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  • Acute adrenal insufficiency in critically ill patients is best referred to as critical illness–related corticosteroid insufficiency (CIRCI).

  • CIRCI may arise due to adrenal insufficiency or tissue resistance to cortisol.

  • Adrenal insufficiency is best diagnosed by a random cortisol <10µg/dL (Type 1 CIRCI) or a delta of <9µg/dL after a 250µg cosyntropin stimulation test (Type II CIRCI).

  • The diagnosis of adrenal insufficiency/CIRCI should not be made on the basis of laboratory criteria alone.

  • Treatment with low-dose hydrocortisone (200 mg/day) or methylprednisolone (60 mg/day) should be considered in patients with septic shock who have responded “poorly” to resuscitation with fluids and vasopressor agents and those with ARDS who have failed to show an improvement within 48 hours of supportive care. The role of low-dose hydrocortisone in patients with severe sepsis and other clinical situations in the ICU remains to be determined.


Exposure of the host to diverse noxious stimuli results in a stereotypic and coordinated response, referred to by Hans Selye as the general adaption syndrome (or stress response) which serves to restore homeostasis and enhance survival.1 The stress response is mediated primarily by the hypothalamic-pituitary-adrenal (HPA) axis as well as the sympathoadrenal system (SAS). Activation of the HPA axis results in increased secretion from the paraventricular nucleus of the hypothalamus of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP). CRH plays a pivotal integrative role in the response to stress. CRH stimulates the production of ACTH by the anterior pituitary, causing the zona fasciculata of the adrenal cortex to produce more glucocorticoids (cortisol in humans).2 AVP is a weak ACTH secretagogue and vasoactive peptide that acts synergistically with CRH to increase secretion of ACTH. The increase in cortisol production results in multiple effects (metabolic, cardiovascular, and immune) aimed at restoring homeostasis during stress. In addition, the HPA axis and immune system are closely integrated in multiple positive and negative feedback loops (see Fig. 102-1). Activation of the SAS results in the secretion of epinephrine and norepinephrine from the adrenal medulla and to an increased production of inflammatory cytokines such as interleukin-6 (IL-6).

FIGURE 102-1

Activation of the hypothalamic-pituitary adrenal axis (HPA) and the interaction with the inflammatory response. ACTH, adrenocorticotrophic hormone; CRH, corticotropin releasing hormone; IL-6, interleukin-6; IL-11, interleukin-11; LIF, leukemia inhibitory factor; POMC, proopiomelanocortin; TGF-β, transforming growth factor-beta; TNF, tumor necrosis factor. (Reproduced with permission from Marik PE, Pastores SM, Annane D, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med. June 2008;36(6):1937-1949.)

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Cortisol (hydrocortisone) is the major endogenous glucocorticoid secreted by the adrenal cortex. Over 90% of circulating cortisol is bound to corticosteroid-binding globulin (CBG) with less than 10% in the free, biologically active form. CBG is the predominant binding protein with albumin binding a lesser amount. During acute illness, particularly sepsis, CBG ...

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