattern under the influence of corticotropin (ACTH) released from the pituitary gland. Corticotropin secretion, in turn, is under the influence of hypothalamic corticotropin-releasing hormone (CRH), and both hormones are subject to negative-feedback control by cortisol. Aldosterone, the primary mineralocorticoid hormone in the body, is also secreted by the adrenal glands. Aldosterone secretion, however, is regulated primarily by the renin-angiotensin system and potassium levels. Circulating cortisol is bound to corticosteroid-binding globulin, with less than 10% in the free bioavailable form. With acute stress in the form of infection, surgery, trauma, burns, or illness, cortisol ...

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