Swelling of the brain is a frequent adverse of TBI and represents a leading cause of morbidity and mortality in severely head-injured patients [4]. Swelling most often represents the macroscopic correlate for cerebral edema although may uncommonly develop as a consequence of cerebral hyperemia.

Cerebral edema is defined by an increased water content of the brain, which may be affect the extracellular space, vasogenic edema, or be the consequence of alterations of cellular homeostasis leading to cytotoxic edema. Vasogenic edema, often considered as the most common form of posttraumatic edema, represents the consequence of structural and functional alterations of the blood-brain barrier leading to a shift of fluid from cerebral vessels into the extracellular space. Cytotoxic edema develops shortly after the injury as the consequence of membrane depolarization leading to a generalized release of glutamate causing the activation of N-methyl-d-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor receptors and the subsequent influx of calcium, sodium, and water within the cells [5]. Intracellular calcium accumulation, along with associated noxious signals such as ischemia and oxidative stress, results in progressive mitochondrial damage and energy crisis. As intracellular ATP availability is compromised, energy-dependent ionic pumps fail, and water and accumulating ions cannot be expelled back in the extracellular space.

Cerebral hyperemia is an uncommon situation characterized by impairment of cerebral autoregulation with sudden onset of cerebral blood flow increased mediated by vasodilation leading to cerebral congestion. This condition may be responsible for a fast increase in ICP and occurs mostly in children and young adults. Accurate diagnosis of this relatively rare condition is essential for it requires specific therapeutic measures that may be even detrimental in the presence of cerebral edema.

Impairment of cerebral blood flow (CBF) following severe TBI has been repeatedly reported [6, 7], particularly in the early posttraumatic period. Oligemia due to increased intracranial pressure and impaired autoregulation has been shown to be associated with unfavorable functional outcome, and signs of ischemia can be found in most instances of lethal TBI. Patients with subdural hematoma and diffuse cerebral swelling are more likely to suffer from cerebral ischemia. Furthermore, CBF may be further compromised throughout the course of illness as the consequence of developing brain swelling and cerebral vasospasm mediated by traumatic subarachnoid hemorrhage [8].

Depressed cerebral metabolism has been identified as an important physiologic hallmark of TBI, and oxidative metabolism rates as low as half the value found under normal conditions have been reported in several studies [9]. Energy crisis has been commonly attributed to compromised oxygen delivery induced by cerebral ischemia, although spreading cortical depression in comatose and sedated patients is another advocated hypothesis. Recent studies, however, have emphasized the pivotal role played by mitochondrial damage mediated by a vast array of noxious stimuli integrated and amplified within the mitochondrion, in failure of ATP production [10]. Furthermore, recent clinical studies have shown that the level of metabolic depression correlated with the level of consciousness, whereas animal studies showed that mitochondrial protection was associated with both improved metabolism and ICP relief [11].

Elevated ICP has been reported to be an independent predictor of increased mortality and is associated with poor functional outcome. Although ICP levels as low as 15 mmHg may be sufficient to prompt cerebral herniation at particular location, a threshold of 20–25 mmHg is currently considered to justify implementation of therapeutic measures [12]. Accordingly, ICP monitoring should be performed in all severe TBI patients. Absence or delay of ICP monitoring has been recently shown to be associated with increased mortality and worse outcome [13].

Mechanical ventilation is commonly initiated at prehospital stage or on admission to the emergency room for airway control in patients with severe TBI. Further, mechanical ventilation is often necessary in patients with impaired consciousness in order to prevent superimposed hypoxemic insults and ICP elevation caused by hypercarbia. Hyperventilation should not be used unless CBF measurements can be obtained and the effect of hypocarbia on cerebral perfusion assessed, especially during the first 24 h of injury and in the presence of cerebral contusions [14, 15]. In severe TBI patients, mechanical ventilation as well as general ICU and nursing procedures may be occasionally painful and generate transient and harmful ICP elevations. For this reason, sedation and analgesics should be liberally implemented in patients’ general care, using drugs that can be easily titrated and characterized by rapid onset and offset. Propofol is currently the sedative of choice as its effect can be reversed within a short time whenever indicated and is anticonvulsant as well. Propofol is also an efficient drug for ICP control. Midazolam may be used alternatively, providing a potent anticonvulsive effect with lesser cardiovascular depression. Muscle relaxants should not be used on a routine basis though may be recommended in the presence of refractory intracranial hypertension [16].

Mannitol is the most commonly used hypo-osmotic agent for reduction of ICP. Its effect is produced by osmotic reduction of the cerebral water content and presumably by a beneficial rheologic effect due to hematocrit reduction and plasma volume increase. The use of mannitol is recommended only in the presence of elevated ICP. Prophylactic use of mannitol is not recommended unless clinical signs of cerebral herniation develop prior initiation of ICP monitoring. Mannitol is contraindicated in the presence of arterial hypertension, serum osmolarity ≥320 m)sm/l, sepsis, and signs of renal failure.