163  /  Perinatal Brain Metabolism  1783

163 Susan J.Vannucci and Robert C.Vannucci

Perinatal Brain Metabolism

CEREBRAL OXIDATIVE METABOLISM
The oxidative events that operate in the immature brain appear
identical to those in the brain of adult animals and humans,
although quantitative differences certainly exist. Cellular respira-
tion is that process whereby an organic substrate is consumed
to produce chemical energy (stored in high-energy phosphate
bonds, represented by ~P), with carbon dioxide and water as
the metabolic byproducts. Respiration is a highly efficient pro-
cess with minimal energy waste. Under physiologic conditions, 1
mole of glucose, the primary cerebral energy fuel, is catabolized
in the presence of oxygen to yield 36 moles of adenosine tri-
phosphate (ATP). Other substrates yield proportionately greater
or lesser energy, depending on their molecular carbon structure
and their point of entry into the oxidative pathway.
The biochemical machinery that comprises the oxidative path-
way is divided into three components—specifically, glycolysis,
a cytoplasmic process, and the tricarboxylic (Krebs) cycle and
the cytochrome system, both of which operate within mitochon-
dria1-3 (Figure 163-1). Glycolysis proceeds under both aerobic
and anaerobic conditions. In the presence of oxygen, glucose is
converted to pyruvic acid, which in turn enters the Krebs cycle
with little or no conversion to lactic acid. When oxygen is not
available, metabolites of the Krebs cycle are depleted, and glycol-
ysis is accelerated, with the formation of lactic acid in an attempt
to maintain cerebral energy stores. However, anaerobic glycolysis
is an inefficient method to generate energy (2 moles of ATP for
each mole of glucose); thus brain function cannot be maintained
on this process alone.
Glycolytic control points—that is, those reactions in which
the activities of specific enzymes govern the rate of metabo-
lism—include hexokinase, phosphofructokinase (PFK), and pos-
sibly pyruvate kinase. Of these enzymes, PFK is predominantly
rate-limiting for glycolysis in both adult and immature brain.4-6
Metabolites known to inhibit PFK activity and thus glycoly-
sis include ATP, citrate, and hydrogen ions, whereas adenosine
diphosphate (ADP), adenosine monophosphate (AMP), and
inorganic phosphate (Pi) stimulate PFK activity.2 These gly-
colytic regulatory mechanisms are of importance in the cell’s
response to hypoxia, acid-base imbalance, and other metabolic
disturbances.
CEREBRAL HIGH-ENERGY METABOLITES
Metabolites known to exist in brain that can store and transfer
energy in the form of anhydride phosphate bonds (~P) include
ATP, ADP, and phosphocreatine (PCr).1,2 Among these three, ATP
plays the critical role in the coupling of energy supply to energy
demand through substrate and oxidative phosphorylation. PCr

Glycolytic Pathway
ATP ADP ATP ADP ADP ATP

Glucose G-6-P F-6-P FDP GAP 1,3-DPG PEP Pyruvate Lactate

NADH NAD +
NAD
+ NADH NAD+
NADH CoA-SH
Co2
Acetyl-S-CoA
CoA-SH
Isocritate
+
NAD Co2
NADH
α -Ketoglutarate
Electron Transport +
NAD Co-SH
ATP ADP ATP ADP ATP ADP NADH Co2
Cyt a-a3 Cyt c Cyt c1 Cyt b Co Q10 Flavoprotein NADH Succinyl-S-CoA
GDP
02 CoA-SH GTP
Succinate
FAD+
FADH
Fumarate
H2O
Malate
+
NAD
NADH
Oxaloacetate

Krebs Cycle

Figure 163-1  Schematic diagram of the oxidative pathway. ADP, Adenosine diphosphate; ATP, adenosine triphosphate; 1,3-DPG,
diphosphoglycerate; FDP, fructose diphosphate; F-6-P, fructose-6-phosphate; GAP, glyceraldehyde phosphate; G-6-P, glucose-6-­
phosphate; NAD+, nicotinamide-adenine dinucleotide (oxidized form); NADH, nicotinamide-adenine dinucleotide (reduced form);
PEP, phosphoenolpyruvate. 
1784  XXI  /  Neurology
TABLE 163-1
Cerebral High-Energy Metabolites in Developing Rats
CONCENTRATION (mmol/kg WET WEIGHT)*
Metabolite Fetus12 Newborn12 1 Week12
ATP 2.66 2.63 2.64
ADP 0.43 0.25† 0.53
AMP 0.03 0.01 0.04
ATP + ADP + AMP 3.11 2.89 3.21
PCr 1.74 3.16† 3.33
Creatine 5.35 3.83† 4.65†
PCr + creatine 7.10 6.99 7.97†
PCr-to-creatine ratio 0.33 0.83† 0.72
*Values represent means for four to seven animals in each age-group. Fetal, new-
born, and 1-week values are for forebrain, whereas adult values are for cerebral
cortex. Data are from cited references.
†P <.05 compared with previous age-group.
ADP, Adenosine diphosphate; AMP, adenosine monophosphate; ATP, adenosine
triphosphate; PCr, phosphocreatine.
acts as a storage metabolite, whereas guanosine triphosphate
(GTP) is important in biosynthetic reactions.
Cerebral high-energy metabolites have been measured in
perinatal and adult animals by enzymatic, chromatographic, and
magnetic resonance (MR) spectroscopic techniques.4,7-11 Of the
nucleotides, ATP predominates and remains stable from term
fetal life through adulthood12,13 (Table 163-1). Lower concentra-
tions have been found in embryonic brain tissue.11 PCr concen-
tration is lower in the brains of newborn animals than in adults,
as is that of total creatine (PCr + creatine), but the PCr-to-creatine
ratio changes little with postnatal development.12,13 The lower
PCr-to-creatine ratio in the fetus presumably is the result of a
lower brain pH, owing to increased tissue lactate concentrations
and hypercapnia (the creatine kinase equilibrium reaction is
pH-dependent).12
MR spectroscopy is a technique whereby the concentration
of an organic compound in tissue can be determined by the
realignment of selected molecules using a supraconducting mag-
net.14 Almost any substance can be analyzed according to the
strength, duration, and other characteristics of the magnetic field.
Commonly examined metabolites in brain are the phosphorus-­
containing compounds, including PCr, ATP, mono- and diphos-
phate esters (including AMP and ADP, respectively), and Pi.15-18
Proton MR spectroscopy provides a measurement of numerous
hydrogen-containing metabolites; including lactate and cre-
atine.19-21 Thus MR spectroscopy is capable of ascertaining the
energy status of brain tissue in vivo under both physiologic and
pathophysiologic conditions, although usually the measurements
are semiquantitative in nature (Figure 163-2).
An investigation using MR spectroscopy in premature and
full-term newborn infants confirmed evidence from earlier stud-
ies in animals indicating that ATP levels remain relatively stable
throughout maturation.17 A more recent study, however, has sug-
gested that ATP concentrations in the human brain almost double
between the newborn period and adulthood.18 As in animals, lev-
els of PCr, Pi, and the phosphodiesters are low at birth, increas-
ing with advancing age. Calculated intracellular pH, as measured
from the chemical shift of the Pi peak relative to the PCr peak, is
7.1 in healthy newborn infants. As anticipated, the PCr-to-Pi and
the PCr-to-ATP ratios are lower in newborn infants than in adult
animals. Although the reported findings in newborn infants are
preliminary in nature, the continued use and further sophistica-
tion of MR spectroscopy can be expected to contribute substan-
tially to a full understanding of the bioenergetics of the perinatal
human brain (see further on).
PME
αATP
δ ATP
Adult13 PDE β ATP
Pi P-Cr
2.76
0.38
0.03
3.17
4.90† Newborn human infant
5.63†
10.53†
0.87
PME PDE
Pi δ ATP αATP
P-Cr β ATP
Newborn dog
Figure 163-2  Representative phosphorus nuclear magnetic
spectra for the brain of a newborn human infant and of a new-
born dog. PME, Phosphorus monoesters; Pi, inorganic phos-
phate; PDE, phosphorus diesters; P-Cr, phosphocreatine; δATP,
αATP, βATP, δ-, α-, β-adenosine triphosphate.  (Data sources:
infant:Younkin DP, et al: Unique aspects of human newborn
cerebral metabolism evaluated with phosphorus nuclear
magnetic resonance spectroscopy, Ann Neurol 16:581, 1984;
dog:Young RSK, et al: 31P NMR study of cerebral metabolism
during prolonged seizures in the neonatal dog, Ann Neurol
18:14, 1985.)
QUANTITATIVE ASPECTS OF OXIDATIVE
METABOLISM
Measurements of cerebral oxygen consumption give a quantita-
tive estimation of energy production by the brain, since oxygen is
required for the oxidative phosphorylation of ADP to ATP in elec-
tron transport by way of the cytochrome system (see previous dis-
cussion). Oxygen consumption measurements often are referred
to as the cerebral metabolic rate for oxygen (CMRo2), expressed
as mL/100 g/minute. Estimates of the CMR in developing ani-
mals initially were obtained in vitro with the use of the Warburg
respirometer to measure oxygen consumption in brain slices or
homogenates in nutrient media. Himwich and co-workers22 found
that the oxygen consumption (expressed as wet weight of tissue)
of minced cerebral tissue with glucose as substrate is 38% lower
in 7-day postnatal rats than in adults. Subsequent in vitro studies
of oxygen consumption in either the whole brain or cerebral cor-
tex from other species, including humans, indicated that the CMR
is low at birth and increases with maturation22-25 (Figure 163-3).
Changes in the rates of glucose utilization during development
tend to parallel the increases in oxygen consumption.24
Both immature and adult animals exhibit regional differences
in brain oxygen consumption in vitro.24,26,27 Himwich and
­Fazekas27 found that although total oxygen consumption in the
brain of 1-week postnatal dogs is 83% of the adult level, signifi-
cant regional differences exist that change with increasing age.
The medulla oblongata exhibits the highest rate of consumption
in the immediate newborn period but has the lowest rate for all
regions studied in the adult brain (see Figure 163-3). By contrast,
the oxygen consumption in the cerebral cortex is the lowest for
all regions analyzed in the newborn period but doubles within
5 weeks of development. These in vitro findings of regional
 163  /  Perinatal Brain Metabolism  1785

100 TABLE 163-2

Rabbit cortex Cerebral Metabolic Rate for Oxygen (CMRo2) in Developing
Oxygen consumption ( µ mol/g/hr)

Rat cortex Animals and Humans

80
Rat brain stem
CMRo2 (mL/100 g/minute)

60 Species* Fetal Newborn Adult

Dog cortex
Sheep28-31 2.0-3.7 3.9-4.8 4.2
40 Dog32,33 — 1.1 2.8
Dog brain stem Monkey34,35 — 1.1 3.2
Humans36-38 — 1.5 3.2-3.3
Human cortex
20 * *Data from cited references.
Human brain stem
*
0 TABLE 163-3
10 20 30 40 50
Postnatal age (days) Cerebral Blood Flow and Cerebral Metabolic Rates for Oxygen
in Newborn and Adult Dogs*
Figure 163-3  In vitro oxygen consumption in brains of develop-
ing animals and human fetus.  (Data sources: dog: Himwich HE, CBF (mL/100 CMRo2 (mL/100
Age-Group† g/minute) A − Vo2 (vol %) g/minute)
et al: The respiratory metabolism of infant brain, Am J Physiol
125:601, 1939; rat: Tyler DB, van Harreveld A: The respiration Newborn 24 ± 14 5.6 ± 2.5 1.1 ± 0.3
of the developing brain, Am J Physiol 136:600, 1942; rabbit: puppy33
Swaiman KF, et al: Interrelationships of glucose and glu- Adult dog32 56 ± 14 5.0 ± ? 2.8 ± 0.8
tamic acid metabolism in developing rat brain, J Neurochem
10:635, 1963; human fetus: Himwich HE, et al: Mechanisms for *Values represent means ± SD for seven newborn and adult dogs.
†Data from cited references.
the maintenance of life in the newborn during anoxia, Am J A − Vo2, Arteriovenous oxygen difference; CBF, cerebral blood flow; CMRo2,
Physiol 135:387, 1942; rabbit brain stem: data not available.) cerebral metabolic rate for oxygen.

differences in brain metabolism between young and adult ani-
mals, including humans, have been substantiated by more
recently developed in vivo techniques to measure metabolism
(see further on).
Oxygen consumption can be calculated in vivo from the Fick
principle by measuring cerebral blood flow (CBF) and the arte-
riovenous difference for oxygen across the brain:
CMRo2 = CBF (A−Vo2 )
With use of this technique, oxygen consumption has been
determined in immature animals of several species, including
humans.28-38 As shown in Table 163-2, notable species differences
exist for the rates of oxygen consumption by brain, which reflect
the age and functional immaturity of the animal at the time of the
measurement as well as species variations in the brain’s intrinsic
metabolic requirements. Specifically, CMRo2 is lower in perinatal
animals than in adults of the same species, and the more imma-
ture the animal at birth, the lower the rate of oxygen consump-
tion.This assumption is supported by measurements in newborn
dogs, which are functionally immature at birth, with values for
both CBF and CMRo2 that are 40% of respective values in adult
dogs32,33 (Table 163-3). By contrast, the newborn lamb is rela-
tively mature at birth and already exhibits a CMRo2 that is equal
to or even greater than that in adult sheep.
Oxygen consumption of the brain also has been determined in
humans, including newborn infants. The CMRo2 in young, healthy
adults is 3.3 mL/100 g/minute.37 Oxygen consumption in unanes-
thetized healthy children aged 3 to 10 years actually is higher by
23% than it is in adults; Kennedy and Sokoloff39 reported a value
of 5.2 mL/100 g/minute. Settergren and colleagues38 measured
CMRo2 in children aged 11 days to 15 years who were anesthe-
tized with nitrous oxide.The mean value for CMRo2 was 3.2 for the
entire group, and no age-related differences could be ascertained.
Garfunkel and co-workers36 found CMRo2 values of 1.1 to 2.1
mL/100 g/minute in three newborn infants anesthetized with bar-
biturate.These low values may not apply to healthy, awake infants,
however, because barbiturates are known to depress the CMRo2,40
and the subjects had severe central nervous system anomalies.
With the use of positron emission tomography (PET), the cere-
bral metabolic rate for oxygen as well as cerebral glucose utiliza-
tion (see further on) can be ascertained in human subjects. PET
is based on computed tomography (CT) except that the source
of radiation for external detection is transmitted from within the
brain outward, rather than passed through the brain as x-rays.
In PET, a positron-emitting, rapid-decay isotope, prepared by a
cyclotron, is administered to the subject.The substance circulates
to the brain, where it is metabolized, during which its positrons
combine with electrons to form γ-rays. The γ-rays penetrate the
brain, skull, and scalp and are recorded externally on a circu-
lar array of scintillation detectors. A computer mathematically
reconstructs the spatial distribution of the radioactivity within
the brain, which either is quantified or is displayed on a cathode
ray screen.Thus PET offers a noninvasive regional assessment not
only of CMRo2 but also of many other biologic processes.
Using PET with 15O-labeled water as the positron-emitting iso-
tope, Altman and colleagues41 measured CMRo2 in 11 newborn
infants of gestational ages ranging from 26 to 40 weeks. CMRo2 was
low in all of the infants and was beyond the lower range of detec-
tion in two. In those infants in whom radioactivity was detectable,
CMRo2 ranged from 0.2 to 1.3 mL/100 g/minute, well below the
measured value for human adults of 3.3  mL/100  g/­minute. The
findings indicate that as discussed earlier for perinatal animals,
cerebral oxidative metabolism, especially in small premature
infants, is low, reflecting the functional immaturity of the brain
(as also suggested by the work of ­Yoxall and Weindling42). A less
likely proposal, offered by Altman’s group,41 is that the energy
requirements of the fetal and prematurely newborn brain are met
by nonoxidative metabolism, that is, anaerobic glycolysis (but see
further on).
GLYCOLYSIS
As mentioned previously, rates of glycolysis or the glycolytic flux
is controlled by specific, rate-limiting enzymes that are either
inhibited or activated by changes in the biochemical milieu of
the cytoplasm. Thus aerobic glycolysis is stimulated by those
1786  XXI  /  Neurology
stresses that increase the energy demands of the tissue—spe-
cifically, stimulant drugs and hormones, hyperthermia, and sei-
zures. Anaerobic glycolysis is stimulated by hypoxia or cerebral
ischemia, or both, in an attempt to maintain optimal cellular
energy balance despite the oxygen debt. Glycolysis is inhibited
by sedative and anesthetic agents, hypothermia, and acidosis, all
of which are associated with reduced energy needs of the tis-
sue. Glycolysis can never cease completely, because at least some
energy is always required to maintain ionic gradients across cel-
lular and subcellular membranes, without which cellular integ-
rity is compromised.
The extent to which glycolysis and thus oxidative metabolism
can be turned on or off is not entirely known. In adult animals,
deep barbiturate anesthesia sufficient to produce an isoelectric
signal on the electroencephalogram reduces metabolism by no
more than 50%,43 suggesting that up to 50% of cellular energy
production is required for maintenance of biochemical and
morphologic integrity, whereas the remainder is devoted to the
generation of action potentials and to biosynthetic processes.
The extent to which glycolysis can be stimulated (glycolytic
capacity) also is conjectural, although studies in experimental
animals suggest that glycolytic flux can be accelerated up to
8- to 10-fold during extreme metabolic stress, that is, seizures or
hypoxia-ischemia.2 In this regard, both basal glycolytic flux and
glycolytic capacity are lower in immature animals than in their
adult counterparts, in keeping with intrinsically lower rates of
oxygen consumption and hence metabolic demands. For exam-
ple, the calculated rate of cerebral glycolysis of the perinatal
rat is approximately 10 μmol of glucose/100 g/minute,44 which
is one tenth of the calculated rate for adult rat cerebral cor-
tex.45 During total cerebral ischemia, produced by decapitation,
glycolytic flux in newborn rat brain increases five-fold, com-
pared with an eight-fold increase in adult rat brain.44,45 Thus
the ability of perinatal animals to survive a prolonged period
of hypoxia or anoxia compared with that of adults46 cannot
be explained by a heightened capacity of the immature brain
to generate energy equivalents through anaerobic glycolysis.
Rather, lower cerebral energy demands and hence metabolic
requirements underscore the perinatal animal’s resistance to
hypoxia-ischemia.9,44
MITOCHONDRIAL DEVELOPMENT
Because the mitochondria produce the vast bulk of energy
utilized for cellular needs, these “powerhouses” have been
investigated during maturation of the brain. Investigators have
demonstrated a relative deficiency in the oxidative phosphor-
ylating capacity of mitochondria that characterizes the imma-
ture brain.47 Simply put, the immature brain appears to be less
able to synthesize ATP per molecule of oxygen consumed. This
coupling of ATP to oxygen, expressed in terms of the ATP/O or
P/O ratio, is 3 for the oxidized form of nicotinamide-adenine
dinucleotide (NAD+)-linked cytochrome components in adult
rat brain.48 Holtzman and Moore49 have measured P/O ratios in
several regions of rat brain during maturation. Ratios for 1.5 for
NAD+-linked substrates were found in animals 1 to 11 days of
postnatal age.Thereafter, ratios increased to 2.4 in pons-medulla
and 2.8 in cerebral cortex.The data ­indicate that the brain cell’s
increasing efficiency for oxidative phosphorylation (improved
coupling) reflects both an increase in the number of mitochon-
dria and an inherent change in their function.
The functional advantage of these mitochondrial changes
appears to lie in the pattern of growth of the central ner-
vous ­system. A striking increase in mitochondrial cell number
accompanies neuronal and glial cell hypertrophy secondary
to axonal and dendritic expansion.50 Furthermore, as individ-
ual cells enlarge, the cell surface-to-volume ratio increases—
a ­circumstance that raises the energy required to maintain
ionic gradients across the membrane and to propagate action
potentials.51
CEREBRAL ENERGY UTILIZATION
Energy utilization by the brain can be inferred from measure-
ments of oxygen or substrate consumption, because under
steady-state conditions, energy demand and supply are equiva-
lent. Cerebral energy utilization also can be measured directly
in the experimental animal by a novel decapitation technique.4
Lowry and co-workers4 devised this technique to determine the
rate of energy use in brain during the total cerebral ischemia that
follows decapitation.The investigators assumed that because the
isolated head is a closed metabolic compartment (no inflow or
outflow), rates of depletion of potential (glucose + glycogen) and
endogenous (ATP + ADP + PCr) high-energy stores would be a
direct measure of cerebral energy utilization occurring before
decapitation. Using this method, various investigators have
shown that the calculated rate of cerebral energy use in perinatal
animals, like the CMRo2, is substantially less than in adults.4,9,44
For example, the energy use rate of the 1-day postnatal rat is
1.3 mmol of ~P/kg/minute,44 20-fold less than the calculated rate
of 27 mmol of ~P/kg/minute for the adult rat brain.45
CMRo2 can be calculated from the rate of cerebral energy use if
the ADP/O or P/O ratio is known.As already mentioned, P/O ratios
for immature rat brain are 1.5 for NAD+ and 1.2 for the oxidized
form of flavin-adenine dinucleotide (FAD+)-linked substrates.49 A
source of ATP other than that derived from oxidative phosphory-
lation of ADP is substrate phosphorylation, which occurs twice
in glycolysis and once in the Krebs cycle. Substrate phosphoryla-
tion yields 6 moles of ATP for every mole of glucose consumed;
2 moles are required for the initial phosphorylation of glucose and
fructose-6-phosphate in glycolysis.Thus, for every mole of glucose
consumed, 4 moles of ATP are ultimately generated by a source
other than oxidative phosphorylation; this amounts to 20% of the
total energy production. Assuming a yield of 3 moles of ~P/mole
of oxygen reduced (P/O ratio of 1.5), and taking into account the
ATP formed by both oxidative and substrate phosphorylation,
the rate of cerebral energy utilization for newborn rats translates
to a CMRo2 of [1.3 − (1.3 × 0.2)]/3 = 0.35 mmol/kg/minute, or
0.78 mL/100 g/minute.This value is far less than in adult rat brain,
for which the measured CMRo2 value is 5.4 mL/100 g/minute52—
nearly six-fold higher.The fetal rat at term exhibits a rate of cerebral
energy utilization comparable with that in the newborn rat pup.44
The low cerebral energy requirements of most mammals at
birth reflect an immaturity of the central nervous system at this
stage of development. It has been suggested that cerebral energy
demands in the fetal brain are even less well developed than in
the newborn brain53 and that such demands in embryonic life
are met predominantly or entirely by anaerobic glycolysis, with
only a small contribution from oxidative metabolism.23,50 Using
the aforementioned Lowry technique to evaluate cerebral energy
utilization, Gonya-Magee and Vannucci11 measured rates of cere-
bral metabolism in chick embryos at 9, 14, 16, and 19 days of
incubation and in newly hatched peeps (Table 163-4). Calcu-
lated cerebral metabolic rates were not different in the 9-, 14-,
and 16-day-old embryos but doubled between 16 and 19 days
and doubled again between 19 days and hatching. The extent to
which total cerebral energy utilization could be derived from
anaerobic glycolysis (Δ lactate/Δ ~P) increased from a low at day
9 (0.29) to a maximum at day 16 (0.78).The findings in this inves-
tigation suggest that cerebral oxidative metabolism becomes
progressively lower with decreasing embryonic age, but that a
nadir is reached below which metabolism can no longer support
cerebral function and growth. Furthermore, the data indicate
that despite the low metabolic activity of the embryonic brain,
at no time during development is anaerobic glycolysis capable of
entirely supporting the energy needs of the tissue.
 163  /  Perinatal Brain Metabolism  1787
CEREBRAL GLUCOSE UTILIZATION used radioactive 2-[14C]-deoxyglucose (2-DG) to measure CGU in
In all animal species studied, including humans, glucose is the 30 or more component structures of adult rat brain.The rationale
predominant or exclusive organic fuel for cerebral metabo- for the use of 2-DG rather than [14C]-glucose is that the radioactive
lism under physiologic conditions. This dictum also appears to analogue of native glucose is lost from the brain as carbon dioxide
hold true for the fetus and developing postnatal animal. As with and water during the course of an experiment, so calculated CGU
CMRo2, glucose consumption in brain can be measured from a would underestimate the true CGU value. Deoxyglucose, like glu-
knowledge of CBF and the arteriovenous difference for glucose: cose, is taken up by brain and phosphorylated by hexokinase but,
unlike glucose, is unable to be metabolized further along the gly-
CMRglucose = CBF (A−Vglucose )
colytic pathway. The theoretical basis for this technique and its
When CMRglucose (or other organic substrate) and CMRo2 are successful application in the experimental animal together sup-
measured simultaneously, the substrate-oxygen quotient, which port its usefulness for measuring rCGU in humans by means of
expresses the relative contribution of the substrate to overall oxi- PET. Furthermore, because glucose is the predominant cerebral
dative metabolism, can be ascertained: energy fuel, and glucose utilization is stoichiometrically related to
Substrate CMRsubstrate (number of C atoms) × 100 oxygen consumption (see previous discussion), the measurement
= of rCGU is considered to reflect local rates of cerebral energy uti-
O2 CMRo2 lization and intrinsic functional activity.59
Using these measurements, cerebral glucose utilization has Using the 2-DG technique, rCGU has been investigated in fetal
been determined in several perinatal animal species as well as sheep and in newborn rats, lambs, dogs, and monkeys.61-65 The
in postnatal human infants35,38,54-56 (Table 163-5). As in adult studies confirm early in vitro experiments (see preceding dis-
humans,57,58 glucose serves as the major organic substrate to cussion) that CGU in the perinatal animal is high in brain stem
support cerebral metabolism in all species studied. Furthermore, gray matter structures, declining in a caudal-to-rostral progression
the vast bulk of glucose consumed is aerobically degraded to car- through the neuraxis to the cerebral cortex62,63 (Table 163-6;
bon dioxide and water or is used in biosynthesis, with little or ­Figure 163-4).As in adults, CGU is lowest in subcortical and other
no production of lactic acid (anaerobic glycolysis). Thus, at least white matter structures. Duffy and co-workers62 suggest that the
under physiologic conditions, glucose is efficiently utilized to hierarchy of rates of glucose consumption reflects the functional
produce the maximal amount of chemical energy possible. immaturity of the perinatal animal, with its limited, albeit present,
In the past,only global estimates of glucose consumption in brain sensory and motor capabilities but with little or no memory or
could be ascertained, using the method described earlier. Thanks learning abilities at this early stage of development.
to the pioneering work of Sokoloff and colleagues,59,60 regional Using PET with [18F]fluoro-2-deoxyglucose as the positron-
cerebral glucose utilization (rCGU) now can be determined in emitting isotope, Chugani and Phelps66,67 measured rCGU in
both experimental animals and humans. These investigators60 humans from full-term birth through adulthood (Figure 163-5).
In infants 5 weeks of age and younger, glucose utilization was
highest in the sensorimotor cerebral cortex, thalamus, midbrain-
TABLE 163-4 brainstem, and the cerebellar vermis—a distribution of glucose
Cerebral Energy Use Rates and Maximal Glycolytic Capacities consumption similar to that described in term fetal sheep and in
newborn dogs and monkeys (see Figure 163-4).61-63 By the age of
of Chick Embryos and Newly Hatched Peeps 3 months, glucose metabolic activity in the infants had increased
RATE OR CAPACITY (mmol/kg wet weight)* in the parietal, temporal, and occipital cortices and in the basal
ganglia, with subsequent increases in frontal and various associa-
Age Group Δ ~P Δ Lactate Δ Lactate/Δ ~P tion regions of cerebral cortex occurring by 8 months. Little fur-
ther change in rCGU was observed between 8 and 18 months of
Embryos (days)
9 2.84 0.79 0.29
postnatal age.The investigators emphasized that the maturational
14 3.25 1.51† 0.54† increases in rCGU, measured with PET, are in agreement with the
16 2.76 2.04† 0.78†
19 5.76† 3.22† 0.56†
Peeps 8.98† 5.09† 0.56 TABLE 163-6
*Values represent means for four to six animals in each age-group. The ratio Δ Regional Cerebral Glucose Utilization (RCGU)
lactate/Δ ~P is an indication of the maximal contribution of anaerobic metabolism in Developing Monkeys
to the cerebral metabolic rate.
†P <.05 compared with the previous age-group. UTILIZATION RATE
Data from Gonya-Magee T, Vannucci RC: Ontogeny of cerebral oxidative metabo- (µmol/100 g/minute)*
lism in the chick embryo,  J Neurochem 38:1387, 1982.
Structure Newborn Pubescent % Difference

TABLE 163-5 Frontal cortex 28 50 +44†

Parietal cortex 29 47 +38†
Substrate Equivalents and Extent of Anaerobic Metabolism Occipital cortex 32 59 +46†
in Newborn Animals and Humans Hippocampus 25 39 +36*
Corpus callosum 15 11 −36
% TOTAL CEREBRAL UTILIZATION* Caudate nucleus 23 52 +56
Thalamus 35 54 +35†
Substrate Sheep56 Dog55 Monkey35 Human38 Substantia nigra 28 29 +3
Glucose 99.5 93.5 70.4 91.1 Inferior colliculus 180 103 −75
β-Hydroxybutyrate 0.5 0.5 14.6 5.5 Cerebellar hemisphere 22 31 +29
Acetoacetate 0.0 2.0 4.9 3.4 *Values represent means for six to seven animals in each group.
Lactate 0.0 4.0 10.1 0.0 †P <.01.
Totals 100 100 100 100 Data from Kennedy C: Energy metabolism of the brain. In Sinclair JC, Warshaw
% Glucose → lactate 2.6% 0.0% 0.0% 5.2% JB, Bloom RS (eds): Perinatal brain insult: Mead Johnson symposium on perinatal
and developmental medicine #17, Evansville, Ind, 1981, Mead Johnson and Com-
*Data from cited references. pany, pp 30-42.
1788  XXI  /  Neurology

Figure 163-4  Representative 14C-deoxyglucose autoradiogram of brain from a newborn monkey. Lighter areas denote regions with
higher utilization rates (see scale). Note the high rates of glucose consumption in selected brain stem structures relative to the cere-
bral hemispheres.  (Courtesy Charles Kennedy, MD.)

Figure 163-5  Representative [18F]fluoro-2-deoxyglucose positron emission tomograms during human maturation. Shown are three
horizontal levels of brain at different ages: postnatal day 5, 1 year, and adulthood.  (From Chugani HT, et al: Positron emission
tomography study of human brain functional development, Ann Neurol 22:487, 1987.)

behavioral, neurophysiologic, and anatomic changes known to
occur during infant development.
Other investigators have used PET to measure global and
regional rCGU in premature newborn infants.68,69 Gestational
ages ranged from 25 to 37 weeks.Whole brain CGU was less than
that in full-term infants, when the two age groups were com-
pared.68 As in full-term infants, glucose utilization was higher in
brain stem and cerebellar structures compared with cerebral cor-
tex.The lower rCGU in premature infants correlates with the low
CMRo2 observed at similar gestational ages.41
 163  /  Perinatal Brain Metabolism  1789
Human
RELATIONSHIP BETWEEN CEREBRAL BLOOD FLOW 120 Monkey
AND GLUCOSE UTILIZATION (FLOW-METABOLISM Dog,Cat
Sheep
Rat
COUPLE) 100
With the availability of methods to measure CBF and metabo-

CBF(mL/100 g/min)
lism in animals and humans, investigators were quick to recog- 80
nize a quantitative relationship between these two important
biologic processes in brain. Further investigation revealed that
60
under physiologic conditions, CBF was essentially controlled by
intrinsic mechanisms that reflect local rates of metabolism, that
is, the extent of tissue carbon dioxide and hydrogen ion accu- 40
mulation. Thus it is not surprising that CBF and metabolism are
tightly linked or coupled. Specifically, when the rate of oxidative 20
metabolism in brain is high, so is CBF, and vice versa. Metabolic
diseases are capable of altering this critical relationship, during 0
which neurologic dysfunction occurs and, if the disturbance is 0 1 2 3 4 5 6 7 8 9
severe enough, brain damage supervenes. CMRO2(mL/100 g/min)
The brain flow-metabolism couple appears to be a universal
phenomenon that encompasses all animal species of all ages Figure 163-6  Relationship between cerebral blood flow (CBF)
and under all physiologic conditions* (Figure 163-6). In those and the cerebral metabolic rate for oxygen (CMRo2) in several
animals in which CBF and CMRo2 have been measured simul- species of animals. Symbols represent values from animals of
taneously, the relationship has been apparent regardless of age, varying ages.The line denotes the slope of a linear regression
although differences in the intrinsic rates of metabolism do exist analysis, with y = 12.1x + 16.7; r = 0.85; P < .001. 
among species. A regional coupling of CBF to metabolism also
exists in both adult and immature animals60,62-64 when rCBF,
determined with an inert, radioactive tracer, is compared with 30 Cerebellum
rCGU64 (Figure 163-7). A visual comparison of the published
figures depicting rCBF and rCGU, using PET, also suggests the
existence of a regional CBF-metabolism couple in the newborn 25
human infant.66,67,73 Occasional exceptions to the rule have been
rCGU(µmol/100 g/min)

observed for individual structures (e.g., cerebellum), which may 20

reflect local differences in the contribution of glucose versus
alternate substrates to overall metabolism or to the use of glu-
cose in biosynthetic processes (see further on). 15

ALTERNATIVE SUBSTRATES FOR OXIDATIVE 10

­METABOLISM
As mentioned previously, glucose is the predominant or exclu-
sive cerebral energy fuel at all ages under physiologic conditions.
In certain clinical situations, however, glucose availability to the
brain is limited by hypoglycemia. In such circumstances, the
perinatal brain is capable of incorporating and metabolizing sub-
stitute organic substrates, the most notable of which are lactic
acid and the ketone bodies, β-hydroxybutyrate and acetoacetate.
Indeed, the immature brain appears to be capable of consuming
a large number of organic metabolites, including free fatty acids
and amino acids as well, so long as they are available in reason-
able concentrations in blood and the appropriate enzymes for
their degradation are present in brain.
The most widely studied substitute fuels for metabolism in peri-
natal brain have been the ketone bodies and lactic acid. Because
all developing mammals are nourished with milk with a high fat
content, these animals readily generate ketone bodies by means
of the liver, which in turn appear in substantial concentrations
in blood. Thus, during suckling, ketone bodies partially substi-
tute for glucose to sustain cerebral metabolism and can account
for up to 20% of total energy production.74-76 As in adults, nutri-
ent fasting induces endogenous ketone body formation, which
contributes significantly to overall cerebral metabolism during
starvation-induced hypoglyclemia.77
Hypoglycemia also is encountered in the immediate newborn
period before the initiation of sustained oral or parenteral feed-
ing. During this time, as well as during fetal life, ketone bodies are
essentially nonexistent in blood and therefore contribute little
*See references 28, 30-36, 38, 39, 52, 58, 70-72.
5
0
0 10 20 30 40 50 60 70
rCBF(mL/100 g/min)
Figure 163-7  Relationship between regional cerebral glucose
utilization (rCGU) and regional cerebral blood flow (rCBF) in
newborn dogs. Symbols represent values from specific regions
of brain.The line denotes the slope of a linear regression analy-
sis (excluding cerebellum), with y = 0.24x + 7.0; r = 0.93;
P < .001.  (Data from Mujsce DJ, et al: Regional cerebral blood
flow and glucose utilization during hypoglycemia in new-
born dogs, Am J Physiol 256:H1659, 1989.)
to cerebral metabolism.78,79 By contrast, lactic acid is elevated
in late fetal and early postnatal life to the extent that its con-
centration often exceeds that of glucose.80-82 Studies in newborn
dogs have shown that during hypoglycemia, lactic acid not only
is incorporated into the perinatal brain but also is consumed to
the extent that the metabolite can support up to 58% of total
cerebral oxidative metabolism55,83 (Figure 163-8). The versatility
of the immature brain in its capacity to utilize substitute fuels,
sparing glucose, undoubtedly contributes to the resistance of
the newborn nervous system to the known deleterious effects
of hypoglycemia.
The ability of the immature brain to incorporate and metabo-
lize alternate energy fuels resides, at least in part, in the unique
1790  XXI  /  Neurology
Ketone bodies
Lactate
Glucose
Normoglycemia
Figure 163-8  Substrate-oxygen quotients as percentage of total cerebral oxidative metabolism in normoglycemic and hypoglycemic
newborn dogs. Substrate-oxygen quotients were calculated according to a formula described in the text.  (Data from Hernandez MJ,
et al: Cerebral blood flow and metabolism during hypoglycemia in newborn dogs, J Neurochem 35:622, 1980.)
characteristics of its blood-brain barrier. All organic metabolites
enter the brain from blood predominantly by way of a carrier-
mediated transport system. Cremer and co-workers74,84 first
demonstrated the existence of a transport “carrier” for monocar-
boxylic acids, including ketone bodies and lactate, in the brain of
immature rats, the Michaelis constant (Km) of which is 10 times
greater than that demonstrated for adult rat brain. The blood-
brain uptake capabilities for β-hydroxybutyrate, acetoacetate,
and lactate actually exceed those for glucose at an early postnatal
age, facilitated by the high capacity of this transport system.Thus
alternative substrates can be readily transported into the peri-
natal brain to support oxidative metabolism during periods of
systemic glucose deficiency.
GLUCOSE AND MONOCARBOXYLIC ACID
­TRANSPORTERS
Transport of these nutrient substrates from the blood to the brain,
as well as into neurons and glia, occurs by facilitated diffusion
mediated by specific integral membrane transport proteins.These
integral membrane proteins comprise two distinct families: the
facilitative glucose transporter proteins (GLUTs) and the mono-
carboxylic acid transporter proteins (MCTs), the latter of which
mediate proton-coupled co-transport. GLUT1 was cloned in 1985,
and today, this and other similar proteins with distinct tissue dis-
tribution and kinetic characteristics—GLUT1 to GLUT12 and
HMIT, the myoinositol transporter—are collectively known as the
SLC2 family of proteins.85 Although all 13 of these proteins have
been detected in mammalian brain, GLUT1 and GLUT3 are the
isoforms primarily involved in cerebral glucose uptake and uti-
lization.86 The initial transport of glucose across the endothelial
cells of the blood-brain barrier is mediated by a heavily glycosyl-
ated form of GLUT1, 55-kDa GLUT1; a less glycosylated product of
the same gene, 45-kDa GLUT1, is highly concentrated in choroid
plexus and the ependymal lining of the ventricles and also in glial
cells. GLUT3 is the neuronal glucose transporter.86 The 14 MCT
proteins were cloned a decade later and make up the SLC16 fam-
ily; of these, only MCT1 to MCT4 have been definitively shown to
transport metabolically relevant monocarboxylic acids.87 MCT1,
the most widely distributed, is detected in cerebral microvessels
and appears to be expressed by all neural cells, whereas MCT2
expression is more restricted and primarily neuronal.
Both the GLUTs and the MCTs are developmentally regulated
in brain.88 GLUT concentrations are quite low in immature rat
brain,89 in keeping with the well-described low rates of cerebral
glucose transport into immature rat brain,84 and increase sharply
after the second postnatal week (Figure 163-9). The observation
Ketone bodies
Lactate
Glucose
Hypoglycemia
GLUT3 GLUT1:45kDa GLUT1:55kDa
100
GLUT/mg protein, % adult
80
60
40
20
0
0 7 14 21 28 35
Postnatal age, days
Figure 163-9  Brain glucose transporter proteins (GLUTs) during
development in the immature rat. Isolated microvessels and
cortical membranes were prepared from postnatal rats between
birth and 30 days of age and adults. GLUT1 and GLUT3 mem-
brane protein content was determined by Western blot analysis
with specific antipeptide antisera for GLUT1 and GLUT3 and
125I-protein A. Representative autoradiograms are depicted in
the upper part of the figure. S, Brain microsomal membrane
“standard” included in all blots for purposes of interblot com-
parisons and quantification. Lower part of the figure represents
the quantification of values for four to six animals in each age
group, expressed as a percent of the adult value. 
of greatly reduced brain glucose concentrations during hypoxia-
ischemia (see further on) provides evidence that GLUT con-
centration is limiting to cerebral glucose utilization at this age.
Because the delivery of glucose from the blood into the brain is a
function of both the substrate concentration in the blood and the
transporter concentration, an increase in substrate concentration
produced by glucose supplementation maintains a near-normal or
even elevated brain glucose level. In addition, although calculated
intracellular glucose concentrations in immature rats become
very low during hypoxia-ischemia, the level of glucose in the cere-
brospinal fluid—as a reflection of the concentration in the brain
extracellular compartments—does not decrease.90 Accordingly, it
appears that an even greater limitation may be imposed at the
level of the neurons and glial cells than at the blood-brain barrier.
The developmental expression of the MCTs shows the reverse
pattern. Rodent milk is very high in fat, and suckling pups are
naturally ketotic, with circulating levels of β-hydroxybutyrate

approaching the millimolar range by the second postnatal
week.88,91 At this time, cerebral ketone body utilization also is
maximal,91 and this is further reflected in the level and extent
of expression of MCT1, especially in the cerebral microvessels.88
Thus the high levels of ketone body transporter in the blood-
brain barrier, as well as in neurons and glial cells, not only facili-
tate ketone body transport into the brain but also can aid in the
uptake and clearance of lactic acid. With cerebral maturation and
the switch to reliance on glucose as the primary oxidative fuel of
the brain, blood-brain barrier MCT1 falls to adult levels coincident
with the rise in blood-brain barrier GLUT1 and the nonvascular
glucose transporter proteins, especially neuronal GLUT3.88 Some
years ago, Magistretti and colleagues proposed that it is the astro-
cytes that play the primary role in cerebral glucose utilization by
first metabolizing glucose to lactate, which subsequently is trans-
ported to the neuron to be oxidized to fuel neuronal energetics.92
Although this theory, referred to as the astrocytes-neuron lactate
shuttle hypothesis (ANLSH),92 gained wide favor for several years,
a more recent modeling of cerebral nutrient uptake and utilization
that incorporated the concentrations and kinetic parameters of
these transport proteins has demonstrated that the neurons are
indeed the primary consumers of glucose, and actually produce
lactate on activation.93 Thus, although both lactate and ketone bod-
ies are important fuels for neuronal metabolism in the fetal brain,
cerebral development involves the transition to glucose utilization.
CEREBRAL ENERGY METABOLISM
IN HYPOXIA-ISCHEMIA
Hypoxia-acidosis or asphyxia is a frequent cause of acute brain
damage in human fetuses and newborn infants and contributes
substantially to the chronic neurologic sequelae of cerebral palsy
with or without associated mental retardation, epilepsy, or learn-
ing disability. Experimental and clinical evidence indicates that
hypoxia alone does not produce brain damage but that super-
imposed cerebral ischemia is a necessary prerequisite for tissue
injury to occur. Cerebral ischemia in the setting of asphyxia is a
consequence of hypoxic-acidotic cardiovascular depression with
secondary systemic hypotension. Cerebral ischemia also may be
secondary to occlusive vascular disease of the brain (reviewed by
Vannucci RC94,95).
Brain hypoxia denotes a cellular oxygen debt, owing to inad-
equate oxygen delivery (CBF × oxygen saturation [Sao2]) by
nutrient arteries. When the tissue (mitochondria) partial pres-
sure of oxygen falls below a critical value (<0.1 mm Hg), the
cytochrome system of mitochondria becomes unsaturated, and
reducing equivalents (NADH, FADH) begin to accumulate.96,97
ATP production by oxidative phosphorylation is curtailed, with
concurrent increases in cellular ADP and AMP, because cyto-
solic ATP hydrolysis continues to drive endergonic reactions.2
The elevations in ADP and AMP serve to stimulate glycolysis,
through activation of its key regulatory enzyme, PFK (see earlier
discussion). Unlike oxidative phosphorylation, which produces
36 moles of ATP for every mole of glucose consumed, glycolysis
is an inefficient method to generate ATP by substrate phosphory-
lation, with net production of only 2 moles of ATP for each mole
of glucose consumed. To produce the amount of ATP equiva-
lent to that generated by oxidative phosphorylation, glycolysis
would need to increase to a rate of 18 times its basal flux. In
reality, glycolysis, even when maximally stimulated, is capable of
increasing only four- to five-fold, owing in part to the concur-
rent accumulation of H+ ions derived from the accumulated
NADH, which ions serve to inhibit PFK activity.4,44 In the imma-
ture rat, hypoxia-ischemia leads to a 135% stimulation of glyco-
lytic flux, which equates to 62% of its maximal capacity.98 Thus
glycolysis can never completely substitute for mitochondrial
oxidation, although its stimulation can supplement oxidative
phosphorylation under conditions of a partial oxygen debt.
163  /  Perinatal Brain Metabolism  1791
Cerebral hypoxia-ischemia severe enough to produce irrevers-
ible tissue injury is always associated with major perturbations in
the energy status of the brain.2,99,100 Alterations occur not only in
the adenine nucleotides but also in PCr, in which changes ­actually
precede those in ATP, ADP, and AMP. These perturbations have
been well characterized in an experimental model of perinatal
hypoxic-ischemic brain damage.101 During hypoxia-ischemia,
changes in the tissue concentrations of the high-energy phosphate
reserves occur early during the course of the metabolic insult
and persist well into the recovery period102-104 (Figure 163-10).
As expected, greater depletions in PCr relative to ATP occur as
the cell attempts to maintain optimal levels of ATP through the
CK equilibrium reaction driven also by the accumulation of ADP
and H+ ions.With the eventual decline in tissue ATP,ADP and AMP
accumulate in proportion to the loss of ATP. Ultimately, the total
adenine nucleotide pool (ATP + ADP + AMP) also decreases as
AMP is catabolized slowly to adenosine and further breakdown
products.The concentrations of ATP and the total adenylate com-
pounds never completely recover after resuscitation, and their
persisting partial depletions reflect the presence and severity of
tissue destruction102-104 (see Figure 163-10).
Of necessity, the loss of cellular ATP during hypoxia-ischemia
severely compromises those metabolic processes that require
energy for their completion. Thus ATP-dependent Na+ extrusion
(efflux) through the plasma membrane in exchange for K+ is cur-
tailed with a resultant intracellular accumulation of Na+ and Cl− as
well as water (cytotoxic edema). Equally vital to cellular function is
the prompt restoration of high-energy phosphate reserves during
and after resuscitation. Without regeneration of ATP, endergonic
reactions cannot resume, especially those involving the critical
event of ion pumping at plasma and subcellular membranes. Intra-
cellular Na+ and Cl− ions and water will continue to accumulate,
and electrochemical gradients cannot be reestablished. Just how
long the cell can survive under these conditions is not known,
but other factors are called into play that prominently influence
ultimate cellular integrity; including the secretion of potentially
toxic excitatory amino acids into the synaptic cleft, the intracel-
lular accumulation of free calcium, the intracellular production of
nitric oxide, and the production of oxygen free radicals, the last
especially during the recovery period (Figure 163-11).
The mechanisms by which ATP disruption persists into the
recovery period relate to lingering alterations in the function of
mitochondria. In this regard, the classic histopathologic studies
of Brown and Brierley105,106 indicate that the earliest morpho-
logic alteration of the neuron arising from hypoxia-ischemia is
a dilation of mitochondria with an accompanying separation of
their cristae. Biochemical studies support the morphologic alter-
ations to the extent that after hypoxia-ischemia in vitro, analysis
of mitochondria reveals a disturbance in substrate oxidation, sug-
gesting an “uncoupling” of oxidative phosphorylation.107-109 An
in vivo investigation in immature rats recovering from cerebral
hypoxia-ischemia also suggests the occurrence of an uncoupling
of oxidative phosphorylation before or concurrent with the
development of morphologically apparent tissue injury.110 It is
assumed that reducing equivalents are oxidized in the presence
of oxygen but ATP is not formed from the energy generated. Such
energy is consumed internally (not transferred to the cytosol) or
is lost as heat. That oxidative phosphorylation is compromised
after hypoxia-ischemia is confirmed also by studies showing that
the brain can be well oxygenated concurrent with a persistent
depletion in ATP.103,111-113
The experimental data regarding the persistent depletion of
cerebral high-energy phosphate reserves during recovery from
hypoxia-ischemia have relevance to the clinical situation in the
asphyxiated newborn human infant. Using MR spectroscopy
(as described previously), investigators have shown a correla-
tion between lingering alterations between the ratio of PCr to
Pi or of ATP to Pi and ultimate brain damage as measured by
1792  XXI  /  Neurology

3.0

ATP + ADP + AMP PCr

2.5

ATP + ADP + AMP

Metabolite (mmol/kg) 2.0
ATP
ATP
1.5

PCr
1.0

0.5

0
0 1 2 3 1 4 8 24 72
Hypoxia-Ischemia Recovery
Time (hours)

Figure 163-10  Changes in cerebral high-energy phosphate reserves during and after hypoxia-ischemia in the immature rat. Seven-day
postnatal rats were subjected to unilateral common carotid artery ligation followed by exposure to systemic hypoxia with 8% oxygen
at 37° C. Symbols represent means for ATP, PCr, and total adenine nucleotides (ATP + ADP + AMP). ADP, Adenosine diphosphate;
AMP, adenosine monophosphate; ATP, adenosine triphosphate; PCr, phosphocreatine.  (Data from Rice JE 3rd, et al: The influence
of immaturity on hypoxic-ischemic brain damage in the rat, Ann Neurol 9:131, 1981; Palmer C, et al: Carbohydrate and energy
metabolism during the evolution of hypoxic-ischemic brain damage in the immature rat, J Cereb Blood Flow Metab 10:227,
1990; and Welsh FA, et al: Columnar alterations of NADH fluorescence during hypoxia-ischemia in immature rat brain, J Cereb
Blood Flow Metab 2:221, 1982.)

neurodevelopmental status or neurologic assessment.16,114,115 In
this regard, PCr/Pi ratios can be normal in the human infant even
when brain damage is present,16,115 as has also been shown in
experimental animals.102,104,116
A secondary depletion in brain PCr occurs at 18 to 24 hours
of recovery from hypoxia-ischemia and beyond in immature
experimental animals (see Figure 163-10),102-104,117,118 which
mimics the late changes in PCr/Pi observed in newborn human
infants suffering asphyxial encephalopathy.16,114,115 In newborn
pig experiments, PCr/Pi ratios are depressed initially by hypoxia-
ischemia only to normalize in the early recovery interval.117,118
Thereafter, a secondary decrease in the ratio occurs, as indicated
by measurements at 24 hours and again at 48 hours of recovery.
From the human and animal studies, it has been proposed that
the secondary failure in cerebral energy status after hypoxia-­
ischemia is a significant contributor to the ultimate brain damage
and neurologic compromise.
However, the secondary decline in PCr does not necessar-
ily denote a delayed energy failure of the brain but rather may
reflect a loss of total creatine from the tissue or its conversion
to creatinine. The late reduction in PCr, be it in an experimental
animal or a human infant, appears to occur as a mass action effect
of the CK equilibrium reaction.104 Furthermore, the loss of cre-
atine from the brain or its conversion to creatinine, which also
would be lost, should result in detectable or increased concentra-
tions of one or both metabolites in cerebrospinal fluid (CSF).The
presence of these compounds in CSF may potentially serve as a
biochemical marker of previous cerebral hypoxia-ischemia in a
manner similar to and perhaps more sensitive than the adenine
nucleotide derivatives xanthine and hypoxanthine.119
To clarify the issue of whether or not the secondary energy fail-
ure causes or contributes to the ultimate brain damage, Vannucci
and associates120 subjected immature rats to hypoxia-ischemia
of the brain. During recovery, the brains were individually pro-
cessed for histopathologic analysis and measurements of high
energy reserves and the neuronal protein markers MAP-2 and
SNAP-25. PCr and ATP, initially depleted during hypoxia-ischemia,
both were partially restored during the first 18 hours of recov-
ery, with secondary depletions at 24 and 48 hours (see earlier).
During the initial recovery phase (6 to 18 hours), a significant
correlation was observed between PCr and the severity of brain
damage determined on histopathologic analysis, but not for ATP.
During the late recovery phase (24 to 48 hours), a highly sig-
nificant correlation was found between all measured energy
metabolites and the severity of brain damage. Significant correla-
tion also was observed between the neuronal markers MAP-2 and
SNAP-25 and PCr, as well as the sum of PCr and creatine at both
phases of recovery. The close correspondence of PCr with histo-
logic brain damage and the loss of the neuronal markers during
both the early and late recovery intervals suggest evolving cellu-
lar destruction as the primary event, which precedes and lead to
the secondary energy failure.
CEREBRAL ACIDOSIS IN HYPOXIA-ISCHEMIA
Hypoxia-ischemia of a severity sufficient to produce brain
damage also is associated with a tissue acidosis, owing to the
accumulation of lactic acid.2,99,100 The intracellular lactacidosis
results from a shift in glucose utilization from oxidative metabo-
lism to either partial or total anaerobic glycolysis which occurs
during the tissue oxygen debt. Indeed, some investigators have
suggested that lactacidosis is a major contributor to hypoxic-
ischemic injury in vulnerable regions of the brain and that a
minimum concentration of 15 to 20 mmol of lactate/kg of brain
 163  /  Perinatal Brain Metabolism  1793

Ca++
VSCC AOCC

ATP ADP
Ca++ Ca++ Glucose O2

Ca++ H+
↓Glucose

↑Lactate
↑Ca++
↑NADH/NAD + H+
↑↓NADH
↓ATP; PCr

↑Ca++
↓ATP

↑↓ Cytosol

Pyruvate
Mitochondrion Nucleus

Hypoxic-Ischemic Phase

Figure 163-11  Cellular metabolism during cerebral hypoxia-ischemia. During a cellular oxygen debt, anaerobic glycolytic flux is
accelerated, resulting in a depletion of intracellular glucose and an accumulation of lactate and H+ ions (acidosis).The energy gener-
ated from anaerobic glycolysis cannot keep pace with energy demand, and ATP and PCr decline in the cytosol and mitochondria.
Calcium entry into the cell is accentuated by voltage-sensitive (VSCC) and agonist-operative (AOCC) calcium channels, by which cal-
cium accumulates in the cytosol and mitochondria.These disturbances are only partially reversed during reoxygenation and reperfu-
sion, and continuing metabolic perturbations ultimately result in brain damage. ATP, Adenosine triphosphate; PCr, phosphocreatine. 

tissue is required for irreversible damage to occur.121-123 Further-
more, it has been shown that the injection of lactic acid into the
cerebral cortex of adult rats leads to histopathologic alterations
resembling those characteristic of ischemic infarction—an injury
that does not occur after the injection of other organic acids of
comparable pH.124-126 In general, the more severe the tissue lac-
tacidosis, the more profound the cerebral blood flow and meta-
bolic alterations that occur after cessation of the insult,123,127,128
portending greater ultimate brain damage.
It must be emphasized that hypoxia-ischemia leads to cellular
acidosis by means of sources of H+ ions in addition to lactic acid.
Major sources of reducing equivalents include products of the
acid hydrolysis of ATP and the formation of NADH + H+, which
accumulates during the cellular energy debt.129 In this regard,
Welsh and colleagues103 examined the oxidation-reduction
(redox) state of immature rat brain undergoing hypoxia-ischemia
by the technique of reflectance fluorometry (Figure 163-12).
Alterations in regional fluorescence, representing the intracellu-
lar accumulation of NADH (+ H+), were prominent in the cere-
bral cortex and the CA1 sector of the hippocampus during the
first hour of hypoxia-ischemia.The pattern of NADH fluorescence
mimicked closely the distribution of selective neuronal necrosis
observed in this model of perinatal injury. The close correspon-
dence between altered NADH fluorescence and neuropathologic
outcome suggests an important role for intracellular acidosis
in the pathogenesis of hypoxic-ischemic brain damage. That a
cellular acidosis occurs during the course of cerebral hypoxia-
ischemia in the immature rat also is indicated by a progressive
reduction in intracellular pH, calculated from the tissue concen-
trations of high-energy phosphate reserves.130
Using proton MR spectroscopy, several investigators have dem-
onstrated a persistent elevation in brain lactate after cerebral
hypoxia-ischemia in human newborn infants.20,21,131-133 The per-
sisting elevations in lactate concentration were associated with
a brain alkalosis. The previously asphyxiated infants uniformly
demonstrated severe neurodevelopmental impairment at 1 year
of age. Robertson and associates133 suggested that the accompa-
nying cerebral lactic alkalosis is the consequence of a prolonged
change in the redox state within neuronal tissue, the presence
of phagocytic cells, the proliferation of glial cells, or altered buff-
ering mechanisms. Further research can be expected to clarify
these lingering biochemical abnormalities after cerebral hypoxia-
ischemia in newborn human infants.
CONCLUSIONS AND OUTLOOK
In the overview of current knowledge on the major aspects
of perinatal cerebral metabolism presented in this chapter, the
emphasis is on substrate and energy transformations under phys-
iologic conditions and during hypoxia-ischemia.These and other
disturbances recently have undergone extensive investigation
in both experimental animals and human newborn infants. Fur-
ther characterization of the mechanisms underlying the cerebral
metabolic derangement that characterizes hypoxia-ischemia will
be fundamental to development of a rational approach to preven-
tion and treatment.
1794  XXI  /  Neurology

Figure 163-12  Coronal section of immature rat brain showing alterations in NADH fluorescence (right) during hypoxia-ischemia and
histopathologic alterations (left) at 24 hours of recovery. Seven-day postnatal rats were subjected to unilateral cammon carotid artery
ligation followed by systemic hypoxia with 8% oxygen at 37° C.100 During hypoxia-ischemia, the rat brain was frozen in situ and the
coronal section illuminated with ultraviolet light; the fluorescent image then was recorded photographically.102 Note the columnar
pattern of NADH fluorescence (lighter areas) in cerebral cortex and the enhanced fluorescence in the CA1 and CA3 sectors of the
hippocampus, which correspond closely to the distribution of selective neuronal necrosis seen on histopathologic examination.
NADH, Nicotinamide-adenine dinucleotide (reduced form). 

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ACKNOWLEDGMENTS
Work for preparation of this chapter was supported by grants from the National
Institute of Child Health and Human Development, the National Institute of Neu-
rologic Disease and Stroke, the American Heart Association, and the American Dia-
betes Association.