Emerging insights into the use of dexamethasone for high-altitude illness: bridging basic pharmacology and clinical practice
DOI:
https://doi.org/10.18203/2319-2003.ijbcp20254169Keywords:
Dexamethasone, Acute mountain sickness, High-altitude cerebral edema, High-Altitude Pulmonary Edema, Glucocorticoid receptor, Hypoxia-inducible factorAbstract
Acute mountain sickness (AMS) and its severe forms high-altitude cerebral edema (HACE) and high-altitude pulmonary edema (HAPE) result from hypobaric hypoxia that triggers vascular leak, inflammation, and metabolic stress. Among preventive agents, acetazolamide remains conventional, but dexamethasone has emerged as the most potent pharmacologic safeguard due to its rapid and multi-level protective mechanisms. Acting through both genomic and non-genomic pathways, dexamethasone suppresses NF-κB and HIF-1α signalling, reinforces endothelial barrier integrity, reduces cytokine-driven edema, and enhances mitochondrial energy efficiency, collectively restoring vascular and metabolic stability under hypoxic stress. Evidence from randomized trials and meta-analyses demonstrates a 60-70% reduction in AMS incidence and accelerated recovery in HACE and HAPE with dexamethasone therapy. Multi-omics analyses further reveal that the drug reprograms over a thousand genes involved in immune, oxidative, and metabolic regulation, underscoring its system-wide impact. Recent advances including inhaled, transdermal, and depot formulations, as well as pharmacogenomic-guided dosing are transforming dexamethasone from a symptom-relief drug to a precision altitude pharmacology agent. Its unmatched combination of anti-inflammatory, anti-edematous, and metabolic-stabilizing actions firmly establishes dexamethasone as the most comprehensive and mechanistically validated therapy for both prevention and treatment of high-altitude illness.
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