OR17-1 Changes in the Hypothalamic-Pituitary-Adrenal Axis during Pediatric Critical Illness

Abstract

Critical illness in adults is hallmarked by prolonged hypercortisolism and a rapid decrease in ACTH. The high cortisol is explained by reduced cortisol breakdown and a decrease in cortisol binding proteins, rather than by adrenal production. In critically ill children, the evolution of the changes in the HPA axis and underlying mechanisms remain to be studied. Also, the impact hereon of nutritional management is unknown. In the PEPaNIC RCT, accepting low macronutrient intake up to day 8 in the pediatric intensive care unit (PICU) by withholding early supplemental parenteral nutrition (PN) accelerated recovery as compared with initiating supplemental PN early. In this preplanned secondary analysis of the PEPaNIC RCT, we assessed the changes over time in the HPA axis and their prognostic value during critical illness in children and investigated the impact on these changes of withholding early PN. We quantified plasma ACTH, total cortisol, CBG and albumin and calculated free cortisol upon PICU admission, day 3 and last PICU day for 223 short-stay (<3 days) and 309 long-stay patients (≥3 days) who did not receive corticosteroids before sampling, in comparison with 64 matched healthy children. Upon admission, ACTH was elevated in short-stay patients (P=0.02) and comparable with healthy children in long-stay patients (P=0.75), whereas total and free cortisol were elevated in both groups (P<0.0001). In short-stay patients, ACTH became subnormal on the last day (P<0.0001). Also total and free cortisol decreased, but remained higher than in healthy children (P=0.003-0.005). In long-stay patients, ACTH decreased towards day 3 (P<0.0001) and remained low on the last day (P<0.0001), whereas total and free cortisol were normal on day 3 (P=0.37-0.62) and on the last day (P=0.30-0.74). CBG and albumin were low throughout PICU stay in both groups. The rapid decrease in cortisol over time in PICU likely excludes negative feedback by cortisol on pituitary ACTH secretion as cause of the decrease in ACTH. In multivariable analysis, the decrease in ACTH was also not associated with drugs commonly used in PICU, that have been suggested to affect the HPA axis in adults. High total and free cortisol upon admission were associated with 90-day mortality and prolonged length of stay in univariable analysis. This association disappeared when adjusting for baseline risk factors. Withholding early PN did not affect the changes in the HPA axis from admission to day 3 or to last day for short-stay patients. In conclusion, the time course of the changes in the HPA axis during critical illness in children differs from that in adults, with a rapid normalization of cortisol together with a decrease in ACTH over time. Further investigation of the mechanism underlying this ACTH decrease is warranted, since it might be iatrogenic or related to a possibly more immature central secretion during critical illness in children as compared with adults.