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.

TABLE 331-6 Relationship between Skull Fracture and Intracranial Hematoma in Patients with Severe, Moderate, and Minor Head Injury

Subdural Hematoma

Subdural hematomas (SDHs) are located between the dura and arachnoid layer and may occur as a result of arterial or venous hemorrhage. Classically, SDHs are due to tearing of bridging veins that span the subdural space to drain cortical blood directly into dural sinuses. Many SDHs, however, result from bleeding from other structures adjacent to the subdural space, such as superficial cortical vessels. SDH can be classified as acute, subacute, or chronic, although there is no uniformity of nomenclature.^71,112,113 Pathologically, an acute SDH is composed of clot and blood (within 48 hours), a subacute SDH represents a mixture of clotted blood and fluid (2 to 14 days), and a chronic SDH is one that is in fluid phase (>14 days; Table 331-7).⁷¹ Clinically, an acute SDH becomes evident within 3 days of injury, subacute between 3 and 21 days, and chronic if more than 21 days pass between injury and clinical presentation. Radiographically, acute SDHs are hyperdense on CT scan, subacute are hyperdense to isodense, and chronic are hypodense relative to adjacent brain.

TABLE 331-7 Subdural Hematoma Classification

Acute Subdural Hematoma

Acute SDHs account for 50% to 60% of all subdural hematomas. They are most common after sudden head movements that occur with assaults or falls.⁷⁹ In a review of patients with acute SDH, 72% had suffered falls or assault, whereas only 24% experienced a motor vehicle crash.³³ Rarely, acute SDH may occur spontaneously (or after minor trauma) in patients receiving chronic anticoagulation therapy^114,115 or after rupture of a posterior communicating artery aneurysm (only four of these cases have been seen by the senior author (JPM) in more than 30 years of practice).

Most acute SDHs result from venous vascular injury at the brain surface, resulting in two distinct pathologies.¹¹⁶ The first type of hematoma, produced by contact forces and associated with contusions or lacerations, results from cortical bleeding into the adjacent subdural space and is most common at the temporal pole. This complex of subdural hematoma and damaged and necrotic brain is termed burst lobe. The second type of SDH is located over the cerebral convexity and is produced by inertial forces that tear bridging veins.^33,116 The underlying brain damage in this type of injury is usually milder and is primarily due to local ischemia from mass effect or compromised venous outflow. Rapid deterioration, as in the case of classic EDH, may accompany these lesions, especially if cortical arteries are ruptured. Despite the often relatively minor underlying brain damage, prognosis is generally poor in these patients unless the hematoma is rapidly evacuated.¹¹⁷

Cerebral ischemia plays a critical role in the pathology of SDH and has been demonstrated both experimentally¹¹⁸ and in postmortem studies.¹¹⁹ The mechanisms responsible for ischemia after SDH are poorly understood but are likely due to compressive effects of the hematoma and elevated ICP with resultant compromised CPP. Evidence of brain compression resulting in ischemia was reported by Schroder and colleagues¹²⁰; in two patients with acute SDH, preoperative CBF was in the ischemic range (<18 mL/100 g per minute), and cerebral blood volume (CBV) was about half of normal. These values normalized immediately after surgical evacuation. In a small series of five patients with acute SDHs and low GCS scores (≤5), Verweij and colleagues found ICP between 40 and 80 mm Hg, CPP between 10 and 60 mm Hg, low jugular venous oxygen saturation (40% to 60%), and low cerebral blood flow (CBF) measured with laser Doppler immediately before hematoma evacuation.¹²¹ Values began to normalize with elevation of the bone flap, opening of the dura, and subsequent hematoma removal.

Timely clot evacuation (within 4 hours) generally results in significantly improved neurological outcome.¹²² Patients with initial CT evidence of significant hemispheric or generalized brain swelling have extremely poor outcome with or without early surgery.¹²³ The prognosis of SDH is still poor in many cases. It is thought that the coexisting brain damage (DAI, contusion, laceration) is responsible for poor neurological function after injury. In a subset of patients, compression of the microcirculation and resultant low CBF may explain the poor clinical condition and outcome. Patients who deteriorate after a lucid interval (i.e., patients who “talk and die”) may be the subset of patients that experience this type of insult.¹²⁰

Chronic Subdural Hematoma

Chronic subdural hematomas typically result from nominal trauma that does not result in primary or secondary brain injury. They are most common in elderly patients, very young patients, and patients with brain atrophy and an expanded subdural space. Chronic SDHs typically evolve over weeks after a minor head injury; as a result, most patients are unable to recall a traumatic incident. Patients with chronic alcoholism, epilepsy, coagulopathy, or chronic use of anticoagulants are at increased risk for developing chronic SDH.

Chronic SDH typically results from tearing of bridging veins as they exit the subarachnoid space to drain venous blood to the transverse sinuses. In the subdural space, these vessels lack the support of arachnoid trabeculae and are tethered between the brain and adjacent venous sinus. Because these hematomas slowly expand over weeks, intracranial compensatory mechanisms allow for large clots to develop before significant mass effects occur. For example, an acute SDH that results in 10 mm of midline shift will typically result in ICP elevations above 50, but patients with chronic SDHs with midline shifts of up to 20 mm have been shown to have normal ICP. Once spatial compensation is exhausted, significant brain distortion and gradual elevation in ICP likely result in neurological deficits that lead to clinical presentation and diagnosis.

Membrane formation around a chronic SDH is a characteristic process attributed to an inflammatory response from the dura. The inner dural layer is highly vascular, and direct contact with blood products, fibrin, and fibrin degradation products in the subdural cavity is thought to elicit a nonspecific inflammatory reaction.¹²⁴ Because the arachnoid membrane has a much lower reaction potential, the inner capsule of chronic SDHs has no significant vascularity.¹²⁵

Secondary enlargement of a chronic SDH is common, but the precise cause is unknown. Gardner proposed that the membrane surrounding a chronic SDH acts as an osmotic barrier, allowing cerebrospinal fluid (CSF) diffusion into the hyperosmotic hematoma.¹²⁶ Zollinger and Gross also proposed an osmotic mechanism for enlargement of the hematoma; they thought that flow across the membrane was the result of an increase of osmotic pressure from a breakdown of hemoglobin molecules in red cells.¹²⁷ Weir, however, could not find a significant increase in osmolality of the hematoma with increasing age, nor were there any significant differences between the osmolality of blood and hematoma.¹²⁸ Sato and Suzuki used light and electron microscopy to examine the capsules of chronic subdural hematomas in 33 cases and found that in patients with neurological deficits, capillary endothelial cells in the capsule had many cytoplasmic protrusions and fenestrations, suggesting high permeability of the capillary wall.¹²⁹ Observations by Yamashima and Yamamoto¹³⁰ revealed that gap junctions frequently form between adjacent endothelial cells. Numerous blood components, including red blood cells and plasma, can be seen squeezing or spilling into the interstitial space of the outer membrane. It is no longer thought that an osmotic mechanism plays a significant role in hematoma enlargement. Either repeated microhemorrhages from the neocapillary network in the outer membrane or abnormally high vascular permeability is thought to be responsible for hematoma enlargement.^125,131

The presentation and pathophysiology of chronic SDHs are distinct from acute SDH, and neurological signs and symptoms are typically due to extra-axial brain compression rather than neurological injury. In a study by Tanaka and coworkers,¹³² chronic SDHs were shown to have no significant effect on global ICP, CPP, or CBF, but instead resulted in mechanical distortion of central brain regions (e.g., thalamus) with secondary cortical effects. As a result, neurological recovery from evacuation of chronic SDHs is often excellent. Risk for recurrence of chronic SDH after surgical evacuation has been associated with hematoma width and density, lower GCS at time of presentation, ambulation within the first 72 hours, and pneumocephalus that persists beyond 7 days after surgery.^133–135

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

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.

TABLE 331-9 Circulatory Phases after Severe Head Injury

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

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.