Association Between Hyperchloremia and Neurological Outcomes in Traumatic Brain Injury: A Narrative Review

Background/Objectives: Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide. Electrolyte disturbances are common in this patient cohort, with serum chloride frequently elevated. Chloride dysregulation may be associated with poor neurological outcomes through mechanisms including paradoxical gamma amino butyric acid receptor excitation, cytotoxic edema, and ferroptosis. The aim of this review was to evaluate the relationship between serum chloride levels and outcomes in patients with TBI. Methods: A literature review was performed to identify all potential studies that reported on serum chloride levels and TBI. All study types and patient groups were included. Studies were included if they reported on serum chloride measurements as well as outcomes such as mortality, surgical intervention, intracranial pressure, and neurological/functional outcome scores in patients with TBI. References and citations were also reviewed. Results: A small number of mostly retrospective studies with modest patient numbers demonstrate an association between high chloride levels and increased mortality in patients with TBI, with this relationship persisting independent of hypernatremia. Recent large, randomized trials showed that balanced crystalloid solutions, despite lower chloride content, may be associated with worse outcomes in TBI patients compared to saline. No studies directly correlated chloride levels with intracranial pressure measurements. Chloride level rather than total chloride load appears more strongly associated with adverse outcomes, with non-hypertonic saline sources contributing substantially to chloride burden. Mechanistic evidence links chloride channel dysregulation to ferroptosis and cytotoxic edema, with sex-specific patterns of transporter expression. Conclusions: Limited available evidence suggests that hyperchloremia is independently associated with increased mortality in TBI though causality remains unestablished. The findings regarding balanced solutions challenge conventional fluid management assumptions and highlight the complexity of chloride's role in TBI pathophysiology. The absence of studies directly correlating chloride with intracranial pressure represents a critical evidence gap. Future studies with larger patient numbers, prospective designs, and multimodal neuromonitoring should further define these relationships to inform evidence-based chloride management strategies.