An Update on Osmotherapy in Acute Brain Injury: Current and Emerging Strategies.

Intracranial hypertension is a major modifiable pathway of secondary brain injury after acute neurological insults. Osmotherapy is an early cornerstone of tiered intracranial pressure management. Hypertonic saline and mannitol reliably reduce intracranial pressure through osmotic reduction in brain water, with additional haemodynamic and rheological effects. However, neither agent has shown consistent improvement in survival or long-term neurological recovery. Current practice is therefore guided by physiological rather than patient-centred outcomes. This review summarises the physiological basis, clinical evidence, and practical limitations of conventional osmotherapy, and explores investigational chloride-free osmotherapies including sodium lactate, sodium bicarbonate, sodium ascorbate, and sodium acetate. Chloride-free therapies aim to preserve sodium-driven osmotic efficacy while reducing chloride exposure or targeting metabolic and oxidative pathways implicated in secondary brain injury. At present, evidence is limited to small physiological trials, retrospective cohort studies, and mechanistic human studies. Future progress requires large collaborative trials that combine pragmatic treatment comparisons with multimodal neuromonitoring, biochemical safety endpoints and patient-centred outcomes.