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Fig. 1. Schematic showing the relation between CBF and ischemic duration/tissue infarction. (Adapted with permission from Jones et al., 1981.)

arterio venous difference of oxygen (AVDO2) of (13-6.7) = 6.3 vol% (ml of 02/100ml of blood). Knowing how much blood is flowing to the brain (~50ml/100g brain tissue/min) and how much oxygen the brain extracts from this blood (AVD02), one can calculate cerebral metabolic rate of oxygen (CMR02):

CMR02 = CBF x AVD02

which is generally 3.2ml (of 02/100g of brain tissue/min) (Gibbs et al., 1942).

Cerebrovascular reactivity

There are two circumstances in which the brain governs its own flow. In one, CBF changes proportionally with changes in CMR02 — metabolic autoregulation. In the other, CBF remains constant despite changes in blood pressure or ICP (together CPP = MABP - ICP, where CPP is cerebral perfusion pressure and MABP is mean arterial blood pressure) — pressure autoregulation — and blood viscosity — viscosity autoregulation (McHenry et al., 1974; Muizelaar et al., 1986; Muizelaar, 1989).

Metabolic-, pressure-, and viscosity-autoregula-tion have in common that AVD02 remains essentially constant (under physiologic conditions), considering CMR02 = CBF x AVD02.

Another important factor to be considered is carbon dioxide (C02) reactivity: with hyperventilation (resulting in low blood C02 levels) cerebral vasoconstriction occurs with an ensuing lower CBF and higher AVD02, whereas with high blood C02 levels the reverse occurs (Muizelaar et al., 1991). Autoregulation is fundamentally different from C02 reactivity: while in both metabolic and pressure autoregulation vessel diameter changes are compensatory responses to maintain a constant AVD02, in C02 reactivity the diameter changes are primary and CBF and AVD02 follow passively. Thus, C02 reactivity differs from any before-mentioned type of autoregulation in that AVD02 changes. It appears not to be an adaptive response of the brain to changing circumstances.

Physiology of cerebral blood flow (CBF) and cerebral blood volume (CBV)

The factors governing CBF are expressed in the Hagen-Poiseuille equation:

CPP x d4

8 x / x v where k is a constant, CPP cerebral perfusion pressure in turn defined by mean arterial blood pressure (MABP) minus intracranial pressure (ICP), d diameter of the blood vessel, l the length of the blood vessel (which is practically constant), and v blood viscosity. The most powerful factor in this equation is vessel diameter. For instance, the maximum constriction that can be obtained by hyperventilation is ~20% from normal baseline (Kontos et al., 1977). This however, leads to a decrease in CBF of ~60% from a normal value of 50 ml/100 g/min to 20 ml/100 g/min. Practically all of this diameter regulation takes place in the microcirculation, especially in the arterioles with a diameter of 300-15 m (Kontos et al., 1977, 1987).

The most intense changes in diameter and therefore, cerebral blood volume occur in the microcirculation. Although it is unclear how much blood is to be found in this part of the cerebral circulation, it is estimated to be one-third of 60 ml of total blood volume in the brain, i.e., 20ml under normal conditions (Muizelaar, 1989). With diameter ranging between 80 and 160% of baseline, this translates into volume ranging between 64 and 256% of the baseline 20 ml; 13 ml with maximum vasoconstriction, and 51 ml with maximal vasodilatation.

Although many different factors are essential in maintaining adequate CBF, it is suggested that local metabolic factors are of primary importance in the local tissue regulation. Under normal circumstances, in areas of increased brain activity, vasoactive substances are released which alter vascular tone and local perfusion. Increased perfusion then creates a washout effect, which leads to reduction of perfusion. This feedback system allows for the modification of CBF for short periods during times of increased metabolic requirements. Several metabolic factors play a role in the autoregulation of CBF under normal conditions, such as CO2/H+ (pH), K+, adenosine, prostaglandins, and nitric oxide (NO), as well as serotonin, histamine, neuropeptide Y, vasoactive intestinal peptide, calcitonin generated peptide, and others.

Brain tissue oxygen tension

Under physiological conditions, a linear relationship exists between arterial PO2 and brain PO2 with arterial levels being ~90mm Hg and cerebrovenous levels ~35 mm Hg. Because oxygen is consumed in the tissue, cerebral tissue PO2 is best described as a continuum that can vary from ~90mm Hg very close to capillaries to much less than 34 mm Hg in more distal regions (Zauner et al., 2002).

Reductions of partial pressure of arterial oxygen (PaO2) with normal rates of CBF also lead to functional deficits. A reduction of PaO2 to 65mm Hg induces in humans an impaired ability to perform complex tasks. Short-term memory is impaired at 55 mm Hg. A PaO2 of 30 mm Hg causes loss of consciousness (Siesjo, 1978). In animal models, PaO2 reduction to 36 mm Hg cause intracellular acidosis, reductions in phosphocreatine (PCr) and ATP, and increases in intracellular lactate levels (Xiong et al., 1997). Normal human brain has a critical tissue PO2 between 15 and 20 mm Hg, below which infarction (depending on the duration) of tissue may occur (Fleckenstein et al., 1990; Maas et al., 1993; Meixenberger et al., 1993; Kiening et al., 1996; van Santbrink et al., 1996; Wu and Saggau, 1997; Zauner et al., 1997; Van den Brink et al., 2000).

Neuronal mitochondria require an intracellular PO2 of at least 1.5 mm Hg to maintain aerobic metabolism (Chance et al., 1973; Siesjo and Siesjo, 1996). If cellular PO2 is low, the driving force to deliver oxygen to the mitochondria is dramatically reduced. The minimum tissue PO2 required to provide sufficient intracellular oxygen is unknown. In addition, it has been proposed that the diffusion distance for oxygen from the microvasculature may increase after TBI due to astrocytic swelling, generalized tissue swelling, and tissue damage. In these situations the brain might require higher tissue oxygen tensions to maintain sufficient tissue oxygenation (Zauner et al., 2002).

Oxygen and hemoglobin

Flow of oxygen from the alveoli to the mitochondria in the brain is dependent on hemoglobin and PO2.

Once oxygen has diffused from the alveoli into pulmonary blood, it is transported by hemoglobin to the cerebral tissue capillaries where it is released for use, by mitochondria. The presence of hemoglobin in the erythrocytes of the blood allows

Fig. 2. The oxygen-hemoglobin saturation curve, including the effect of hypothermia and hyperventilation. (Adapted with permission from Guyton, 1986.)

Fig. 2. The oxygen-hemoglobin saturation curve, including the effect of hypothermia and hyperventilation. (Adapted with permission from Guyton, 1986.)

transporting 30-100 times as much oxygen as could be transported simply in the form of dissolved oxygen in blood without hemoglobin. The affinity of oxygen for hemoglobin is best expressed by the oxygen-hemoglobin saturation curve as seen in Fig. 2 (Guyton, 1986). This physiological system is unique in that it favors the binding of oxygen to hemoglobin in the lungs and the release of oxygen in the periphery. In the lungs, the curve favors M00% hemoglobin saturation at or around normal alveolar oxygen tensions, whereas in the periphery the rate of oxygen delivery is proportional to the difference in oxygen partial pressure (PO2) between capillary blood and the tissue cells. Oxygen use, by the mitochondria, is responsible for creating the driving force for oxygen delivery.

It is interesting to note the effect of temperature and hyperventilation on tissue oxygenation. A decrease in temperature as well as hyperventilation (alkalosis), shifts P50 (i.e., the oxygen tension at which hemoglobin is 50% saturated) to the left thus reducing tissue oxygenation due to increased Hb-O2 affinity and thus, decreased O2 unloading to tissues.

Cerebral energy metabolism

Under normal circumstances, the brain requires large amounts of energy. Although the brain comprises only 2-3% of whole body weight, up to 20% of energy generated in the whole body is used by the brain.

Fifty percent of the energy produced by the brain is needed for synaptic activity; 25% is used for restoring ionic gradients across the cell membrane. The remaining energy is spent on biosynthesis such as maintaining membrane integrity and other processes. If the synthesis of ATP is insufficient, homeostatic mechanisms deteriorate, intracellular concentration of calcium increases, and cell death is inevitable.

Most of the energy is consumed by the neurons. Although glial cells account for almost half of the brain volume, they have a much lower metabolic rate and account for less than 10% of total cerebral energy consumption (Siesjo, 1984).

Under normal conditions, almost all energy in our body is produced by aerobic metabolism

(Stryer, 1988). Krebs described three stages in the generation of energy:

- Large molecules in food are broken down into smaller units. Proteins are hydrolyzed to amino acids, polysaccharides are hydrolyzed to simple sugars such as glucose, and fats are hydrolyzed to glycerol and fatty acids. No useful energy is generated in this phase.

- These numerous small molecules are degraded to a few simple units that play a central role in metabolism. Most of them are converted in the acetyl unit of acetyl co-enzyme A (acetyl CoA). A small amount of ATP is generated at this stage.

- Acetyl-CoA brings acetyl units into the citric acid cycle, where they are completely oxidized to CO2. Four pairs of electrons are transferred to NAD+ and FAD for each acetyl group that is oxidized. Then ATP is generated as electrons flow from the reduced forms of these carriers to O2 during oxidative phosphorylat-ion. Thus, most of the energy is generated in the third stage.

The metabolic patterns of the brain are strikingly different from other organs in their use of fuel to meet their energy needs (Guyton, 1986). Glucose is virtually the sole fuel for the human brain, except during prolonged starvation. The brain lacks fuel stores and hence requires a continuous supply of glucose, which enters freely at all times. It consumes ~120g daily, which corresponds to an energy input of ~420 kcal. The brain accounts for some 60% of utilization of glucose by the whole body in resting state. During starvation, ketone bodies (acetoacetate and 3-hydroxybuty-rate) partly replace glucose as fuel for the brain. Acetoacetate is activated by the transfer of CoA from succinyl CoA to give acetoacetyl CoA. Cleavage by thiolase then yields two molecules of acetyl CoA, which enter the citric acid cycle. Fatty acids do not serve as fuel for the brain because they are bound to albumin in plasma and so they do not traverse the blood-brain barrier. In essence, ketone bodies are transportable equivalents of fatty acids.

Glycolysis

Figure 3b illustrates the steps in the glycolysis that are carried out in the cytoplasm (Stryer, 1988; Zauner et al., 2002). GLUT-1 transports glucose across the blood-brain barrier. GLUT-1 also mediates uptake into the astrocyte while GLUT-3 does the same for neurons. The expression of these GLUT transporters is up-regulated in experimental models of hypoxia. The latter results in increased import of glucose for energy production.

Glycolysis is regulated by the enzyme phospho-fructokinase-1. Increased ATP demand will activate this enzyme by increasing cellular cAMP levels and thereby increasing the rate of glycolytic ATP generation.

If mitochondria become dysfunctional, even after restoring blood flow, a small amount of ATP can still be formed by glycolysis because this process does not require oxygen. In this process only a few percent of the total energy in the glucose molecule is released.

The law of mass action states that as the end products of a chemical reaction build up in the reacting medium the rate of the reaction approaches zero, thus preventing further production of ATP. The two end products in the glycolytic reactions (pyruvate and hydrogen ions) are combined with NAD+ to form NADH and H + . The quantities of these end products increase and react with each other to form lactic acid. This lactic acid can diffuse readily into the extracellular fluids and even into the intracellular fluids of other less active cells. Therefore, lactic acid represents an "escape" into which the glycolytic end products can be directed, thus allowing glycolysis to proceed far longer than would be possible if the pyruvate and hydrogen were not removed from the reacting medium. Glycolysis could proceed for only seconds without this conversion. Instead, it can proceed for several minutes, supplying the body with "considerable" quantities of ATP. In the human at rest, ~5-10% of the glucose consumed by the body manifests as a net output of lactate into blood (Siesjo, 1978; Guyton, 1986; Sokoloff, 1989; Andersen and Marmarou, 1992).

Once pyruvate has been synthesized it can either reversibly be converted to lactate and accumulated,

Kreb Cycle Within Brain Schematic

Fig. 3. (a) Schematic showing glycolysis and Krebs cycle. (Adapted with permission from Magistretti et al., 1999; Zauner et al., 2002.)

(b) Schematic showing mitochondrial electron transport. (Adapted with permission from Magistretti et al., 1999; Zauner et al., 2002.)

(c) Schematic showing the Magistretti model of coupled metabolism. (Adapted with permission from Magistretti et al., 1999; Zauner et al., 2002.)

Fig. 3. (a) Schematic showing glycolysis and Krebs cycle. (Adapted with permission from Magistretti et al., 1999; Zauner et al., 2002.)

(b) Schematic showing mitochondrial electron transport. (Adapted with permission from Magistretti et al., 1999; Zauner et al., 2002.)

(c) Schematic showing the Magistretti model of coupled metabolism. (Adapted with permission from Magistretti et al., 1999; Zauner et al., 2002.)

converted to amino acid alanine, or enter the citric acid cycle to produce energy via oxidative phosphorylation.

Citric acid cycle

The citric acid cycle that takes place in the mitochondria is shown in Fig. 3a (Stryer, 1988; Zauner et al., 2002). Under aerobic conditions, the next step in the aerobic generation of energy from glucose is the oxidative decarboxylation of pyruvate to form acetyl CoA. This activated acetyl unit is then completely oxidized to CO2 by the citric acid cycle, a series of reactions that is also known as the tricarboxylic acid cycle or the Krebs cycle. The citric acid cycle is the final common pathway for the oxidation of fuel molecules; it also serves as a source of building blocks for biosynthesis.

Oxidative phosphorylation

Figure 3b shows the electron transport chain (Stryer, 1988; Zauner et al., 2002). The NADH and FADH2 formed in glycolysis, fatty acid oxidation, and the citric acid cycle are energy-rich molecules because each contains a pair of electrons with a high transfer potential. These electrons are subsequently donated to molecular oxygen, resulting in a large amount of free energy, which can be used to generate ATP. Oxidative phosphorylation is the process in which ATP is formed as electrons are transferred from NADH or FADH2 to O2 by a series of electron carriers. This process acts as a major source of ATP in aerobic organisms. Some salient features of this process are (Stryer, 1988):

- Respiratory assemblies that are located in the inner membrane of mitochondria carry out oxidative phosphorylation. The citric acid cycle and the pathway of the fatty acid oxidation, which supply most of the NADH and FADH2, are in the adjacent mitochon-drial matrix.

- The oxidation of NADH yields 3 ATP, whereas the oxidation of FADH2 yields 2 ATP. Oxidation and phosphorylation are coupled processes.

- Respiratory assemblies contain numerous electron carriers, such as the cytochromes. The step-by-step transfer of electrons from NADH or FADH2 to O2 through these carriers leads to pumping of protons out of the mitochondrial matrix. A proton-motive force is generated consisting of a pH gradient and a transmembrane electric potential. ATP is synthesized when protons flow back to the mitochondrial matrix through an F0F1 ATP synthase complex. Thus oxidation and phos-phorylation are coupled by a proton gradient across the inner mitochondrial membrane.

Traditionally cerebral energy production has been considered to consist mainly of aerobic metabolism of glucose. Although it has long been assumed that glia and neurons use glucose as their sole energy source, recent information has suggested otherwise; astrocytes may have the ability to transport glucose across the blood-brain barrier via GLUT-1 and anaerobically metabolize it to lactate. Lactate is then released into the extracellular space, where it is taken up by neurons and consumed aerobically to generate energy as seen in Fig. 3c (Vibulsreth et al., 1987; Walz and Mukerji, 1988; Magistretti et al., 1999).

With increasing neuronal activity, potassium and glutamate are released into the extracellular space and are taken up by the astrocytes in an energy-dependent fashion causing increased astrocytic glycolysis. In traumatic brain injury conditions, aerobic metabolism is diminished due to reductions in cellular oxygen, or due to mitochondrial dysfunction, causing increased lactate accumulation.

Mitochondria

Mitochondria are oval-shaped organelles, typically mm in length and 0.5 mm in diameter. Techniques for isolating mitochondria were devised in the late 1940s. Eugene Kennedy and Albert Lehninger subsequently discovered that mitochondria contain the respiratory assembly, the enzymes of both the citric acid cycle and fatty acid oxidation. Electron microscopic studies by George Palade and Fritjof Sjostrand revealed that mitochondria have two membrane systems: an outer membrane and a

Fig. 4. Schematic of mitochondrion.

highly folded inner membrane. The inner membrane is folded into a series of internal ridges called cristae. Hence, there are two compartments in mitochondria: the intermembrane space between the outer and inner membranes, and the matrix, which is bounded by the inner membrane (Fig. 4).

Oxidative phosphorylation takes place in the inner mitochondrial membrane, in contrast with most of the reactions of the citric acid cycle and fatty acid oxidation, which occur in the matrix. The outer membrane is quite permeable to most small molecules and ions because it contains many copies of porin, a transmembrane protein with a large pore. In contrast, the inner membrane is intrinsically impermeable to nearly all ions and polar molecules. Specific protein carriers transport molecules such as adenosine di-phosphate (ADP) and long chain fatty acids across the inner mito-chondrial membrane.

Pathophysiology

Traumatic brain damage injury may be divided into primary and secondary types of injury (Verweij and Muizelaar, 1996). Mechanical forces acting at the moment of injury damage the blood vessels, axons, neurons, and glia of the brain initiating an evolving sequence of secondary changes that result in complex cellular, inflammatory, neurochemical, and metabolic alterations.

It is not within the scope of this review to describe all the changes occurring in the brain after severe head injury; only those directly related to cerebral oxygen transport and energy metabolism will be mentioned: Traumatic intracranial hematomas (intraparenchymal, subdural, and epidural) are also common after head injury. Epidural hematomas (in up to 5% of all patients admitted to hospitals for head injury, and 9% of those with severe head injury) are often the result of skull fractures causing rupture of underlying arteries or veins. If arterial in origin they can enlarge very quickly and cause rapid neurological deterioration. If surgical intervention is prompt, and no other brain injury is present, outcome can be favorable. Acute subdural hematoma (ASDH) occurs in up to 25% of all patients with severe head injury (Richards and Hoff, 1974; Hubschmann and Nathanson, 1985). In comatose patients with TBI, ASDH carries the highest mortality rate: 60-90 (Jamieson and Yelland, 1972; Gennarelli et al., 1989; Wilberger et al., 1991). In this group outcome is strikingly unfavorable due to decreased energy metabolism. On one hand, decreased energy metabolism is due to ischemia caused by increased intracranial pressure and therefore decreased perfusion pressure; on the other hand due to the underlying damaged brain being unable to use oxygen because of damaged mitochondria (Verweij et al., 2000b, 2001).

Hypotension and hypoxia

The majority of the potential clinical events after neurotrauma have been investigated with respect to their frequency of occurrence and impact on outcome, both for the prehospital and intensive care unit (ICU) periods (Chesnut et al., 1993; Jones et al., 1994). These studies have uniformly identified hypotension (SABP<90mm Hg) and hypoxia (Pa02<60torr) as the most influential. These parameters, amenable to therapeutic manipulation, seem to be the most significant predictors of poor outcome, independent of their etiologies and pre-resuscitation of secondary insults.

Admission to the ICU does not eliminate secondary brain injury. Jones et al. (1994) have reported the results of computerized online evaluation of 14 variables in 124 head-injured patients of a variety of grades admitted to the neurosurgical ICU. More than one episode of hypotension occurred in 73% of all patients, with median durations of 29 min (SABP < 90 mm Hg), 22min (SABP <80 mm Hg), and 32 min (SABP<70 mm Hg). In 40% of all cases, more than one episode of hypoxia occurred with an average duration of 12 min (Pa02<60torr), 19 min (PaO2<52 torr), and 20 min (PaO2<45torr). It has also been demonstrated that these secondary insults do not only occur in the ICU, but also during patient transport in X-ray and in OR suites (Andrews et al., 1990).

ICP and cerebral circulation

According to the Monro-Kellie doctrine, ICP is governed by the interplay between the volumes of brain (including cytotoxic edema), cerebrospinal fluid (including vasogenic or extracellular edema) and the blood within the cerebral blood vessels, all of which is within the confines of the rigid skull (Monro, 1783; Kellie, 1824). An increase in volume in one of these compartments (or epidural, subdural, or intracerebral hematoma) leads to a rise in ICP, unless this increase is compensated by an equal decrease in one of the two remaining compartments. The natural defense against rising ICP with brain swelling is the displacement of CSF from the skull: hence small compressed ventricles and absence of basal cisterns on computer tomography (CT) scans after severe trauma. Sometimes this process can be palliated by drainage through a ventricular catheter.

When one considers the Hagen-Poiseuille equation, there are two practical methods of maintaining CBF during vasoconstriction. The first is to increase CPP, which can be done by raising the blood pressure. When pressure autoregulation is intact, this maneuver in and of itself will cause vasoconstriction, and this has occasionally been used to decrease ICP (Muizelaar, 1989). More important, however, is the need to avoid low blood pressure, and hence, the effect of "perfusion pressure therapy'' may be due in part to the simple avoidance of arterial hypotension (Rosner and Daughton, 1990; Bouma et al., 1992a; Rosner et al., 1995). The second method to maintain CBF in the face of decreasing vessel diameter is to decrease blood viscosity. Again, this decrease itself leads to vasoconstriction if viscosity autoregulation is intact, and it has been argued that the viscosity lowering effect mediates a good deal of mannitol's effect on ICP (besides the osmotic effect) (Muizelaar et al., 1983, 1984, 1986). When viscosity autoregulation is not intact, lowering viscosity with mannitol can maintain CBF despite cerebral vasoconstriction associated with hyperventilation (Cruz et al., 1990). As stated previously, CBV can vary between 13 and 51 ml in the microcirculation. To comprehend what these differences in volume mean to ICP, one must consider the pressure volume index (PVI) (Marmarou et al., 1978). Pressure volume index is defined as the amount of fluid (in ml) needed to add to the intra-cranial space to make ICP rise tenfold (or withdraw to decrease ICP tenfold):

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