Corticosteroids in pediatric ARDS: all cards on the table

Intensive Care Med DOI 10.1007/s00134-015-4027-3 Andreas Schwingshackl Gianfranco Umberto Meduri Dai Kimura Stephania A. Cormier Kanwaljeet J. S. Anand Corticosteroids in pediatric ARDS: all cards on the table Accepted: 8 August 2015 O Springer-Verlag Berlin Heidelberg and ESICM 2015 Dear Editor, Hardly any topic in modern critical care medicine remains as controver- sial as steroid administration in acute respiratory distress syndrome (ARDS), despite multiple adult ran- domized controlled trials (RCTs) and recent pediatric data. The article by Yehya et al. [1] and the editorial commentary by Peters et al. [2] are vital, since few, if any, therapeutic approaches are simultaneously asso- ciated with such profound potential benefits and risks as steroid therapy in critically ill patients. Marked contradiction, however, exists between the Yehya et al. data and the findings of well-designed and protocol-driven RCTs in adult ARDS patients. These studies consistently reported significant improvements in markers of systemic inflammation, ventilator-free days, ICU-free days, no changes or actually improved survival, and either no increase or decreases in infection rate [3, 4]. The findings of Yehya et al. cannot be interpreted because the specific indi- cations for corticosteroid use were not reported. To imply that any type of steroid, at any concentration, and CO RRESPONDENCE used for more than 24 h represents a protocol-driven treatment for pedi- atric ARDS (PARDS) is simply not justifiable. Further, grouping short-term (less than 24 h) and non-corticosteroid exposed patients together is an improper control for evaluating ster- oid therapy. Corticosteroids can exert important, non-genomic effects within minutes, including decreased cell adhesion, phosphokinase activa- tion, MCP-1 and H 2 O 2 release, CD63 translocation, TNF-a and IL-6 expression. Possible corticosteroid effects cannot be assessed unless exposed and non-exposed patients are categorically separated. Thus, proposing that this single-center, observational study ‘‘has relevance for clinical practice’’, a conclusion unsupported by data, will likely mis- lead and confound many bedside physicians. Undoubtedly, the most likely explanation for Yehya et al.’s findings are (1) selection of steroid therapy for the sickest patients (con- founding by indication) and (2) rebound effects resulting from abrupt discontinuation of corticosteroids, as is well documented by worsening PaO 2 /FiO 2 ratios and increasing CRP levels. Owing to the wide-ranging impli- cations and inherent responsibility of publishing patient data, it is impera- tive that we treat this topic with the utmost equipoise until clear evidence for or against steroid use in ARDS/ PARDS is gained. Whether compar- ative effectiveness research (CER) can provide such evidence is ques- tionable, since the US Food and Drug Administration, European Medicines Agency, or other labeling agencies do not consider this research methodol- ogy Level 1 evidence. CER studies can ‘‘adjust’’ the outcomes for measured confounders, and boot- strapping techniques like propensity scoring can reduce the margin of inferential errors, but only large, well- designed RCTs can control for unmeasured and non-measurable confounders. We recommend caution in drawing conclusions from a data set with multiple confounding vari- ables and improper controls. Statistical approaches such as propensity score matching can only take into account measured con- founding factors, whereas randomized trials allow for control- ling of both measured and unmeasured confounders. The bene- ficial or no-harm results reported in adult RCTs cannot be disregarded unless systematically investigated in pediatric patients. We recently pub- lished a feasibility RCT investigating prolonged low-dose methylpred- nisolone in pediatric ARDS [5] and, undoubtedly, there is an urgent need to conduct a large-scale, well-de- signed RCT in PARDS. References 1. Yehya N, Servaes S, Thomas NJ, Nadkarni VM, Srinivasan V (2015) Corticosteroid exposure in pediatric acute respiratory distress syndrome. Intensive Care Med. doi: 10.1007/s00134-015-3953-4 2. Peters MJ, Ray S, Kneyber M (2015) Corticosteroids for paediatric ARDS: unjustified—even unjustifiable? Intensive Care Med. doi: 10.1007/s00134-015-3963-2 3. Confalonieri M, Urbino R, Potena A, Piattella M, Parigi P, Puccio G, Della Porta R, Giorgio C, Blasi F, Umberger R, Meduri GU (2005) Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study. Am J Respir Crit Care Med