Critical Illness–Related Corticosteroid Insufficiency

Chapter 16

Critical Illness–Related Corticosteroid Insufficiency

Cortisol is a key hormone in the maintenance of homeostasis in both health and disease. It contributes to several important physiologic processes including immunologic, cardiovascular, and inflammatory modulation. The adrenal glands depend on an intact hypothalamic-pituitary-adrenal (HPA) axis for continuous and appropriate amounts of cortisol production. The adrenal glands must continually synthesize cortisol to meet cellular needs, with very little cortisol actually stored in the glands themselves.

Impairment or dysfunction of the HPA axis is identified in approximately 40% of critically ill humans, depending on the underlying disease, and is most frequently observed in patients with severe sepsis, septic shock, trauma, or hemorrhagic shock. A similar incidence has been recently documented in critically ill dogs. Dysfunction of the HPA axis results in a relative, not necessarily absolute, decrease in cortisol production. This endocrine dysfunction was initially thought to result from insufficient cortisol production by the adrenal glands, and thus it was initially called relative adrenal insufficiency (RAI). Further elucidation of this disease has led clinicians to understand that dysfunction may occur anywhere along the HPA axis, and therefore critical illness–related corticosteroid insufficiency (CIRCI) is now the preferred term. The end result, insufficient production of cortisol to meet physiologic needs during severe illness, contributes significantly to morbidity and mortality within the critical care setting. An easily recognizable sign of critical illness–related HPA axis dysfunction is hypotension that is refractory to fluid resuscitation and vasopressor therapy.


Although exact mechanisms require further investigation, CIRCI is a result of several aberrations evident during critical illness. Primary adrenal dysfunction may be due to hemorrhage or microvascular thrombi within the adrenal glands or due to drugs that suppress steroidogenesis. Secondary adrenal dysfunction occurs higher in the HPA axis, at the level of the hypothalamus or anterior pituitary gland. Inflammatory cytokines may cause suppression at the level of these structures, decreasing production of corticotropin-releasing hormone (CRH) or adrenocorticotropic hormone (ACTH). Finally, increased cortisol clearance, alterations in cortisol transport, or decreased cortisol receptor affinity may also contribute to the development of CIRCI. A glucocorticoid deficiency is the final result of these mechanisms, but mineralocorticoid activity does not appear to be affected and usually remains intact.

There may also be a genetic contribution to the development of CIRCI in dogs. P-glycoprotein plays a role in regulation of the HPA axis, and this axis may be suppressed in dogs with multidrug resistance protein 1 (MDR1) mutations. A study of healthy collies found that dogs with the MDR1 mutation had significantly lower basal plasma cortisol concentrations, as well as lower cortisol concentrations after ACTH stimulation. Some practitioners anecdotally report that herding breeds appear to have worse outcomes in response to stress; increased risk of HPA axis dysfunction and CIRCI may possibly explain this observation. Although this suggests that HPA axis testing is prudent in certain breeds of critically ill dogs, CIRCI may occur in any breed and warrants further investigation in any critically ill dog or cat that demonstrates clinical signs compatible with CIRCI.

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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Critical Illness–Related Corticosteroid Insufficiency

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