Time-dependent efficacy and safety of hypertonic saline versus mannitol in pediatric traumatic brain injury: a systematic review and meta-analysis

Abstract

Background: Traumatic brain injury (TBI) represents a significant cause of morbidity and mortality in children, with secondary injuries such as elevated intracranial pressure (ICP) significantly impacting outcomes. Hyperosmolar therapy is a cornerstone of acute management, with hypertonic saline (HTS) and mannitol as principal agents; however, comparative evidence regarding their efficacy and safety in pediatric populations remains inconclusive. Methods: Comprehensive searches of PubMed, Embase, and CENTRAL were performed up to June 2025. Primary outcomes were ICP reduction and all-cause mortality; secondary outcomes included neurological outcomes, adverse events, ICU/hospital stay, and physiological parameters. Meta-analyses employed random-effects models to pool risk ratios (RR), mean differences (MD), and proportions with 95% confidence intervals (CI). Results: A total of 14 studies, including 680 pediatric patients with TBI, were analyzed. HTS was associated with an increase in serum sodium (mean change 5.47 mEq/L; 95% CI: 1.30–9.64), severe hypernatremia (37%; on resolving heterogeneity rose to 53%), acute kidney injury (2.1%), and acute respiratory distress syndrome (4.5%). Comparative meta-analysis revealed no significant difference in mortality between HTS and mannitol (RR = 0.78; 95% CI: 0.50–1.23) and similar survival rates (RR = 1.05; 95% CI: 0.96–1.14), with high certainty. The pooled mortality rate for HTS was 17% (95% CI: 11%–24%), and survival was 83% (95% CI: 76%–89%). Pooled HTS analyses demonstrated a time-dependent decrease in ICP: 17.35 mmHg at 30 minutes, 9.72 mmHg at 60 minutes, and 8.45 mmHg at 24 hours. No significant differences were found for cerebral perfusion pressure (CPP) at 24 hours, ICU stay, hospital stay, or mechanical ventilation duration. Conclusion: In pediatric TBI, hypertonic saline and mannitol provide comparable efficacy for ICP reduction and mortality, with HTS demonstrating rapid ICP lowering and manageable safety signals. While HTS is generally well tolerated, further high-quality multicenter RCTs with standardized protocols and long-term outcomes are needed to clarify its clinical advantages over mannitol.