Secondary Brain Injury can occur minutes, hours, days or even weeks after the initial biomechanical insult. [36]

This injury occurs as an indirect result of the initial injury and is a complex process involving a variety of mechanisms. [32] [33] Secondary Brain Injury is commonly a result of cerebral oedema, increased intracranial pressure, ischaemia, excitotoxicity, oxidative stress and metabolic dysfunction. [32]

Through timely and appropriate clinical care, the secondary injuries can be mitigated or even prevented. This is achieved by avoiding the secondary insults. [33]

Brief Summary

While the primary injury contributes to the extent of functional deficits, there are also significant contributions from physiological changes that occur during the hours, days and even weeks after injury. [32] [33] [36] It is a cascade of events following the initial injury that leads to further damage. A number of factors contribute to secondary injury, which includes: [32]

  • Excitotoxicity [32] [33]

  • Blood brain barrier disruption [32]

  • Neurometabolic Dysfunction [32]

  • Oxidative Stress [32]

  • Oedema [32]

  • Ischaemia [32]

  • Increase in intracranial pressure [32] [37]

  • Herniation [37] [38]

So, what is this cascade of events?

  • Following the initial injury, there is mass release of excitatory neurotransmitters (e.g. glutamate). [32]

  • This results in unchecked opening of ion channels and widespread depolarisation of neurons. [32] [39]

  • Depolarisation leads to potassium efflux and sodium, calcium influx - this results in an osmotic effect, with influx of H2O into cells. This contributes to cerebral oedema. [32] [39]

  • Cerebral Oedema contributes to an increase in intracranial pressure [32]

  • Presence of excitatory amino acids causes excitotoxicity. [32]

  • Excitotoxicity can cause injury to neuronal mitochondria, leading to neurometabolic dysfunction and formation of free radicals. [32] [39]

  • Formation of free radicals leads to further damage, and impaired cerebral vasoregulation with subsequent reduction of cerebral blood flow, which further contributes to neurometabolic dysfunction. [32] [39]

  • As well as decreased cerebral blood flow, the initial widespread depolarisation also contributes to decreased oxygen availability, with a shift to anaerobic respiration - this produces lactic acid, which can act to further damage tissues. [39]

  • The net result is brain damage and neuronal death. [32]

Treatment of TBI revolves around mitigating this cascade of events. We do this by addressing secondary insults. This should not be confused with secondary injury, as the secondary insults describe mechanisms that worsen damage by potentiating secondary injury. [33] [40] 

See Figure 6 for an outline of these events.


Figure 6   [32]

Intracranial Pressure

As intracranial pressure (ICP) increases, the cerebral perfusion pressure decreases. This leads to worsening ischaemia, which potentiates the cascade of secondary injury. [33] [37]

Increases in intracranial pressure in TBI can be attributed to:

  • Mass effect: Haematoma, blood clots [37]

  • Decreased reabsorption of CSF: hydrocephalus (secondary to subarachnoid haemorrhage) [37]

  • Increased blood flow: Disruption of autoregulation, hypercapnia [32] [37]

  • Cerebral Oedema [32] [37]

As well as contributing to ischaemia, increases in ICP leads to brain tissue herniation. [37] [38]

munro-kellie doctrine

The Munro-Kellie Doctrine describes the relationship between intracranial pressure and the components of the cranium. The cranium is a rigid compartment, and the volume within it can not be changed. [38] [41]

Within the cranium there are three components: [41]

  1. Brain tissue (80%)

  2. Blood (10%)

  3. CSF (10%)

These components exist in equilibrium to maintain a constant state - an increase in one will lead to a decrease in another. [41] In the face of increasing ICP, the brain can compensate to a certain extent - CSF and venous draining will increase in an effort to accomodate the rise in pressure. [41] Once these mechanisms are exceeded, ICP rises exponentially and the last component (brain tissue) will being to shift - this leads to herniation. [41]


Herniation refers to the protrusion of brain tissue through an opening or across a separating structure into a region that it does not normally occupy. There are various types of herniation, each with varying symptoms. Types of herniation are outlined in Figure 7. [38] [41]


Figure 7   [41]

Cushing's triad

Unfortunately, this triad of symptom is often a late sign of increased ICP and imminent brain herniation. [33] [43] When the arterial pressure is less than the intracranial pressure, a reflex called “CNS Ischaemic Response” is initiated by the hypothalamus. [43] [44] This activates the sympathetic nervous system, which aims to increase arterial blood pressure. {43] [44] The increase in blood pressure is detected by baroreceptors in the carotid bodies, inducing a reflex bradycardia. As herniation continues, brain stem compression results in irregular breathing as the medulla is impacted. [43] [44]


Thus, the three symptoms are born:

  • Hypertension (and widening pulse pressure) [43] [44]

  • Reflex Bradycardia [43] [44]

  • Irregular respirations  [43] [44]

Although not a part of the triad, another clue to look for in herniation is fixed and dilated pupils, as the Occulomotor cranial nerve is compressed. 


Hover over the boxes to learn more!

Hypotension causes a decrease in mean arterial pressure, subsequently causing a decrease in cerebral perfusion pressure. This results in a decrease in cerebral blood flow. [32] [33] [44]

This decrease causes further ischaemia and death to neuronal tissue. [32] [33]


The lack of oxygen available to neural tissues causes an increase in anaaerobic respiration and further production of lactic acid. [32] [33]

Furthermore, low levels of oxygen may lead to cerebral vasodilation. Although this vasodilation causes an increase in cerebral blood flow, it also results in an increase in intracranial pressure. [32] [33] [45]

Carbon Dioxide is a potent vasodilator - having high levels of CO2 in the blood alters cerebral autoregulation. [24] This increases cerebral blood flow, however also results in an increase in intracranial pressure. [32]


Hypoglycaemia - The brain is unable to store any glucose. Therefore, low levels of glucose in the blood mean the brain has inadequate supply for ATP production. [32] [33] [47] [48]

Hyperglycaemia - High levels of glucose in the blood following a TBI have been shown to worsen outcomes. [32] [48] [49] There are a few mechanisms that may be responsible, however it includes intracellular acidosis, disruption of blood brain barrier and eventual oedema / necrosis. [32] [48] [49]


Low levels of carbon dioxide in the blood  leads to a net vasoconstriction - this decreases cerebral blood flow. [24] [46] Although this will lower intracranial pressure, it will also increase ischaemia and death of neurons. [32]


Any increase in metabolic demand leads to worsening of ischaemia and increased production of detrimental waste products. [32] [33] [48]

Examples include seizures, hyperthermia and agitation.