Hypothalamic-pituitary-adrenal axis function in healthy and critically ill neonatal foals
Hart, Kelsey Alison
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The corticosteroid hormone cortisol is released when the hypothalamic-pituitary-adrenal (HPA) axis is activated by stress, and is vital for an appropriate response to critical illness. In many critically ill people, though, the cortisol response is inadequate, a diagnosis termed critical illness-related corticosteroid insufficiency (CIRCI). In people, CIRCI is correlated with increased disease severity and decreased survival, and may be managed with cortisol replacement in the form of low-dose hydrocortisone. The overall aim of the studies reported herein was to examine the incidence, importance and potential treatment of CIRCI in foals. First, a paired low-dose/high-dose exogenous adrenocorticotropic hormone (ACTH) stimulation test was developed for use in neonatal foals. The second study characterized HPA axis function during the immediate post-natal period in the healthy full-term foal using this test, to provide references ranges for HPA axis responses in the healthy foal. Both these studies documented some impairment in cortisol responses during the first week of life in healthy full-term foals that may contribute to the development of CIRCI in ill foals. Next, the incidence and impact of CIRCI in critically ill neonatal foals was determined in a prospective clinical study. Approximately 40% of ill foals met criteria for CIRCI, comparable to the incidence in septic people. Further, CIRCI was correlated with increased disease severity and decreased survival in foals as in people. Thus, additional studies were undertaken to refine diagnostic criteria for CIRCI and to develop and evaluate a therapeutic regimen for eventual use in foals with CIRCI. A free cortisol assay was optimized for horses, and free cortisol was measured in healthy adult horses and healthy and septic foals. In constrast to people, free cortisol did not improve diagnostic sensitivity for CIRCI in foals, presumably because foals have much greater proportions of free cortisol than adult horses and people. This increased free cortisol fraction contributed to significant differences in cortisol production and hydrocortisone pharmacokinetics between foals and horses, which were considered during the development of a low-dose hydrocortisone regimen for foals. Finally, this hydrocortisone regimen significantly dampened the pro-inflammatory cytokine responses without impairing neutrophil function in isolated leukocytes from healthy foals.