Therapeutic hypothermia and neuroprotection in traumatic brain injury: biomarker-guided strategies and translational challenges: a narrative review

INTRODUCTION: Traumatic brain injury (TBI) remains a leading cause of global morbidity and mortality, with secondary injury mechanisms — such as neuroinflammation, oxidative stress, and excitotoxicity — driving long-term neurological damage. Despite decades of research, optimizing neuroprotective strategies to mitigate these processes remains a challenge. OBJECTIVE: This narrative review evaluates contemporary neuroprotective approaches for TBI, with a focus on therapeutic hypothermia (TH), pharmacological agents, and non-pharmacological interventions. We critically assess their mechanisms, clinical efficacy, and limitations, while identifying gaps for future research. MATERIALS AND METHODS: A systematic literature search was conducted across PubMed, Scopus, and Web of Science (2010–2024) using keywords including traumatic brain injury, therapeutic hypothermia, neuroprotection, and secondary injury. Clinical trials, meta-analyses, and preclinical studies with translational relevance were prioritized. RESULTS: TH demonstrates potential in reducing intracranial pressure and attenuating neuroinflammation, but clinical outcomes vary due to heterogeneity in cooling protocols (timing, depth, duration) and patient selection. Pharmacological agents (e.g., progesterone, erythropoietin) show inconsistent efficacy in large trials, while non-pharmacological approaches (e.g., hyperbaric oxygen therapy) lack robust validation. Emerging advancements — such as biomarker-guided algorithms (GFAP/UCH-L1), hybrid cooling systems, and combination therapies (e.g., TH with ketogenic diets) — highlight promising yet unproven avenues. CONCLUSIONS: Personalized, multimodal strategies integrating advanced monitoring, biomarker profiling, and optimized TH protocols are essential to improve TBI outcomes. Future research must address knowledge gaps in timing, depth-duration trade-offs, and combinatorial therapies to translate preclinical promise into clinical success.