Weber & Maas (Eds.

)
Progress in Brain Research, Vol. 161
ISSN 0079-6123
Copyright r 2007 Elsevier B.V. All rights reserved

CHAPTER 8

Current concepts of cerebral oxygen transport and

energy metabolism after severe traumatic brain injury

B.H. Verweij1,!, G.J. Amelink1 and J.P. Muizelaar2

1
Rudolf Magnus Institute of Neuroscience, Department of Neurosurgery, University Medical Center Utrecht,
Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
2
Department of Neurosurgery, University of California at Davis Medical Center, 4860 Y Street, Suite 3740, Sacramento,
CA 95817, USA

Abstract: Before energy metabolism can take place, brain cells must be supplied with oxygen and glucose.
Only then, in combination with normal mitochondrial function, sufficient energy (adenosine tri-phosphate
(ATP)) can be produced. Glucose is virtually the sole fuel for the human brain. The brain lacks fuel stores
and requires a continuous supply of glucose and oxygen. Therefore, continuous cerebral blood flow (CBF),
cerebral oxygen tension and delivery, and normal mitochondrial function are of vital importance for the
maintenance of brain function and tissue viability. This review focuses on three main issues: (1) Cerebral
oxygen transport (CBF, and oxygen partial pressure (PO2) and delivery to the brain); (2) Energy metabo-
lism (glycolysis, mitochondrial function: citric acid cycle and oxidative phosphorylation); and (3) The role
of the above in the pathophysiology of severe head injury. Basic understanding of these issues in the normal
as well as in the traumatized brain is essential in developing new treatment strategies. These issues also play
a key role in interpreting data collected from monitoring techniques such as cerebral tissue PO2, jugular
bulb oxygen saturation (SjvO2), near infra red spectroscopy (NIRS), microdialysis, intracranial pressure
monitoring (ICP), laser Doppler flowmetry, and transcranial Doppler flowmetry — both in the experi-
mental and in the clinical setting.

Keywords: traumatic brain injury; metabolism; mitochondrial function; mitochondria; lactate; cerebral
blood flow; ischemia

Cerebral oxygen transport electro-encephalographic slowing and at 20 ml/

Cerebral blood flow
Under normal conditions, the brain has critical
thresholds for cerebral blood flow (CBF) as well as
oxygen tension (PO2). If CBF is reduced, neuronal
events will result (Astrup, 1982). Normal CBF
is !50 ml/100 g brain tissue/min (Sokoloff, 1960).
If CBF is reduced to !25 ml/100 g/min there is
!Corresponding author. Tel.: +31-30-2507059;
Fax: +31-30-2542100; E-mail: bverweij@umcutrecht.nl
100 g/min loss of consciousness occurs, but may be
tolerated without long term functional conse-
quences. Below a CBF of 18 ml/100 g/min, ionic
homeostasis becomes jeopardized and neurons
convert to anaerobic metabolism (Jones et al.,
1981; Siesjo, 1992; Schroder et al., 1996). At a
CBF of 10 ml/100 g/min, membrane integrity is
lost and irreversible brain damage is inevitable.
Tissue infarction is related to CBF but is also time
dependent as shown in Fig. 1 (Jones et al., 1981).
Arterial blood contains 13 vol% of O2, while
jugular venous blood contains 6.7 vol%, for an

DOI: 10.1016/S0079-6123(06)61008-X 111

112
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) ¼ 6.3 vol% (ml of O2/100 ml of blood).
Knowing how much blood is flowing to the brain
(!50 ml/100 g brain tissue/min) and how much
oxygen the brain extracts from this blood
(AVDO2), one can calculate cerebral metabolic
rate of oxygen (CMRO2):
CMRO2 ¼ CBF $ AVDO2
which is generally 3.2 ml (of O2/100 g 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 CMRO2 — meta-
bolic autoregulation. In the other, CBF remains
constant despite changes in blood pressure or ICP
(together CPP ¼ 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 AVDO2 remains essen-
tially constant (under physiologic conditions),
considering CMRO2 ¼ CBF $ AVDO2.
Another important factor to be considered is
carbon dioxide (CO2) reactivity: with hyperventi-
lation (resulting in low blood CO2 levels) cerebral
vasoconstriction occurs with an ensuing lower CBF
and higher AVDO2, whereas with high blood CO2
levels the reverse occurs (Muizelaar et al., 1991).
Autoregulation is fundamentally different from
CO2 reactivity: while in both metabolic and
pressure autoregulation vessel diameter changes
are compensatory responses to maintain a constant
AVDO2, in CO2 reactivity the diameter changes
are primary and CBF and AVDO2 follow
passively. Thus, CO2 reactivity differs from any
before-mentioned type of autoregulation in that
AVDO2 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 $ d 4
CBF ¼ k $
8$l$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 there-
fore, cerebral blood volume occur in the microcir-
culation. 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., 20 ml under normal con-
ditions (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 vasoconstric-
tion, 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 per-
fusion 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 con-
ditions, 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 relation-
ship exists between arterial PO2 and brain PO2 with
arterial levels being !90 mm Hg and cerebrovenous
levels !35 mm Hg. Because oxygen is consumed in
113
the tissue, cerebral tissue PO2 is best described as a
continuum that can vary from !90 mm 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 func-
tional deficits. A reduction of PaO2 to 65 mm 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 (Siesjö, 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; Siesjö and Siesjö,
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 mitochon-
dria 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 hemo-
globin in the erythrocytes of the blood allows
114
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
!100% hemoglobin saturation at or around
normal alveolar oxygen tensions, whereas in the
periphery the rate of oxygen delivery is propor-
tional 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 com-
prises 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 strik-
ingly 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 con-
tinuous supply of glucose, which enters freely at all
times. It consumes !120 g daily, which corres-
ponds 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.
115
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 re-
acting 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 (Siesjö, 1978;
Guyton, 1986; Sokoloff, 1989; Andersen and
Marmarou, 1992).
Once pyruvate has been synthesized it can either
reversibly be converted to lactate and accumulated,
116

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 mi-
tochondria 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 pyruv-
ate 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 oxi-
dation, 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, result-
ing 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.
117
– 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 car-
riers 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 sug-
gested 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 extracel-
lular 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 dys-
function, causing increased lactate accumulation.
Mitochondria
Mitochondria are oval-shaped organelles, typically
!2 mm in length and 0.5 mm in diameter. Techniques
for isolating mitochondria were devised in the late
1940s. Eugene Kennedy and Albert Lehninger sub-
sequently discovered that mitochondria contain the
respiratory assembly, the enzymes of both the citric
acid cycle and fatty acid oxidation. Electron micro-
scopic studies by George Palade and Fritjof
Sjöstrand revealed that mitochondria have two
membrane systems: an outer membrane and a
118
Fig. 4. Schematic of mitochondrion.
highly folded inner membrane. The inner mem-
brane 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, inflamma-
tory, 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 hema-
tomas (intraparenchymal, subdural, and epidural)
are also common after head injury. Epidural hem-
atomas (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 per-
fusion pressure; on the other hand due to the un-
derlying 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 out-
come, both for the prehospital and intensive care
unit (ICU) periods (Chesnut et al., 1993; Jones
et al., 1994). These studies have uniformly identi-
fied hypotension (SABPo90 mm Hg) and hypoxia
(PaO2o60 torr) 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 (SABPo90 mm
Hg), 22 min (SABPo80 mm Hg), and 32 min
(SABPo70 mm Hg). In 40% of all cases, more
than one episode of hypoxia occurred with an av-
erage duration of 12 min (PaO2o60 torr), 19 min
(PaO2o52 torr), and 20 min (PaO2o45 torr). 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 vol-
ume 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 tomo-
graphy (CT) scans after severe trauma. Sometimes
this process can be palliated by drainage through a
ventricular catheter.
When one considers the Hagen–Poiseuille equa-
tion, there are two practical methods of maintaining
CBF during vasoconstriction. The first is to increase
CPP, which can be done by raising the blood pres-
sure. When pressure autoregulation is intact, this
maneuver in and of itself will cause vasoconstric-
tion, 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 hy-
potension (Rosner and Daughton, 1990; Bouma
et al., 1992a; Rosner et al., 1995). The second
method to maintain CBF in the face of decreasing
119
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, lower-
ing viscosity with mannitol can maintain CBF de-
spite cerebral vasoconstriction associated with
hyperventilation (Cruz et al., 1990). As stated pre-
viously, CBV can vary between 13 and 51 ml in the
microcirculation. To comprehend what these differ-
ences 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):
DV
PVI ¼
Log½ICPbefore =ICPafter &
Normal PVI is 20–25 ml (Shapiro et al., 1980).
However PVI has been observed as low as 6 ml
after severe head injury, which indicates that in
going from normoventilation (PaCO2 ¼ 30 mm
Hg) to strong hyperventilation (PaCO2 ¼ 18 mm
Hg) resulting in vasoconstriction, ICP could
theoretically be decreased tenfold (Bouma et al.,
1992a). (That this is not always desirable may be
clear from the following example: PaCO2 36 mm
Hg, ICP 40 mm Hg, MABP 100 mm Hg, CBF
30 ml/100 g/min; AVDO2 6 vol% - CMRO2
1.8 ml/100 g/min; now with hyperventilation to
get ICP below the desired 20 mm Hg: PaCO2 ¼ 22,
ICP 20 mm Hg, MABP 100 mg Hg - CPP from 60
to 80 - CBF to 40 ml/100 g/min.) However, be-
cause of 20% vasoconstriction and diameter being
to the fourth power in the Hagen–Poiseuille equa-
tion, CBF drops to 16 ml — well below the thresh-
old for infarction (Jones et al., 1981), and especially
so after severe head injury. Moreover, as AVDO2
cannot rise above 10, CMRO2 will drop to 1.6 ml/
100 g/min.
If ICP is uncontrollable barbiturates are some-
times administered, lowering the cerebral meta-
bolic demands. If metabolic autoregulation is still
intact this will result in decreased blood volume
and therefore reduced ICP.
120
All of these examples are common in clinical
practice, and thus it may be obvious that a good
monitor is required to guide the management of
ICP, blood pressure, ventilatory parameters, and
blood viscosity. Although monitoring of CBF and/
or AVDO2 is ideal, there are no practical ways to
do this continuously; therefore the authors revert
to a derivate of AVDO2, i.e., SjvO2 (Cruz, 1988;
Robertson et al., 1989; Gopinath et al., 1994).
Ischemia and CMRO2
Secondary cerebral ischemia is very common after
severe head injury and is associated with an un-
favorable outcome (Graham and Adams, 1971;
Bouma et al., 1991; Siesjö and Siesjö, 1996). As
discussed earlier, CBF is closely regulated by a
number of mechanisms. However, after trauma
these mechanisms can fail resulting in ischemia.
This is especially important as the brain seems more
vulnerable to ischemia after trauma and this vul-
nerability persists for at least 24 h (Jenkins, 1989). It
has also been demonstrated that CBF is low in the
hyperacute post-traumatic period (Bouma et al.,
1991, 1992b). Increased intracranial pressure (as in
cerebral edema and subdural hematoma) and there-
fore decreased cerebral perfusion pressure appears
also to be an important cause of ischemia as well as
too vigorous hyperventilation (Muizelaar et al.,
1991; Verweij et al., 2001).
Salvant and Muizelaar suggested that a parallel
reduction in CBF and CMRO2 without an increase
in AVDO2 is consistent with diminished metabo-
lism and may be due to mitochondrial dysfunction.
Verweij et al. (2000b) demonstrated mitochondrial
dysfunction in isolated mitochondria from human
tissue. In a normal coupled relationship between
AVDO2 and CBF (AVDO2 ¼ CMRO2/CBF),
AVDO2 remains unchanged when the CMRO2
changes. If however CMRO2 remains constant,
changes in AVDO2 reflect uncoupled changes in
CBF (Robertson et al., 1989). If CBF decreases
following head injury, AVDO2 will increase as the
brain compensates by extracting a greater amount
of oxygen. A further uncompensated decline in
CBF leads to ischemia and a fall in CMRO2.
Lactate/hyperglycolysis
In animals and humans it has been repeatedly
shown that TBI induces increased brain lactate
production, which normalizes gradually after the
first few days in those who survive, but remains at
levels five to ten times normal in those who suc-
cumb. Microdialysis studies have demonstrated
that extracellular fluid glucose declines to extremely
low levels when lactate is increasing (Goodman
et al., 1999; Zauner et al., 2002). If aerobic metab-
olism fails, anaerobic metabolism remains, resulting
in hyperglycolysis and lactate production. A shift to
anaerobic metabolism will occur if ischemia is
present. If brain oxygen tension levels fall below
!20 mm Hg aerobic metabolism ceases to occur
(Zauner et al., 1997). However, if mitochondrial
dysfunction occurs, aerobic metabolism will also
shift toward anaerobic metabolism inducing the
same phenomena (Verweij et al., 2000b).
In human positron emission tomography (PET)
studies, increases in glucose metabolism are demo-
nstrated especially in the zone around contusions
and in the hemisphere underlying hematomas
(Bergsneider et al., 1997). Such tissues are often
adjacent to ‘‘low-density’’ cytotoxic edema areas
on CT scan. Human PET studies at later time
points (1–4 weeks post-ictus) and mitochondrial
analyses in the acute stage have shown uniformly
decreased metabolism, both for glucose and oxy-
gen in humans (Verweij et al., 2000b, 2001).
Marmarou as well as others have shown through
animal experiments that anaerobic cerebral metab-
olism with generation of lactate appears to occur
even in the absence of blood flow limitation (De
Salles et al., 1987). It has also been found by meas-
uring brain oxygenation, CO2 generation, pH and
temperature in parallel with extracellular fluid lac-
tate, and glucose levels measured by microdialysis
that lactate generation is increased in !65% of
measurements, even in the presence of adequate
CBF and brain oxygen levels (Zauner et al., 1997).
Mitochondrial dysfunction will explain lactate
production in these circumstances (Verweij et al.,
2000b).
High levels of ECF lactate might be harmful
to the injured brain. Marked cerebral acidosis
may exacerbate calcium-mediated damage to

intracellular enzyme systems and may also inter-
fere with ion-channel function (Siesjo, 1992). High
tissue lactate levels could foster a decline in brain
pH, as has been shown in numerous post-
traumatic animal and human studies.
The restoration of circulation after ischemia is
accompanied by normalization of the tissue lactate
concentration and the lactate-to-pyruvate ratio.
Initially there is an increase in pyruvate concen-
tration as lactate is converted back to pyruvate.
Animal studies have demonstrated that if the
resuscitation interval is prolonged, tissue lactate
remains elevated during reperfusion, suggesting
that residual tissue lactic acidosis is a sign of
mitochondrial dysfunction. Since mitochondrial
dysfunction is reversible, therapeutic intervention
might be possible (Verweij et al., 1997; Xiong
et al., 1998; Berman et al., 2000).
Rapid reversal of acidosis may be unfavorable,
as mild acidosis might be beneficial (pH paradox)
during recovery from hypoxia. There is little direct
evidence to demonstrate that lactate alone, or
substantial intracellular acidosis alone, is toxic to
normal cerebral tissues. This may be attributable
to preserved high-energy phosphate concentra-
tions, which allow potential intracellular buffering
and transport of hydrogen ions from the cell.
During ischemia, however, acidosis may injure
neurons by denaturation of proteins, lead to dam-
age of astrocytes owing to failure of membrane
transport systems, and cause promotion of iron-
dependent free radical formation. These events can
cause the inhibition of glycolysis by the complete
inhibition of the glycolytic phosphofructokinase at
a pH of 6.5 or below.
Mild acidosis might be protective in vitro and in
vivo in models of ischemia/hypoxia, by slowing
enzymatic processes and reducing energy consump-
tion and free radical production. Nonetheless,
tissue acidosis is consistently associated with
worsened ischemic outcome in vivo, which may
be augmented by hyperglycemia.
Cerebral tissue PO2/SjvO2
Cerebral oxygenation is currently monitored in two
ways: (1) measurement of jugular bulb oxygen sat-
uration, which reflects the relationship between
121
oxygen delivery to the brain and the extraction of
oxygen by the brain (Cruz, 1988; Cruz et al., 1990;
Gopinath et al., 1994); (2) local brain tissue oxime-
try by a single Clark-type electrode (or multi-
electrode also measuring PCO2, pH, and tempera-
ture), which gives information of local cerebral
tissue PO2. The relationship between SjvO2, cerebral
tissue PO2, and CBF has been well documented.
An increase in the concentration of tissue lactate
in the brain indicates a shift from aerobic to an-
aerobic metabolism in an attempt to maintain ATP
production. This shift occurs in case of low cere-
bral tissue PO2 that has been shown to occur in
!25–39% of patients with severe TBI in the first
12 h post- injury. Low brain tissue PO2 also closely
correlates with low regional CBF. It has also been
shown that low brain tissue PO2 is strongly corre-
lated with high levels of dialysate lactate in the
brain (Zauner et al., 2002). Increasing the concen-
tration of inspired oxygen to 100% has shown to
increase brain tissue PO2. In a study by Menzel
et al. (1999), statistically significant correlation
existed between brain tissue PO2 and CPP. Brain
lactate measured by microdialysis remained high
during the entire period rising later on. No corre-
lations were found between ICP, CPP, brain tissue
PO2, or lactate (brain tissue PO2 increases over the
first 30 h with an overshoot at 36–48 h). The latter
could be explained by mitochondrial dysfunction
(Verweij et al., 2000b).
Mitochondrial function after severe head injury
Mitochondria play a vital role in cell survival and
tissue development by virtue of their role in energy
metabolism and apoptosis (Nicholls and Budd,
2000; Friberg and Wieloch, 2002). Since neuronal
tissue stores and anaerobic glycolysis provides
ATP sufficient to maintain cellular function for
only 1–2 min, mitochondrial generation of ATP is
of vital importance (Siesjo, 1992). Neuronal mito-
chondria have a high capacity to store calcium
ions, thereby protecting neurons against transient
elevations in intracellular calcium concentrations
during neuronal hyperactivity. This calcium se-
questration requires negative mitochondrial matrix
potential and therefore full functional mito-
chondria with access to oxygen and pyruvate.
122

In the past, research efforts in patients with Abbreviations

severe head injury have focused on optimizing the
delivery of oxygen and glucose to the injured brain ADP adenosine diphosphate
in an attempt to maintain the ATP supply and to AMP adenosine monophosphate
avoid neuronal damage. However, limiting factors ASDH traumatic acute subdural hematoma
in synthesizing ATP are not only inadequate ATP adenosine triphosphate
delivery of oxygen and glucose but also impair- AVDO2 arteriovenous oxygen content
ment of mitochondrial function (Verweij et al., difference
1997, 2000b). Severe TBI with or without hypoxia CBF cerebral blood flow
and or ischemia results in a number of biochemical CBV cerebral blood volume
processes such as amino acid efflux and oxygen free CMRO2 cerebral metabolic rate of oxygen
radical production. This ultimately leads to mas- CoA co-enzyme A
sive ion shifts with increased calcium in the intra- CPP cerebral perfusion pressure
cellular compartment (Fineman et al., 1993). It has CSF cerebrospinal fluid
previously been demonstrated that experimental CT computerized tomography
TBI perturbs calcium homeostasis with an over- EEG electro-encephalogram
load of cytosolic calcium and excessive calcium FAD flavin adenine dinucleotide
adsorption by the mitochondrial membranes GCS Glasgow coma scale
(Sciamanna et al., 1992; Verweij et al., 1997; Xiong GLUT glucose transporter
et al., 1997). This inhibits mitochondrial function, ICP intracranial pressure
even when there are sufficient oxygen and substrate MABP mean arterial blood pressure
present. In rats, mitochondrial dysfunction begins NAD nicotinamide adenine dinucleotide
1 h after TBI and persists for at least 14 days, with NIRS near infra red spectroscopy
the maximum level of dysfunction occurring at NO nitric oxide
12–72 h (Verweij et al., 1997). The same phenom- PaCO2 arterial PCO2 tension
ena occur in patients (Verweij et al., 2000b). PaO2 arterial oxygen partial pressure
A number of critical mechanisms have been PET positron emission tomography
elucidated by which mitochondria are involved PO2 oxygen partial pressure
in cell death. Elevated cytosolic Ca2+ and oxida- PVI pressure volume index
tive stress both contribute to the opening of the SABP systolic arterial blood pressure
mitochondrial permeability transition pore (PTP), SjvO2 jugular venous oxygen saturation
which depolarizes the mitochondrion and leads to TBI traumatic brain injury
mitochondrial swelling and subsequent release of
cytochrome ‘‘c’’ from the intermembrane space.
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