Multicenter target trial emulation to evaluate corticosteroids for sepsis stratified by predicted organ dysfunction trajectory

Suraj Rajendran, Zhenxing Xu, Weishen Pan, Chengxi Zang, Ilias Siempos, Lisa Torres, Jie Xu, Jiang Bian, Edward J. Schenck () and Fei Wang ()
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Suraj Rajendran: Cornell University
Zhenxing Xu: Weill Cornell Medicine
Weishen Pan: Weill Cornell Medicine
Chengxi Zang: Weill Cornell Medicine
Ilias Siempos: Weill Cornell Medicine
Lisa Torres: Weill Cornell Medicine
Jie Xu: College of Medicine, University of Florida
Jiang Bian: School of Medicine, Indiana University
Edward J. Schenck: Weill Cornell Medicine
Fei Wang: Weill Cornell Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-10

Abstract: Abstract Corticosteroids decrease the duration of organ dysfunction in sepsis and a range of overlapping and complementary infectious critical illnesses, including septic shock, pneumonia and the acute respiratory distress syndrome (ARDS). The risk and benefit of corticosteroids are not fully defined using the construct of organ dysfunction duration. This retrospective multicenter, proof-of-concept study aimed to evaluate the association between usage of corticosteroids and mortality of patients with sepsis, pneumonia and ARDS by emulating a target trial framework stratified by predicted organ dysfunction trajectory. The study employed a two staged machine learning (ML) methodology to first subphenotype based on organ dysfunction trajectory then predict this defined trajectory. Once patients were classified by predicted trajectory we conducted a target trial emulation. Our analysis revealed that the association between corticosteroid use and 28-day mortality varied by predicted trajectory and between cohorts.Our findings suggest that matching treatment strategies to empirically observed pathobiology may offer a more nuanced understanding of corticosteroid utility.

Date: 2025
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DOI: 10.1038/s41467-025-59643-z

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