General

## **Chapter 1**

## Introductory Chapter: Traumatic Brain Injury

*Youle Su and Xianli Lv*

## **1. Introduction**

Traumatic brain injury (TBI) is a global public health concern and one of the main causes of morbidity, disability, and mortality that has been associated as a risk factor for neurodegeneration and degenerative diseases. Brain injury, secondary to vehicular injury was the most common form of TBI [1]. Yearly, TBI costs the global economy approximately 400 billion US dollars, representing 0.5% of the gross world product [2]. Even with modern diagnosis and treatment, the prognosis for the patient with TBI remains poor. Severe TBI has mortality rates of 30–40% and can cause significant physical, psychosocial, and social deficits in up to 60% of cases [3, 4]. The highest rates of TBI are in children group (0–4 years old) as well as in young age group (15–24 y). There is another high incidence of TBI in old age group (>65 y). The 2 major causes of TBI are falls and motor vehicle accidents generally [5]. Because of the prevalence of TBI, an understanding of the management of this group of patients is vital to the modern health care provider. This introductory chapter based on the 4th edition of the Brain Trauma Foundation guidelines were published in 2016 [6].

## **2. Pathophysiology of TBI**

The pathogenesis of TBI is a complex process, caused by primary and secondary injuries, resulting in temporary or permanent neurological deficits (**Figure 1**) [7]. Primary damage is directly related to the primary external influence on the brain. Secondary injury can occur minutes to days after the primary impact and consists of molecular, chemical, and inflammatory cascades that lead to further brain damage. This cascade involves depolarization of neurons and the release of excitatory neurotransmitters such as glutamate and aspartate, leading to an increase in intracellular calcium. Intracellular calcium activates a series of mechanisms by activating caspases, and free radicals, which lead to cellular degradation, directly or indirectly, through apoptotic processes. This degradation of neuronal cells is associated with an inflammatory response that further damages neuronal cells and triggers disruption of the blood-brain barrier (BBB) and further brain edema. The whole process is also up- and down-regulated through several mediators. The second injury phase is followed by a recovery phase that includes reorganization at the molecular, anatomical, and functional levels.

#### **Figure 1.**

*Secondary injury from oxidative stress, disruption of the blood-brain-barrier (BBB), inflammation, excitotoxicity, and cell death and resulting factors involved in neuronal damage. MS: mitochondrial stress, CKS: cytokines, NO: nitric oxide, PGI: prostaglandins, Glue: glutamate, NMDA: N-methyl-D-aspartate receptor, Ca: calcium, CDP: caspase-dependent 3, CID: caspase-independent factor.*

The volume of the intracranial compartment consists of 3 separate contents: brain parenchyma (83%), cerebrospinal fluid (CSF, 11%) and blood (6%). Each of these contents is interdependent on the homeostatic environment within the skull. However, when the intracranial volume exceeds its normal composition, a series of compensatory mechanisms occur. An increase in intracranial volume can occur in the traumatized brain through mass effects of hematoma, cytotoxic and vasogenic edema, and venous congestion. Because brain tissue is incompressible, edematous brain tissue initially causes CSF to squeeze into the spinal compartment. Eventually, blood, especially from venous channels, is also squeezed out of the brain. Without appropriate intervention, sometimes even the maximal intervention, compensatory mechanisms fail, and the end result is pathological brain compression and subsequent death.

## **3. Neurological exam in TBI**

The Glasgow Coma Scale (GCS) is part of clinical practice guidelines and has been commonly used as a bedside neurological scale in routine office practice since its introduction in 1974 [8]. It helps neurosurgeons assess the patient's level of consciousness to determine the severity of TBI in patients. GCS measures eye-opening (4 points), verbal response (5 points), and optimal motor response (6 points), for a total of at least 3 to a maximum of 15 points. This score correlates with changes in pathophysiological changes after TBI and is reflected in the total score; it ranges from 13 to 15 (mild), 9 to 12 (moderate), and less than 8 (severe TBI) [8, 9].

## **4. Updated medical interventions for TBI**


## **5. Brain multi-modality monitoring**


## **6. Blood pressure thresholds**

1.Maintenance of SBP (systolic blood pressure) ≥ 100 mmHg for patients 50–69 years of age or ≥ 110 mmHg or more for patients aging 15–49 years or 70 years may be considered for reduced mortality and improved outcomes.


## **7. Potential new monitor**

The use of brain tissue oxygen tension (PbtO2) monitoring was originally proposed as a method to avoid cerebral ischemia to control ICP during therapeutic hyperventilation. The most common method for monitoring PbtO2 is an invasive probe using a modified Clark electrode, with a typical pathological threshold of 20 mmHg [10]. In multivariate analysis, PbtO2 was shown to have an impact on patient prognosis. This has led to prospective trials of PbtO2-targeted therapy in addition to standard ICP-driven therapy. A phase II trial (BOOST-II, Brain Tissue Oxygen Monitoring, and Management in Severe Traumatic Brain Injury) demonstrated a significant reduction (74%) in the hypoxic burden during hospitalization in the PbtO2-targeted group, with no substantial safety concerns. According to studies, direct intervention is used for ICP management (if >20 mmHg for >5 min), PbtO2 control (if <20 mmHg for >5 min), or both [10]. The third phase of the randomized study (BOOST-III) will evaluate the clinical efficacy of "a treatment regimen based on PbtO2 monitoring compared to a treatment based on ICP monitoring alone" and will enroll patients in the United States.

## **8. Deep brain stimulation**

DBS (Deep Brain Stimulation) has been shown to be effective for cognitive and motor disorders and has the potential to treat other disorders such as depression [11]. These same clinical disorders (e.g., tremor, depression) are frequently present in patients with TBI due to direct structural brain injury or secondary damage from injury. DBS has shown efficacy in the treatment of subgroups of TBI patients with such comorbidities, but the effect of DBS on higher-order function is unclear.

## **9. Conclusions**

TBI is a major global health challenge and priority. Despite the lack of effective treatments for TBI recovery today, continuous efforts have been made over the past few decades to develop therapeutic strategies for TBI recovery. Standard medical and surgical interventions have always played an important role in the acute management of patients with TBI. The number of TBI survivors has increased due to the emergence of better acute management guidelines in the acute phase of TBI, and the number of TBI survivors with various disabilities has increased.

## **Author details**

Youle Su1 and Xianli Lv2 \*

1 Neurosurgery Department, The Affiliated Hospital of Inner Mongolia Medical University, Huhhot, Inner Mongolia, China

2 Department of Neurosurgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China

\*Address all correspondence to: lvxianli000@163.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Introductory Chapter: Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.105359*

## **References**

[1] Maas AIR, Menon DK,

Adelson PD, Andelic N, Bell MJ, Belli A, et al. Traumatic brain injury: Integrated approaches to improve prevention, clinical care, and research. Lancet Neurology. 2017;**16**(12):987-1048

[2] Taylor CA, Bell JM, Breiding MJ, Xu L. Traumatic brain injury-related emergency department visits, hospitalizations, and deaths—United States, 2007 and 2013. MMWR Surveillance Summaries. 2017;**66**(9):1-16

[3] Marehbian J, Muehlschlegel S, Edlow BL, Hinson HE, Hwang DY. Medical management of the severe traumatic brain injury patient. Neurocritical Care. 2017;**27**(3):430-446

[4] Vella MA, Crandall ML, Patel MB. Acute management of traumatic brain injury. The Surgical Clinics of North America. 2017;**97**(5):1015-1030

[5] Galgano M, Toshkezi G, Qiu X, Russell T, Chin L, Zhao LR. Traumatic brain injury: Current treatment strategies and future endeavors. Cell Transplantation. 2017;**26**(7):1118-1130

[6] Farrell D, Bendo AA. Perioperative management of severe traumatic brain injury: What is new? Current Anesthesiology Reports. 2018;**8**(3):279-289

[7] Crupi R, Cordaro M, Cuzzocrea S, Impellizzeri D. Management of traumatic brain injury: From present to future. Antioxidants (Basel). 2020;**9**(4):297

[8] Mena JH, Sanchez AI, Rubiano AM, Peitzman AB, Sperry JL, Gutierrez MI, et al. Effect of the modified Glasgow Coma Scale score criteria for mild traumatic brain injury on mortality

prediction: Comparing classic and modified Glasgow Coma Scale score model scores of 13. The Journal of Trauma. 2011;**71**(5):1185-1193

[9] Dikmen SS, Machamer JE, Powell JM, Temkin NR. Outcome 3-5 years after moderate to severe traumatic brain injury. Archives of Physical Medicine and Rehabilitation. 2003;**84**(10):1449-1457

[10] Khellaf A, Khan DZ, Helmy A. Recent advances in traumatic brain injury. Journal of Neurology. 2019;**266**:2878-2889. DOI: 10.1007/ s00415-019-09541-4

[11] Kundu B, Brock AA, Englot DJ, Butson CR, Rolston JD. Deep brain stimulation for the treatment of disorders of consciousness and cognition in traumatic brain injury patients: A review. Neurosurgical Focus. 2018;**45**(2):E14

## **Chapter 2**

## Prehospital and Emergency Room Airway Management in Traumatic Brain Injury

*Dominik A. Jakob, Jean-Cyrille Pitteloud and Demetrios Demetriades*

## **Abstract**

Airway management in trauma is critical and may impact patient outcomes. Particularly in traumatic brain injury (TBI), depressed level of consciousness may be associated with compromised protective airway reflexes or apnea, which can increase the risk of aspiration or result in hypoxemia and worsen the secondary brain damage. Therefore, patients with TBI and Glasgow Coma Scale (GCS) ≤ 8 have been traditionally managed by prehospital or emergency room (ER) endotracheal intubation. However, recent evidence challenged this practice and even suggested that routine intubation may be harmful. This chapter will address the indications and optimal method of securing the airway, prehospital and in the ER, in patients with traumatic brain injury.

**Keywords:** prehospital, emergency room, endotracheal intubation, airway, outcomes, traumatic brain injury

## **1. Introduction**

Traumatic brain injury (TBI) is frequently associated with depressed level of consciousness, compromised protective airway reflexes or apnea, which can increase the risk of aspiration or result in hypoxemia and worsen the secondary brain damage. Therefore, patients with TBI and Glasgow Coma Scale (GCS) ≤ 8 have been traditionally managed by prehospital or emergency room (ER) intubation. This practice is also reflected by the current guidelines: the American College of Surgeons Committee on Trauma Advanced Trauma Life Support (ATLS) recommends intubation for patients with a GCS of 8 or lower for airway protection [1]. Also, the practice management guidelines of the Eastern Association for the Surgery of Trauma give a level 1 recommendation for endotracheal intubation of patients with severe cognitive impairment (GCS ≤ 8) [2].

However, the potential benefit of an intubation in TBI, is also associated with risks: Difficult or failed endotracheal intubation may cause hypoxemia, aspiration, and hypotension and requires admission to the intensive care unit (ICU). In fact, there is no direct evidence supporting routine intubation of all patients with a GCS ≤ 8. Consequently, recent evidence challenged the practice of a strict GCS threshold for intubation and even suggested that routine endotracheal intubation for GCS ≤ 8 in TBI may be harmful [3].

The primary goal in the prehospital care of the trauma patient is to secure adequate ventilation until transfer to hospital care. To achieve this goal, various techniques for airway establishment and subsequent ventilation can be performed: endotracheal intubation has been considered as the gold standard. However, ventilation may also be achieved by less invasive and time consuming procedures such bag-valve mask (BVM) ventilation with the optional use of oropharyngeal (OPA) or nasopharyngeal (NPA) adjuncts. More advanced techniques include supraglottic airway (SGA) devices. There is a wide range of medications available to facilitate intubation prehospital or in the ER.

To date, there are no evidence-based guidelines for TBI patients regarding standardized airway management in the prehospital setting or in the ER. This explains also why indications and techniques for airway establishment vary in different systems and countries around the world. In the United States of America (USA) prehospital care is usually provided by emergency medical technicians or trained paramedics, whereas prehospital care in most European countries is provided by physicians [4]. Following these differences of American and European Emergency Medical Service (EMS) systems, the US prehospital care strategy follows more "scoop and run approach" with prioritizing rapid patient transport to trauma centers. In Europe the priority lies more on field triage, on scene assessment and initiation of procedures such as intubation "stay and play approach" [5].

This chapter will address the question what airway management strategy best meet the patients need and is associated with most favorable outcomes in TBI. Indications and optimal method of securing the airway prehospital and in the ER will be discussed. In addition, technical aspects including medication for pretreatment, induction, paralysis and sedation for endotracheal Intubation in the presence of TBI will be outlined.

## **2. Prehospital airway management**

Advanced prehospital care has been practiced for several decades in Western countries. In TBI particularly, prehospital airway management is one of the most critical aspects that determine patient outcomes. The importance of the airway management is reflected by the Advanced Trauma Life Support (ATLS) algorithm [1], in which the airway takes priority over any other therapeutic interventions.

General prehospital TBI guidelines [6] are emphasizing avoidance and treatment of hypoxia, prevention and correction of hyperventilation, and avoidance and treatment of hypotension. The implementation of these prehospital guidelines showed that adjusted survival doubled among patients with severe TBI and tripled in the severe, intubated cohort. Furthermore, guideline implementation was significantly associated with survival to hospital admission [7]. These findings support the widespread implementation of the prehospital TBI treatment guidelines. However, specific evidence-based guidelines are needed to establish the optimal airway management in the prehospital setting.

Patients require an advanced airway under two sets of circumstances: failure to maintain a patent airway and the inability to oxygenate and ventilate the patient adequately [8]. While endotracheal intubation in the OR is a very safe and

## *Prehospital and Emergency Room Airway Management in Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.104173*

straightforward procedure with very low complication rate, emergency intubation of an unstable patient in the field is linked to a high rate of complication with up to 25% mortality in some studies. Emergency intubation remains a hazardous maneuver even under the best conditions. And no matter how skilled the prehospital team is, best conditions are seldom encountered in the field. This is why endotracheal intubation should ideally performed by skilled providers in patients who are likely to benefit from this technique. In a prehospital setting the indication to establish an airway is not always that obvious and depends on multiple factors **(Figure 1)** [9]**.**

a.Severity of patients' condition and the presence of hypoxia: Traumatic brain injury (TBI) is frequently associated with depressed level of consciousness, compromised protective airway reflexes or apnea, which can increase the risk of aspiration or result in hypoxemia and worsen the secondary brain damage. During the past 45 years, the quantitative GCS as a simple and practical numeric method for assessing impairment of the level of conscious has become the universal criterion for mental status assessment [10]. Consequently, the GCS is also a frequently used score to decide whether an intubation should be performed or not. According to the ATLS [1] and the practice management guidelines of the Eastern Association for the Surgery of Trauma [2] intubation is recommended for GCS ≤8. However, there is no scientific evidence supporting this practice. The dogma that patients with a GCS ≤ 8 are at higher risk for aspiration or hypoxic injury has now been challenged. A prospective study from Hong Kong, in 2012, showed that of 33 patients with a GCS ≤ 8 36.4% had intact airway reflexes and potentially

#### **Figure 1.**

*Prehospital airway-management. The indication to establish an airway in a prehospital setting depends on: the severity of patients' condition and the presence of hypoxia; the training and skills of the EMS personnel including the available equipment; and the safety and environment on scene. Figure provided by Clerc EMS Monthey, Switzerland.*

capable of maintaining their own airway, whilst many patients with a GCS > 8 have impaired airway reflexes and potentially be at risk for aspiration [11].

The need for immediate establishment of an obstructed or impaired airway or hypoxia is unquestionably associated with better outcomes. However, performing an intubation in a suboptimal environment in the field, especially if performed by paramedics, may be challenging and require multiple attempts and in some cases may result in the loss of airway with catastrophic consequences. A difficult intubation may result in hypoxemia, aspiration, and hypotension, factors that may contribute to worse outcomes. Also, prehospital intubation and hand ventilation is often associated with hyperventilation and hypocapnia, which could worsen brain edema and secondary brain damage. Finally, prolonging the prehospital time and delaying definitive care, may have adverse effects on the patient, especially in the presence imminent herniation due to increased intracranial pressure (ICP) or an ongoing hemorrhage.

In conclusion, it is important to identify those patients who might benefit from prehospital endotracheal intubation and those who can potentially be harmed by the procedure. At this moment there is no class I evidence supporting any specific approach. It might be appropriate to attempt prehospital intubation in a small number of selected patients with imminent airway obstruction or hypoxia not responding to oxygen administration.

b.Training and skills of the EMS personnel and the available equipment: In the United States of America (USA) prehospital care is usually provided by emergency medical technicians for basic life support (BLS) or trained paramedics for advanced life support (ALS), whereas prehospital care in most European countries is provide by physicians. Basic providers are restricted to splinting, bandaging, alignment of displaced limbs, the administration of oxygen including BVM ventilation, chest compression and the use of an automated external defibrillator (AED) in case of cardiac arrest. However, especially in the USA many of BLS providers have obtained an intermediate level (EMT-I); these individuals can obtain a more definitive airway such as using a SGA device or even perform endotracheal intubation. Paramedics are trained and performed endotracheal intubation. However, very often many paramedics, especially in areas with no large trauma volumes may not use this skill very often and may become less competent with the procedure. On the other hand, especially an experienced physician proficient with endotracheal intubation, is more likely to perform an intubation more liberally, often unnecessarily. In the United States, prehospital care strategy follows the principle of "scoop and run" with prioritizing rapid patient transport to trauma centers and minimal interventions on scene. In Europe there is a strong element on field triage and initiation of more advanced therapeutic interventions, such as intubation. This prehospital strategy is also known as "stay and play". A matched cohort study compared patients with isolated severe TBI in Switzerland and the United States [12]. In line with the described differences in prehospital strategies, patients in Switzerland had significantly longer scene times (23 vs. 9 minutes, p < 0.001) and prehospital endotracheal intubation was more frequently performed (31% vs. 18.7%, p = 0.034). However, no significant differences in outcomes were observed between the two cohorts. The results what prehospital strategy should be prioritized and if an endotracheal intubation should be performed remain controversial, although there is evidence that a

### *Prehospital and Emergency Room Airway Management in Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.104173*

"scoop and run" approach is preferable for penetrating trauma. In these scenarios the number of meaningful interventions that can be made by prehospital providers is limited and rapid transportation to the hospital is the most important aspect, because in-hospital surgery is typically needed for hemorrhage control.

c.Safety and environment on scene: The safety aspect on scene, as well as the transportation mode and the expected time to reach the next hospital are important for considering airway interventions on scene. Especially for longer transports, the time-saving aspect of the scoop and run approach without airway interventions becomes less important and early establishment of an airway may improve patient outcomes.

Considering all factors above, complexity of the decision to perform a prehospital intubation becomes obvious, and it is not surprising that the literature on this topic remains contradictory. A retrospective multicenter study including 13,625 patients with moderate to severe TBI showed that prehospital intubation was independently associated with a decrease in survival [13]. Several other studies implicated outof-hospital intubation as a factor associated with negative outcomes [14, 15]. In a recently published study prehospital airway management in severe TBI patients did not have a significant impact on mortality or long-term neurological outcomes [16]. Other investigations have also demonstrated no difference or even improved outcomes with field intubation [17, 18].

Besides intubation, different other options for airway management are available in a prehospital setting. The simplest approaches such as the jaw thrust or chin lift maneuver are included in the first aid. Oropharyngeal (OPA) or nasopharyngeal (NPA) adjuncts may be inserted orally or nasally to secure an open airway. More advanced airway techniques include the establishment of an airway using an SGA device and finally the performance of endotracheal intubation. In particular cases, a surgical airway must also be considered. A major challenge in prehospital airway management is to determine the appropriate approach for the individual patient in the present environment and setting. **Table 1** shows various airway management techniques and summarizes advantages and disadvantages in prehospital use.

A recently published systematic review [19] was assessing comparative benefits and harms across three different airway management approaches (BVM, SGA, and endotracheal intubation) for patients with trauma, cardiac arrest, or medical emergencies requiring prehospital ventilatory support or airway protection. Overall, 99 studies involving 630,397 patients from 1990 to September 2020 were considered for analysis. The evaluated outcomes included mortality, neurological function, return of spontaneous circulation (ROSC), and successful advanced airway insertion. Different meta-analyses were stratified first by study design (RCTs or observational studies), and then by emergency type (cardiac arrest, trauma, medical) and population age (adult, pediatric, mixed-age). All meta-analyses outcomes were reported as favoring one of the two compared approaches, or no difference. Sufficient evidence was not available to address all outcomes and all patient characteristics, provider characteristics, and variations in techniques that were specified a priori. For adult trauma patients 1-month post incidence survival was not different when BVM was compared to endotracheal intubation. Other comparisons for adult trauma patients did not show sufficient evidence to favor an airway management strategy over another. Potential harms of airway management for the entire study population were also compared. When comparing BVM vs. SGA and BVM vs. endotracheal intubation, no difference



*Prehospital and Emergency Room Airway Management in Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.104173*

was found. When comparing SGA to endotracheal intubation, SGA was superior in terms of multiple insertion attempts; endotracheal intubation was superior in terms of inadequate ventilation. No difference was recorded for aspiration, oral/ airway trauma and regurgitation. The authors concluded that the currently available evidence does not indicate benefits of more invasive airway approaches based on survival, neurological function, ROSC, or successful airway insertion. However, most included studies were observational. This supports the need for high-quality randomized controlled trials to advance clinical practice and EMS education and policy, and improve patient-centered outcomes.

## **3. Airway management in the ER**

Similar to the prehospital setting the standard indications for an advanced airway establishment in the ER, include low GCS, failure to maintain a patent airway and the inability to oxygenate and ventilate the patient adequately. In the presence of a TBI a diminished level of consciousness with the concern for the loss of airway control is very common and likely the most frequent indication for ER intubation. Therefore, the GCS is most commonly used to decide whether an intubation should be performed or not.

Patients with TBI and a GCS ≤ 8 have been traditionally managed by ER endotracheal intubation. However, this practice is based mainly on expert opinion and long-standing dogma. There is very little evidence to support this policy! Recent work has challenged this practice! A recently published study including patients with isolated severe head injuries suggested that routine endotracheal intubation in the ER for GCS of 7 and 8 may be even harmful [3]. In this study 2727 patients with GCS 7/8 and isolated blunt head trauma were included. Overall, 1866 (68.4%) patients were intubated within 1 hour of admission (immediate intubation), 223 (8.2%) had an intubation >1 hour of admission (delayed intubation), and 638 (23.4%) patients were not intubated at all. After correcting for age, gender, overall comorbidities, tachycardia, GCS, alcohol, illegal drug use, and head injury severity, immediate intubation was independently associated with higher mortality (OR 1.79, CI 95% 1.31–2.44, p < 0.001) and more overall complications (OR 2.46, CI 95% 1.62–3.73, p < 0.001).

A study [20] evaluating a general trauma population with GCS of 6–8 came to a similar conclusion. An intubation within 1 hour of arrival was associated with an increase in mortality and longer ICU and overall length of stay compared to patients without an intubation. The authors also performed a subgroup analysis of patients with head injury and found similar results to that of the overall trauma population.

These two studies showing worse outcomes associated with immediate intubation and suggest that the existing GCS threshold to mandate intubation in patients with isolated head injuries should be revisited.

Beside the GCS, additional clinical criteria may help to guide the decision to intubate TBI patients in the future. A recently published study showed that head abbreviated injury scale (AIS), tachycardia and younger age were independent clinical factors associated with intubation [3]. These factors could potentially be taken into account to formulate a more selective approach to immediate intubation. In the mentioned study a policy of intubating all isolated blunt head injury patients ≤45 years with head AIS 5 and GCS 7 would have improved intubation management, with 7 immediate instead of delayed intubations and only three potentially unnecessary intubations. If these defined criteria are met (high specificity), an early intubation should be strongly considered. On the other hand, the defined criteria are not suitable to identify patients who definitely do not require an intubation (low sensitivity). Future research should focus on defining more adequate clinical parameters to identify patients requiring immediate intubation and should avoid fixed GCS threshold.

Muakkassa et al. [21] compared trauma patients who were intubated because of combativeness, and not because of medical necessity. In line with the findings above intubating for combativeness was associated with longer hospital LOS, increased rates of pneumonia, and worse discharge status when compared with matched non-intubated patients. It appears that the risks and adverse events of intubation may outweigh the potential benefits of intubation in specific trauma populations.

Therefore, the following potential risks associated with intubation in TBI patients need to be considered by every health care provider. Laryngoscopy and the endotracheal tube can cause a sympathetic or parasympathetic stimulation. Sympathetic stimulation may increase heart rate, blood pressure [22] and ICP [23], whereas parasympathetic stimulation can trigger bronchospasm or hypotension. Especially the increase in ICP from the sympathetic surge can cause an increase in cerebral blood volume, cerebral edema, and development of worsening hemorrhage or hematoma. Finally, both, sympathetic and parasympathetic stimulations may increase mortality and brain injury.

Ventilation after intubation need to be monitored closely, because both hyper- and hypoventilation can contribute to worse outcomes. Severe hyperventilation (arterial pCO2 below 25 mm Hg) should be avoided due to the risk of vasoconstriction and cerebral ischemia. In general, a normo-ventilation with an arterial pCO2 within 35–45 mm Hg should be targeted. However, mild hyperventilation (arterial pCO2 within 30–34 mm Hg) is commonly used to address high intracranial pressure and may potentially be beneficial [24]. More important to address the elevated ICP in TBI patients is the initiation of hyperosmolar therapy with mannitol or hypertonic saline when additional bleeding is suspected [25].

Technical aspects and medications for endotracheal intubation carries also risks for TBI patients. The following section gives an overview including recommendations for pretreatment, induction, paralysis, and sedation of patients with TBI to prevent secondary brain damage.

## **4. Technical aspects including medication for pretreatment, induction, paralysis and sedation for endotracheal intubation in the presence of TBI**

Endotracheal intubation remains the gold standard for airway management in trauma patients and should be performed via the oral route and a manual in-line stabilization maneuver [26]. Rapid sequence induction (RSI) is widely used for emergency intubation and often considered as the gold standard for trauma patients. This technique uses a fast acting anesthetic in combination with a fast acting relaxant to achieve rapid intubation. Only a few people are aware that this technique was formally described by P. Safar back in 1970 [27]. The primary goal of this technique was to prevent regurgitation during induction of anesthesia in patients with bowel obstruction. Hypoxemia and hypotension were hardly considered at that time, when advanced monitoring and pulse oximetry were still tools of the future. From today's point of view, this technique is not ideally suited to prevent hypoxemia and hypotension. While in standard OR practice, such short events will hardly result in more than *Prehospital and Emergency Room Airway Management in Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.104173*

a check on the Q/A sheet, they may have devastating consequences on outcomes in patients with TBI.

In addition, complication rate increases significantly with the number of intubation attempts, with a sharp increase if more than 2 attempts are needed [28]. This suggests that first pass success should be the gold standard in emergency intubation, and return to basic maneuvers or surgical airway should be considered if 2 attempts have failed.

Another important aspect is efficient airway clearance before intubation, which has been shown to significantly increase first pass success [29]. That is why suction of the airway, while having little relevance in the OR can be a game changer in emergency intubation.

Good oxygenation throughout the procedure is paramount in brain injured patients, so meticulous attention should be paid to optimizing precondition. A recent study [30] has shown that when intubation is attempted in a patient with a SpO2 < 93%, there is almost 100% incidence of severe hypoxemia while incidence goes down to 17% if SpO2 is 95% or more. While optimizing oxygenation status may take some time, it certainly pays off in terms of patient outcome.

Last but not least a close monitoring during intubation is mandatory. Studies have shown that episodes of hypoxemia during intubation attempts often go unrecognized, both in the field and in the ER. Furthermore, after intubation attention should be taken to avoid hyperventilation as it can cause hypocapnia and thus cerebral vasoconstriction; it also can impair venous return leading to hypotension. As trivial as it might seem, having a team member watching the vital signs is an important factor in the intubation process.

In the following section medication for pretreatment, induction, paralysis and sedation for endotracheal intubation in the presence of TBI are discussed.

There is currently no evidence to support the use of intravenous lidocaine as an intubation pretreatment for RSI in patients with TBI [23]. High-dose fentanyl (at 2–3 mcg/kg) can help to blunt the sympathetic stimulation of intubation and is currently recommended for neuroprotection in patients with increased ICP.

In TBI the induction with etomidate is popular all over the world because of its mild hemodynamic profile. Particularly, in TBI a drop in mean arterial pressure (MAP) and the subsequent decrease in cerebral perfusion pressure (CPP) may have devasting consequences. It's important to be aware that etomidate has no analgesic properties, and neuroexcitation may need to be addressed separately.

Ketamine for induction is a good option, with the additional benefit of analgesic properties. The concern of sympathetic stimulation, leading to an increase in ICP is no longer valid. On the contrary, ketamine may, in fact, be neuroprotective due to an increase in MAP and CPP [31], without an increase in cerebral oxygen consumption or reducing regional glucose metabolism [32]. Ketamine may best be used for induction in the presence of hypotension because of for the described effect of increasing MAP and CPP [33].

For paralysis succinylcholine or rocuronium can be utilized [34]. Succinylcholine, as a depolarizing neuromuscular blocking agent has the advantage of rapid onset and offset properties, which is beneficial in TBI patients regarding early neurological examinations. Rocuronium on the other hand can lead to delays in proper neurological examinations due to prolonged paralysis. A retrospective study of 2016 compared 233 TBI patients requiring intubation in the ER. RSI was either performed with succinylcholine or rocuronium. Overall mortality rate was similar between the two groups. However, for patients with a high head AIS score (4–6), succinylcholine was associated with increased mortality compared with rocuronium (44% vs. 23%, odds

ratio (OR) 4.10, 95% confidence interval (CI) 1.18–14.12; p = 0.026). Prospective studies are need to clarify these findings.

Propofol in TBI patients for post-intubation sedation is widely used and has the advantage of rapid onset of action and short duration of action. However, since it has no analgesic effect, it needs to be combined with medication for pain control. Furthermore, care should be taken in hypotensive patients because it may lower the MAP and subsequently the CPP. For post-intubation continuous sedation, a combination of propofol and fentanyl in the normotensive or hypertensive patient is therefore recommended. Fentanyl is a potent analgesia without appropriate sedation properties. While the hemodynamic properties of fentanyl are relatively stable, a decrease in MAP and HR frequently occur due to the cessation of the sympathetic stimulus triggered by pain. In addition, an increase in ICP has been described in several studies. A minimal appropriate dose for TBI patients is therefore recommended.

In hypotensive patients a combination of midazolam and fentanyl or ketamine alone is a good option. Midazolam as a sedative has the additional benefit of anxiolytic and anticonvulsant properties. Compared to propofol the effect on ICP and CPP are comparable. However, it's important to have in mind that the onset and offset action of midazolam is initially relatively fast but tissue accumulation over time may be associated with delayed awakening. This is particularly disadvantageous in patients with TBI, as rapid clinical assessment after cessation of the drug is wanted.

A relatively new approach for emergency intubation is the delayed sequence induction (DSI) technique described by Weingart and colleagues [35]. In contrast to RSI, the technique of delayed sequence intubation temporally separates administration of the induction agent from the administration of the muscle relaxant to allow adequate pre-intubation preparation. This technique uses ketamine sedation to optimize preoxygenation with CPAP or assisted ventilation before muscle relaxant is given and intubation performed. Recent studies have shown an improved safety profile in emergency intubation using this technique. A ketamine-only breathing intubation, in which ketamine is used without a paralytic is another promising alternative. In this case the patient continues to breathe spontaneously, while ketamine provide hemodynamic benefits compared to standard RSI and is also a valuable agent for postintubation analgesia and sedation. When RSI is not an optimal airway management strategy, ketamine's unique pharmacology can be harnessed to facilitate alternative approaches that may increase patient safety [36].

## **5. Conclusion**

Airway control is particularly important for patients with TBI because hypoxemia and hypercarbia may cause secondary brain damage.

In a prehospital setting the indication to establish an airway depends on multiple factors such as (a) severity of patients' condition including the presence of hypoxia, (b) the training and skills of the EMS personnel including the available equipment, (c) the safety and environment on scene.

In the presence of a TBI a diminished level of consciousness with the concern for the loss of airway control is very common and likely the most frequent indication for intubation. Traditionally patients with TBI and Glasgow Coma Scale (GCS) ≤ 8 have been managed by prehospital or ER endotracheal intubation. However, recent evidence challenged this practice and even suggested that routine intubation may be harmful. There is evidence that intubation according to a strict GCS threshold is associated with

*Prehospital and Emergency Room Airway Management in Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.104173*

risks and adverse events that may outweigh the potential benefits of intubation in TBI patients. Future research should focus on defining more adequate clinical parameters to identify patients requiring immediate intubation and should avoid fixed GCS threshold. Furthermore, less invasive airway management strategies such as BVM ventilation or the use of SGA devices may be equally effective and potentially associated with less complications. The cornerstone of prehospital airway management should focus on aggressive prevention and treatment of hypoxemia, hypotension, and, if the patient receiving positive pressure ventilation, prevention of hyperventilation. If an intubation is performed in a TBI patient induction with etomidate or ketamine in the presence of hypotension is recommended. For paralysis succinylcholine or rocuronium can be used. Recommendations for post-intubation continuous sedation medications include a combination of propofol and fentanyl in the normotensive or hypertensive patient. A combination of midazolam and fentanyl or ketamine alone should be considered in the hypotensive patient. Delayed sequence induction (DSI) or a ketamine-only intubation, in which ketamine is used without a paralytic are very promising options for emergency intubation and may become the standard of care in the future. The benefit of these strategies compared to RSI need to be confirmed in large randomized clinical trials.

## **Acknowledgements**

We thank Clerc EMS Monthey, Switzerland for providing **Figure 1**.

## **Conflict of interest**

The authors declare no conflict of interest.

## **Author details**

Dominik A. Jakob1,2, Jean-Cyrille Pitteloud3 and Demetrios Demetriades1 \*

1 Division of Trauma and Surgical Critical Care, Department of Surgery, Los Angeles County + University of Southern California Medical Center, University of Southern California, Los Angeles, CA, USA

2 Department of Surgical Emergency Unit, Inselspital University of Bern, Bern, Switzerland

3 Hospital du Jura Bernois, Saint-Imier, Switzerland

\*Address all correspondence to: demetrios.demetriades@med.usc.edu

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

[1] Henry SM. American College of Surgeons Committee on Trauma. Student course manual ATLS ® Advanced Trauma Life Support ®. 10th edn. Chicago, IL; 2018

[2] Mayglothling J, Duane TM, Gibbs M, McCunn M, Legome E, Eastman AL, et al. Emergency tracheal intubation immediately following traumatic injury: An Eastern Association for the Surgery of Trauma practice management guideline. Journal of Trauma and Acute Care Surgery. 2012;**73**(5 Suppl. 4):S333-S340. DOI: 10.1097/TA.0b013e31827018a5

[3] Jakob DA, Lewis M, Benjamin ER, Demetriades D. Isolated traumatic brain injury: Routine intubation for Glasgow Coma Scale 7 or 8 may be harmful! Journal of Trauma and Acute Care Surgery. 2021;**90**(5):874-879. DOI: 10.1097/TA.0000000000003123

[4] Oestern HJ, Trentz O, Uranues S. General trauma care and related aspects: Trauma surgery II. New York, NY: Springer; 2013

[5] Choi J, Carlos G, Nassar AK, Knowlton LM, Spain DA. The impact of trauma systems on patient outcomes. Current Problems in Surgery. 2021;**58**(1):100849. DOI: 10.1016/j. cpsurg.2020.100849

[6] Badjatia N, Carney N, Crocco TJ, Fallat ME, Hennes HM, Jagoda AS, et al. Guidelines for prehospital management of traumatic brain injury 2nd edition. Prehospital Emergency Care. 2008;**12**(Suppl. 1):S1-S52. DOI: 10.1080/10903120701732052

[7] Spaite DW, Bobrow BJ, Keim SM, Barnhart B, Chikani V, Gaither JB, et al. Association of statewide implementation of the prehospital traumatic brain injury treatment guidelines with patient survival following traumatic brain injury: The excellence in prehospital injury care (EPIC) study. JAMA Surgery. 2019;**154**(7):e191152. DOI: 10.1001/ jamasurg.2019.1152

[8] Broderick ED, Sauerberg N, Reed JJ. EMS Pros And Cons Of Drug-Assisted Intubation. Treasure Island (FL): StatPearls; 2022

[9] Pepe PE, Roppolo LP, Fowler RL. Prehospital endotracheal intubation: Elemental or detrimental? Critical Care. 2015;**19**:121. DOI: 10.1186/ s13054-015-0808-x

[10] Teasdale G, Maas A, Lecky F, Manley G, Stocchetti N, Murray G. The Glasgow Coma Scale at 40 years: Standing the test of time. Lancet Neurology. 2014;**13**(8):844-854. DOI: 10.1016/S1474-4422(14)70120-6

[11] Rotheray KR, Cheung PS, Cheung CS, Wai AK, Chan DY, Rainer TH, et al. What is the relationship between the Glasgow coma scale and airway protective reflexes in the Chinese population? Resuscitation. 2012;**83**(1):86-89. DOI: 10.1016/j. resuscitation.2011.07.017

[12] Haltmeier T, Schnuriger B, Benjamin E, Brodmann Maeder M, Kunzler M, Siboni S, et al. Isolated blunt severe traumatic brain injury in Bern, Switzerland, and the United States: A matched cohort study. Journal of Trauma and Acute Care Surgery. 2016;**80**(2):296-301. DOI: 10.1097/ TA.0000000000000892

[13] Davis DP, Peay J, Sise MJ, Vilke GM, Kennedy F, Eastman AB, et al. The

*Prehospital and Emergency Room Airway Management in Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.104173*

impact of prehospital endotracheal intubation on outcome in moderate to severe traumatic brain injury. The Journal of Trauma. 2005;**58**(5):933-939. DOI: 10.1097/01.ta.0000162731. 53812.58

[14] Davis DP, Fakhry SM, Wang HE, Bulger EM, Domeier RM, Trask AL, et al. Paramedic rapid sequence intubation for severe traumatic brain injury: Perspectives from an expert panel. Prehospital Emergency Care. 2007;**11**(1):1-8. DOI: 10.1080/ 10903120601021093

[15] Davis DP, Peay J, Serrano JA, Buono C, Vilke GM, Sise MJ, et al. The impact of aeromedical response to patients with moderate to severe traumatic brain injury. Annals of Emergency Medicine. 2005;**46**(2):115-122. DOI: 10.1016/j. annemergmed.2005.01.024

[16] Gamberini L, Giugni A, Ranieri S, Meconi T, Coniglio C, Gordini G, et al. Early-onset ventilator-associated pneumonia in severe traumatic brain injury: Is there a relationship with prehospital airway management? The Journal of Emergency Medicine. 2019;**56**(6):657-665. DOI: 10.1016/j. jemermed.2019.02.005

[17] Bernard SA, Nguyen V, Cameron P, Masci K, Fitzgerald M, Cooper DJ, et al. Prehospital rapid sequence intubation improves functional outcome for patients with severe traumatic brain injury: A randomized controlled trial. Annals of Surgery. 2010;**252**(6):959-965. DOI: 10.1097/SLA.0b013e3181efc15f

[18] Warner KJ, Cuschieri J, Copass MK, Jurkovich GJ, Bulger EM. The impact of prehospital ventilation on outcome after severe traumatic brain injury. The Journal of Trauma. 2007;**62**(6):1330- 1336, discussion 6-8. DOI: 10.1097/ TA.0b013e31804a8032

[19] Carney N, Totten AM, Cheney T, Jungbauer R, Neth MR, Weeks C, et al. Prehospital airway management: A systematic review. Prehospital Emergency Care. 2021:1-12. DOI: 10.1080/10903127.2021.1940400

[20] Hatchimonji JS, Dumas RP, Kaufman EJ, Scantling D, Stoecker JB, Holena DN. Questioning dogma: Does a GCS of 8 require intubation? European Journal of Trauma and Emergency Surgery. 2021;**47**(6):2073-2079. DOI: 0.1007/s00068-020-01383-4

[21] Muakkassa FF, Marley RA, Workman MC, Salvator AE. Hospital outcomes and disposition of trauma patients who are intubated because of combativeness. The Journal of Trauma. 2010;**68**(6):1305-1309. DOI: 10.1097/ TA.0b013e3181dcd137

[22] Tong JL, Ashworth DR, Smith JE. Cardiovascular responses following laryngoscope assisted, fibreoptic orotracheal intubation. Anaesthesia. 2005;**60**(8):754-758. DOI: 10.1111/j. 1365-2044.2005.04238.x

[23] Robinson N, Clancy M. In patients with head injury undergoing rapid sequence intubation, does pretreatment with intravenous lignocaine/lidocaine lead to an improved neurological outcome? A review of the literature. Emergency Medicine Journal. 2001;**18**(6):453-457. DOI: 10.1136/ emj.18.6.453

[24] Svedung Wettervik T, Howells T, Hillered L, Nilsson P, Engquist H, Lewen A, et al. Mild hyperventilation in traumatic brain injury-relation to cerebral energy metabolism, pressure autoregulation, and clinical outcome. World Neurosurgery. 2020;**133**:e567-ee75. DOI: 10.1016/j.wneu.2019.09.099

[25] Cook AM, Morgan Jones G, Hawryluk GWJ, Mailloux P, McLaughlin D, Papangelou A, et al. Guidelines for the acute treatment of cerebral edema in neurocritical care patients. Neurocritical Care. 2020;**32**(3):647-666. DOI: 10.1007/ s12028-020-00959-7

[26] Langeron O, Birenbaum A, Amour J. Airway management in trauma. Minerva Anestesiologica. 2009;**75**(5):307-311

[27] Stept WJ, Safar P. Rapid inductionintubation for prevention of gastriccontent aspiration. Anesthesia and Analgesia. 1970;**49**(4):633-636

[28] Sakles JC, Chiu S, Mosier J, Walker C, Stolz U. The importance of first pass success when performing orotracheal intubation in the emergency department. Academic Emergency Medicine. 2013;**20**(1):71-78. DOI: 10.1111/ acem.12055

[29] Root CW, Mitchell OJL, Brown R, Evers CB, Boyle J, Griffin C, et al. Suction assisted laryngoscopy and airway decontamination (SALAD): A technique for improved emergency airway management. Resuscitation Plus. 2020;**1-2**:100005. DOI: 10.1016/j. resplu.2020.100005

[30] Davis DP, Hwang JQ, Dunford JV. Rate of decline in oxygen saturation at various pulse oximetry values with prehospital rapid sequence intubation. Prehospital Emergency Care. 2008;**12**(1):46-51. DOI: 10.1080/ 10903120701710470

[31] Green SM, Roback MG, Kennedy RM, Krauss B. Clinical practice guideline for emergency department ketamine dissociative sedation: 2011 update. Annals of Emergency Medicine. 2011;**57**(5):449-461. DOI: 10.1016/j. annemergmed.2010.11.030

[32] Hudetz JA, Pagel PS. Neuroprotection by ketamine: A review of the experimental and clinical evidence. Journal of Cardiothoracic and Vascular Anesthesia. 2010;**24**(1):131-142. DOI: 10.1053/j.jvca.2009.05.008

[33] Kramer N, Lebowitz D, Walsh M, Ganti L. Rapid sequence intubation in traumatic brain-injured adults. Cureus. 2018;**10**(4):e2530. DOI: 10.7759/ cureus.2530

[34] Tran DT, Newton EK, Mount VA, Lee JS, Wells GA, Perry JJ. Rocuronium versus succinylcholine for rapid sequence induction intubation. Cochrane Database of Systematic Reviews. 2015;**10**:CD002788. DOI: 10.1002/ 14651858.CD002788.pub3

[35] Weingart SD, Trueger NS, Wong N, Scofi J, Singh N, Rudolph SS. Delayed sequence intubation: A prospective observational study. Annals of Emergency Medicine. 2015;**65**(4): 349-355. DOI: 10.1016/j. annemergmed.2014.09.025

[36] Merelman AH, Perlmutter MC, Strayer RJ. Alternatives to rapid sequence intubation: Contemporary airway management with ketamine. The Western Journal of Emergency Medicine. 2019;**20**(3):466-471. DOI: 10.5811/ westjem.2019.4.42753

## **Chapter 3**

## Neuroinflammation in Traumatic Brain Injury

*Grace Y. Kuo, Fawaz Philip Tarzi, Stan Louie and Roy A. Poblete*

## **Abstract**

Neuroinflammation following traumatic brain injury (TBI) is an important cause of secondary brain injury that perpetuates the duration and scope of disease after initial impact. This chapter discusses the pathophysiology of acute and chronic neuroinflammation, providing insight into factors that influence the acute clinical course and later functional outcomes. Secondary injury due to neuroinflammation is described by mechanisms of action such as ischemia, neuroexcitotoxicity, oxidative stress, and glymphatic and lymphatic dysfunction. Neurodegenerative sequelae of inflammation, including chronic traumatic encephalopathy, which are important to understand for clinical practice, are detailed by disease type. Prominent research topics of TBI animal models and biomarkers of traumatic neuroinflammation are outlined to provide insight into the advances in TBI research. We then discuss current clinical treatments in TBI and their implications in preventing inflammation. To complete the chapter, recent research models, novel biomarkers, and future research directions aimed at mitigating TBI will be described and will highlight novel therapeutic targets. Understanding the pathophysiology and contributors of neuroinflammation after TBI will aid in future development of prophylaxis strategies, as well as more tailored management and treatment algorithms. This topic chapter is important to both clinicians and basic and translational scientists, with the goal of improving patient outcomes in this common disease.

**Keywords:** neuroinflammation, traumatic brain injury, inflammatory cytokines, metabolomics and lipidomics, blood-brain barrier, ischemia, neuronal excitotoxicity, chronic traumatic encephalopathy

## **1. Introduction**

Traumatic brain injury (TBI) remains a significant source of morbidity, mortality and increased global healthcare burden and costs. Even among survivors and those classified as having mild TBI, outcomes are often poor [1–3]. This highlights the need for continued research into understanding the pathophysiology of disease and its association with clinical outcomes.

Secondary injury after TBI is exacerbated by several biochemical processes post trauma, including inflammation [4]. Through the neuroinflammatory cascade,

traumatic injuries affect brain structure and function far beyond the acute phase, resulting in heterogeneity of TBI outcomes [5, 6]. Although the primary intent for the inflammatory response is tissue repair, collateral damage can occur if left unregulated and sustained [7]. Animal models have demonstrated that targeting neuroinflammation can alter the biologic process of injury. Unfortunately, effective pharmacological strategies to decrease inflammation in vitro still have not translated into benefit in clinical trials. Continuing research and understanding of neuroinflammation in TBI will provide important guidance into future prognostication methods and therapeutic targets.

## **2. The pathophysiology of inflammation**

While trauma such as blunt force, penetrating injury, or shearing energy, causes the primary injury in TBI, secondary injury can occur in delayed fashion. Pathologic processes that underlie secondary brain injury can persist for days to years after the initial trauma. Neuroinflammation following TBI is a principal driver of secondary injury and is characterized by complex intercellular signaling and profound histochemical changes.

## **2.1 The acute neuroinflammatory response**

Tissue and neuronal injury occurring after trauma activates the release of danger signals. Also known as damage-associated molecular pattern molecules (DAMPs), these trigger an innate immune response and inflammasome activation [6, 8]. Various intracellular molecules can act as DAMPs, including DNA, RNA, high mobility group box 1 (HMGB1), S100 proteins, adenosine triphosphate (ATP), uric acid, lysophospholipids, and lipid peroxidation-derived carbonyl adducts of proteins [9]. Early cytokines are released in damaged tissues within minutes of trauma which typically peak within the first 24 hours [6]. A classic DAMP is HMGB1, which signals through toll-like receptors 2 (TLR-2) and 4 (TLR-4) to increase cytokine production and release [8, 10]. HMGB1, a nuclear protein present in all cell types, attaches onto TLR-4 and activates the NLRP3 inflammasome complex, priming it for further inflammation in response to stressors. The activated inflammasome complex cleaves cytokine precursors such as pro-IL1ß and pro-caspase to create its active metabolite [10].

Responding to early DAMPs release, activated microglia with a pro-inflammatory phenotype release additional cytokines into the extracellular space, potentiating the neuroinflammatory response [3]. Tumor necrosis factor (TNF), and interleukins (ILs) are two primary inflammatory cytokines implicated in neuroinflammation. In animal models, an increase in IL-1β expression is seen as early as 1 hour after trauma [11, 12]. Similarly, increased TNF levels are observed in brain tissue within 17 minutes of injury in a murine model [13]; however, correlation between early cytokine levels and functional outcomes has been conflicting [6]. Studies have not been able to correlate TNF levels with raised ICPs and poor neurological outcomes [14]; TNF levels are also not a good predictor of additional neuronal injury in the immediate hours post injury [15]. Chemokines such as CXCL8 and chemoattractant molecules like CCL2 are observed to be increased in response to cytokines such as IL-1B and TNF, which are elevated after brain injury, and associated with neurological deficit after ischemia [16–19]. Further studies of these cytokines and their role in predicting TBI outcomes are still necessary to elucidate their clinical utility.

### *Neuroinflammation in Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.105178*

Apart from microglia, several other resident central nervous system (CNS) immune cells are capable of expressing cytokines to regulate post-traumatic inflammation. Neutrophils are the earliest and most abundant immune cells to enter the CNS in response to chemokines, with natural killer (NK) cells, dendritic cells and T-lymphocytes also being observed but in less abundance [8, 20]. Matrix metalloproteinases (MMPs) and reactive oxygen species (ROS) are released by neutrophils to promote cellular repair; but, in the acute post-traumatic milieu, these molecules potentiate the breakdown of the blood brain barrier (BBB), promoting migration of immune cells into the CNS, and can lead to delayed secondary hemorrhagic complications after trauma [8, 9]. Within the CNS, astrocyte activity increases within the first few days after injury, undergoing reactive gliosis. Glial fibrillary acidic protein (GFAP) is subsequently upregulated and cytokine production is increased [21]. Highlighting the importance of the inflammatory cascade in mediating secondary brain injury, GFAP levels have been correlated with clinical outcomes in TBI patients [22], and may serve as a biomarker for disease severity.

## **2.2 The role of chronic neuroinflammation in traumatic brain injury pathology**

In addition to the acute and subacute post-trauma inflammatory response, TBI survivors are prone to the development of chronic neuroinflammation that persists for years after injury [8, 23–25]. How acute inflammation transitions to a chronic pro-inflammatory state is not fully understood. Mouse models of TBI have shown that cortical inflammation persists even 30 days post injury and is associated with increased microglial activity [26, 27]. In contrast, mice with genetically depleted microglia did not display the same level of inflammatory response as their wild type counterparts, suggesting the central role of microglia in establishing chronic inflammation [28]. Microglial dysfunction and increased white matter phagocytosis is also associated with chronic neuroinflammation in TBI survivors [23]. Imaging studies in rat TBI models have demonstrated a persistent increase in BBB permeability up to 10 months post injury, and an elevation in CD68, a marker for activated microglia and macrophages, in perilesional cortical tissue up to 11 months post injury [29]. These findings suggest that monocyte extravasation from the blood and into the CNS are capable of sustaining chronic inflammation.

Chronic neuroinflammation may also involve activation of systemic inflammation. Effects of post-traumatic microglial activation can also be observed in regions distant to the brain [24, 28]. Macrophage biomarker studies have also shown chronically elevated serum TNF levels after TBI, with increased TNF levels being associated with unfavorable behavioral outcomes [30]. Plasma levels of pro-inflammatory chemokines and cytokines including interferon gamma (IFN-γ), TNF, IL-8, IL-17A, IL-9, eotaxin, macrophage inflammatory protein-1-beta (MIP-1β), and monocyte chemoattractant protein 1 (MCP-1) remain elevated for over 12 months even in patients with mild TBI with normal magnetic resonance imaging (MRI) brain imaging [31]. Chronic inflammation of both the CNS and systemically likely contributes to long-term neuropsychiatric and poor functional outcomes in post-TBI survivors and those with chronic traumatic encephalopathy (CTE). Ongoing research and expert opinion further implicate long-term systemic inflammation as underlying the etiology psychiatric, neurologic, cardiovascular, renal and liver disease, as well as cancer and metabolic syndrome (**Figure 1**) [32, 33].

**Figure 1.** *Timeline of neuroinflammation post-TBI.*

## **3. Mechanisms of secondary brain injury mediated by neuroinflammation**

Following TBI, primary injury occurs at the time of trauma as a direct result of the force transferred to the head and brain tissue. This leads to contusion, vascular injury, and axonal shearing. Secondary brain injury results from a complex TBI pathophysiology that leads to extensive and persistent neurologic structural and functional changes. While primary injury is considered irreversible, secondary brain injury is hypothetically preventable. As neuroinflammation is a central mediator of secondary brain injury, it is an important target for research and therapeutic development. Here, we describe primary pathologic processes that are associated with neuroinflammation after TBI.

#### **3.1 Increased blood-brain barrier permeability**

The BBB is formed by tightly connected cerebrovascular endothelial cells supported by astrocyte foot processes, pericytes, and basement membrane. It is highly regulated and functions as the interface between peripheral circulation and the CNS. Loss of BBB integrity after brain injury can contribute to neuronal cell death and affect the brain's response to pharmacologic therapy. The underlying structural changes leading to increased BBB permeability following TBI are not fully elucidated. Brain injury has been associated with an increase in the numbers of endothelial caveolae, leading to an increase in transcytosis of plasma proteins and a decrease in the expression of junctional adhesion and tight junction proteins [34, 35]. Under ischemic conditions, BBB integrity may be lost independent of tight junctions and occurs following endothelial swelling and disruption of the basement membrane [36, 37].

The breakdown of the BBB has been strongly linked to inflammation. Within tight junctions, upregulation of vascular endothelial growth factor-A (VEGF-A) from neutrophils and astrocytes act to reduce the expression of tight junction protein claudin-5, leading to BBB leakage [38]. In pro-inflammatory states, activated microglia and recruited neutrophils can sequester in the tissues and elaborate a network of DNA, MMPs, proteases and eicosanoids which is referred to as neutrophil

#### *Neuroinflammation in Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.105178*

extracellular traps (a process commonly termed NETosis). NETotic neutrophils release MMPs and neutrophil elastase (NE) that contribute to degradation of the extracellular matrix [39]. In parallel, microglia promote the expression of Aquaporin-4 (AQP-4), contributing to fluid shifts into the CNS [40].

Once BBB integrity is lost, the influx of peripheral neutrophils, macrophages, natural killer cells, T helper cells, and cytotoxic T cells intended to facilitate tissue repair can sustain neuroinflammation, BBB permeability, and promote secondary brain injury. Elevations of these immune cells and other inflammatory mediators are measurable following human TBI [41, 42]. Extravasation of albumin and other plasma proteins also contribute to the activation of microglia and astrocytes to trigger the release cytokines, chemokines and MMPs [41]. The formation of ROS is associated with MMP activation, resulting in further tissue damage and BBB disruption [43]. Tissue debris from both primary and secondary brain injury contain DNA, RNA, proteins and lipids that can activate TLRs and exacerbate neuroinflammation. These findings highlight the ability of inflammation to be self-propagating and dependent on BBB permeability.

The clinical impact of BBB disruption after TBI is profound. Cerebral edema is the major clinical consequence of BBB dysfunction and occurs due to the increased permeability of the BBB to protein-rich fluid and neuroinflammatory cells into the extracellular space leading to interstitial edema [38]. Cerebral edema is often symptomatic, can lead to increased intracranial pressure and reduced cerebral perfusion and oxygenation, and can be life-threatening when it results in brain compression and herniation.

#### **3.2 Ischemia and tissue hypoxia**

Ischemia and hypoxia occur after TBI for several reasons that include intracranial hypertension, reduced cerebral perfusion pressures, and abnormal cerebral autoregulation that result in the inadequate supply of oxygen-rich blood to vulnerable brain regions [44]. Independent of hemodynamics, tissue-mediated clotting and neuroinflammation promote microcirculatory failure and increased ischemic burden that may go clinically unrecognized. Neuroinflammation can directly contribute to microvascular disruption by causing endothelial dysfunction. Functionally, endothelial-dependent vasodilation is diminished after TBI due to impaired nitric oxide (NO) production from uncoupling of endothelial nitric oxide synthase (NOS) [45]. Additionally, reduced capacity for oxygen diffusion due to endothelial cell edema leads to diminished levels of brain oxygen tension in CNS tissue after TBI [46]. Structurally, the activation of MMPs and increased oxidative stress leads to the degradation of vascular basement membrane proteins which results in endothelium instability and loss of cellular integrity [47].

Other factors promote hypoxia and ischemia during neuroinflammation. Neuronal death from cellular hypoxia causes the release of pro-inflammatory cytokines and chemokines. Excess neutrophil activation exacerbates inflammation and competes with neurons for limited oxygen [48]. During NETosis, neutrophil pseudopods that adhere to the endovascular endothelium hinder microcirculatory function and further promote hypoperfusion and neutrophils adherence. Additionally, hypoxic events after TBI induce hypoxia-inducible factor -1a and nuclear factor kappa B (NF-kB) leading to prolongation of neutrophil survival time and activation [49].

The clinical implications of ischemia and tissue hypoxia are significant. A large portion of TBI patients experience ischemic-hypoxic injury [50]; however, the real ischemic burden in TBI is likely underestimated. Anoxic brain injury following TBI is strongly associated with worse functional outcomes [51]. Ischemic burden, therefore, may be an important intermediate surrogate of disease in TBI research.

#### **3.3 Neuroexcitotoxicity and energy dysfunction**

Neuroexcitotoxicity and disrupted energetics after TBI potentiate neuroinflammatory cascades. At injury onset, mechanical stretching of neurons elicits glutamateindependent neuronal activation, inhibiting the magnesium blockade of calcium channels on the cell membrane. In this environment, neurons and glial cells transition into an excessively neuroexcitatory state [52]. Secondary brain injury ensues if reduced cerebral perfusion or ischemia occur in the setting of increased metabolic demand.

Glutamate-dependent pathways are the primary drivers of neuroexcitotoxicity. Glutamate, the most abundant excitatory neurotransmitter of the CNS, contributes to the excitotoxic milieu and is released in large amounts after neuron lysis [8, 53, 54]. Animal models demonstrate an increased extracellular glutamate concentration posttrauma due to altered glutamate transport receptor function and concentration [55, 56]. The acute elevation in glutamate levels overwhelm NMDA and AMPA receptors, exacerbating neuronal injury and death. Ultimately, an influx of calcium into the cell activates apoptosis [57]. Apart from cellular effects, NMDA receptor activation induces inflammatory gene expression. Additionally, TNF and IL-1ß glutamate transporters on astrocytes interfere with glutamate clearance; together, this creates sustained excitotoxicity and inflammation [58].

The post-trauma brain is also affected by disturbed ionic homeostasis and increased energy demands from post-injury repair mechanisms. Microdialysate studies in clinical and experimental TBI models have shown increases in interstitial lactate, adenosine and a concurrent decrease in glucose, consistent with a state of metabolic crisis [59, 60]. Murine TBI models have demonstrated that both acute and delayed changes in energy metabolism occur. Increased glucose consumption and decreased ATP availability were observed on days 1 and 3 post-trauma [61]. Furthermore, mitochondrial fission is disrupted after TBI, contributing to the inability of neurons and glial cells to meet metabolic needs [62].

#### **3.4 Oxidative stress**

Oxidative stress describes a state where oxygen-derived free radicals overwhelm the scavenging antioxidant system and is closely related to metabolic dysfunction. Ischemia is an important trigger that promotes anaerobic metabolism and cellular acidosis that activates pH-dependent calcium channels [63]. Decreased cytoplasmic pH triggers increased ROS production which is ultimately involved in lipid peroxidation. Proton extrusion by microglia further exacerbates extracellular acidosis seen in TBI [64].

Post-TBI oxidative stress is regulated by microglia. Following brain injury, microglia activate nicotinamide adenine dinucleotide phosphate oxidase (NOX) and inducible nitric oxide synthase (iNOS). Upregulation of iNOS leads to the production of NO, which when coupled with superoxide, leads to the formation of peroxynitrite. The damaging role of peroxynitrite has been shown indirectly by the ability of peroxynitrite-derived free radical scavengers to attenuate brain injury in TBI [65]. NOX is present in other neuroinflammatory cells such as neutrophils and phagocytic cells, contributing to oxidative stress through the production of superoxide and hydroxyl radicals [66].

### *Neuroinflammation in Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.105178*

ROS will directly target mitochondria, impair ATP synthesis and lead to secondary injury [67]. Additionally, calcium overload in CNS mitochondria will disrupt fusion and fission, two important mechanisms essential in mitochondrial function. This promotes additional free radical formation [68]. Mitochondrial dysfunction due to oxidative stress results in functional impairment and is associated with reduced neuronal repair. Oxidative stress occurs even in mild TBI [69], with ongoing pre-clinical research investigating the effectiveness of anti-oxidant therapy in TBI [70].

## **3.5 Glymphatic and lymphatic dysfunction**

The glymphatic system is a complex transport system that facilitates the exchange of cerebrospinal (CSF) and interstitial fluid by aiding the movement of water, metabolites and immune molecules [71]. Facilitated by AQP-4 channels, glymphatics provide a drainage route for CSF and aid in the surveillance of the CNS by carrying macromolecules and activated antigen-bearing dendritic cells to local lymph nodes where antigens can be presented to activate the adaptive immune response.

TBI and neuroinflammation have been shown to impair glymphatic system drainage. In animal models, TBI dramatically impairs the paravascular influx of CSF MRI tracer, especially in the ipsilateral cortex [72]. A > 25% reduction in glymphatic solute clearance is observed after TBI [73]. Glymphatic function is dependent on AQP-4 channels localized on astrocytes. TBI-induced damage to AQP4 channels contributes glymphatic dysfunction [74]. Re-localization of AQP4 channels away from astrocytic end feet is associated with reduced waste and immune cell clearance [75, 76]. In addition to glymphatics, CNS clearance is also facilitated by lymphatic vessels lining the dura and meningeal vessels. These are rich in T and B cells that readily migrate to injured brain region [77].

Failure of glymphatic and lymphatic function will lead to the accumulation of damage and waste products such as tau, beta-amyloid, pro-inflammatory mediators, and astrocytic proteins [74]. Glial scar formation and reactive astrogliosis may also

**Figure 2.** *Conceptual schematic of neuroinflammatory Cascade.*

occur [73]. The accumulation of both immune cells and waste products triggers further neuroinflammation by activation of pattern recognition receptors on microglia. These cells and peptides have an important role in the development of neurofibrillary tangle pathology and neurodegeneration in secondary brain injury and the development of CTE (**Figure 2**) [73].

## **4. Neurodegeneration and long-term sequelae of neuroinflammation**

Neurodegeneration and chronic symptomatology occur in survivors of both single and repeated TBI, such as military personnel and contact sport athletes. Progressive symptoms long after trauma has been described as early as the 1920s [78], but the underlying pathogenesis is complex. Recent advances in research implicate chronic inflammation in the development of post-TBI neurodegenerative disease. Autopsy investigation of those who survive >1 year after TBI revealed increased amounts of CNS microglia compared to control tissue [24, 79]. Similarly, positron emission tomography (PET) imaging of professional football players showed greater levels of microglia compared to age-matched controls [80]. Here, we describe distinct pathological and clinical findings that are associated with chronic inflammation following TBI.

#### **4.1 Cerebral microhemorrhage and amyloid angiopathy**

The presence of cerebral microhemorrhage is often an indicator of traumatic axonal injury [81, 82]. Older TBI patients are particularly at risk of developing cerebral microbleeds post-TBI due to the senescent BBB having a higher permeability exacerbated by chronic neuroinflammation [83]. Cerebral amyloid angiopathy (CAA) is also a risk factor for microhemorrhage formation, as amyloid accumulation in the vessel walls, especially in the elderly, make them prone to rupture [84, 85]. Apolipoprotein E4 (ApoE4), an important regulator of chronic neuroinflammation, might play a central role. The ApoE4 allele predisposes later development of CAA in TBI survivors [86]. Further study is needed to elucidate the specific mechanism that ApoE4-mediated neuroinflammation results in CAA.

Trauma-induced microhemorrhage and CAA can occur in younger populations, especially with repetitive trauma. In a study of sport-related repetitive head trauma, athletes participating in high-risk sports had increased CAA burden in the frontal and leptomeningeal regions compared to a control population [87]. Microhemorrhage and CAA is seen in TBI survivors in their second and third decades [86, 88]. Since CAA is often a post-mortem diagnosis, the causality of trauma on CAA is still under investigation. Recently, animal models have demonstrated that increased transforming growth factor (TGF-β) expression is associated with the development of CAA after TBI [89].

#### **4.2 Dementia and other neurodegenerative diseases after brain trauma**

Early population studies have linked TBI to cognitive decline in both Alzheimer's dementia (AD) and non-Alzheimer's dementia [90–93]. More recent epidemiologic analysis suggests that TBI is significantly associated with dementia, but not AD specifically [90].

#### *Neuroinflammation in Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.105178*

Amyloid beta (Aβ) and tau-induced inflammation are important in the pathogenesis of neurodegenerative disease. A rat TBI model demonstrated that progressive atrophy and neuronal cell death continues >1 year after the trauma [94]. PET imaging studies have shown increased Aβ deposition after TBI [95]. Neuroinflammation plays a role in the pathogenesis of tau accumulation [96]. Both acute and chronic activation of the innate immune system exacerbates tau phosphorylation [96–98]. In a rat model of chronic inflammation, implantation of slow-release IL-1β pellets was associated with increased tau phosphorylation [99]. Knocking out receptors that suppress microglial activation results in an enhanced neuroinflammatory response and tau phosphorylation [100]. Conversely, immune suppression is associated with a reduction of p-tau [101]. Anti-inflammatory medications such as infliximab, an TNF-α antagonist, also reduced levels of p-tau in murine models [102]; however, in vitro application of TNF-α and IL-6 did not increase tau levels [103, 104]. Further investigation is needed to better understand the mechanisms by which inflammation after TBI promotes tau pathology.

Parkinson-like symptoms also occur after trauma, suggesting a potential α-synucleinopathy in chronic TBI survivors [105, 106]. Scientific evidence for the importance of α-synuclein pathology is less robust compared to Aβ and tauopathies. Murine models have demonstrated an increase in α-synuclein accumulation in the substantia nigra ipsilateral to the trauma. Furthermore, a notable upregulation of inflammatory cells was observed in the substantia nigra and cerebral peduncles, suggesting that inflammation mediates alpha-synucleinopathies post TBI [105].

## **4.3 Neuroinflammation in chronic traumatic encephalopathy**

Chronic traumatic encephalopathy is a syndrome of neuropsychiatric, cognitive and motor deterioration after repeated exposure to head trauma. Pathologically, CTE is a tauopathy characterized by perivascular accumulation of p-tau in neurons and astrocytes within the cortex [107]. As previously described, neuroinflammation is involved in the formation of p-tau. Immunohistologic analysis of samples from the Boston University-VA Concussion Legacy Foundation Brain Bank showed that a longer history of repeated head injury was associated with increased neuroinflammation [108]. CTE genetic transcripts from brain tissue contain dysregulated neuronal genes that result in inflammatory glial dysfunction. Furthermore, CTE astrocytes express gene transcripts that were associated with neuroinflammation and aging [109]. Autopsy investigation of mild CTE brain tissue revealed increased microglia activation in perivascular regions of subcortical white matter [106, 110, 111]. In vivo diagnostics of National Football League (NFL) athletes utilizing PET imaging revealed an increase in translocator protein expression by activated microglia and reactive astrocytes compared to controls [80, 95]. Further research is needed to elucidate the pathway and time course of inflammation and development of CTE, as well as genetic and epigenetic risk factors that increases the likelihood of CTE after head trauma.

## **5. Animal models of post-injury neuroinflammation**

The initiation and propagation of neuroinflammation is a complex and multifaceted process. Animal models are necessary to study disease mechanisms, identify novel biomarkers, and study the pharmacologic effects of investigational drugs. Given the current limited treatment options in TBI management, translational research should prioritize research that is validated, feasible and most readily will impact patient care.

#### **5.1 Selection of animals**

Several animal models have been used in TBI research. Interspecies differences in cerebral anatomy, complexity, and size are important factors when selecting the model. Animal intelligence varies significantly, although brain size is not correlated with overall intelligence [112]. Most preclinical TBI research is conducted in rodents. Rats and mice are cost-effective, have a large physiological database, permit extensive behavioral testing and have the ability to utilize transgenic animals. A disadvantage is the small lissencephalic brain, characterized by less white matter compared with higher species. In particular, the utilization of genetically engineered mice has aided in the evaluation of key molecules related to microglia activation and neuroinflammation following TBI [26].

More recently, the use of large animals in TBI research has increased. The effect of brain injury on lissencephalic animals as compared to larger ones with gyrencephalic structures differ, at least in part by differences in brain structure and mechanics related to the presence of large gyri [113, 114]. The porcine model has been proposed as an ideal pre-clinical animal model based on feasibility and the anatomic and physiologic similarities to humans in comparison to rodents [115]. This includes cortical structure and proportion of gray-to-white matter that more closely resembles humans [116]. Both mild and more severe TBI can be modeled in the pig.

#### **5.2 Models of injury**

Several models of injury have been developed to resemble the pathophysiology of human TBI [113]. The most used ones are the lateral fluid percussion (LFP) model, the controlled cortical impact (CCI) model, the weight drop-impact (WD) model, and the blast model. The chosen mechanism of injury is based on researcher experience and the type of TBI being modeled. Traumatic injury can be delivered over an intact skull to mimic concussion or diffuse injury or delivered to exposed dura to mimic more severe and focal TBI.

The CCI model was first described in the 1980s and is now one of the most used TBI models. It utilizes a pneumatic or electromechanical device with an impactor tip to induce brain displacement. The impact location, velocity, depth, and dwell time can be controlled. Compared to other methods of mechanical injury, namely LFP and WD injury, CCI allows for more control of the force of injury, showing high reproducibility, low animal mortality, and reduced rebound injury [117]. Current CCI rodent models produce the most optimal conditions for understanding the molecular, cellular and biochemical mechanisms of secondary brain injury after focal blunt-force TBI [118].

The WD and LFP models are also used to study neuroinflammation. In WD injury, a fixed amount of weight is dropped from a set height onto either exposed dura or closed skull. The closed-head model can be utilized to cause diffuse neuronal injury and has been shown to result in elevation of apoptotic and neuroinflammatory markers. The LFP model was first established in rabbit and cat models but has since been adapted for rodents. It involves the generation of a fluid pulse that impacts against an exposed dural surface of the brain and produces more diffuse injury compared to CCI. Reproducibility requires extensive preparation and model experience to minimize injury variability. The blast model mimics the injuries commonly encountered in war. The force is produced by utilizing shockwave tubes or open field detonation. This model has been utilized to study CTE and its associated neuroinflammation [119].

## **6. Biomarkers of neuroinflammation**

Plasma biomarkers of post-TBI inflammation are commonly used in translational research given their accessibility, the ability to serially sample, the presence of validated assays for detection, and the ability to form large biorepositories and databases. Brain tissue and CSF biosamples can be difficult to obtain but may offer a more accurate picture of the local environment. There has been growing interest in identifying and validating in vivo markers of neuroinflammation with special focus on using functional MRI and PET to measure intermediate biomarkers of disease.

The number of biomarkers of neuroinflammation studied is rapidly increasing [26]. No gold standard biomarker has been established. Understanding the mechanisms of expression of these markers will advance our understanding of TBI and help develop future therapeutics targeting the acute and chronic consequences of neuroinflammation. Here, we aim to introduce biomarkers of importance and emerging interest in the field of post-TBI neuroinflammation and discuss potential limitations.

## **6.1 Peptide biomarkers**

Peptide cytokines are the most used biomarkers of inflammation. In the acute period, TBI induces damage to the cellular membrane, leading to the release of DAMPs and upregulation of TNF-α and other cytokines from microglia and astrocytes. Historically, the cytokines most studied include INF-γ and several ILs. There are important limitations to consider when using cytokine biomarkers. Changes in cytokine expression can be non-specific, and their relationship with clinical outcomes is variable. TNF-α is generally considered a pro-inflammatory cytokine associated with detrimental effects in TBI [120, 121]; however, studies have suggested that it also has an anti-inflammatory component that promotes motor recovery after TBI [122]. Several studies have found limited correlation between ILs such as IL-1β and IL-6 and outcome in human TBI [123, 124]. Chemokines, generated by activated microglia and astrocytes to recruit peripheral immune cells to the site of injury, can also be assayed from biofluids. The CCL and CXCL subclasses of chemokines have been most extensively characterized in animal models of post-TBI inflammation [26]. The expression of cytokines and chemokines is regulated several ways; therefore, measurements may provide a general description of the inflammatory response post-TBI but might lack the specificity in describing specific biochemical pathways or differentiating between CNS and systemic inflammation.

More novel peptide biomarkers of interest include neurotransmitter levels and protein aggregates. Post-TBI, a large increase in the release of extracellular glutamate and other amino acids can be studied. Glutamate is an excitatory amino acid that can lead to toxic effects via activation of different receptors such as N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPA) [53, 54]. In clinical research, glutamate can be measured longitudinally using bedside microdialysis techniques [125]. Protein aggregates such as Aβ, tau and α-synuclein are challenging to measure. Historically, they have been limited to post-mortem analysis; however, recent advances in PET imaging have allowed in vivo assessment of tau burden [126].

#### **6.2 Glial and immune cells**

Microglial activation and neutrophil recruitment and activation have been of principle interest in post-TBI neuroinflammation research. Common immunohistochemical measures of microglial activation include Iba-1 and CD68 and downstream markers such as TLRs and NF-kβ [26, 127]; however, flow cytometry-based analysis of microglia remains the gold standard. The identification of translocator protein 18 kDa (TSPO), located on the mitochondrial membrane of microglia, has allowed the development of radioligands with PET visualization of activated microglia in vivo [128].

Activated neutrophils and NETosis are measured commonly by TLR4 expression, CitH3 localization, and DNase-I expression, which acts to degrade neutrophil-derived extracellular traps [129]. Measures of endothelial adhesion molecules including selectins, vascular cell adhesion molecules (VCAMs), and intercellular adhesion molecules (ICAMs) provide an indirect measurement of peripheral immune cell recruitment across the BBB. Antibodies against several of these adhesion molecules have been developed and utilized for in vivo visualization by MRI but is mostly validated in ischemic stroke models [130–132]. The longitudinal study of glial and immune cell phenotypes in chronic post-TBI inflammation may further demonstrate their importance mediating long-term morbidity after brain injury.

#### **6.3 Omics-based biomarkers**

Multi-omics, including genomics, proteomics, metabolomics and lipidomics can be used to characterize the complex chemical pathways involved in TBI pathogenesis for use in prediction models and drug development. Genetic analysis can elucidate the genetic influence on post-TBI outcomes and would allow precision treatment based on genetic traits. In analysis of a large biologic database, genetic modules that showed greatest change in expression were primarily associated with neurodevelopment and immune inflammation [133]. As previously discussed, the ApoE-4 allele is also of special interest in the field of chronic TBI-induced inflammation. ApoE protein is a mediator of cholesterol and lipid transport in the brain and has been shown to attenuate glial activation and CNS inflammatory responses. In experimental models, a small peptide of ApoE [133–149] was shown to significantly improve histological and functional outcomes following TBI [134].

Lipid biomarker analysis might hold several advantages over proteomics and peptide biomarkers in TBI. Limitations of proteomics include a bias towards highly abundant proteins, difficulty in measuring protein aggregates, and challenges in using plasma samples to assay proteins generated in the CNS [135]. In comparison, lipids are abundant in the CNS and cross the BBB by active transport. Bioactive lipids that mediate inflammation are of particular interest due to their role in both pro-inflammatory cell signaling and resolution of inflammation. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), including eicosatetraenoic acid and docosahexaenoic acid, are active compounds with anti-neuroinflammatory properties. In pro-inflammatory states, they are metabolized by lipoxygenases (e.g. 15-LOX and 5-LOX) to specialized pro-resolving lipid mediators (SPMs) such as resolvins, protectins, and maresins. In experimental models, ω-3 PUFAs act as a neuroprotectant in TBI by modulating neuroinflammation through SIRT1 mediated deacetylation of the HMGB1/NF-kb pathway [136]. A greater understanding of the biologic actions of SPMs and other

lipid signaling molecules, and the mechanisms of lipid metabolism dysregulation related to TBI would identify novel therapeutic targets.

## **7. Current therapies with anti-inflammatory properties**

Attenuating neuroinflammation following TBI has been a treatment target for several decades to generally mixed results. Certain current standard treatments potentially work through anti-inflammatory pathways, while neuroinflammation remains a focus for novel therapeutic development.

### **7.1 Steroidal and non-steroidal anti-inflammatory drugs**

Steroids are not routinely used in the management of TBI. They were initially investigated for their potential to decrease neuroinflammation and intracranial pressure in severe TBI. Several randomized trials were conducted with conflicting results. The CRASH trial, a randomized placebo-controlled multicentric trial evaluated the use of high dose methylprednisolone after TBI. Interim analysis of the first 10,008 patients demonstrated increased mortality in patients receiving steroids, resulting in early study closure [137]. The mechanisms of harm are not fully understood; however, there is little interest in a future study of the effect of high-dose steroids in TBI.

The use of non-steroidal anti-inflammatory drugs (NSAIDs), such as COX-1 and COX-2 inhibitors ibuprofen and indomethacin, have shown varied results in pre-clinical studies. Although a strong anti-inflammatory action is observed if dosed shortly before or after injury, clinical effect has not been demonstrated [138]. Ibuprofen can cross the BBB and localize in injured tissues and has been studied as an anti-inflammatory agent in post-TBI stem cell grafting [139]. In a rat model of TBI, extended use of high dose ibuprofen significantly worsened neurocognitive outcomes [140]. Indomethacin administration is associated with reduced intracranial pressure secondary to reduced CBF [141], however, it has limited therapeutic potential due to its inability to cross the BBB [142]. Additional concerns over bleeding due to inhibition of platelet cyclooxygenase further limit their use acutely after TBI.

Minocycline, a second-generation tetracycline antibiotic, has been extensively studied in TBI due to its anti-inflammatory, neuroprotective and anti-apoptotic properties [143]. In a murine model, minocycline administration resulted in marked reductions of activated microglia and decreased tissue IL-1B levels [144]. In a gerbil model, when administered shortly after ischemia, minocycline was neuroprotective against brain ischemia by preventing activation of microglia and the appearance of NADPH reactive cells [145]. A clinical trial of 15 patients, performed to assess the safety and feasibility of minocycline showed that it was safe for moderate-to-severe TBI with a potential effect on clinical outcomes [146]; however, long-term use may be associated with gastrointestinal and neurologic adverse events [147]. The current use of minocycline is limited due to the lack of large longitudinal clinical evidence to support its use for TBI-related neuroinflammation.

### **7.2 Anti-epileptic drugs**

Seizures are a common consequence of TBI. Their occurrence is associated with worse functional outcomes and if uncontrolled, can contribute to long-term neurodegeneration [148]. Neuroinflammation has been proposed as a mechanistic cause of seizures post-TBI. Pro-inflammatory cytokines like TNF-α and IL-1β can lead to hyperexcitability through their action on glutamate and NMDA receptors, increasing susceptibility to seizures [149]. Classical anti-epileptics such as phenytoin and benzodiazepines have not been shown to reduce the risk of developing late post-traumatic epilepsy but rather decrease the early post-traumatic seizures occurring within the first 7 days [150]. Whether anti-epileptic drugs are generally pro-inflammatory or anti-inflammatory is still not verified. Levetiracetam interestingly has been found to mediate its anti-epileptogenic effects, at least partially, through modulation of inflammation in seizing brain regions. This was demonstrated by the reduction of reactive gliosis and IL-1β following administration of levetiracetam in epileptic animals [151]. In comparison, an in vitro model of epilepsy showed increased microglial activation in cultures treated with valproic acid when compared to carbamazepine, gabapentin, and phenytoin [152].

## **7.3 Hyperosmolar fluids**

Hyperosmolar therapy is widely used to treat TBI-related cerebral edema and elevated intracranial pressure. The early action is primarily due to the creation of an osmotic gradient that draws interstitial fluid from the brain tissue into the intravascular space. Hyperosmolar therapies, typically hypertonic saline or mannitol, have been investigated for their anti-inflammatory properties. In a rat model of intracerebral hemorrhage, hyperosmolar fluid reduced microglial activation and promoted phagocytic anti-inflammatory M2-like phenotype in perihematomal and contralateral tissues [153]. In a clinical study of 65 patients with severe TBI, hypertonic saline was found to attenuate expression of pro-inflammatory cytokines such as TNF-α and IL-10 [154]. Additionally, hyperosmolar therapy was found to downregulate AQP-4 expression in perivascular astrocytes [155]. These findings add further support to hyperosmolar therapy for their neuroinflammatory modulation.

In clinical practice, bolus doses of hyperosmolar therapy are standard of care for clinical or radiographic cerebral herniation; however, the use of continuous hypertonic saline infusion after TBI remains controversial with a recent randomized controlled trial showing no benefit of this therapy on 6-month functional outcomes [156]. Further study is needed to determine the anti-inflammatory properties of hyperosmolar therapy, and which patients are most likely to benefit from treatment.

## **7.4 Tranexamic acid**

Tranexamic acid (TXA) is a lysine analogue that is widely studied as an antifibrinolytic in life-threatening hemorrhage. In TBI, TXA is more widely accepted and used based on recent clinical trial data. The CRASH 3 trial demonstrated that TXA reduces head injury-related deaths without increasing the thrombotic risk [157]. TXA has been shown to have both pro-inflammatory and anti-inflammatory effects in the surgical literature [158, 159]. In animal models, it inhibits plasmin which normally activates the migration of macrophages through modulation of BBB integrity by degrading laminin, fibronectin, and collagen [160]. Specifically in models of TBI, early TXA has been shown to reduce TBI-induced coagulopathy. Reduced bleeding and blood products in the CNS might limit pro-inflammatory triggering. TXA may generally suppress circulating immune cells; however, measurable reductions in antiinflammatory markers were not observed in a mouse model of TBI [161]. Although

TXA is approved to be safe and well-studied in TBI, its full impact on neuroinflammation has not been validated.

## **7.5 Hypothermia**

Hypothermia has been investigated in several acute neurological conditions. In TBI, humoral and cellular neuroinflammation is temperature-dependent. In preclinical trials, hypothermia has been shown to decrease free radicals, TNF-α mRNA levels, and BBB permeability [162]. Several clinical trials of hypothermia have been done in TBI, with overall low-quality evidence. A meta-analysis in 2014 suggested a possible trend towards reduced rates of death, vegetative state, and disability with hypothermia [163]; however, the report was inconclusive. Larger clinical trials are needed to assess the efficacy and safety of hypothermia in reducing neuroinflammation in TBI and improving clinical outcomes.

## **8. Future research directions**

Advances in novel therapies that target neuroinflammation after TBI has been limited by an incomplete understanding of the pathologic mechanisms of disease. Translational and clinical research is needed to further identify both modifiable and non-modifiable factors that influence the inflammatory response, and how acute neuroinflammation after brain injury transitions to a chronic inflammatory state. Characterizing both acute and chronic processes will lead to biomarker discovery and support the development of novel therapeutic agents aimed at improving long-term patient outcomes.

## **8.1 Determining how biologic factors modify the inflammatory response post-injury**

Non-modifiable biologic factors such as age, sex, and ethnicity likely influence the post-TBI inflammatory response. A better understanding of these effects will improve patient-tailored treatments. In animal models, age appears to exacerbate inflammatory-mediated secondary brain injury. In comparison to younger animals, aged rodents show higher mortality after CCI, more pronounced brain edema formation, and worse neurobehavioral scores [164]. This was associated with an early rise of inflammatory markers in aged animals compared to the delayed response observed in younger mice. Peripherally derived CCR2(+) macrophages accumulate in greater amounts in aged brains after TBI compared to young animals and likely mediate the enhanced neuroinflammatory response associated with age [165]; however, the role of other immune cells has been suggested [166]. Ketone metabolism, which improves energetics and reduces inflammation, is reduced in older age [167, 168]. Additional research is necessary to fully describe the age-dependent effects of TBI and how age influences the efficacy of candidate drugs.

Although the majority of TBI occurs in males, sex-based differences in TBI pathophysiology and outcomes should be understood. Elevations in endogenous sex hormones, specifically progesterone and allopregnanolone, have been demonstrated to have anti-inflammatory and neuroprotective properties [169]. Sex steroids are also known to regulate astrogliosis and microglia activation and may account for sex differences [170]. Investigational drugs, including steroids, likely have differential impact

in men and women, highlighting the need to study efficacy in diverse patient populations. Although many identified differences in physiology between sexes exist, the literature of the impact of sex on functional outcomes after TBI is conflicting [171].

#### **8.2 Important research questions for novel therapeutic approaches**

Despite the large body of anti-inflammatory drugs studied in both preclinical and clinical research [172], their standard use in human TBI has not yet been supported by high-quality evidence. Many important questions remain, including the identification of drugs that should be prioritized for clinical trials. Candidate drugs or anti-inflammatory drug classes may not be mutually exclusive and could have a synergistic effect when used together. In animal models, combination of progesterone and vitamin D, fresh frozen plasma and valproic acid, and C3a and C5a receptor blockers demonstrated greater anti-inflammatory and neuroprotective effects then when used individually [173–175]. The optimal timing and duration of potential treatments are also unknown. Given both the acute and chronic inflammatory phases of TBI contribute to functional outcomes, future study is needed to determine the utility of anti-inflammatory drugs administered beyond the acute phase.

Both short and long-term outcome measures are necessary to establish the efficacy of novel therapies. In pre-clinical research, measures of inflammatory cytokines are insufficient to characterize the complex pathogenesis of TBI. Of emerging interest, use of "omics" that encompass genomics, proteomics, metabolomics and lipidomics will provide a comprehensive picture of the molecular pathways leading to secondary brain injury and would allow for precision medicine [176]. Given the chronic morbidity in TBI survivors, the use of long-term outcomes, including biomarkers of neurodegeneration and neurocognitive and functional outcomes are needed in both animal models and clinical trials. Demonstrating reduced mortality in TBI can be difficult, especially in moderate-to-severe TBI where outcomes are generally poor, while alternative outcome measures described may be more sensitive and meaningful.

TBI is a ubiquitous disease impacting all ages, genders, racial, socioeconomic and geographic backgrounds. Preferred drug therapies should be safe, feasible and effective across mixed patient populations and medical environments. Behavioral modifications may play a role in attenuating sequelae of neuroinflammation. Complementary therapies such as meditation and massage may reduce inflammation [177], while dietary changes can also impact chronic inflammation [178, 179]. Ultimately, a multi-disciplinary and systems-based approach to TBI is needed to further our understanding of this challenging disease and promote the development of novel treatment approaches.

#### **8.3 Conclusion**

In conclusion, post-TBI neuroinflammation is a complex blend of processes that is involved in acute and chronic brain injury. Although it is intended to promote repair, ongoing neuroinflammation can impede recovery. The inflammatory cascade in TBI affects the CNS milieu and brain functions long after the initial traumatic phase. Although pre-clinical research suggests that treating neuroinflammation as a therapeutic target may be beneficial, clinical trials have not yielded measurable benefits. Understanding the intricacy of these processes will assist clinicians and scientists in creating an individualistic approach to monitor and limit inflammation after TBI with the goal to reduce secondary brain injury, enhance neurological repair, and improve patient outcomes.

*Neuroinflammation in Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.105178*

## **Author details**

Grace Y. Kuo1 \*, Fawaz Philip Tarzi1 , Stan Louie2 and Roy A. Poblete1

1 Department of Neurology, Keck School of Medicine of the University of Southern California, United States

2 Department of Clinical Pharmacy, University of Southern California School of Pharmacy, United States

\*Address all correspondence to: grace.kuo@med.usc.edu

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

[1] CDC. TBI Data | Concussion | Traumatic Brain Injury | CDC Injury Center. 2021. Available from: https:// www.cdc.gov/traumaticbraininjury/ data/index.html

[2] Haarbauer-Krupa J, Pugh MJ, Prager EM, Harmon N, Wolfe J, Yaffe K. Epidemiology of chronic effects of traumatic brain injury. Journal of Neurotrauma. 2021;**38**(23):3235-3247

[3] Xiong Y, Mahmood A, Chopp M. Current understanding of neuroinflammation after traumatic brain injury and cell-based therapeutic opportunities. Chinese Journal of Traumatology. 2018;**21**(3):137-151

[4] Jassam YN, Izzy S, Whalen M, McGavern DB, El Khoury J. Neuroimmunology of traumatic brain injury: Time for a paradigm shift. Neuron. 2017;**95**(6):1246-1265

[5] Pagulayan KF, Temkin NR, Machamer J, Dikmen SS. A longitudinal study of health-related quality of life after traumatic brain injury. Archives of Physical Medicine and Rehabilitation. 2006;**87**(5):611-618

[6] Woodcock T, Morganti-Kossmann MC. The role of markers of inflammation in traumatic brain injury. Frontiers in Neurology. 2013;**4**:18

[7] Finnie JW. Neuroinflammation: Beneficial and detrimental effects after traumatic brain injury. Inflammopharmacology. 2013;**21**(4):309-320

[8] Simon DW, McGeachy M, Bayır H, Clark RSB, Loane DJ, Kochanek PM. Neuroinflammation in the evolution of secondary injury, repair, and chronic

neurodegeneration after traumatic brain injury. Nature Reviews Neurology. 2017;**13**(3):171-191

[9] Corps KN, Roth TL, McGavern DB. Inflammation and neuroprotection in traumatic brain injury. JAMA Neurology. 2015;**72**(3):355-362

[10] Frank MG, Weber MD, Watkins LR, Maier SF. Stress sounds the alarmin: The role of the danger-associated molecular pattern HMGB1 in stressinduced neuroinflammatory priming. Brain, Behavior, and Immunity. 2015;**48**:1-7

[11] Fan L, Young PR, Barone FC, Feuerstein GZ, Smith DH, McIntosh TK. Experimental brain injury induces expression of interleukin-1 beta mRNA in the rat brain. Brain Research. Molecular Brain Research. 1995;**30**(1):125-130

[12] Kamm K, Vanderkolk W, Lawrence C, Jonker M, Davis AT. The effect of traumatic brain injury upon the concentration and expression of interleukin-1beta and interleukin-10 in the rat. The Journal of Trauma. 2006;**60**(1):152-157

[13] Frugier T, Morganti-Kossmann MC, O'Reilly D, McLean CA. In situ detection of inflammatory mediators in post mortem human brain tissue after traumatic injury. Journal of Neurotrauma. 2010;**27**(3):497-507

[14] Shiozaki T, Hayakata T, Tasaki O, Hosotubo H, Fuijita K, Mouri T, et al. Cerebrospinal fluid concentrations of anti-inflammatory mediators in earlyphase severe traumatic brain injury. Shock. 2005;**23**(5):406-410

*Neuroinflammation in Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.105178*

[15] Hayakata T, Shiozaki T, Tasaki O, Ikegawa H, Inoue Y, Toshiyuki F, et al. Changes in CSF S100B and cytokine concentrations in early-phase severe traumatic brain injury. Shock. 2004;**22**(2):102-107

[16] Kasahara T, Mukaida N, Yamashita K, Yagisawa H, Akahoshi T, Matsushima K. IL-1 and TNF-alpha induction of IL-8 and monocyte chemotactic and activating factor (MCAF) mRNA expression in a human astrocytoma cell line. Immunology. 1991;**74**(1):60-67

[17] Semple BD, Kossmann T, Morganti-Kossmann MC. Role of chemokines in CNS health and pathology: A focus on the CCL2/CCR2 and CXCL8/CXCR2 networks. Journal of Cerebral Blood Flow and Metabolism. 2010;**30**(3):459-473

[18] Taupin V, Toulmond S, Serrano A, Benavides J, Zavala F. Increase in IL-6, IL-1 and TNF levels in rat brain following traumatic lesion. Influence of pre- and post-traumatic treatment with Ro5 4864, a peripheral-type (p site) benzodiazepine ligand. Journal of Neuroimmunology. 1993;**42**(2):177-185

[19] Chen Y, Hallenbeck JM, Ruetzler C, Bol D, Thomas K, Berman NE, et al. Overexpression of monocyte chemoattractant protein 1 in the brain exacerbates ischemic brain injury and is associated with recruitment of inflammatory cells. Journal of Cerebral Blood Flow and Metabolism. 2003;**23**(6):748-755

[20] Clark RS, Schiding JK, Kaczorowski SL, Marion DW, Kochanek PM. Neutrophil accumulation after traumatic brain injury in rats: Comparison of weight drop and controlled cortical impact models. Journal of Neurotrauma. 1994;**11**(5):499-506

[21] Burda JE, Bernstein AM, Sofroniew MV. Astrocyte roles in traumatic brain injury. Experimental Neurology. 2016;**275**(Pt 3):305-315

[22] Wang KK, Yang Z, Zhu T, Shi Y, Rubenstein R, Tyndall JA, et al. An update on diagnostic and prognostic biomarkers for traumatic brain injury. Expert Review of Molecular Diagnostics. 2018;**18**(2):165-180

[23] Gentleman SM, Leclercq PD, Moyes L, Graham DI, Smith C, Griffin WST, et al. Long-term intracerebral inflammatory response after traumatic brain injury. Forensic Science International. 2004;**146**(2-3):97-104

[24] Johnson VE, Stewart JE, Begbie FD, Trojanowski JQ, Smith DH, Stewart W. Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Brain (London, England : 1878). 2013;**136**(Pt 1):28-42

[25] Ramlackhansingh AF, Brooks DJ, Greenwood RJ, Bose SK, Turkheimer FE, Kinnunen KM, et al. Inflammation after trauma: Microglial activation and traumatic brain injury. Annals of Neurology. 2011;**70**(3):374-383

[26] Chiu C-C, Liao Y-E, Yang L-Y, Wang J-Y, Tweedie D, Karnati HK, et al. Neuroinflammation in animal models of traumatic brain injury. Journal of Neuroscience Methods. 2016;**272**:38-49

[27] Loane DJ, Kumar A, Stoica BA, Cabatbat R, Faden AI. Progressive neurodegeneration after experimental brain trauma: Association with chronic microglial activation. Journal of Neuropathology and Experimental Neurology. 2014;**73**(1):14-29

[28] Witcher KG, Bray CE, Chunchai T, Zhao F, O'Neil SM, Gordillo AJ, et al. Traumatic brain injury causes chronic cortical inflammation and neuronal dysfunction mediated by microglia. The Journal of Neuroscience. 2021;**41**(7):1597-1616

[29] van Vliet EA, Ndode-Ekane XE, Lehto LJ, Gorter JA, Andrade P, Aronica E, et al. Long-lasting bloodbrain barrier dysfunction and neuroinflammation after traumatic brain injury. Neurobiology of Disease. 2020;**145**:105080

[30] Juengst SB, Kumar RG, Arenth PM, Wagner AK. Exploratory associations with tumor necrosis factor-α, disinhibition and suicidal endorsement after traumatic brain injury. Brain, Behavior, and Immunity. 2014;**41**:134-143

[31] Chaban V, Clarke GJB, Skandsen T, Islam R, Einarsen CE, Vik A, et al. Systemic inflammation persists the first year after mild traumatic brain injury: Results from the prospective trondheim mild traumatic brain injury study. Journal of Neurotrauma. 2020;**37**(19):2120-2130

[32] Bauer ME, Teixeira AL. Inflammation in psychiatric disorders: What comes first? Annals of the New York Academy of Sciences. 2019;**1437**(1):57-67

[33] Furman D, Campisi J, Verdin E, Carrera-Bastos P, Targ S, Franceschi C, et al. Chronic inflammation in the etiology of disease across the life span. Nature Medicine. 2019;**25**(12):1822-1832

[34] Nag S, Manias JL, Stewart DJ. Expression of endothelial phosphorylated caveolin-1 is increased in brain injury. Neuropathology and Applied Neurobiology. 2009;**35**(4):417-426

[35] Yeung D, Manias JL, Stewart DJ, Nag S. Decreased junctional adhesion molecule—A expression during blood–brain barrier breakdown. Acta Neuropathologica. 2008;**115**(6):635-642

[36] Krueger M, Bechmann I, Immig K, Reichenbach A, Hartig W, Michalski D. Blood-brain barrier breakdown involves four distinct stages of vascular damage in various models of experimental focal cerebral ischemia. Journal of Cerebral Blood Flow and Metabolism. 2015;**35**(2):292-303

[37] Krueger M, Hartig W, Reichenbach A, Bechmann I, Michalski D. Blood-brain barrier breakdown after embolic stroke in rats occurs without ultrastructural evidence for disrupting tight junctions. PLoS One. 2013;**8**(2):e56419

[38] Argaw AT, Gurfein BT, Zhang Y, Zameer A, John GR. VEGF-mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown. Proceedings of the National Academy of Sciences. 2009;**106**(6):1977-1982

[39] Yang H, Biermann MH, Brauner JM, Liu Y, Zhao Y, Herrmann M. New insights into neutrophil extracellular traps: Mechanisms of formation and role in inflammation. Frontiers in Immunology. 2016;**7**:302

[40] Neri M, Frati A, Turillazzi E, Cantatore S, Cipolloni L, Di Paolo M, et al. Immunohistochemical evaluation of Aquaporin-4 and its correlation with CD68, IBA-1, HIF-1alpha, GFAP, and CD15 expressions in fatal traumatic brain injury. International Journal of Molecular Sciences. 2018;**19**(11):3544

[41] Corrigan F, Mander KA, Leonard AV, Vink R. Neurogenic inflammation after traumatic brain injury and its

*Neuroinflammation in Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.105178*

potentiation of classical inflammation. Journal of Neuroinflammation. 2016;**13**(1):264

[42] Holmin S, Söderlund J, Biberfeld P, Mathiesen T. Intracerebral inflammation after human brain contusion. Neurosurgery. 1998;**42**(2):291-298

[43] Ranaivo HR, Hodge JN, Choi N, Wainwright MS. Albumin induces upregulation of matrix metalloproteinase-9 in astrocytes via MAPK and reactive oxygen speciesdependent pathways. Journal of Neuroinflammation. 2012;**9**(1):645

[44] Rangel-Castilla L, Gasco J, Nauta HJW, Okonkwo DO, Robertson CS. Cerebral pressure autoregulation in traumatic brain injury. Neurosurgical Focus. 2008;**25**(4):E7-EE

[45] Villalba N, Sackheim AM, Nunez IA, Hill-Eubanks DC, Nelson MT, Wellman GC, et al. Traumatic brain injury causes endothelial dysfunction in the systemic microcirculation through Arginase-1-dependent uncoupling of endothelial nitric oxide synthase. Journal of Neurotrauma. 2017;**34**(1):192-203

[46] Schilte C, Bouzat P, Millet A, Boucheix P, Pernet-Gallay K, Lemasson B, et al. Mannitol improves brain tissue oxygenation in a model of diffuse traumatic brain injury. Critical Care Medicine. 2015;**43**(10):2212-2218

[47] Abdul-Muneer PM, Chandra N, Haorah J. Interactions of oxidative stress and neurovascular inflammation in the pathogenesis of traumatic brain injury. Molecular Neurobiology. 2015;**51**(3):966-979

[48] Liu Y-W, Li S, Dai S-S. Neutrophils in traumatic brain injury (TBI): Friend or foe? Journal of Neuroinflammation. 2018;**15**(1):146

[49] Walmsley SR, Print C, Farahi N, Peyssonnaux C, Johnson RS, Cramer T, et al. Hypoxia-induced neutrophil survival is mediated by HIF-1α– dependent NF-κB activity. Journal of Experimental Medicine. 2005;**201**(1):105-115

[50] Padayachy LC, Rohlwink U, Zwane E, Fieggen G, Peter JC, Figaji AA. The frequency of cerebral ischemia/ hypoxia in pediatric severe traumatic brain injury. Child's Nervous System. 2012;**28**(11):1911-1918

[51] Cullen NK, Crescini C, Bayley MT. Rehabilitation outcomes after anoxic brain injury: A case-controlled comparison with traumatic brain injury. PM&R. 2009;**1**(12):1069-1076

[52] Tehse J, Taghibiglou C. The overlooked aspect of excitotoxicity: Glutamate-independent excitotoxicity in traumatic brain injuries. European Journal of Neuroscience. 2019;**49**(9):1157-1170

[53] Palmer AM, Marion DW, Botscheller ML, Bowen DM, DeKosky ST. Increased transmitter amino acid concentration in human ventricular CSF after brain trauma. Neuroreport. 1994;**6**(1):153-156

[54] Ruppel RA, Kochanek PM, Adelson PD, Rose ME, Wisniewski SR, Bell MJ, et al. Excitatory amino acid concentrations in ventricular cerebrospinal fluid after severe traumatic brain injury in infants and children: The role of child abuse. The Journal of Pediatrics. 2001;**138**(1):18-25

[55] Dorsett CR, McGuire JL, Niedzielko TL, DePasquale EAK, Meller J, Floyd CL, et al. Traumatic brain injury induces alterations in cortical glutamate uptake without a reduction in glutamate

transporter-1 protein expression. Journal of Neurotrauma. 2017;**34**(1):220-234

[56] Pajarillo E, Rizor A, Lee J, Aschner M, Lee E. The role of astrocytic glutamate transporters GLT-1 and GLAST in neurological disorders: Potential targets for neurotherapeutics. Neuropharmacology. 2019;**161**:107559

[57] Baracaldo-Santamaría D, Ariza-Salamanca DF, Corrales-Hernández MG, Pachón-Londoño MJ, Hernandez-Duarte I, Calderon-Ospina C-A. Revisiting excitotoxicity in traumatic brain injury: From bench to bedside. Pharmaceutics. 2022;**14**(1):152

[58] Viviani B, Boraso M, Marchetti N, Marinovich M. Perspectives on neuroinflammation and excitotoxicity: A neurotoxic conspiracy? Neurotoxicology. 2014;**43**:10-20

[59] Faroqi AH, Lim MJ, Kee EC, Lee JH, Burgess JD, Chen R, et al. In vivo detection of extracellular adenosine triphosphate in a mouse model of traumatic brain injury. Journal of Neurotrauma. 2021;**38**(5):655-664

[60] Marklund N, Salci K, Ronquist G, Hillered L. Energy metabolic changes in the early post-injury period following traumatic brain injury in rats. Neurochemical Research. 2006;**31**(8):1085-1093

[61] Buczek M, Alvarez J, Azhar J, Zhou Y, Lust WD, Selman WR, et al. Delayed changes in regional brain energy metabolism following cerebral concussion in rats. Metabolic Brain Disease. 2002;**17**(3):153-167

[62] Fischer TD, Hylin MJ, Zhao J, Moore AN, Waxham MN, Dash PK. Altered mitochondrial dynamics and TBI pathophysiology. Frontiers in Systems Neuroscience. 2016;**10**:29

[63] Angeloni C, Prata C, Vieceli Dalla Sega F, Piperno R, Hrelia S. Traumatic brain injury and NADPH oxidase: A deep relationship. Oxidative Medicine and Cellular Longevity. 2015;**2015**:1-10

[64] Ritzel RM, He J, Li Y, Cao T, Khan N, Shim B, et al. Proton extrusion during oxidative burst in microglia exacerbates pathological acidosis following traumatic brain injury. Glia. 2021;**69**(3):746-764

[65] Deng-Bryant Y, Singh IN, Carrico KM, Hall ED. Neuroprotective effects of tempol, a catalytic scavenger of peroxynitrite-derived free radicals, in a mouse traumatic brain injury model. Journal of Cerebral Blood Flow & Metabolism. 2008;**28**(6):1114-1126

[66] Cooney SJ, Bermudez-Sabogal SL, Byrnes KR. Cellular and temporal expression of NADPH oxidase (NOX) isotypes after brain injury. Journal of Neuroinflammation. 2013;**10**(1):917

[67] Uzhachenko R, Boyd K, Olivares-Villagomez D, Zhu Y, Goodwin JS, Rana T, et al. Mitochondrial protein Fus1/Tusc2 in premature aging and age-related pathologies: Critical roles of calcium and energy homeostasis. Aging. 2017;**9**(3):627-649

[68] Magenta A, Dellambra E, Ciarapica R, Capogrossi MC. Oxidative stress, microRNAs and cytosolic calcium homeostasis. Cell Calcium. 2016;**60**(3):207-217

[69] Petronilho F, Feier G, de Souza B, Guglielmi C, Constantino LS, Walz R, et al. Oxidative stress in brain according to traumatic brain injury intensity. The Journal of Surgical Research. 2010;**164**(2):316-320

[70] Hakiminia B, Alikiaii B, Khorvash F, Mousavi S. Oxidative stress and mitochondrial dysfunction

*Neuroinflammation in Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.105178*

following traumatic brain injury: From mechanistic view to targeted therapeutic opportunities. Fundamental & Clinical Pharmacology. 2022;**36**(4):612-662

[71] Rasmussen MK, Mestre H, Nedergaard M. The glymphatic pathway in neurological disorders. The Lancet Neurology. 2018;**17**(11):1016-1024

[72] Yang L, Kress BT, Weber HJ, Thiyagarajan M, Wang B, Deane R, et al. Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer. Journal of Translational Medicine. 2013;**11**(1):107

[73] Iliff JJ, Chen MJ, Plog BA, Zeppenfeld DM, Soltero M, Yang L, et al. Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. The Journal of Neuroscience. 2014;**34**(49):16180-16193

[74] Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Science Translational Medicine. 2012;**4**(147):147ra111

[75] Iliff JJ, Lee H, Yu M, Feng T, Logan J, Nedergaard M, et al. Brain-wide pathway for waste clearance captured by contrastenhanced MRI. Journal of Clinical Investigation. 2013;**123**(3):1299-1309

[76] Taoka T, Masutani Y, Kawai H, Nakane T, Matsuoka K, Yasuno F, et al. Evaluation of glymphatic system activity with the diffusion MR technique: Diffusion tensor image analysis along the perivascular space (DTI-ALPS) in Alzheimer's disease cases. Japanese Journal of Radiology. 2017;**35**(4):172-178

[77] Utagawa A, Truettner JS, Dietrich WD, Bramlett HM. Systemic inflammation exacerbates behavioral and histopathological consequences of isolated traumatic brain injury in rats. Experimental Neurology. 2008;**211**(1):283-291

[78] Faden AI, Loane DJ. Chronic neurodegeneration after traumatic brain injury: Alzheimer disease, chronic traumatic encephalopathy, or persistent neuroinflammation? Neurotherapeutics. 2014;**12**(1):143-150

[79] Smith C, Gentleman SM, Leclercq PD, Murray LS, Griffin WS, Graham DI, et al. The neuroinflammatory response in humans after traumatic brain injury. Neuropathology and Applied Neurobiology. 2013;**39**(6):654-666

[80] Coughlin JM, Wang Y, Minn I, Bienko N, Ambinder EB, Xu X, et al. Imaging of glial cell activation and white matter integrity in brains of active and recently retired national football league players. JAMA Neurology. 2017;**74**(1):67-74

[81] Glushakova OY, Johnson D, Hayes RL. Delayed increases in microvascular pathology after experimental traumatic brain injury are associated with prolonged inflammation, blood-brain barrier disruption, and progressive white matter damage. Journal of Neurotrauma. 2014;**31**(13):1180-1193

[82] Liu J, Kou Z, Tian Y. Diffuse axonal injury after traumatic cerebral microbleeds: An evaluation of imaging techniques. Neural Regeneration Research. 2014;**9**(12):1222-1230

[83] Irimia A, Van Horn JD, Vespa PM. Cerebral microhemorrhages due to traumatic brain injury and their effects on the aging human brain. Neurobiology of Aging. 2018;**66**:158-164

[84] Dada MA, Rutherfoord GS. Medicolegal aspects of cerebral amyloid angiopathy. A case report. The American Journal of Forensic Medicine and Pathology. 1993;**14**(4):319-322

[85] Wakui K, Seguchi K, Kuroyanagi T, Sakai T, Tanaka Y, Kamijoh Y, et al. Multiple intracerebral hemorrhages due to cerebral amyloid angiopathy after head trauma. No Shinkei Geka. 1988;**16**(11):1287-1291

[86] Leclercq PD, Murray LS, Smith C, Graham DI, JaR N, Gentleman SM. Cerebral amyloid angiopathy in traumatic brain injury: Association with apolipoprotein E genotype. Journal of Neurology, Neurosurgery, and Psychiatry. 2005;**76**(2):229-233

[87] Standring OJ, Friedberg J, Tripodis Y, Chua AS, Cherry JD, Alvarez VE, et al. Contact sport participation and chronic traumatic encephalopathy are associated with altered severity and distribution of cerebral amyloid angiopathy. Acta Neuropathologica. 2019;**138**(3):401-413

[88] Nakayama Y, Mineharu Y, Arawaka Y, Nishida S, Tsuji H, Miyake H, et al. Cerebral amyloid angiopathy in a young man with a history of traumatic brain injury: A case report and review of the literature. Acta Neurochirurgica. 2016;**159**(1):15-18

[89] Wyss-Coray T, Masliah E, Mallory M, McConlogue L, Johnson-Wood K, Lin C, et al. Amyloidogenic role of cytokine TGF-beta1 in transgenic mice and in Alzheimer's disease. Nature. 1997;**389**(6651):603-606

[90] Wang H-K, Lin S-H, Sung P-S, Wu M-H, Hung K-W, Wang L-C, et al. Population based study on patients with traumatic brain injury suggests increased risk of dementia. Journal of Neurology,

Neurosurgery, and Psychiatry. 2012;**83**(11):1080-1085

[91] Mortimer JA, van Duijn CM, Chandra V, Fratiglioni L, Graves AB, Heyman A, et al. Head trauma as a risk factor for Alzheimer's disease: A collaborative re-analysis of casecontrol studies. EURODEM risk factors research group. International Journal of Epidemiology. 1991;**20**(Suppl. 2):S28-S35

[92] Guo Z, Cupples LA, Kurz A, Auerbach SH, Volicer L, Chui H, et al. Head injury and the risk of AD in the MIRAGE study. Neurology. 2000;**54**(6):1316-1323

[93] Lee YK, Hou SW, Lee CC, Hsu CY, Huang YS, Su YC. Increased risk of dementia in patients with mild traumatic brain injury: A nationwide cohort study. PLoS One. 2013;**8**(5):e62422

[94] Smith DH, Chen XH, Pierce JE, Wolf JA, Trojanowski JQ, Graham DI, et al. Progressive atrophy and neuron death for one year following brain trauma in the rat. Journal of Neurotrauma. 1997;**14**(10):715-727

[95] Hong YT, Veenith T, Dewar D, Outtrim JG, Mani V, Williams C, et al. Amyloid imaging with carbon 11–Labeled Pittsburgh compound B for traumatic brain injury. JAMA Neurology. 2014;**71**(1):23-31

[96] Collins-Praino LE, Corrigan F. Does neuroinflammation drive the relationship between tau hyperphosphorylation and dementia development following traumatic brain injury? Brain, Behavior, and Immunity. 2017;**60**:369-382

[97] Lee CY, Landreth GE. The role of microglia in amyloid clearance from the AD brain. Journal of Neural Transmission (Vienna). 2010;**117**(8):949-960

*Neuroinflammation in Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.105178*

[98] Sy M, Kitazawa M, Medeiros R, Whitman L, Cheng D, Lane TE, et al. Inflammation induced by infection potentiates tau pathological features in transgenic mice. The American Journal of Pathology. 2011;**178**(6):2811-2822

[99] Sheng JG, Zhu SG, Jones RA, Griffin WS, Mrak RE. Interleukin-1 promotes expression and phosphorylation of neurofilament and tau proteins in vivo. Experimental Neurology. 2000;**163**(2):388-391

[100] Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT. Regulation of tau pathology by the microglial fractalkine receptor. Neuron. 2010;**68**(1):19-31

[101] Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron. 2007;**53**(3):337-351

[102] Shi J-Q, Shen W, Chen J, Wang B-R, Zhong L-L, Zhu Y-W, et al. Anti-TNF-α reduces amyloid plaques and tau phosphorylation and induces CD11cpositive dendritic-like cell in the APP/ PS1 transgenic mouse brains. Brain Research. 2011;**1368**:239-247

[103] Hull M, Eistetter J, Fiebich BL, Bauer J. Glutamate but not interleukin-6 influences the phosphorylation of tau in primary rat hippocampal neurons. Neuroscience Letters. 1999;**261**(1-2):33-36

[104] Li Y, Liu L, Barger SW, Griffin WS. Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. The Journal of Neuroscience. 2003;**23**(5):1605-1611

[105] Acosta SA, Tajiri N, Idl P, Bastawrous M, Sanberg PR, Kaneko Y, et al. Alpha-synuclein as a pathological link between chronic traumatic brain injury and Parkinson's disease. Journal of Cellular Physiology. 2015;**230**(5):1024-1032

[106] Saing T, Dick M, Nelson PT, Kim RC, Cribbs DH, Head E. Frontal cortex neuropathology in dementia pugilistica. Journal of Neurotrauma. 2012;**29**(6):1054-1070

[107] VanItallie TB. Traumatic brain injury (TBI) in collision sports: Possible mechanisms of transformation into chronic traumatic encephalopathy (CTE). Metabolism: Clinical and Experimental. 2019;**100S**:153943

[108] Cherry JD, Tripodis Y, Alvarez VE, Huber B, Kiernan PT, Daneshvar DH, et al. Microglial neuroinflammation contributes to tau accumulation in chronic traumatic encephalopathy. Acta Neuropathologica Communications. 2016;**4**(1):112

[109] Chancellor KB, Chancellor SE, Duke-Cohan JE, Huber BR, Stein TD, Alvarez VE, et al. Altered oligodendroglia and astroglia in chronic traumatic encephalopathy. Acta Neuropathologica. 2021;**142**(2):295-321

[110] Goldstein LE, Fisher AM, Tagge CA, Zhang XL, Velisek L, Sullivan JA, et al. Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model. Science Translational Medicine. 2012;**4**(134): 134ra60

[111] McKee AC, Gavett BE, Stern RA, Nowinski CJ, Cantu RC, Kowall NW, et al. TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. Journal of Neuropathology and Experimental Neurology. 2010;**69**(9):918-929

[112] Falk D, Gibson KR. Evolutionary Anatomy of the Primate Cerebral Cortex. Cambridge: Cambridge University Press; 2001

[113] Xiong Y, Mahmood A, Chopp M. Animal models of traumatic brain injury. Nature Reviews Neuroscience. 2013;**14**(2):128

[114] Ho J, Kleiven S. Can sulci protect the brain from traumatic injury? Journal of Biomechanics. 2009;**42**(13):2074-2080

[115] Kinder HA, Baker EW, West FD. The pig as a preclinical traumatic brain injury model: Current models, functional outcome measures, and translational detection strategies. Neural Regeneration Research. 2019;**14**(3):413-424

[116] Ahmad AS, Satriotomo I, Fazal J, Nadeau SE, Dore S. Considerations for the optimization of induced white matter injury preclinical models. Frontiers in Neurology. 2015;**6**:172

[117] Dean DD, Frank JA, Turtzo LC. Controlled cortical impact in the rat. Current Protocols in Neuroscience. 2017;**81**:9.62.1-9.62.12

[118] Ma X, Aravind A, Pfister BJ, Chandra N, Haorah J. Animal models of traumatic brain injury and assessment of injury severity. Molecular Neurobiology. 2019;**56**(8):5332-5345

[119] Aravind A, Ravula AR, Chandra N, Pfister BJ. Behavioral deficits in animal models of blast traumatic brain injury. Frontiers in Neurology. 2020;**11**:990

[120] Ramilo O, Sáez-Llorens X, Mertsola J, Jafari H, Olsen KD, Hansen EJ, et al. Tumor necrosis factor alpha/ cachectin and interleukin 1 beta initiate meningeal inflammation. The Journal of Experimental Medicine. 1990;**172**(2):497-507

[121] Ross SA, Halliday MI, Campbell GC, Byrnes DP, Rowlands BJ. The presence of tumour necrosis factor in CSF and plasma after severe head injury. British Journal of Neurosurgery. 1994;**8**(4):419-425

[122] Scherbel U, Raghupathi R, Nakamura M, Saatman KE, Trojanowski JQ, Neugebauer E, et al. Differential acute and chronic responses of tumor necrosis factor-deficient mice to experimental brain injury. Proceedings of the National Academy of Sciences of the United States of America. 1999;**96**(15):8721-8726

[123] Perez-Barcena J, Ibáñez J, Brell M, Crespí C, Frontera G, Llompart-Pou JA, et al. Lack of correlation among intracerebral cytokines, intracranial pressure, and brain tissue oxygenation in patients with traumatic brain injury and diffuse lesions. Critical Care Medicine. 2011;**39**(3):533-540

[124] Winter CD, Pringle AK, Clough GF, Church MK. Raised parenchymal interleukin-6 levels correlate with improved outcome after traumatic brain injury. Brain: A Journal of Neurology. 2004;**127**(Pt 2):315-320

[125] Chamoun R, Suki D, Gopinath SP, Goodman JC, Robertson C. Role of extracellular glutamate measured by cerebral microdialysis in severe traumatic brain injury. Journal of Neurosurgery. 2010;**113**(3):564-570

[126] Wang YT, Edison P. Tau imaging in neurodegenerative diseases using positron emission tomography. Current Neurology and Neuroscience Reports. 2019;**19**(7):45

[127] Donat CK, Scott G, Gentleman SM, Sastre M. Microglial activation in traumatic brain injury. Frontiers in Aging Neuroscience. 2017;**9**:208

*Neuroinflammation in Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.105178*

[128] Banati RB, Myers R, Kreutzberg GW. PK ('peripheral benzodiazepine')--binding sites in the CNS indicate early and discrete brain lesions: Microautoradiographic detection of [3H]PK11195 binding to activated microglia. Journal of Neurocytology. 1997;**26**(2):77-82

[129] Guo Y, Zeng H, Gao C. The role of neutrophil extracellular traps in central nervous system diseases and prospects for clinical application. Oxidative Medicine and Cellular Longevity. 2021;**2021**:9931742

[130] Hoyte LC, Brooks KJ, Nagel S, Akhtar A, Chen R, Mardiguian S, et al. Molecular magnetic resonance imaging of acute vascular cell adhesion molecule-1 expression in a mouse model of cerebral ischemia. Journal of Cerebral Blood Flow and Metabolism. 2010;**30**(6):1178-1187

[131] McAteer MA, Sibson NR, von Zur MC, Schneider JE, Lowe AS, Warrick N, et al. In vivo magnetic resonance imaging of acute brain inflammation using microparticles of iron oxide. Nature Medicine. 2007;**13**(10):1253-1258

[132] Gauberti M, Montagne A, Marcos-Contreras OA, Le Behot A, Maubert E, Vivien D. Ultra-sensitive molecular MRI of vascular cell adhesion molecule-1 reveals a dynamic inflammatory penumbra after strokes. Stroke. 2013;**44**(7):1988-1996

[133] Ma Y, Liu Y, Ruan X, Liu X, Zheng J, Teng H, et al. Gene expression signature of traumatic brain injury. Frontiers in Genetics. 2021;**12**:646436

[134] Lynch JR, Wang H, Mace B, Leinenweber S, Warner DS, Bennett ER, et al. A novel therapeutic derived from apolipoprotein E reduces brain inflammation and

improves outcome after closed head injury. Experimental Neurology. 2005;**192**(1):109-116

[135] Sowers JL, Wu P, Zhang K, DeWitt DS, Prough DS. Proteomic changes in traumatic brain injury: Experimental approaches. Current Opinion in Neurology. 2018;**31**(6):709-717

[136] Chen X, Chen C, Fan S, Wu S, Yang F, Fang Z, et al. Omega-3 polyunsaturated fatty acid attenuates the inflammatory response by modulating microglia polarization through SIRT1 mediated deacetylation of the HMGB1/ NF-κB pathway following experimental traumatic brain injury. Journal of Neuroinflammation. 2018;**15**(1):116

[137] Roberts I, Yates D, Sandercock P, Farrell B, Wasserberg J, Lomas G, et al. Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): Randomised placebo-controlled trial. Lancet. 2004;**364**(9442):1321-1328

[138] Girgis H, Palmier B, Croci N, Soustrat M, Plotkine M, Marchand-Leroux C. Effects of selective and non-selective cyclooxygenase inhibition against neurological deficit and brain oedema following closed head injury in mice. Brain Research. 2013;**1491**:78-87

[139] Wallenquist U, Holmqvist K, Hånell A, Marklund N, Hillered L, Forsberg-Nilsson K. Ibuprofen attenuates the inflammatory response and allows formation of migratory neuroblasts from grafted stem cells after traumatic brain injury. Restorative Neurology and Neuroscience. 2012;**30**(1):9-19

[140] Browne K, Iwata A, Putt M, Smith D. Chronic ibuprofen administration worsens cognitive

outcome following traumatic brain injury in rats. Experimental Neurology. 2006;**201**(2):301-307

[141] Parepally JMR, Mandula H, Smith QR. Brain uptake of nonsteroidal anti-inflammatory drugs: Ibuprofen, flurbiprofen, and indomethacin. Pharmaceutical Research. 2006;**23**(5):873-881

[142] Martín-Saborido C, López-Alcalde J, Ciapponi A, Sánchez Martín CE, Garcia Garcia E, Escobar Aguilar G, et al. Indomethacin for intracranial hypertension secondary to severe traumatic brain injury in adults. Cochrane Database of Systematic Reviews. 2019;**2019**(11):CD011725

[143] Bye N, Habgood MD, Callaway JK, Malakooti N, Potter A, Kossmann T, et al. Transient neuroprotection by minocycline following traumatic brain injury is associated with attenuated microglial activation but no changes in cell apoptosis or neutrophil infiltration. Experimental Neurology. 2007;**204**(1):220-233

[144] Homsi S, Federico F, Croci N, Palmier B, Plotkine M, Marchand-Leroux C, et al. Minocycline effects on cerebral edema: Relations with inflammatory and oxidative stress markers following traumatic brain injury in mice. Brain Research. 2009;**1291**:122-132

[145] Yrjänheikki J, Keinänen R, Pellikka M, Hökfelt T, Koistinaho J. Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proceedings of the National Academy of Sciences. 1998;**95**(26):15769-15774

[146] Meythaler J, Fath J, Fuerst D, Zokary H, Freese K, Martin HB, et al. Safety and feasibility of minocycline in treatment of acute traumatic brain injury. Brain Injury. 2019;**33**(5):679-689

[147] Gordon PH, Moore DH, Miller RG, Florence JM, Verheijde JL, Doorish C, et al. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: A phase III randomised trial. The Lancet Neurology. 2007;**6**(12):1045-1053

[148] Bramlett HM, Dietrich WD. Long-term consequences of traumatic brain injury: Current status of potential mechanisms of injury and neurological outcomes. Journal of Neurotrauma. 2015;**32**(23):1834-1848

[149] Webster KM, Sun M, Crack P, O'Brien TJ, Shultz SR, Semple BD. Inflammation in epileptogenesis after traumatic brain injury. Journal of Neuroinflammation. 2017;**14**(1):10

[150] Kirmani BF, Robinson DM, Fonkem E, Graf K, Huang JH. Role of anticonvulsants in the management of posttraumatic epilepsy. Frontiers in Neurology. 2016;**7**:32

[151] Kim J-E, Choi H-C, Song H-K, Jo S-M, Kim D-S, Choi S-Y, et al. Levetiracetam inhibits interleukin-1β inflammatory responses in the hippocampus and piriform cortex of epileptic rats. Neuroscience Letters. 2010;**471**(2):94-99

[152] Dambach H, Hinkerohe D, Prochnow N, Stienen MN, Moinfar Z, Haase CG, et al. Glia and epilepsy: Experimental investigation of antiepileptic drugs in an astroglia/microglia co-culture model of inflammation. Epilepsia. 2014;**55**(1):184-192

[153] Schreibman DL, Hong CM, Keledjian K, Ivanova S, Tsymbalyuk S, Gerzanich V, et al. Mannitol and hypertonic saline reduce *Neuroinflammation in Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.105178*

swelling and modulate inflammatory markers in a rat model of intracerebral Hemorrhage. Neurocritical Care. 2018;**29**(2):253-263

[154] Rhind SG, Crnko NT, Baker AJ, Morrison LJ, Shek PN, Scarpelini S, et al. Prehospital resuscitation with hypertonic saline-dextran modulates inflammatory, coagulation and endothelial activation marker profiles in severe traumatic brain injured patients. Journal of Neuroinflammation. 2010;**7**(1):5

[155] Zeng HK, Wang QS, Deng YY, Fang M, Chen CB, Fu YH, et al. Hypertonic saline ameliorates cerebral edema through downregulation of aquaporin-4 expression in the astrocytes. Neuroscience. 2010;**166**(3):878-885

[156] Roquilly A, Moyer JD, Huet O, Lasocki S, Cohen B, Dahyot-Fizelier C, et al. Effect of continuous infusion of hypertonic saline vs standard care on 6-month neurological outcomes in patients with traumatic brain injury. Journal of the American Medical Association. 2021;**325**(20):2056

[157] Collaborators C-t. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): A randomised, placebo-controlled trial. Lancet. 2019;**394**(10210):1713-1723

[158] Barrett CD, Moore HB, Kong Y-W, Chapman MP, Sriram G, Lim D, et al. Tranexamic acid mediates proinflammatory and anti-inflammatory signaling via complement C5a regulation in a plasminogen activator–dependent manner. Journal of Trauma and Acute Care Surgery. 2019;**86**(1):101-107

[159] Grant AL, Letson HL, Morris JL, McEwen P, Hazratwala K, Wilkinson M, et al. Tranexamic acid is associated with selective increase in inflammatory markers following total knee arthroplasty (TKA): A pilot study. Journal of Orthopaedic Surgery and Research. 2018;**13**(1):149

[160] Wu X, Benov A, Darlington DN, Keesee JD, Liu B, Cap AP. Effect of tranexamic acid administration on acute traumatic coagulopathy in rats with polytrauma and hemorrhage. PLoS One. 2019;**14**(10):e0223406-e

[161] Boudreau RM, Johnson M, Veile R, Friend LA, Goetzman H, Pritts TA, et al. Impact of tranexamic acid on coagulation and inflammation in murine models of traumatic brain injury and hemorrhage. Journal of Surgical Research. 2017;**215**: 47-54

[162] Lotocki G, de Rivero Vaccari JP, Perez ER, Alonso OF, Curbelo K, Keane RW, et al. Therapeutic hypothermia modulates TNFR1 signaling in the traumatized brain via early transient activation of the JNK pathway and suppression of XIAP cleavage. European Journal of Neuroscience. 2006;**24**(8):2283-2290

[163] Crossley S, Reid J, McLatchie R, Hayton J, Clark C, MacDougall M, et al. A systematic review of therapeutic hypothermia for adult patients following traumatic brain injury. Critical Care. 2014;**18**(2):R75-R7R

[164] Timaru-Kast R, Luh C, Gotthardt P, Huang C, Schafer MK, Engelhard K, et al. Influence of age on brain edema formation, secondary brain damage and inflammatory response after brain trauma in mice. PLoS One. 2012;**7**(8):e43829

[165] Morganti JM, Riparip LK, Chou A, Liu S, Gupta N, Rosi S. Age exacerbates the CCR2/5-mediated

neuroinflammatory response to traumatic brain injury. Journal of Neuroinflammation. 2016;**13**(1):80

[166] Delage C, Taib T, Mamma C, Lerouet D, Besson VC. Traumatic brain injury: An age-dependent view of posttraumatic neuroinflammation and its treatment. Pharmaceutics. 2021;**13**(10)

[167] Appelberg KS, Hovda DA, Prins ML. The effects of a ketogenic diet on behavioral outcome after controlled cortical impact injury in the juvenile and adult rat. Journal of Neurotrauma. 2009;**26**(4):497-506

[168] Prins ML, Fujima LS, Hovda DA. Age-dependent reduction of cortical contusion volume by ketones after traumatic brain injury. Journal of Neuroscience Research. 2005;**82**(3):413-420

[169] Djebaili M, Hoffman SW, Stein DG. Allopregnanolone and progesterone decrease cell death and cognitive deficits after a contusion of the rat pre-frontal cortex. Neuroscience. 2004;**123**(2):349-359

[170] Barreto G, Veiga S, Azcoitia I, Garcia-Segura LM, Garcia-Ovejero D. Testosterone decreases reactive astroglia and reactive microglia after brain injury in male rats: Role of its metabolites, oestradiol and dihydrotestosterone. The European Journal of Neuroscience. 2007;**25**(10):3039-3046

[171] Ma C, Wu X, Shen X, Yang Y, Chen Z, Sun X, et al. Sex differences in traumatic brain injury: A multidimensional exploration in genes, hormones, cells, individuals, and society. Chinese Neurosurgical Journal. 2019;**5**:24

[172] Bergold PJ. Treatment of traumatic brain injury with anti-inflammatory drugs. Experimental Neurology. 2016;**275**(Pt 3):367-380

[173] Garrett MC, Otten ML, Starke RM, Komotar RJ, Magotti P, Lambris JD, et al. Synergistic neuroprotective effects of C3a and C5a receptor blockade following intracerebral hemorrhage. Brain Research. 2009;**1298**:171-177

[174] Imam AM, Jin G, Duggan M, Sillesen M, Hwabejire JO, Jepsen CH, et al. Synergistic effects of fresh frozen plasma and valproic acid treatment in a combined model of traumatic brain injury and hemorrhagic shock. Surgery. 2013;**154**(2):388-396

[175] Tang H, Hua F, Wang J, Yousuf S, Atif F, Sayeed I, et al. Progesterone and vitamin D combination therapy modulates inflammatory response after traumatic brain injury. Brain Injury. 2015;**29**(10):1165-1174

[176] Abu Hamdeh S, Tenovuo O, Peul W, Marklund N. "Omics" in traumatic brain injury: Novel approaches to a complex disease. Acta Neurochirurgica. 2021;**163**(9):2581-2594

[177] Lurie DI. An integrative approach to neuroinflammation in psychiatric disorders and neuropathic pain. Journal of Experimental Neuroscience. 2018;**12**:1179069518793639

[178] Shaito A, Hasan H, Habashy KJ, Fakih W, Abdelhady S, Ahmad F, et al. Western diet aggravates neuronal insult in post-traumatic brain injury: Proposed pathways for interplay. eBioMedicine. 2020;**57**:102829

[179] Yu J, Zhu H, Taheri S, Mondy W, Perry S, Kindy MS. Impact of nutrition on inflammation, tauopathy, and behavioral outcomes from chronic traumatic encephalopathy. Journal of Neuroinflammation. 2018;**15**(1):277
