Continuous 3% Saline Infusion Combined with 7.5% Hypertonic Saline Bolus is Associated with Lower Mortality in Patients with Severe Brain Injury: A Single-Center Retrospective Cohort Study

BACKGROUND: Bolus hypertonic saline (HTS) is a cornerstone for managing intracranial hypertension, yet its transient effect mandates repeated dosing and may induce wide sodium fluctuations. Whether augmenting bolus 7.5% HTS with continuous 3% saline infusion to sustain osmotic gradients improves outcomes in neurocritical patients remains unknown. METHODS: We conducted a retrospective cohort study of 993 neurocritical patients treated with 7.5% HTS at a tertiary academic hospital in South Korea. Patients were classified as bolus-alone (n = 851) or combined therapy (7.5% bolus plus 3% continuous infusion; n = 142). The primary analysis focused on patients with severe brain injury (Glasgow Coma Scale [GCS] 3-9; n = 212). Inverse probability of treatment weighting (IPTW) was used to adjust for confounding. Robustness was confirmed through five sensitivity analyses, including multiple imputations and E-value assessment for unmeasured confounding. RESULTS: In the severe brain injury subgroup, combined therapy was associated with markedly lower ICU mortality (16.2% vs. 41.1%; adjusted odds ratio [OR] 0.23, 95% CI 0.08-0.65, p = 0.006) and 28-day mortality (18.9% vs. 45.7%; adjusted OR 0.20, 95% CI 0.07-0.55, p = 0.002). All five sensitivity analyses consistently confirmed these findings. In the overall cohort, trends favored combined therapy but did not reach significance (ICU mortality: OR 0.58, p = 0.121; 28-day mortality: OR 0.59, p = 0.110), although time-to-event analysis showed a significant overall survival benefit (Kaplan-Meier log-rank p = 0.006). Strikingly, despite a greater total sodium load, the combined group achieved lower peak serum sodium yet superior ICP control, suggesting that sustained osmotic gradients-not peak sodium-drive the benefit. CONCLUSIONS: In patients with severe brain injury, combined 7.5% HTS bolus and 3% continuous saline infusion was associated with substantially lower mortality compared with bolus therapy alone. These findings support further prospective investigation of combination osmotic therapy in neurocritical care. These observational findings should be interpreted with caution; despite IPTW adjustment and high E-values, confounding by indication cannot be fully excluded, and prospective validation is required before clinical adoption.