Pranav Sosale

Background: Traumatic Brain Injury (TBI) affects an estimated 55-74 million people globally each year and presents a major clinical challenge due to its complex pathophysiology and long-term consequences.¹ A key complication of TBI is cerebral edema, or swelling of brain tissue due to fluid accumulation, which can exacerbate secondary injury and worsen neurological outcomes.¹ The glymphatic system, blood-brain barrier (BBB), and inflammatory responses play central roles in the formation of cerebral edema.⁶ Novel therapeutic strategies are urgently needed, particularly due to variability in patient outcomes and limitations of existing treatments.⁸

Objective: This narrative review explores the mechanisms and treatments of cerebral edema following TBI, with specific focus on targeting noradrenaline-mediated glymphatic impairment and comparing it with other conventional interventions.

Search Methods: An online search in the PubMed database was conducted from 2018 to 2025 using the following keywords: “Traumatic Brain Injury”, “cerebral edema”, and “glymphatic drainage”.

Results: Excessive noradrenaline released post-TBI constricts glymphatic vessels and disrupts CSF drainage, resulting in fluid buildup.¹ Pan-adrenergic inhibition is administered as a pharmacological cocktail including prazosin (α1-adrenergic receptor antagonist), atipamezole (α2-adrenergic receptor antagonist), and propranolol (β-adrenergic receptor antagonist), was found to reduce brain water content and lower noradrenaline levels in both cerebrospinal fluid and plasma in C57BL/6 mice aged 8 to 12 weeks.¹ Mice treated with PPA (prazosin, propranolol, and atipamezole) exhibited improved functional cognitive recovery, determined using the string suspension grip test and the Morris Water Maze.¹ Mannitol is a hyperosmolar agent used to osmotically draw water out of swollen brain tissue that has shown improved patient Glasgow Outcome at Discharge Scale scores.² This treatment needs to be administered within 24 hours of injury and additional monitoring must be performed to prevent rebound edema and renal complications.² Esmolol is a β1-selective blocker that can mitigate the hyperadrenergic surge after TBI.⁴ Decreased intracranial pressure was seen by a lower Therapy Intensity Level (TIL) score over 96 hours but further investigation must be carried out on this treatment’s uniqueness to other β1-selective blockers.⁴ Decompressive Craniectomy (DC) is a surgical intervention that relieves elevated intracranial pressure by removing a portion of the skull.⁵ Reducing midline shift and brainstem herniation are found but mortality rate remains high after treatment.⁵ These findings support the potential for integrating multiple treatment strategies to create more personalized and effective care plans tailored to the specific needs to TBI patients.

Conclusions: The treatment of cerebral edema following TBI requires a multi-faceted approach targeting distinct pathophysiological mechanisms. Among the interventions studied, pan-adrenergic inhibition (PPA) shows the greatest promise in preclinical models by directly addressing the underlying cause—glymphatic impairment via noradrenaline. While mannitol and esmolol offer effective early intervention strategies, DHA provides anti-inflammatory support and decompressive craniectomy remains a last-resort surgical option. Continued research is needed to translate these findings into tailored, patient-specific therapies.

Works Cited:

1. Hussain R, Tithof J, Wang W, et al. Potentiating glymphatic drainage minimizes post-traumatic cerebral oedema. Nature. 2023;623(7989):992-1000. doi:10.1038/s41586-023-06737-7
2. Syahrul S, Musadir N, Hidayaturrahmi H, Suryadi T, Syahrul AN. Effectiveness of Mannitol Use on Clinical Outcomes of Severe Traumatic Brain Injury Patients. F1000Res. 2024;13:548. Published 2024 May 28. doi:10.12688/f1000research.148102.1
3. Liu ZH, Chen NY, Tu PH, et al. DHA Attenuates Cerebral Edema Following Traumatic Brain Injury via the Reduction in Blood-Brain Barrier Permeability. Int J Mol Sci. 2020;21(17):6291. Published 2020 Aug 31. doi:10.3390/ijms21176291
4. Baumer T, Higginbotham G, Hayes K, Thomas M; EBB-TBI Investigators. The Effect of Early Beta-Blockade with Esmolol on Therapy Intensity Level in Adults with Severe Traumatic Brain Injury. Neurotrauma Rep. 2024;5(1):982-987. Published 2024 Oct 2. doi:10.1089/neur.2024.0055
5. Geyik AM, Geyik S, Dogan A, Kayhan S, İnanç Y. Role of early decompressive craniectomy in traumatic brain injury: Our clinical experience. Travmatik beyin hasarında erken dekompresif kraniyektominin yeri: Klinik deneyimimiz. Ulus Travma Acil Cerrahi Derg. 2022;28(8):1088-1094. doi:10.14744/tjtes.2021.23176
6. Jha RM, Raikwar SP, Mihaljevic S, et al. Emerging therapeutic targets for cerebral edema. Expert Opin Ther Targets. 2021;25(11):917-938. doi:10.1080/14728222.2021.2010045
7. Akins PT, Guppy KH. Does Impaired Glymphatic Drainage Cause Glymphedema? A Review Tailored to Neurocritical Care and Neurosurgery. Neurocrit Care. 2021;35(2):545-558. doi:10.1007/s12028-021-01224-1
8. Rasmussen MK, Mestre H, Nedergaard M. The glymphatic pathway in neurological disorders. Lancet Neurol. 2018;17(11):1016-1024. doi:10.1016/S1474-4422(18)30318-1
9. Gao Y, Liu K, Zhu J. Glymphatic system: an emerging therapeutic approach for neurological disorders. Front Mol Neurosci. 2023;16:1138769. Published 2023 Jul 6. doi:10.3389/fnmol.2023.1138769
10. Park M, Shim Y, Choo YH, Kim HS, Kim J, Ha EJ. Should Hypertonic Saline Be
    Considered for the Treatment of Intracranial Hypertension? A Review of Current
    Evidence and Clinical Practices. Korean J Neurotrauma. 2024;20(3):146-158.
    Published 2024 Sep 26. doi:10.13004/kjnt.2024.20.e35
11. Cash A, Theus MH. Mechanisms of Blood-Brain Barrier Dysfunction in Traumatic
    Brain Injury. Int J Mol Sci. 2020;21(9):3344. Published 2020 May 8.
    doi:10.3390/ijms21093344