Download PDF
Semin Respir Crit Care Med
DOI: 10.1055/a-2762-8278
Review Article

Limitations in the Design of Critical Care Studies and Suggestions for Future Research Directions

Authors

  • Guanfranco Umberto Meduri

    1   Department of Medicine and Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, United States

  • Simone Lannini

    2   Department of Medicine, University of Udine, Azienda Sanitaria Friuli Centrale Clinica di Malattie Infettive Udine, Italy

  • Jim M. Smit

    3   Department of Intensive Care, Erasmus University Medical Center, Rotterdam, The Netherlands
    4   Pattern Recognition & Bioinformatics Group, Delft University of Technology, Delft, The Netherlands
Further Information
   Permissions and Reprints

Abstract

Glucocorticoid (GC) therapy has been a cornerstone of critical care; however, its full potential has been constrained by fixed-dose regimens and trial designs that predate current insights into the dynamic, phase-specific functions of glucocorticoid receptor α (GRα). This study shifts focus from mechanistic pathways to the clinical implications of phase-adaptive care, emphasizing how GC therapy can be optimized through individualized, response-guided strategies tailored to illness trajectory and biological variability. Rather than reiterating GRα's mechanistic role, which is discussed in Chapter 3, this work highlights its practical relevance in therapeutic decision-making across the three sequential phases of critical illness: priming, modulatory, and restorative. In this clinically oriented framework, phase-specific treatment adjustments are informed by real-time changes in systemic stress markers, immune dynamics, and metabolic indicators. Earlier randomized controlled trials were instrumental in establishing safety but often failed to account for evolving physiological demands or receptor variability, contributing to inconsistent outcomes. To bridge this translational gap, this study proposes the integration of response-guided protocols utilizing accessible clinical biomarkers—such as C-reactive protein, interleukin-6, D-dimer, and lactate—allowing for adaptive dosing and tapering strategies aligned with patient-specific recovery patterns. Moving beyond pharmacologic dosing, the study outlines adjunctive clinical strategies—including targeted micronutrient supplementation and microbiome-supportive therapies—not as theoretical possibilities but as practical co-interventions that can be incorporated into intensive care unit protocols. Furthermore, it explores how artificial intelligence-enabled clinical decision systems and adaptive trial designs can operationalize precision care by dynamically stratifying patients and tailoring interventions to shifting biological profiles. Together, these applied strategies support a transition from static treatment paradigms to a precision medicine model in critical care—one that aligns GC therapy with individualized recovery trajectories, maximizes therapeutic responsiveness, and reduces treatment-related risks through multimodal, phase-responsive interventions.

Keywords

Critical Illness - glucocorticoid treatment - phase-specific therapy - homeostatic correction - biomarker-guided treatment - micronutrient and microbiome integration

Contributors' Statement

G.U.M. conceived and wrote the manuscript; J.M.S. authored the section on artificial intelligence; and S.L. authored the section on redesigning clinical trials for complex, multisystem conditions.


Note

A comprehensive literature review was conducted using Google Scholar and the Consensus database to identify relevant articles published between 1995 and 2025. Manual screening of references from key review articles and clinical guidelines was also performed to ensure completeness and relevance to this translational synthesis.


Supplementary Material



Publication History

Received: 28 May 2025

Accepted: 02 December 2025

Article published online:
15 January 2026

© 2026. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA