Principles of Neuroprotection Following Traumatic Brain Injury

In the next installment of our Trauma Sciences series, we explore the principles of neuroprotection following traumatic brain injury (TBI). Although the subject spans entire textbooks, this article aims to introduce the key physiological concepts underpinning modern neuroprotective strategies and highlight emerging areas of research. Surgical management is beyond the scope of this article, but it should be remembered that neurosurgical intervention forms a key component of multidisciplinary TBI care.

Primary and Secondary Brain Injury

Every year, approximately 69 million people sustain a traumatic brain injury worldwide, with 1 million hospital attendances in the UK due to head injury (1, 2). While around 70% of presentations are mild, this article focuses on moderate and severe TBI, where preventing secondary injury is fundamental to improving outcomes (3).

Primary brain injury occurs at the moment of impact and includes contusions, intracranial haemorrhage and diffuse axonal injury (which refers to widespread axonal disruption throughout the brain, usually do acceleration-deceleration forces; 4). Once this mechanical injury has occurred, it is irreversible. In the early stages of injury, effective haemorrhage control is paramount, and NICE recommends administering a bolus of tranexamic acid in all patients suspected of moderate or severe TBI to encourage haemostasis (5). In those taking anticoagulants, such as warfarin or DOACs, reversal of intracranial bleeding is required such as in the form of IV vitamin K, prothrombin complex concentrate (PCC) or andexanet alfa (6).

Secondary brain injury, however, evolves over hours to days and is driven by cerebral oedema, inflammation, oxidative stress, mitochondrial dysfunction, impaired autoregulation and cerebral ischaemia (4). These processes result in progressive neuronal death despite no further traumatic insult.

Neuroprotective measures therefore aim not to reverse the primary injury, but to minimise secondary insults by maintaining cerebral perfusion, preventing hypoxia and hypotension, and controlling raised intracranial pressure (ICP).

Intracranial Pressure and Monitoring

Following TBI, disruption of the blood-brain barrier and progressive inflammation result in cerebral oedema, increasing intracranial pressure (ICP; 4). According to the Monro–Kellie doctrine, the rigid cranial vault contains three components – brain tissue, blood and cerebrospinal fluid (CSF). As compensatory mechanisms become exhausted, rising ICP reduces cerebral perfusion pressure (CPP = MAP – ICP), compromising cerebral blood flow and increasing the risk of ischaemia (7).

For patients with severe TBI, invasive ICP monitoring can be via two modalities. Intraparenchymal monitors (or “bolts”) allow for relatively easy insertion and are less prone to blockage and complications, making them common choices in intensive care units (8). However, external ventricular drains (EVDs) provide the dual benefit of continuous monitoring and therapeutic CSF drainage and have historically been regarded as the “gold standard” for ICP monitoring. Importantly, ICP monitoring is not a treatment in itself but guides interventions aimed at maintaining adequate cerebral perfusion and preventing secondary injury (7).

The Brain Trauma Foundation emphasises that no single intervention provides comprehensive neuroprotection (9). Instead, successful management relies on careful optimisation of physiological parameters and the selective application of evidence-based therapies, described below.

Anti-epileptic Prophylaxis

Post-traumatic seizures occur in approximately 2–30% of patients with TBI and may worsen secondary brain injury by increasing cerebral metabolic demand, oxygen consumption and ICP (10). Antiepileptic prophylaxis is therefore recommended to prevent early post-traumatic seizures during the first seven days after injury.

Although phenytoin has traditionally been the standard agent, levetiracetam has become increasingly popular because of its favourable adverse-effect profile, minimal drug interactions and lack of therapeutic drug monitoring. While seizure prophylaxis reduces early seizures, it has not consistently been shown to reduce late seizures or improve long-term neurological outcomes. Consequently, prophylaxis is generally limited to the first week following severe TBI (9).

Therapeutic Hypothermia

Temperature has a profound influence on cerebral metabolism. Fever increases cerebral oxygen consumption, excitotoxicity (the process in which release of excitatory neurotransmitters contribute to neuronal damage) and the inflammatory response, making avoidance of hyperthermia an important aspect of neuroprotective care (11).

Therapeutic hypothermia aims to reduce cerebral metabolism and oedema by lowering core body temperature to 32–35°C. Although effective at reducing refractory ICP, randomised trials have failed to demonstrate consistent improvements in long-term neurological outcomes. Furthermore, hypothermia carries risks including coagulopathy, arrhythmias, electrolyte disturbances and infection (11).

Current guidelines therefore do not recommend routine prophylactic hypothermia. Instead, maintaining normothermia and actively preventing fever remain the standard of care, with therapeutic hypothermia reserved for selected patients with refractory intracranial hypertension (9).

Hyperventilation and Hypocapnia

Carbon dioxide is a potent vasodilator. Hyperventilation lowers arterial CO₂, producing cerebral vasoconstriction that reduces cerebral blood volume and rapidly lowers ICP (12).

However, this reduction in cerebral blood flow comes at the expense of oxygen delivery. Excessive or prolonged hypocapnia may therefore precipitate cerebral ischaemia, meaning hyperventilation treats raised ICP rather than the underlying injury. Current practice favours normocapnia for most patients, with temporary mild hypocapnia (PaCO₂ 4.0–4.5 kPa) reserved as a rescue measure during acute neurological deterioration or impending cerebral herniation while definitive treatment is arranged (9,12).

Hyperosmolar Therapy

Hyperosmolar therapy forms a key component of tiered ICP management (13). Both mannitol and hypertonic saline increase plasma osmolality, drawing water from oedematous brain tissue into the intravascular space. They also improve cerebral microcirculatory flow, reducing cerebral blood volume and ICP.

Choosing between the two agents requires careful consideration of the patient’s physiology. Mannitol produces an osmotic diuresis that may lead to hypovolaemia and hypotension if not carefully monitored, whereas hypertonic saline expands intravascular volume, making it particularly attractive in haemodynamically unstable patients. There is insufficient evidence currently to conclude superiority of one agent agent over the other (13). The NIHR is currently conducting a national multi-centre study aimed at determining which, if either approach, is associated with superior outcomes and is due to conclude this year (14). Therefore current clinical guidelines do not advocate for one approach over the other, and treatment is therefore individualised according to the patient’s clinical status and local practice (9).

Antibiotics: More Than Infection Prevention?

Antibiotics are routinely used to prevent or treat infection following open skull fractures, penetrating injuries and neurosurgical procedures. Interestingly, experimental studies suggest that agents – including doxycycline, minocycline and ceftriaxone – may also possess neuroprotective properties through reducing neuroinflammation, oxidative stress and neuronal apoptosis (1).

However, these promising findings have yet to translate into convincing clinical benefit, and no antibiotic is currently recommended specifically for neuroprotection. Nevertheless, modulation of neuroinflammation remains an exciting area of ongoing TBI research.

Conclusion

Despite decades of research, no single intervention can reverse the primary injury sustained after TBI. Instead, successful neuroprotection relies on meticulous critical care: maintaining cerebral perfusion, avoiding secondary insults such as hypoxia, hypotension and raised ICP, and applying evidence-based therapies cautiously. As our understanding of cerebral metabolism, neuroinflammation and neuromonitoring continues to evolve, future treatments may move beyond supportive principles to disease-modifying mechanisms. Until then, the greatest neuroprotective intervention remains timely multidisciplinary trauma, neurosurgical and critical care.

References

1. Ritter K, Somnuke P, Hu L, Griemert EV, Schafer M. Current state of neuroprotective therapy using antibiotics in human traumatic brain injury and animal models. BMC Neurosci. 2024;25:11.
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10. Caballero GC, Goodwin H, Baccino D, Shonnard N, Fuller M, Zach V, et al. Retrospective analysis of levetiracetam compared to phenytoin for seizure prophylaxis in adults with traumatic brain injury. Hosp Pharm.2013;48(9):757–61.
11. Urbano LA, Oddo M. Therapeutic hypothermia for traumatic brain injury. Curr Neurol Neurosci Rep.2012;12(5):580–91.
12. Svedung Wettervik T, Howells T, Hillered L, Nilsson P, Engquist H, Lewén A, et al. Mild hyperventilation in traumatic brain injury: Relation to cerebral energy metabolism, pressure autoregulation, and clinical outcome. World Neurosurg. 2020;133:e567–75.
13. Jung M-K, Roh TH, Kim H, Ha EJ, Yoon D, Park CM, et al. Hyperosmolar therapy response in traumatic brain injury: Explainable artificial intelligence based long-term time series forecasting approach. Expert Syst Appl.2024;255:124795.
14. National Institute for Health and Care Research. Sugar or Salt (SOS) trial: Hyperosmolar therapy in traumatic brain injury [Internet]. London: NIHR. Available from: https://fundingawards.nihr.ac.uk/award/17/120/01

Written by Dr Jack Bonnington