Brain Contusion

Brain contusions represent focal regions of subpial hemorrhage and swelling and are present in 31% of patients on initial CT scan.^68,69 When the overlying pia mater is compromised, the lesion is termed a laceration, although this distinction is typically not clear. Contusions are most common in regions that contact bony surfaces in the cranial vault during trauma: frontal and temporal poles, orbitofrontal gyri, perisylvian cortices, and inferolateral temporal lobe surfaces.

Contusions can be characterized by mechanism, anatomic location, or adjacent injuries. For example, fracture contusions result from direct contact injuries and occur immediately adjacent to a skull fracture.⁷⁰ Coup contusions refer to those that occur at the site of impact in the absence of a fracture, whereas contrecoup contusions are those that are diametrically opposite to the point of impact. Gliding contusions are focal hemorrhages involving the cortex and adjacent white matter of the superior margins of the cerebral hemispheres; they are due to rotational mechanisms rather than contact forces.⁷¹ Intermediary contusions are lesions that affect deep brain structures, such as the corpus callosum, basal ganglia, hypothalamus, and brainstem.⁷¹ Herniation contusions can occur in areas where the medial parts of the temporal lobe contact the tentorial edge (i.e., uncal herniation) or where the cerebellar tonsils contact the foramen magnum (i.e., tonsillar herniation).

Contusions typically result in varying degrees of neurological deficits depending on the area involved. Occasionally, contusions can cause significant mass effect owing to surrounding edema or hemorrhagic progression to an intracerebral hematoma (discussed later). Contusions also represent a significant source of secondary injury to adjacent tissue through release of neurotransmitter and local biochemical changes.⁵ Adams and colleagues proposed a method for quantifying cerebral contusions (contusion index) caused by nonmissile head injury.^72,73 They found that contusions are most severe in the frontal and temporal lobes and do not consistently correlate with injury mechanism. Contusions are more severe when associated with a skull fracture, less severe in patients with DAI, and more severe in patients who do not experience a lucid interval.

Traumatic Intracranial Hematoma

Intracranial hematomas represent mass lesions that are potential therapeutic targets of surgical intervention (as opposed to most contusions). They are more common in patients with skull fractures (Table 331-6). About half of patients with severe TBI and skull fracture have a sizeable intracranial hematoma on initial head CT.^10,74 The three major types of traumatic intracranial hematomas are distinguished by their location relative to the meninges: epidural, subdural, and intracerebral.

Intracerebral Hematoma

Intracerebral hematomas (ICHs) account for 20% of all traumatic intracranial hematomas.¹³⁶ They are associated with extensive lobar contusions, from which they are often difficult to distinguish.^137,138 ICHs differ from cerebral contusions in that a large proportion of these lesions are composed of blood, but they often result from growth or coalescence of smaller cerebral contusions. By definition, an ICH is a parenchymal lesion composed of at least two-thirds blood; otherwise, the lesion is described as disrupted tissue with areas of microscopic hemorrhage.¹³⁹ A hemorrhagic mass should be considered an intracerebral hematoma when there is a homogeneous collection of blood with relatively well-defined margins. Multiple intracerebral hematomas are found in about 20% of TBI cases.¹⁴⁰

Because ICHs typically result from rupture of intrinsic cerebral vessels (a small parenchymal artery in most cases), they often arise from cerebral contusions. As a result, most traumatic ICHs occur in the orbitofrontal and temporal lobes, as do most cerebral contusions.^{109,136,137,141,142} Deeper ICHs, such as those occurring in the basal ganglia and internal capsule, are less common and found in about 2% of TBI patients. ICHs are most common in focal head injuries, such as missile injuries, perforating wounds, and depressed skull fractures.¹⁴³ In a series of 400 civilian TBI cases with depressed skull fracture, 61% of intracranial hematomas were ICHs.¹⁴⁴ Patients on chronic anticoagulation therapy are at increased risk for developing ICH, even after mild head injury.¹⁴³ Recent studies^145,146 suggest that treatment with recombinant factor VIIa may reduce expansion of traumatic intracranial hemorrhages, but randomized trials are needed to determine whether this therapy results in improved neurological outcome.

Concussion

Concussion is the mildest form of diffuse injury and is thought to be due to rotational acceleration of the head in the absence of significant mechanical contact. In its classic form, patients with concussion experience a transient loss of consciousness followed by a rapid return to a normal state of alertness. However, concussion is not as harmless as previously thought, and repeat concussions often result in some degree of permanent neurological impairment.^148–150

The pathophysiology of concussion is poorly understood and may be due to disturbances of consciousness from lesions of the brainstem and diencephalon.¹⁵¹ Recent studies suggest that patients with concussion often have diffuse cerebral hemisphere involvement, and brainstem lesions are far less common.¹⁵² DTI reveals signs of cytotoxic edema in the brain despite a normal head CT and GCS of 15.^153,154

Diffuse Axonal Injury

DAI results from severe angular and rotational acceleration and deceleration that delivers shear and tensile forces to axons. As a result, DAI is responsible for most TBI patients that are severely impaired despite lack of gross parenchymal contusions, lacerations, or hematomas. DAI was described by Stritch in 1956¹⁵⁵ in her report of a series of patients with severe posttraumatic dementia and “diffuse degeneration of the white matter.” Others have described this injury as shearing injury, diffuse damage to the white matter of the immediate impact type, and diffuse white matter shearing injury,^{1,152,156–158} but DAI is the preferred terminology. Coronal or lateral acceleration injuries produce the most severe DAIs,¹⁵⁹ whereas acceleration in the oblique or sagittal plane results in less severe to minimal DAI.

The histologic findings of DAI have been well described and include disruption and swelling of axons, “retraction balls” (swollen proximal ends of severed axons), and punctate hemorrhages in the pons, midbrain, and corpus callosum.¹⁶⁰ Many of these abnormalities, including axonal severing, are not present initially but develop over the course of several hours or days after injury.¹⁶¹ In many cases, it is difficult to distinguish axonal damage due to mechanical shearing (primary injury) from damage caused by biochemical and metabolic sequelae of TBI (secondary injury). Animal studies suggest that axonal injury is often secondary or delayed, and there is some confirmation of this in humans.^161,162 These findings have critical implications for the treating physician because clinical interventions can occur before or during onset of these biochemical cascades.

DAI is often associated with punctate hemorrhages, termed Strich hemorrhages, that represent bleeding from small cerebral vessels.¹⁶⁰ Strich hemorrhages are typically found in areas that experience maximal acceleration forces during trauma: corpus callosum, peri-third ventricular (hypothalamus, columns of the fornix, anterior commissure), internal capsule, basal ganglia, dorsolateral brainstem, and superior cerebellar peduncles. The location and severity of axonal injuries are important determinants of functional recovery. Adams and associates¹ developed a grading system for patients with DAI (Table 331-8) that predicts length of coma and persistent neurological deficits.

TABLE 331-8 Neuropathologic Classification of Diffuse Axonal Injury

From Adams JH, Doyle D, Ford I, et al. Diffuse axonal injury in head injury: definition, diagnosis and grading. Histopathology 1989;15:49-59.

DAI lesions are often difficult to visualize on conventional CT and are better imaged using MRI techniques. T2-weighted gradient-echo (GE) imaging is particularly sensitive for hemorrhagic lesions after DAI, whereas diffusion-weighted (DW) sequences are more effective in identifying shear injuries.^163,164 DW images detect some lesions that are missed by GE sequences and correlate better with neurological prognosis following TBI.¹⁶³ Recently, DTI has been used to more effectively characterize white matter lesions after TBI. DTI in the early period after TBI has been shown to correlate with GCS score and eventual outcome at discharge (using modified Rankin score).¹⁶⁵ Xu and colleagues⁵⁶ recently demonstrated that DTI is more accurate than conventional MRI in demonstrating the extent of white matter injury after severe TBI. Benson and colleagues¹⁶⁶ found that DTI can be used to more accurately characterize injury severity, and Wang and coworkers⁵⁵ found that quantitative diffusion tensor tractography in the acute period after head injury is highly predictive of outcome. As imaging techniques (and availability) continue to develop, MRI will likely play a larger role in predicting outcome and directing care for patients with DAI.

Traumatic Subarachnoid Hemorrhage and Posttraumatic Vasospasm

The centripetal theory of Ommaya and Gennarelli suggests that lesion depth is dependent on the force of injury.¹⁶⁷ Accordingly, traumatic subarachnoid hemorrhage (SAH) results from relatively severe injury to the brain: high angular acceleration of long duration is necessary to produce a strain that causes rupture of the superficial vessels in subarachnoid cisterns. Traumatic SAH is relatively common after severe TBI, occurring in about 33% to 60% of all cases,^67,168,169 and strongly correlates with worse neurological outcome.^{168,170–173}

Posttraumatic vasospasm (PTV) is a significant secondary insult to the injured brain that is an independent predictor of permanent neurological deficit and poor outcome.^{170,174–181} The incidence of PTV varies by frequency of screening and diagnostic modality but is estimated to be 18.6% to 50% in the anterior circulation^{170,179,182–190} and 19% to 37% in the posterior circulation.^180,191,192 It typically develops between 12 hours and 5 days after injury and lasts anywhere between 12 hours and 30 days.^{170,180,185–187,189–191,193,194} PTV can also occur in a more delayed fashion and may involve both anterior and posterior circulation arteries.¹⁹⁵

In an earlier study, Martin and colleagues used CBF and transcranial Doppler measurements to identify three different circulatory stages after severe head injury: phase I (hypoperfusion), phase II (hyperemia), and phase III (vasospasm) (Table 331-9).¹⁸⁶ Phase I occurs on the day of injury (day 0) and is defined by low CBF, normal middle cerebral artery (MCA) velocity, normal hemispheric index (ratio of MCA velocity to internal carotid artery velocity), and normal arteriovenous difference of oxygen (AVDO₂). The cerebral metabolic rate of oxygen (CMRO₂) is about 50% of normal during this phase and remains depressed during the second and third phases. In phase II (relative hyperemia phase, days 1 to 3), CBF increases, AVDO₂ falls, MCA velocity rises, and hemispheric index remains less than 3. In phase III (vasospasm phase, days 4 to 15), there is a fall in CBF, a further increase in MCA velocity, and a pronounced rise in the hemispheric index.

The mechanisms resulting in PTV are poorly understood but may involve extension of intradural blood into CSF spaces (subarachnoid, intraventricular, and subdural).¹⁷⁷ Romner and associates¹⁸⁷ found anterior circulation PTV incidence increased from 28% to 41% with traumatic SAH, a correlation that has been supported by other authors as well.^{177,189,196,197} Key differences do exist between traumatic and aneurysmal SAH. For example, traumatic SAH has a different distribution, often involving supratentorial, cortical convexity, sulcal and interhemispheric spaces. PTV also differs in its time course, occurring earlier and resolving more quickly on serial CT than aneurysmal SAH.¹⁹⁸ PTV results in decreased CBF with decreased transcranial Doppler velocity. Finally, development of PTV is not always associated with significant SAH and has been reported in patients with extra-axial hematomas^{177,189,190,199} or no radiographic evidence of SAH whatsoever.^190,199

Fukuda and colleagues reported that unlike aneurysmal SAH, in which all low-density areas on CT scans corresponded to vascular territories, low-density areas in patients with traumatic SAH were rarely associated with vascular territories.¹⁹⁸ Instead, the low-density areas contained deep-seated or gliding contusions. As discussed in detail later, vasospasm of the large intracranial arteries is accompanied by an increase in CBV, owing to compensatory dilation of the vessels in the microcirculation. Reduced CBF in the presence of increased CBV thus supports the diagnosis of large artery spasm. Schroder and colleagues simultaneously evaluated early CBF and CBV in seven patients with severe head injury.²⁰⁰ These patients were selected from a larger series of 51 patients because they exhibited both nonischemic and ischemic (CBF < 18 mL/100 g per minute) areas on stable xenon CT measurements. Both CBF and CBV were significantly lower in the ischemic zones, indicating that in the early phase after injury, compromise of the microvasculature is the cause of ischemia, rather than vasospasm of the larger conductance vessels. No simultaneous studies have been performed at a later stage (i.e., when the highest incidence of vasospasm is expected).

Intraventricular Hemorrhage

About 25% of patients with severe TBI have CT evidence of intraventricular hemorrhage (IVH). Development of IVH typically requires a large force to the head and is only occasionally present after mild TBI.²⁰¹ Patients with IVH are also more likely to demonstrate intraparenchymal and basal ganglia hemorrhages.^202,203 Postmortem examinations have shown that most patients with primary IVH (no significant parenchymal blood) had a high incidence of damage to the septum pellucidum, choroid plexus, and subependymal vein in the fornix.²⁰⁴ Tearing of these veins is likely the result of negative pressure generated from a sagittal impact to the skull that transiently increases ventricular diameter.²⁰²

Although traumatic IVH has the potential of obstructing CSF flow, acute hydrocephalus is an uncommon manifestation. In a review by LeRoux and associates,²⁰³ only 4 of 43 patients with traumatic IVH required ventricular drainage for acute hydrocephalus. In a study by Hashimoto and coworkers, 20 of 32 patients with traumatic IVH did not survive their injuries.²⁰⁴

Cerebral Metabolism

Normal cell metabolism involves the consumption of adenosine triphosphate (ATP) during work and the ensuing consumption of metabolic substrates to resynthesize ATP from adenosine diphosphate (ADP). ATP is generated in both the cytosol (by glycolysis) and mitochondria (by oxidative phosphorylation).

Glucose is the primary energy substrate of the brain and can be metabolized aerobically or anaerobically. Under normal circumstances, 95% of the energy requirement of the brain comes from the aerobic conversion of glucose to water (H₂O) and carbon dioxide (CO₂). ATP generation is highly efficient—glycolysis and subsequent oxidative phosphorylation result in the generation of 38 molecules of ATP for each molecule of glucose:

Under conditions of hypoxia, conversion of glucose takes place by anaerobic glycolysis, which is far less efficient—two molecules of ATP and two molecules of lactate are generated for each molecule of glucose:

Two terms are common in reference to metabolic turnover of glucose and oxygen: the cerebral metabolic rate of oxygen (CMRO₂) and the cerebral metabolic rate of glucose (CMRglc). Under normal circumstances, in awake adults, the CMRO₂ is about 3.3 mg/100 g brain tissue per minute,²⁰⁵ and the CMRglc is 5.5 mg/100 g per minute.²⁰⁶ The lactate-oxygen index (LOI) is sometimes used as a measure of the ratio of the amount of glucose metabolized anaerobically to the amount metabolized aerobically (LOI = AVDL/AVDO₂), although it does not accurately reflect the stoichiometry of glucose metabolism. AVDL is the arteriovenous difference of lactate, and AVDO₂ is the arteriovenous difference of oxygen.²⁰⁶ Both are calculated by subtracting the jugular venous oxygenation (SjvO₂) from the systemic arterial oxygenation (SaO₂), followed by a correction for hemoglobin oxygen-carrying capacity in the latter:

Using 2-fluoro-2-deoxy-D-glucose (FDG)–positron emission tomography (PET), Bergsneider and associates²⁰⁷ described a metabolic ratio (MR = CMRO₂/CMRglc) to compare the amount of oxygen versus glucose utilization. Reference values of metabolism are summarized in Table 331-10. The global arteriovenous difference of glucose (AVDglc) has been estimated at 9.6 mL/dL but requires careful interpretation because reliable AVDglc values are difficult to obtain. The absolute AVDglc value is near or within the accuracy limits of plasma glucose levels of most clinical laboratories.

TABLE 331-10 Normal Values of Parameters of Cerebral Metabolism and Circulation in Healthy Adults

AVDG, arteriovenous difference of glucose; AVDO₂, arteriovenous difference of oxygen; CBF, cerebral blood flow; CMRG, cerebral metabolic rate of glucose; CMRO₂, cerebral metabolic rate of oxygen; LOI, lactate-oxygen index; MR, metabolic ratio.

Of the total energy generated, 50% is used for neurotransmitter production, release, and uptake (synaptic activity); 25% is used for maintenance and restoration of ion gradients across the cell membrane; and the remaining 25% is used for molecular transport, biosynthesis, and other unidentified processes.^208,209 Although glial cells account for 50% of the brain, they have a much lower metabolic rate and account for less than 10% of total cerebral energy expenditure.²⁰⁹ Compared with other organs, the metabolic demand of the brain is high: the brain accounts for only 2% to 3% of total body weight and does not do any mechanical work, yet it receives 20% of cardiac output.

Regulation of Cerebral Blood Flow

Glucose and glycogen stores in astrocytes are extremely limited, and there is no significant storage capacity for oxygen in the brain. Therefore, the brain depends on continuous blood flow to meet its glucose and oxygen needs. In general, substrate availability is determined by three factors: concentration of substrate in blood, flow volume, and the rate of substrate passage across the blood-brain barrier. The brain possesses several mechanisms to ensure substrate availability, both under normal circumstances and during times of physiologic stress.

Normally, CBF is regulated to provide an adequate supply of substrates to the brain. This is primarily accomplished through changes in caliber of resistance vessels, arterioles with a diameter of 30 to 300 µm.²¹⁰ This process, termed autoregulation,²¹¹ occurs in response to metabolic signals (metabolic autoregulation), blood pressure (pressure autoregulation), and viscosity (viscosity autoregulation) and reacts to changes in the arterial partial pressure of CO₂ (carbon dioxide reactivity).

Pressure Autoregulation

Maintenance of constant CBF in the context of changing CPP is termed pressure autoregulation. Poiseuille’s equation of laminar flow through a cylindrical tube can be adapted to cerebral arterial circulation: CBF = k (CPP × d(4))/(8 × l × v), in which k is constant, CPP is cerebral perfusion pressure, d is vessel diameter, l is vessel length, and v is blood viscosity. With viscosity remaining constant in the acute period, a sudden change in CPP must be counterbalanced by alterations in vessel diameter to maintain constant CBF.

In a healthy person, pressure autoregulation is extremely effective in maintaining relatively constant CBF in the CPP range of 50 to 150 mm Hg (Fig. 331-4). When CPP drops below these limits, vessels are maximally dilated and can no longer maintain adequate CBF in the context of dropping CPP. When CPP exceeds these limits, vessels can no longer remain constricted due to high intravascular pressure and experienced forced dilation; this condition is called pressure breakthrough.

FIGURE 331-4 Pressure autoregulation in humans. ABP, arterial blood pressure; CBF, cerebral blood flow; CPP, cerebral perfusion pressure; ICP, intracranial pressure.

Defining autoregulation as constancy of CBF despite changes in CPP is not completely accurate however, because small changes in CBF normally occur during CPP changes within the limits of autoregulation. Therefore, some authors instead define pressure autoregulation in terms of cerebrovascular resistance (CVR), that is, the change in CVR (calculated as CPP/CBF) that occurs in response to a given change in CPP.²¹² Pressure autoregulation is considered intact when 0 < Δ% CPP/ Δ% CVR < 2.^213–215

Theories of Autoregulation

The mechanisms responsible for coupling regional CBF to regional metabolism and mediating pressure and viscosity autoregulation are poorly understood. It is likely that a similar process is involved in all three types of autoregulation, but this is yet to be firmly established. There is some evidence suggesting that the vascular endothelium plays a critical role in mediating cerebral autoregulation.

Metabolic coupling is thought to be due to vasoactive metabolites released from active neurons. This concept was first introduced in 1890 by Roy and Sherrington: “The chemical products of cerebral metabolism contained in the lymph, which bathes the walls of the arterioles of the brain, can cause variations in the caliber of the cerebral vessels. In the reaction the brain possesses an intrinsic mechanism by which its vascular supply can be varied locally in correspondence with local variations of functional activity.”²¹⁹ The identity of these vasoactive agents, however, remains unclear. Agents that are directly influenced by local energy metabolism, such as CO₂, H⁺, O₂, adenosine, and the ions K⁺ and Ca²⁺, have been proposed.^210,220,221 However, there are problems with each of these compounds as a sole factor.²⁰⁹

The vascular endothelium plays an important role in maintaining the normal physiologic function of the blood vessel wall by releasing relaxing and contracting factors. Endothelial-derived relaxing factor–nitric oxide (EDRF-NO) is the primary mediator of endothelin-dependent relaxation.²²² The role of EDRF-NO in autoregulation is controversial, and many authors think its main role is maintenance of basal CBF.^223,224 Garthwaite and colleagues, however, found that EDRF-NO may mediate a functional coupling of metabolism and CBF in certain types of neural activation.²²⁵ During glutamate activation of the N-methyl-D-aspartate (NMDA) receptors, they noted calcium-dependent release of a substance with properties similar to that of EDRF-NO. The observed vasodilation after glutamate activation was inhibited by administration of both an NMDA antagonist and an NO synthase inhibitor, suggesting coupling of neuronal activation and CBF through EDRF-NO release.

Goadsby and colleagues simultaneously studied cerebral neuronal activity and local blood flow in cats by the induction of spreading depression (a wave of depolarization).²²⁶ Neuronal activity and CBF in the parietal cortex were measured simultaneously. They found that intravenous administration of NG-nitro-L-arginine methyl ester (1-NAME), a potent NO synthase inhibitor, resulted in a complete blockade of the hyperemia associated with spreading depression, but did not cause a change in either resting cell firing or spreading depression-evoked increases in firing rate.

Rapid elevation of transmural pressure triggers vasoconstriction (the Bayliss effect), a response that is prevented by removal of the endothelium.^227,228 Pressure autoregulation is thought to be mediated by the endothelium. Two major endothelium-derived contracting factors can be identified: thromboxane A₂ and endothelin.²²³ Martinez-Orgado and coworkers studied the influence of endothelial factors on pressure autoregulation in a porcine model.²²⁹ Middle cerebral arteries from 3- to 4-day-old piglets were cannulated, and diameter changes after transmural pressure variation were measured. Segments with endothelium showed vasodilation during pressure decrease and vasoconstriction during pressure increase, whereas segments without endothelium responded passively to pressure change. Their results suggested an endothelium-dependent autoregulatory mechanism, with involvement of NO and K-Ca channels in vasodilation during transmural pressure decrease and mediation of vasoconstriction by endothelin-1 (through endothelin A receptors) and prostanoids during pressure increase.

Winn and colleagues have extensively studied the role of adenosine in regulating pial vessel diameter and vascular resistance and have implicated its role as a metabolic trigger for autoregulation.^230–234 The mechanisms of its actions are not completely understood but may include nitric oxide release from astrocytes,²³⁵ recruitment of cyclic guanosine monophosphate–dependent pathways,²³⁶ changes in blood-brain barrier permeability to excitatory amino acids,²³⁷ and direct activity on arteriolar adenosine receptors.²³²

Carbon Dioxide Reactivity

Vascular caliber and CBF are also responsive to changes in arterial CO₂, a mechanism commonly referred to as CO₂ reactivity. Within the range of 20 to 60 mm Hg, every 1 mm Hg change in PacO₂ results in 2% to 3% change in CBF. Hypercarbia (hypoventilation) results in vasodilation and elevated CBF, and hypocarbia (hyperventilation) results in vasoconstriction and lower CBF. The process of CO₂ reactivity is fundamentally different from autoregulation, which is a compensatory or adaptive response that adjusts CBF to metabolism. CO₂ reactivity results in vessel caliber changes that secondarily affect CBF irrespective of CMRO₂ and CMRglc.

The effects of hypocarbia and hypercarbia are mediated by pH changes in the perivascular space. The effects of CO₂ changes on blood vessel diameter persist for less than 20 to 24 hours; at a constant level of PacO₂, the pH in the perivascular space normalizes, and cerebral blood vessel diameter returns to baseline.²³⁸ To maintain a constant supply of substrates to support metabolism (CMRO₂), changes in CBF due to hypocarbia or hypercarbia are compensated for by changes in AVDO₂. Again, this is fundamentally different from metabolic, pressure, and viscosity autoregulation, whereby AVDO₂ remains constant and CBF is “tuned” to metabolism.

Disturbances of Cerebral Metabolism

In patients with severe TBI that are comatose, CMRO₂ is typically reduced from a normal value of 3.2 mL/100 g per minute to between 1.2 and 2.3 mL/100 g per minute. Soustiel and associates recently correlated CMRO₂ after head injury with GCS and neurological outcome.²³⁹ Inadequate CBF, cerebral hypoxia, and mitochondrial failure following TBI compromise normal oxidative metabolism and shift cells to ATP generation through anaerobic glycolytic pathways. As a result of this shift, lactate production increases, as does the metabolic ratio (MR): MR = CMRglc/CMRO₂, or LOI. This shift toward hyperglycolysis has been demonstrated in both animal and clinical studies after severe head injury.^{153,207,240–243}

One consequence of hyperglycolysis following TBI is cerebral acidosis, which occurs frequently after severe injuries. Although lactic acid is a byproduct of anaerobic metabolism, it may have neuroprotective effects in the injured brain. For example, acidosis shifts the hemoglobin-oxygen dissociation curve to the right, improving oxygen delivery to damaged tissue. Also, acidosis optimizes tissue pH for glycolysis and causes vasodilation, which maximizes available collateral flow to the damaged region. Despite these effects, however, the recovery potential of tissue in the presence of high lactate and resultant acidosis is poor. The mechanisms by which acidosis results in cell damage likely involve electrolyte disturbances, delayed reversal of decreased CBF, and denaturation of vital proteins.^244–246

In the past, increased anaerobic glycolytic turnover was thought to simply result from compromised oxygen supply. This was largely based on the work of Vink and coworkers,²⁴⁷ who demonstrated normal mitochondrial function after severe head injury. However, calcium-free media was used in these studies, and more recent experiments have shown that TBI results in significant mitochondrial dysfunction. This mitochondrial damage appears to occur through calcium-mediated interference of respiratory chain–linked functions. This may help explain decreased AVDO₂ and increased anaerobic glycolytic turnover in patients with severe TBI. However, the fact that initial elevations of CSF lactate normalize within 12 hours of injury, before the onset of relative hyperemia and low AVDO₂, suggests that CSF lactic acidosis is still primarily due to cerebral ischemia.²⁴⁸

Recent evidence suggests that lactic acid may represent a fuel source for the injured brain.^{13,239,249,250} Following head injury, a condition of “relative hyperglycolysis” occurs during which glucose uptake is in excess of what would be predicted from oxygen consumption and lactate production.^{13,207,249,251,252} In other words, glucose is used in the brain through a pathway that is not accounted for by oxidative metabolism or glycolysis. Recent clinical studies after severe TBI have demonstrated that this is likely due to increased flux through the pentose phosphate cycle (PPC). In a recent glucose-labeling study by Dusick and colleagues,²⁵³ patients with severe TBI demonstrated an increase in PPC flux from 6.9% (control data) to 19.6%. It has been hypothesized that this increased PPC flux provides additional NADPH, which allows for recycling of the free radical scavenger glutathione and promotes fatty acid synthesis.^254–256 The PPC also produces substrates necessary for DNA repair and replication and messenger RNA synthesis, which may promote amino acid and neurotransmitter production.

Disturbances of Cerebral Blood Flow

Cerebral Ischemia

Cerebral ischemia occurs when CBF is inadequate to meet the metabolic demands of the brain. This represents a significant mechanism of secondary injury that can dramatically worsen patient outcome. Eighty percent of patients who die after severe TBI have histologic evidence of cerebral ischemia.²⁵⁷ In one study, Bouma and associates found that cerebral ischemia (CBF < 18 mL/dL with high AVDO₂ values) in the first 4 to 12 hours after injury occurs in 20% to 33% of patients with severe TBI and is predictive of worse outcome.⁹¹

Cerebral ischemia is most common in patients with acute SDH and diffuse cerebral swelling. TBI significantly lowers the brain’s threshold for ischemia—ischemic insults that are well-tolerated under normal conditions can have devastating effects after head injury.⁴ This increased vulnerability is likely due to the combined effects of abnormal excitatory neurotransmitter release, metabolic derangements, and biochemical imbalances.²²⁰

When CBF begins to decline, due to failure of pressure autoregulation or severe hypotension, protective mechanisms are recruited to increase extraction of oxygen. This results in increased AVDO₂ from baseline values of about 6.7 mL/100 mL to a maximum of about 13 mL/100 mL.²²⁰ Once maximized, further reduction of CBF results in neuronal abnormalities such as synaptic dysfunction (50% of energy expenditure). This is followed by membrane failure, sodium-potassium pump arrest, cell swelling and dysfunction, and eventual cell death. Using an arterial occlusion model of ischemia, the CBF threshold at which these changes occur is at 18 mL/100 g per minute.²⁵⁸ Following severe TBI, however, this threshold is likely elevated to about 20 mL/100 g per minute.²⁵⁹ Neuronal dysfunction and death depend on both the duration and magnitude of CBF depression after injury (Fig. 331-5). Langfitt and Obrist suggested three hypothetical states of brain dysfunction after head injury: brain regions that are irreversibly damaged, brain regions that are dysfunctional, and ischemic brain (Table 331-11).²⁶⁰

FIGURE 331-5 Cerebral blood flow (CBF) and neuronal dysfunction.

TABLE 331-11 Three Hypothetical States of Brain Dysfunction after Head Injury

Although microdialysis (MD) probes can be used to monitor markers of cerebral metabolism, these do not always correlate with cerebral ischemia. This was recently demonstrated by Vespa and associates,²⁶¹ who performed both MD probe and PET monitoring in patients with severe TBI. MD data demonstrated a 25% incidence of elevated lactate-to-pyruvate ratio (to above 40) and a 2.4% incidence of ischemia; however, only 1% of patients had ischemia on PET. The authors concluded that TBI results in a “metabolic crisis” that may affect intracellular metabolic pathways, but this does not necessarily represent cerebral ischemia.

Impaired Cerebrovascular Reactivity

Although cerebrovascular reactivity and autoregulation are often abnormal after severe head injury, there is significant variability with respect to the incidence, magnitude, and duration of this disturbance. Derangements are often confined to local brain regions^262–265 and may affect different mechanisms of cerebrovascular regulation in varying ways.²²⁰ For example, CO₂ reactivity is often preserved in the presence of impaired pressure autoregulation.^262,266,267

Metabolic Autoregulation

Although comatose patients typically experience reduction of CMRO₂ from a normal value of 3.3 mL/100 g per minute to about 2.1 mL/100 g per minute,²⁶⁸ this is not always accompanied by a proportional decrease in CBF. This disturbance in metabolic coupling has been demonstrated in both pediatric and adult TBI patients and is most common in the first 24 hours after injury.^215,269,270 In fact, only 45% of patients with severe TBI demonstrate normal metabolic coupling after injury.²⁷⁰

Metabolic uncoupling occurs when CBF exceeds CMRO₂, a phenomenon termed luxury perfusion or hyperemia. Obrist and colleagues defined luxury perfusion in comatose head-injured patients as CBF above 33 mL/100 g per minute; CBF of 33 to 55 mL/100 g per minute represents relative hyperemia, and CBF above 55 mL/100 g per minute is absolute hyperemia.²⁷⁰ These limits were based on reports that patients with severe TBI normally demonstrate CMRO₂ values that are half of normal (i.e., 1.6 mL/100 g per minute). Therefore, CBF values above half of normal suggest uncoupling of metabolism and flow, and values that are more than 2 standard deviations above the mean CBF found in head-injured patients reflect absolute hyperemia. Similarly, an AVDO₂ value of less than 4 has been considered a threshold value for uncoupling, with CBF exceeding metabolic demand. Hyperemia is most prevalent between 1 and 5 days after TBI.^{271, 272}

Hyperemia is a critical concept in TBI because it is strongly associated with diffuse cerebral swelling and elevated ICP.^270,273 It should be noted that these observations were based on measurements of CBF, and because of the complex physiology after TBI, it is likely that CBF does not accurately reflect CBV. Subsequent studies by Bouma and associates²⁷⁴ found that although CBV is significantly increased in many patients with elevated ICP, increased CBV does not consistently correlate with radiographic evidence of cerebral swelling. In these patients, therefore, factors other than vascular engorgement (e.g., cytotoxic edema) may play a critical role. In fact, in patients with acute SDH, elevated ICP, and cerebral ischemia, CBV is half of normal. In the acute setting after TBI, therefore, severely increased ICP is likely not due to vascular engorgement.

Hyperemia or vascular engorgement has long been implicated in diffuse cerebral swelling and raised ICP in children after severe head injury. This was based, in large part, on observations by Bruce and colleagues²⁷³ of diffuse bilateral swelling on CT in 63 of 214 children with severe head injury. Density of deep frontal white matter (expressed in Hounsfield units) during and after resolution of swelling was measured in 12 children in this study. Although there was a significant difference between these two time points, no density differences were found between children with edema and controls.²⁷³ Nonetheless, the concept of hyperemia has influenced therapy for the treatment of high ICP in young children. Vigorous hyperventilation to lower ICP has been advocated because it was thought that children have adequate reserve to protect from induced ischemia. However, prolonged hyperventilation may have detrimental effects in children after TBI. In a study of 23 children with severe TBI, Skippen and coworkers²⁷⁵ demonstrated regions of ischemia (defined as CBF < 18 mL/100 g per minute) in 73.1% of the patients when PacO₂ was decreased below 25 mm Hg.

Defining hyperemia after severe head injury requires an understanding of normal CBF levels in children. In a previous publication, we discussed the findings of Suzuki and colleagues,²⁷⁶ who obtained CBF data in a large series of normal unanesthetized children using the xenon-133 method.²⁷⁷ As illustrated in Figure 331-6, CBF is at its lowest value shortly after birth (mean, 40 mL/100 g per minute), then increases to a peak at 3 to 4 years of age (108 mL/100 g per minute, double the normal adult value), then decreases to 71 mL/100 g per minute at about 9 years of age, after which it slowly reaches adult levels. Similar findings were reported by Chiron and associates,²⁷⁸ although peak CBF values were not as pronounced in this study. Therefore, when interpreting CBF measurements, values should be referenced to age-appropriate normal values. Fortunately, vigorous hyperventilation has been largely abandoned by most practitioners, and current guidelines only recommend short-term use in the setting of acute neurological deterioration or ICP elevation.

FIGURE 331-6 Changes in mean regional cerebral blood flow (CBF) with age.

(From Suzuki T, Ishii I, Inoue S, et al: [Reproducibility of a non-invasive quantitative assessment of cerebral blood flow using 123I-IMP SPECT]. Kaku Igaku. 1990;27:1331.)

It is important to note that luxury perfusion is defined in terms of CMRO₂, and many assume that cerebral metabolism must be depressed after severe TBI because it is primarily oxidative in nature. However, CBF is functionally coupled to CMRglc,^279,280 and what is termed “luxury” may actually be an appropriate response to increased glucose turnover (hyperglycolysis) after TBI.^207,281 As suggested by Bergsneider and colleagues,²⁰⁷ the metabolic state of the brain should be differentially defined in terms of glucose and oxygen metabolism. This is particularly important in the management of severe TBI because certain therapeutic interventions (e.g., hyperventilation) may affect so-called luxury CBF that is, in fact, essential for ATP generation.

Pressure Autoregulation

Because many neurocritical care interventions can affect vascular hemodynamics, pressure autoregulation after severe TBI is a topic of significant interest.^{215,266,267,282,283} Enevoldsen and Jensen²⁶⁵ found that pressure autoregulation is usually intact during the first few days after head injury and is only temporarily dysfunctional, with no apparent effect on outcome. Others have found that pressure autoregulation is always intact during the first 36 hours after injury, but then absent in 50% of patients between 36 and 96 hours after injury.²⁶⁷ Overgaard and Tweed²⁸³ related autoregulatory capacity to clinical outcome and found that patients had a better outcome when autoregulation was intact in the first 7 days after injury; however, no such correlation could be found after the first week.

Bouma and associates²⁸² performed autoregulation tests in 117 severely head-injured patients. CBF measurements were used to monitor the effects of increases (through administration of phenylephrine, an α-adrenergic agonist that does not affect cerebral vessels)^284–286 and decreases (through administration of trimethaphan camsylate, a ganglion blocker without effect on cerebral vessels)²⁸⁷ in mean arterial pressure (MAP). Autoregulation was intact if the percentage change in CBF per percentage change in CVR was between 0% and 2%.^213–215 After performing 158 tests in 117 adult patients, they found that autoregulation was intact in 51% of patients. However, no specific temporal pattern or relation to clinical status could be determined.

The mechanisms responsible for abnormal pressure autoregulation after TBI are poorly understood. One clinical study suggests that brainstem lesions from severe TBI may affect an “autoregulatory center” that is necessary for normal pressure autoregulation.²⁶⁶ In a study of multimodality evoked potentials in severely head-injured children, Muizelaar and associates²¹⁵ did not find a relationship between autoregulatory status and lesion site. In this study, pressure autoregulation was defective in 15 of 37 children.

Endothelial damage may be responsible for the perturbation of pressure autoregulation. In experimental brain injury, endothelial lesions are often present with severe ischemia or trauma.²⁸⁸ Oxygen radicals generated after injury may also cause endothelial damage.^289,290 There are data suggesting that impairment of vascular reactivity can be prevented with administration of oxygen radical scavengers.^291,292

Viscosity Autoregulation

Few studies have specifically evaluated the status of viscosity autoregulation after severe TBI.^216,217 Viscosity autoregulation was first suggested by Muizelaar and associates²¹⁸ following observations in cats, and subsequent clinical studies have evaluated the response of CBF to bolus administration of mannitol.¹⁷ In patients with intact pressure autoregulation, 18% demonstrate a 10% increase in CBF following mannitol administration. On the other hand, 79% of patients with defective pressure autoregulation experience greater than 10% increase in CBF after mannitol administration. In total, 38% of patients demonstrated impaired viscosity autoregulation after head injury. Mannitol resulted in at least 10% decrease in ICP in 86% of patients with intact pressure autoregulation, but in only 35% of those with impaired pressure autoregulation (Table 331-12). These findings suggest a close correlation between the response of CBF and ICP to mannitol and the status of viscosity autoregulation.

TABLE 331-12 Changes in Intracranial Pressure (ICP) and Cerebral Blood Flow (CBF) Larger than 10% of Baseline after Mannitol Administration

	AUTOREGULATION INTACT	AUTOREGULATION DEFECTIVE
Decreased ICP	86%	36%
Decreased CBF	18%	79%

Data from Muizelaar JP, Lutz HA, Becker DP. Effect of mannitol on ICP and CBF and correlation with pressure autoregulation in severely head-injured patients. J Neurosurg. 1984;61:700-706.

Hypertonic saline also has beneficial effects on ICP and CPP, likely due to similar mechanisms involving serum osmolarity and blood rheology. Although some authors advocate its use as resuscitation fluid or an intermittent therapy for elevated ICP,^293–297 there are insufficient data to support its general use in current TBI guidelines.²⁹⁸

Carbon Dioxide Reactivity

CO₂ reactivity is typically preserved after severe head injury. Although it may be mildly decreased in the first 24 hours, in most cases it returns to a normal 3% change per mm Hg CO₂ after day 1.^{266,267,270,283,299–301} In experimental studies, CO₂ reactivity is transiently decreased in the first few hours after injury but then normalizes.^13,302 Patients with persistently impaired CO₂ reactivity after TBI typically die or survive with severe neurological deficits.^270,283 The pathologic mechanisms leading to disturbed CO₂ regulation are poorly understood but may involve free radical pathways. In a feline model of TBI, free radical scavengers have been shown to prevent the loss of CO₂ reactivity following injury.³⁰²

Marion and colleagues²⁷¹ used stable xenon-enhanced CT to determine CO₂ vasoresponsivity in 17 patients with severe TBI. Hemispheric, lobar, basal ganglia, and midbrain CBF values before and after hyperventilation were used to determine CO₂ reactivity as the percentage change in CBF per mm Hg PcO₂. This study found that 16 of 17 patients had significant differences between global reactivity and regional CO₂ reactivity in at least one brain region. These differences were sometimes as large as 50%, particularly in patients with SDH or diffuse cerebral contusions. The clinical implications of this finding are discussed later in this chapter.

Cerebral Blood Flow, Cerebral Blood Volume, Arteriovenous Difference in Oxygen, and Autoregulation

The autoregulatory status of patients with TBI determines the effects of many therapeutic interventions, particularly those that manipulate ICP or CPP. As discussed previously, CBF is influenced by vascular diameter, blood viscosity, and CPP, whereas CBV is determined by vascular diameter alone. Therefore, alterations in CBF, CBV (ICP), and AVDO₂ in response to a variety of physiologic and pathologic conditions can be understood (Table 331-13):

Elevated Intracranial Pressure

Elevated ICP (>20 mm Hg) is a common complication of severe TBI that is persistent in 50% of patients with intracranial mass lesions and 33% of those with diffuse injuries.³⁰³ ICP higher than 20 is a significant independent determinant of outcome,³⁰⁴ and a recent study of 233 patients found ICP greater than 15 to be one of five independent risk factors for death.³⁰⁵ Patients whose ICP is maintained below 20 mm Hg have significantly better outcome.³⁰⁶ A recent systematic review found that ICP of 20 to 40 increased mortality by 3.5-fold, and ICP above 40 increases mortality by 6.9-fold; raised but reducible ICP increases mortality by 3- to 4-fold, and refractory ICP is associated with an odds ratio for death of 114.3.³⁰⁷ The number and duration of elevated ICP episodes significantly correlates with worse functional outcome and death after TBI.^303,308,309

Intracranial pressure is often measured from CSF pressure, which is defined as the pressure one must exert against a needle introduced into the CSF space to prevent escape of fluid.³¹⁰ Four parameters describe the static and dynamic CSF pressure: (1) the rate of CSF production, (2) the variable compliance given by the exponential relationship of CSF pressure to volume, (3) the outflow resistance, and (4) the intradural sinus pressure.³¹¹

The Monro-Kellie doctrine states that the total volume of intracranial contents (CBV, CSF, and brain parenchyma) is constant. An increase in one of the three compartments must be accompanied by an equal decrease in one of the other compartments to maintain constant ICP.^13,312–314 Much of this compensation occurs by translocation of CSF and venous blood from the intracranial vault, but at a certain point (decompensation), this volume-buffering capacity is exhausted, and an exponential pressure rise occurs with further volume addition (Fig. 331-7). Marmarou and associates plotted this curve on a semilogarithmic scale to create a straight line (Fig. 331-8).³¹¹ The slope of this line is the pressure-volume index (PVI), the amount of volume that must be added or withdrawn from the craniospinal axis to increase or decrease ICP 10-fold:

FIGURE 331-7 The exponential pressure-volume curve. ICP, intracranial pressure.

FIGURE 331-8 Relation between pressure and volume plotted on a semilogarithmic scale. PVI, pressure-volume index.

Change in volume is represented by ΔV, ICPo is the pressure before volume change, and ICPi is the pressure after volume change. Thus, PVI is a measure of compliance (ΔV/ΔP) or tightness of the brain. Brain compliance can be estimated by injecting or withdrawing small quantities of fluid into or from the CSF space with simultaneous recording of ICP. This involves repeated injections of 2 to 3 mL into the CSF space, typically through lumbar infusion. Compliance can also be estimated or derived by analyzing the slope and amplitude of the ICP pressure wave.^315–317

Normal PVI is 26 ± 4 mL³¹⁸: 26 mL of volume raises ICP from 1 to 10 mm Hg, but the same volume also raises ICP from 10 to 100 mm Hg. Conversely, the addition of only 6.4 mL increases ICP from 10 mm Hg to the treatment threshold of 20 mm Hg, demonstrating the sensitivity of ICP to volume changes.^319,320

Another measure of brain compliance is the volume-pressure ratio (VPR). VPR represents the slope of the pressure-volume curve at a given level of ICP and is defined as the change in ICP achieved by a 1-mL bolus addition of CSF volume.^321,322 Under steady-state circumstances, VPR is related to PVI by the following equation: VPR = Po/(0.434 PVI).³¹⁹

The precise sequence of events leading to ICP elevation and the exact contribution of each component remain elusive. The following five pathways of intracranial volume increase were described by Marmarou³¹⁹: (1) CSF system, (2) CBV, (3) blood-brain barrier damage–associated edema (vasogenic edema), (4) neurotoxic edema, and (5) ischemic edema. CSF components (CSF resistance to outflow and absorption) account for about one third of ICP elevation. This component can increase substantially in patients with SAH who experience outflow resistance owing to blockage of CSF flow through arachnoid villi. The remaining two thirds of ICP elevation is attributed to a vascular component: increased blood volume (pathway 2) and increased tissue water (vasogenic, neurotoxic, and ischemic edema—pathways 3, 4, and 5).³²³ Neurotoxic and ischemic edema are thought to be of cellular origin, whereas edema due to blood-brain barrier damage is extracellular in nature.

CBV is determined by the total diameter of the cerebrovascular bed. Most blood volume is contained in cerebral veins, with only 20 mL (one third of total CBV) located in cerebral resistance vessels (15 to 300 µm). Autoregulatory and CO₂-dependent responses result in diameter variations between 80% and 160% of baseline, resulting in volume changes between 64% and 256% of baseline. With a baseline CBV of 20 mL in the resistance vessels, CBV ranges from 13 mL (maximal vasoconstriction) to 51 mL (maximal vasodilation). Assuming a PVI of 26, a change from maximal vasoconstriction to maximal vasodilation would be accompanied by an almost 29-fold change in ICP (assuming other regulatory mechanisms such as CSF outflow are not operant).

Klatzo categorized cellular edema into neurotoxic and ischemic.³²⁴ Ischemic edema is primarily due to disturbance of cellular osmoregulation from ionic pump failure. Neurotoxic edema is caused by excessive release of excitatory amino acids, loss of calcium and potassium homeostasis, and generation of free radicals. In a series of experiments at the Medical College of Virginia, Barzo and colleagues^325,326 investigated the role of vasogenic and cellular edema in a rodent model of diffuse brain injury. Using diffusion-weighted MRI to determine the apparent diffusion coefficient and T1 sequencing to map total brain water, they found a biphasic development of vasogenic and cellular edema. The apparent diffusion coefficient increased with vasogenic edema and decreased with cytotoxic edema. Initially (i.e., in the first 40 minutes), an increase in the apparent diffusion coefficient was observed, consistent with an increase in extracellular fluid. This increase in extracellular volume is thought to be the result of blood-brain barrier compromise. Total water content was increased slightly 1 hour after injury. Forty to 60 minutes after injury, however, the apparent diffusion coefficient started to decrease, reaching a minimum in the second week after TBI. Total brain water remained increased, suggesting delayed intracellular fluid accumulation or cellular edema. No distinction between neurotoxic and ischemic edema could be made in this study.

Secondary Displacement of the Brain

Any discrete, expanding intracranial mass lesion can lead to brain herniation or shift of brain tissue through existing rigid openings in the dura and skull, thereby causing brain compression and raised ICP. Displacement of the brain by expanding lesions and raised ICP are important mechanisms of secondary injury. Brain herniation occurs in five major patterns, and each is associated with a characteristic clinical presentation (Table 331-14).¹⁴³

TABLE 331-14 Sites of Brain Herniation, Structures Involved, and Resulting Clinical Symptoms

Systemic Hypotension

Hypotension is one of the five most powerful indicators of outcome after TBI^2,304 and strongly correlates with poor neurological recovery.^{2,304,329–331} A single episode of hypotension after TBI increases morbidity and doubles mortality,² whereas two or more episodes increase the relative risk for mortality to 8.1.³³⁰ During the initial resuscitation phase, hypotension, and not hypoxia, significantly affects patient outcome.³³⁰ The total duration of hypotensive episodes is a significant predictor of morbidity and mortality.³³² In a review of the TCDB, hypotension occurred in 35% of 717 patients with severe TBI and resulted in a 150% increase in mortality.² In patients with intact pressure autoregulation, hypotension may trigger cerebral vasodilation with subsequent ICP elevation. Therefore, a management protocol that aggressively prevents hypotension has been shown to significantly improve outcome after TBI.^333,334Currently published guidelines recommend maintaining systemic blood pressure (SBP) above 90 mm Hg after TBI.³² However, more recent reports from the IMPACT study suggest that this threshold should be raised to 135 mm Hg. In this report, “best outcomes” were found in patients with SBP of about 135 mm Hg and MAP of about 90 mm Hg, with lower or higher levels corresponding to worse neurological outcome.³³⁵

Systemic Hypoxia

Hypoxemia is also one of five powerful indictors of patient outcome after TBI.² Severe oxygen desaturation (<60%) during transport to the hospital is associated with a 3.5-fold increase in mortality,³³⁶ and duration of in-hospital oxygen desaturation (<90%) is an independent predictor of mortality.³³² A more recent study of TBI patients transported by helicopter from the scene of an accident found that a secondary hypoxic insult during transportation occurred in 24.7% and corresponded to a mortality rate of 37%.³³⁷ In this study, in patients with severe TBI, hypoxia occurred in 35% and doubled patient mortality.³³⁸ Data from the TCDB demonstrated an increase in mortality after severe TBI from 27% to 50% when hypoxia occurred. Data from the IMPACT study have also demonstrated the strong correlation between postinjury hypoxia and poor neurological outcome,³³¹ and current published guidelines recommend maintaining oxygen saturation above 90% and PaO₂ above 60 mm Hg at all times.³²

In clinical practice, it is important to identify mechanisms that typically result in hypoxia after head injury. For example, in the acute injury phase, hypoxia is typically due to severe hypoventilation, airway obstruction, aspiration, or hemothorax and pneumothorax. On the other hand, in the first 24 to 48 hours after TBI, most episodes result from lung contusions, atelectasis, fat emboli, pneumonia, or acute lung disease.

TBI followed by hypoxia results in widespread edema, ischemic changes, and poor functional outcome.^339,340 The effects of hypoxia are not limited to disturbance in substrate supply but may also involve changes in ICP. During a hypoxic episode, CBF is increased by compensatory vasodilation to support CMRO₂. This results in increased CBV and resultant elevation of ICP, particularly in patients with poor brain compliance (PVI). In normal adults, a PaO₂ of 40 mm Hg increases CBF by 35%, and a PaO₂ of 35 mm Hg increases CBF by 70%.³⁴¹ An even more detrimental CBF response to hypoxia has been described in a feline model of fluid percussion injury: higher levels of injury (>2 atmospheres) severely impaired cerebrovascular reactivity such that hypoxia resulted in an actual decrease in CBF in some animals.³⁴²

Other Causes of Secondary Cerebral Damage