• An Jacobs, Inge Derese, Sarah Vander Perre, Pieter J Wouters, Sascha Verbruggen, Jaak Billen, Pieter Vermeersch, Garcia Guerra Gonzalo G http://orcid.org/0000-0001-6407-0823 Department of Pediatrics, Intensive Care Unit, Stollery Children's Hospital, University o, Koen Joosten, Ilse Vanhorebeek, and Greet Van den Berghe.
• Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, 3000, Leuven, Belgium.
• Intensive Care Med. 2020 Jan 1; 46 (1): 70-81.

PurposeIncreased systemic cortisol availability during adult critical illness is determined by reduced binding-proteins and suppressed breakdown rather than elevated ACTH. Dynamics, drivers and prognostic value of hypercortisolism during pediatric critical illness remain scarcely investigated.MethodsThis preplanned secondary analysis of the PEPaNIC-RCT (N = 1440), after excluding 420 children treated with corticosteroids before PICU-admission, documented (a) plasma ACTH, (free)cortisol and cortisol-metabolism at PICU-admission, day-3 and last PICU-day, their prognostic value, and impact of withholding early parenteral nutrition (PN), (b) the association between corticosteroid-treatment and these hormones, and (c) the association between corticosteroid-treatment and outcome.ResultsACTH was normal upon PICU-admission and low thereafter (p ≤ 0.0004). Total and free cortisol were only elevated upon PICU-admission (p ≤ 0.0003) and thereafter became normal despite low binding-proteins (p < 0.0001) and persistently suppressed cortisol-metabolism (p ≤ 0.03). Withholding early-PN did not affect this phenotype. On PICU-day-3, high free cortisol and low ACTH independently predicted worse outcome (p ≤ 0.003). Also, corticosteroid-treatment initiated in PICU, which further suppressed ACTH (p < 0.0001), was independently associated with poor outcomes (earlier live PICU-discharge: p < 0.0001, 90-day mortality: p = 0.02).ConclusionIn critically ill children, systemic cortisol availability is elevated only transiently, much lower than in adults, and not driven by elevated ACTH. Further ACTH lowering by corticosteroid-treatment indicates active feedback inhibition at pituitary level. Beyond PICU-admission-day, low ACTH and high cortisol, and corticosteroid-treatment, predicted poor outcome. This suggests that exogenously increasing cortisol availability during acute critical illness in children may be inappropriate. Future studies on corticosteroid-treatment in critically ill children should plan safety analyses, as harm may be possible.

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