Corticosteroids in septic shock: mechanisms, heterogeneous treatment effects, and trajectory-guided precision pharmacotherapy
- 1Second Clinical Medical College of Shandong Medical and Pharmaceutical University (Yantai Affiliated Hospital)
- 2Department of Critical Care Medicine, Yantai Yuhuangding Hospital
Abstract
Corticosteroid therapy in septic shock has evolved from empirical high-dose anti-inflammatory treatment to low-dose adjunctive pharmacotherapy aimed primarily at restoring vascular responsiveness and accelerating shock reversal. Population-level randomized evidence supports a modest average corticosteroid benefit, most consistently reflected in faster shock reversal and earlier vasopressor liberation, whereas mortality effects remain regimen- and population-dependent. This divergence suggests that average treatment effects alone are insufficient to guide individual decisions. We review how pharmacology, randomized evidence, candidate treatment-effect modifiers, and prespecified longitudinal phenotypes may inform the development of individualized corticosteroid strategies, while defining the evidence required before such strategies can guide clinical care. Glucocorticoid and mineralocorticoid receptor biology provides plausible pathways for both benefit and harm, but no single mechanism, cortisol test, transcriptomic endotype, or clinical trajectory is currently validated for routine treatment selection. Candidate enrichment signals must be distinguished as prognostic, predictive, pharmacodynamic, or safety-related and must be available before corticosteroid exposure when used for treatment selection. Observational studies require explicit alignment of eligibility, time zero, treatment strategies, and follow-up; target trial emulation can reduce avoidable temporal bias but cannot substitute for randomization or remove unmeasured confounding. Trajectory-guided enrichment remains investigational: any candidate trajectory used for treatment selection must be assigned or predicted from information available before exposure, and differential treatment effects require explicit evaluation rather than prognostic association alone. Treatment evaluation should extend beyond mortality to shock reversal, organ-support liberation, kidney outcomes, metabolic toxicity, infection, neuromuscular effects, and longer-term function. Clinical decision support should remain a future, clinician-supervised implementation layer that translates validated evidence into time-stamped actions rather than an autonomous prescribing system. Progress toward precision corticosteroid therapy now requires prespecified enrichment hypotheses, direct regimen comparisons, harmonized outcomes, prospective validation, and trials demonstrating clinical utility.
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BibTeX
@article{jia2026corticosteroids,
title = {{Corticosteroids in septic shock: mechanisms, heterogeneous treatment effects, and trajectory-guided precision pharmacotherapy}},
author = {Zifei Jia and Xuanyu Zhao and Xiangtian Liu and Xiaoli Li},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1962609},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1962609/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Corticosteroids in septic shock: mechanisms, heterogeneous treatment effects, and trajectory-guided precision pharmacotherapy
AU - Zifei Jia
AU - Xuanyu Zhao
AU - Xiangtian Liu
AU - Xiaoli Li
PY - 2026
DA - 2026/10/14
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1962609
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1962609/full
AB - Corticosteroid therapy in septic shock has evolved from empirical high-dose anti-inflammatory treatment to low-dose adjunctive pharmacotherapy aimed primarily at restoring vascular responsiveness and accelerating shock reversal. Population-level randomized evidence supports a modest average corticosteroid benefit, most consistently reflected in faster shock reversal and earlier vasopressor liberation, whereas mortality effects remain regimen- and population-dependent. This divergence suggests that average treatment effects alone are insufficient to guide individual decisions. We review how pharmacology, randomized evidence, candidate treatment-effect modifiers, and prespecified longitudinal phenotypes may inform the development of individualized corticosteroid strategies, while defining the evidence required before such strategies can guide clinical care. Glucocorticoid and mineralocorticoid receptor biology provides plausible pathways for both benefit and harm, but no single mechanism, cortisol test, transcriptomic endotype, or clinical trajectory is currently validated for routine treatment selection. Candidate enrichment signals must be distinguished as prognostic, predictive, pharmacodynamic, or safety-related and must be available before corticosteroid exposure when used for treatment selection. Observational studies require explicit alignment of eligibility, time zero, treatment strategies, and follow-up; target trial emulation can reduce avoidable temporal bias but cannot substitute for randomization or remove unmeasured confounding. Trajectory-guided enrichment remains investigational: any candidate trajectory used for treatment selection must be assigned or predicted from information available before exposure, and differential treatment effects require explicit evaluation rather than prognostic association alone. Treatment evaluation should extend beyond mortality to shock reversal, organ-support liberation, kidney outcomes, metabolic toxicity, infection, neuromuscular effects, and longer-term function. Clinical decision support should remain a future, clinician-supervised implementation layer that translates validated evidence into time-stamped actions rather than an autonomous prescribing system. Progress toward precision corticosteroid therapy now requires prespecified enrichment hypotheses, direct regimen comparisons, harmonized outcomes, prospective validation, and trials demonstrating clinical utility.
SN - 1663-9812
ER -