**3. TBI physiopathology and oxygen importance**

TBI presents two main classifications for intracranial lesions: focal or diffused [7–9]. Focal brain damage is the consequence of cortical lacerations, compression, or concussion forces, compromising blood supply and culminating in neuronal and glial necrosis. The structural injury is resulted from the brain collision to rigid structures, depressed skull fractures, vascular injuries or penetrating trauma [8–11].

Diffuse brain damage is caused by acceleration/deceleration forces, that shears and stretches brain tissue, causing functional disturbance, culminating in brain swelling or diffuse axonal injury [8–11]. The co-existence of both types of injuries are frequently present, as a result from the mechanical distortion of the head that leads to a combination of neural and vascular events [10–13].

Additionally, the TBI process can be breakdown in two successive, intertwined, pathophysiological moments, labeled as primary and secondary injury.

#### **3.1 Primary injury**

The primary injury arises from the mechanical damage occurring at the time of the impact, being exclusively responsive to preventive measures [8, 14]. On the macroscopic level, damage can be recognized by shearing of white-matter tracts, diffuse swelling, focal contusions, and intracerebral and extracerebral hematomas [15–17].

On the cellular level, mechanoporation of axolemma (caused by the traumatic axonal injury) results in sodium channelopaty [18] and unregulated influx of Ca2+, which initiates calpain activation and mitochondrial swelling [19–22]. Calpain activation and cytochrome *c* accumulation increases axonal injury, detachment and apoptosis [23]. This cascade of events occurs 24 to 72 hours after the trauma and is denominated as secondary axotomy [11]. Injured axons are also susceptible to demyelination [17].

The microvasculature suffers from injury changes, such as swelling of perivascular astrocytic end-feet, increased adherence of intravascular leukocyte, perivascular hemorrhage, transvascular erythrocytes diapedesis, and increased activity of endothelial microvacuolation and micropseudopodia [24, 25].

#### **3.2 Secondary injury**

The second injury emerges from a complex series of molecular and cellular interrelated events, resulted from the biochemical cascades triggered by the trauma [9, 11]. An essential goal in the critical care is to establish recognition and treatment for secondary injury, and prevent secondary insults, which worsen patient's outcomes [26, 27].

Post-traumatic edema likely occurs by the dysfunction of sodium-potassium pump, due to pH-induced conformational change or cellular energy failure, resulting in water and sodium accumulation within the cell [11, 25]. Other factors that contributes to intracranial edema are excitotoxicity (induces intracellular sodium accumulation) [28], and membrane disruption [29] and depolarization (induced by influx of chloride, due to sodium influx) [30].

**155**

**Figure 1.**

*TBI's sequence of events.*

*Benefits of Early Tracheostomy in TBI Patients DOI: http://dx.doi.org/10.5772/intechopen.93849*

rupted and the ICP raises exponentially [7, 16].

Excitotoxicity is the result of the excess of excitatory amino acids (EAA) that are released in the extracellular space, such as glutamate and aspartate, which raises intracellular sodium, calcium, chloride and water [10, 15]. This accumulation results in organelle and plasma membrane swelling [31], apoptosis, activation of destructive enzymes (such as calpain, nitric oxide synthase) [32], positive feedback

Besides other secondary brain injuries, such as calcium dysregulation (which leads to cytoskeletal degradation), patients experience superimposed secondary insults (with intracranial or systemic repercussions) [10, 14, 15, 27]. Systemic repercussions are hypotension, hypoxia, hyperthermia, and hypoxemia. **Figure 1** recapitulate TBI's

Intracranial insults include cerebral ischemia, elevated ICP (or intracranial hypertension), and cerebral fluid-mediated swelling. The Monro Kellie doctrine (**Figure 3**) demonstrates the constancy relationship in the sum of volumes of brain, intracranial blood and cerebrospinal fluid (CSF) [7, 36, 37]. Once the brain suffers from the intracranial insults and equal volumes of CSF and intracranial blood are compressed, ICP remains normal (compensated state). When the brain enters in a decompensate state (after exhaustion of compensate state), the balance is inter-

It is important to mention that secondary injury does not have the same meaning

as a secondary insult [11, 14]. Secondary insult occurs at the organ system level, being considered as a second hit event, exacerbating the damage from the primary

loop by voltage-gated calcium channels [33], and necrosis [34].

sequence of events. **Figure 2** recapitulate TBI's neurometabolic cascade.

*Benefits of Early Tracheostomy in TBI Patients DOI: http://dx.doi.org/10.5772/intechopen.93849*

*Advancement and New Understanding in Brain Injury*

**3. TBI physiopathology and oxygen importance**

leads to a combination of neural and vascular events [10–13].

endothelial microvacuolation and micropseudopodia [24, 25].

influx of chloride, due to sodium influx) [30].

pathophysiological moments, labeled as primary and secondary injury.

injuries.

**3.1 Primary injury**

demyelination [17].

**3.2 Secondary injury**

outcomes [26, 27].

TBI can be classified following its severity: Mild, Moderate and Severe [7]. This classification is based on the Glasgow Coma Scale (GCS), with Mild - GCS Score 13–15; Moderate - GCS Score 9–12; and Severe - GCS Score 8–3. Subsequent TBI management will rely on the first evaluation and the prevention of secondary

TBI presents two main classifications for intracranial lesions: focal or diffused [7–9]. Focal brain damage is the consequence of cortical lacerations, compression, or concussion forces, compromising blood supply and culminating in neuronal and glial necrosis. The structural injury is resulted from the brain collision to rigid structures, depressed skull fractures, vascular injuries or penetrating trauma [8–11]. Diffuse brain damage is caused by acceleration/deceleration forces, that shears and stretches brain tissue, causing functional disturbance, culminating in brain swelling or diffuse axonal injury [8–11]. The co-existence of both types of injuries are frequently present, as a result from the mechanical distortion of the head that

Additionally, the TBI process can be breakdown in two successive, intertwined,

The primary injury arises from the mechanical damage occurring at the time of the impact, being exclusively responsive to preventive measures [8, 14]. On the macroscopic level, damage can be recognized by shearing of white-matter tracts, diffuse swelling, focal contusions, and intracerebral and extracerebral hematomas [15–17]. On the cellular level, mechanoporation of axolemma (caused by the traumatic axonal injury) results in sodium channelopaty [18] and unregulated influx of Ca2+, which initiates calpain activation and mitochondrial swelling [19–22]. Calpain activation and cytochrome *c* accumulation increases axonal injury, detachment and apoptosis [23]. This cascade of events occurs 24 to 72 hours after the trauma and is denominated as secondary axotomy [11]. Injured axons are also susceptible to

The microvasculature suffers from injury changes, such as swelling of perivascular astrocytic end-feet, increased adherence of intravascular leukocyte, perivascular hemorrhage, transvascular erythrocytes diapedesis, and increased activity of

The second injury emerges from a complex series of molecular and cellular interrelated events, resulted from the biochemical cascades triggered by the trauma [9, 11]. An essential goal in the critical care is to establish recognition and treatment for secondary injury, and prevent secondary insults, which worsen patient's

Post-traumatic edema likely occurs by the dysfunction of sodium-potassium pump, due to pH-induced conformational change or cellular energy failure, resulting in water and sodium accumulation within the cell [11, 25]. Other factors that contributes to intracranial edema are excitotoxicity (induces intracellular sodium accumulation) [28], and membrane disruption [29] and depolarization (induced by

**154**

Excitotoxicity is the result of the excess of excitatory amino acids (EAA) that are released in the extracellular space, such as glutamate and aspartate, which raises intracellular sodium, calcium, chloride and water [10, 15]. This accumulation results in organelle and plasma membrane swelling [31], apoptosis, activation of destructive enzymes (such as calpain, nitric oxide synthase) [32], positive feedback loop by voltage-gated calcium channels [33], and necrosis [34].

Besides other secondary brain injuries, such as calcium dysregulation (which leads to cytoskeletal degradation), patients experience superimposed secondary insults (with intracranial or systemic repercussions) [10, 14, 15, 27]. Systemic repercussions are hypotension, hypoxia, hyperthermia, and hypoxemia. **Figure 1** recapitulate TBI's sequence of events. **Figure 2** recapitulate TBI's neurometabolic cascade.

Intracranial insults include cerebral ischemia, elevated ICP (or intracranial hypertension), and cerebral fluid-mediated swelling. The Monro Kellie doctrine (**Figure 3**) demonstrates the constancy relationship in the sum of volumes of brain, intracranial blood and cerebrospinal fluid (CSF) [7, 36, 37]. Once the brain suffers from the intracranial insults and equal volumes of CSF and intracranial blood are compressed, ICP remains normal (compensated state). When the brain enters in a decompensate state (after exhaustion of compensate state), the balance is interrupted and the ICP raises exponentially [7, 16].

It is important to mention that secondary injury does not have the same meaning as a secondary insult [11, 14]. Secondary insult occurs at the organ system level, being considered as a second hit event, exacerbating the damage from the primary

**Figure 1.** *TBI's sequence of events.*

#### **Figure 2.**

*[35] TBI's neurometabolic cascade. (1) nonspecific depolarization; (2) neurotransmitter release - excitatory neurotransmitters (EAAs); (3) increase potassium efflux; (4) increased membrane pumping to restore homeostasis; (5) Hyperglycolysis to increase adenosine triphosphate (ATP) availability; (6) lactate accumulation; (7) calcium sequestration and mitochondria dysfunction resulting in oxidative metabolism; (8) decreased ATP production; (9) Calpain activation and apoptosis initiation. A - Axolemma and calcium influx. B - Neurofilament compaction. C - microtubule disassembly. D - axonal swelling and secondary axotomy. K+ : potassium; Na+ : sodium; Glut: glutamate; Mg2+: magnesium; Ca2+: calcium; NMDA: N-methyl-D-aspartate; AMPA: d-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid.*

TBI. The same reasoning is applied to the primary insult, which alters the cerebral metabolism and blood flow, resulting in cellular dysfunction and predisposition to cognitive impairment, seizures, hypotension and hypoxia [8].

#### **3.3 Oxygen and TBI**

The brain requires an uninterrupted supply of glucose and oxygen to maintain cellular viability and metabolism, consuming up to 20% of individual's total oxygen, with an average of cerebral metabolic rate of oxygen (CMRO2) between 3 and 3.8 ml/100 g/min [38–41]. Brain metabolism represents the largest source of energy consumption in the human body, since neuronal activity is supported through the production of adenosine triphosphate (ATP), which consumes nearly 60% of oxygen [42, 43]. When cerebral oxygenation is maintained, minimization of secondary insult can be achieved [44].

Brain's energy consumption fluctuates following neuronal activity on localized regions, and in order to provide adequate energy supply, neurovascular and neurometabolic coupling mechanisms are involved [42]. However, within hypoxia or low oxygen conditions, prolyl hydroxylase domain-containing enzymes (PHDs) are

**157**

**Figure 3.**

*The Monro Kellie doctrine.*

*Benefits of Early Tracheostomy in TBI Patients DOI: http://dx.doi.org/10.5772/intechopen.93849*

inhibited, reducing inproline hydroxylation, and altering availability of hypoxiainducible factor-1α (HIF-1α), which assist the metabolism adaptation and function during hypoxic conditions [42, 45–47]. Then, nuclear accumulation of HIF-1α enhance transcriptional activity within HIF-β, promoting gene expression that contains a hypoxia response element (HRE) [42, 46, 48]. Remarkably, HIF-2α is also induced in hypoxic brain, being expressed in astrocytes and endothelial cells [49]. This dysfunction is associated with poor neurological outcomes [50].

In order to cope hypoxia stress, this adaptive response converts cellular metabolism to anaerobic metabolism and inducts erythropoiesis, glycolysis, angiogenesis (by vascular endothelial growth factor), among other events [46, 48, 51]. Nevertheless, anaerobic glycolysis is unable to apport sufficient energy to sustain brain demands, depleting ATP stores, which results in failure of ATP dependent membrane ionic pumps [52]. Likewise, under chronic hypoxic conditions, there is an increase in oxidative stress, cell death, inflammation and the interruption of cerebral blood flow (CBF), directly affecting brain structure and function, leading to neuronal damage and death [51, 53, 54]. A normal average of CBF in adults is 44–45 ml/100 g/min. However, the CBF threshold for irreversible tissue damage (in TBI) occurs with the decrease to 15 ml/100 g/min [27, 41, 55] and cellular function is disrupted under 10 ml/100 g/min [56]. Neurons in the hippocampus, striatum and cortical regions die

after 5, 10, and 15–20 min of ischemia [57, 58], respectively.

*Benefits of Early Tracheostomy in TBI Patients DOI: http://dx.doi.org/10.5772/intechopen.93849*

*Advancement and New Understanding in Brain Injury*

TBI. The same reasoning is applied to the primary insult, which alters the cerebral metabolism and blood flow, resulting in cellular dysfunction and predisposition to

*: sodium; Glut: glutamate; Mg2+: magnesium; Ca2+: calcium; NMDA: N-methyl-*

*[35] TBI's neurometabolic cascade. (1) nonspecific depolarization; (2) neurotransmitter release - excitatory neurotransmitters (EAAs); (3) increase potassium efflux; (4) increased membrane pumping to restore homeostasis; (5) Hyperglycolysis to increase adenosine triphosphate (ATP) availability; (6) lactate accumulation; (7) calcium sequestration and mitochondria dysfunction resulting in oxidative metabolism; (8) decreased ATP production; (9) Calpain activation and apoptosis initiation. A - Axolemma and calcium influx. B - Neurofilament compaction. C - microtubule disassembly. D - axonal swelling and secondary* 

The brain requires an uninterrupted supply of glucose and oxygen to maintain cellular viability and metabolism, consuming up to 20% of individual's total oxygen, with an average of cerebral metabolic rate of oxygen (CMRO2) between 3 and 3.8 ml/100 g/min [38–41]. Brain metabolism represents the largest source of energy consumption in the human body, since neuronal activity is supported through the production of adenosine triphosphate (ATP), which consumes nearly 60% of oxygen [42, 43]. When cerebral oxygenation is maintained, minimization of secondary

Brain's energy consumption fluctuates following neuronal activity on localized regions, and in order to provide adequate energy supply, neurovascular and neurometabolic coupling mechanisms are involved [42]. However, within hypoxia or low oxygen conditions, prolyl hydroxylase domain-containing enzymes (PHDs) are

cognitive impairment, seizures, hypotension and hypoxia [8].

*D-aspartate; AMPA: d-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid.*

**156**

**3.3 Oxygen and TBI**

*: potassium; Na+*

**Figure 2.**

*axotomy. K+*

insult can be achieved [44].

*The Monro Kellie doctrine.*

inhibited, reducing inproline hydroxylation, and altering availability of hypoxiainducible factor-1α (HIF-1α), which assist the metabolism adaptation and function during hypoxic conditions [42, 45–47]. Then, nuclear accumulation of HIF-1α enhance transcriptional activity within HIF-β, promoting gene expression that contains a hypoxia response element (HRE) [42, 46, 48]. Remarkably, HIF-2α is also induced in hypoxic brain, being expressed in astrocytes and endothelial cells [49]. This dysfunction is associated with poor neurological outcomes [50].

In order to cope hypoxia stress, this adaptive response converts cellular metabolism to anaerobic metabolism and inducts erythropoiesis, glycolysis, angiogenesis (by vascular endothelial growth factor), among other events [46, 48, 51]. Nevertheless, anaerobic glycolysis is unable to apport sufficient energy to sustain brain demands, depleting ATP stores, which results in failure of ATP dependent membrane ionic pumps [52]. Likewise, under chronic hypoxic conditions, there is an increase in oxidative stress, cell death, inflammation and the interruption of cerebral blood flow (CBF), directly affecting brain structure and function, leading to neuronal damage and death [51, 53, 54]. A normal average of CBF in adults is 44–45 ml/100 g/min. However, the CBF threshold for irreversible tissue damage (in TBI) occurs with the decrease to 15 ml/100 g/min [27, 41, 55] and cellular function is disrupted under 10 ml/100 g/min [56]. Neurons in the hippocampus, striatum and cortical regions die after 5, 10, and 15–20 min of ischemia [57, 58], respectively.

Considering that the brain is susceptible to ischemic injury, cerebral perfusion and oxygenation are vital to be maintained. In TBI setting, cerebral ischemia occurs due to different mechanisms: damage to blood vessels, hypotension, mechanical compression, and reduced perfusion (impaired autoregulation, which leads to greater propensity to hypoperfusion) [16, 59]. Hypoxemia can represent a relative risk of mortality of 75%, when associated with hypotension [7].

According to the Brain Trauma Foundation [60], patients with severe TBI present pulmonary aspiration risks or compromised airway function, and initial treatment goals include early airway protection, adequate supplemental oxygen, and circulation support, ensuring that adequate oxygen and blood flow are delivered to the brain [61].
