Abstract
Glucocorticoids (GCs) remain central to managing dysregulated systemic inflammation
in critical illness, yet therapeutic response varies widely due to multifactorial
glucocorticoid resistance (GCR). This chapter provides a translational framework to
guide clinicians in identifying and overcoming GCR, with a central emphasis on restoring
glucocorticoid receptor α (GRα) function. Mechanisms of resistance include reduced
GRα expression, GRβ dominance, impaired nuclear translocation, oxidative stress, mitochondrial
dysfunction, micronutrient depletion, and epigenetic suppression. Pharmacokinetic
and pharmacodynamic barriers—such as suboptimal dosing, impaired tissue penetration,
accelerated clearance, erratic dosing schedules, and premature tapering—further compromise
GRα engagement and treatment efficacy. In addition, interindividual variability in
GR responsiveness is shaped by genetic polymorphisms, isoform balance, and local tissue
conditions, compounded by up to 10-fold variability in circulating drug levels within
the same patient. This chapter outlines evidence-based strategies to optimize GC therapy,
including dose refinement, continuous infusion protocols, biomarker-guided escalation,
and structured tapering. Adjunctive therapies—such as antioxidants, micronutrients,
probiotics, and melatonin—are also highlighted for their role in enhancing mitochondrial
resilience, redox stability, and GRα signaling across key regulatory phases. Importantly,
many of these disruptions—whether arising from mitochondrial dysfunction, epigenetic
changes, or intestinal dysbiosis—converge on shared molecular pathways such as nuclear
factor kappa-B (NF-κB) activation, mitogen-activated protein kinase (MAPK) signaling,
histone deacetylase 2 (HDAC2) inhibition, and oxidative stress, all of which compromise
GRα function across systems. Recognizing this mechanistic convergence helps explain
the multisystem nature of steroid resistance. It supports a unified therapeutic approach
that targets oxidative stress, restores mitochondrial function, modulates the microbiome,
and reinforces epigenetic regulation—working together to preserve GRα signaling across
affected systems. While this framework is grounded in mechanistic and translational
evidence, its application in clinical practice—including tapering strategies, biomarker
thresholds, and adjunctive therapies—requires validation in randomized controlled
trials.
Keywords
critical illness - glucocorticoid receptor-α - glucocorticoid resistance - homeostatic
correction - mitochondrial dysfunction - systemic inflammation
