0031-3998/00/4704-0431

PEDIATRIC RESEARCH Vol. 47, No. 4, 2000

Copyright © 2000 International Pediatric Research Foundation, Inc. Printed in U.S.A.

COMMENTARY

Perinatal Hypoxia-Ischemia and

Brain Injury
Commentary on the article by Nakai et al. on page 451

A. D. EDWARDS AND D.V. AZZOPARDI

Weston Laboratory, Department of Paediatrics, Division of Paediatrics,

Obstetrics and Gynaecology, Imperial College School of Medicine,
Hammersmith Hospital, Du Cane Road, London W12 0NN, UK

onsiderable doubt has recently been cast on the assumption
C that perinatal hypoxia-ischemia is the primary cause of
neonatal encephalopathy and cerebral palsy. Important epide-
miological studies have suggested a wide range of alternative
causal pathways, for example, stressing associations with ma-
ternal thyroid disease, or abnormalities of the hemostatic and
immune systems (1, 2). A relation to inflammation has
emerged: maternal fever in labor increases the offspring’s risk
of cerebral palsy even when there is no clinical evidence of
impaired intrauterine gas exchange (3). The likelihood of
specific genetic predispositions is often raised, with supporting
evidence beginning to appear in some particular cases such as
neonatal focal stroke.
The most consistent finding of the various epidemiological
studies is that children with cerebral palsy only infrequently
have evidence of perinatal hypoxia-ischemia. This should
probably not surprise us. Not only can cerebral accidents
presumably occur in unfortunate or predisposed individuals
during the long period of intrauterine life, but the imprecise
measures of fetal cerebral oxygenation and blood flow avail-
able to clinical researchers make it difficult to define perinatal
hypoxia-ischemia with any certainty. Commonly quoted vari-
ables such as cardiotocography or meconium staining of the
liquor are at best poor surrogate markers of brain metabolism
which might be expected to predict neurologic outcome poorly
(4).
So, are researchers who study the mechanisms of acute
hypoxic-ischemic injury to the developing brain misguided?
Not really. The most powerful epidemiological data relate to
developed countries, while in the third world both neonatal
encephalopathy and perinatal problems are probably more
common (5). Even in the United States and Europe, accurate
neuro-investigative techniques have defined at least a subgroup
of infants with neonatal encephalopathy who have cerebral
metabolic changes entirely characteristic of acute cerebral
hypoxia-ischemia in the perinatal period (6).
Some of the first such results were obtained using magnetic
resonance spectroscopy (MRS), which allows noninvasive as-
431
sessment of intracellular pH (pHi), and the cerebral concentra-
tions of ATP, phosphocreatine (PCr), inorganic phosphate (Pi),
and lactate. When ATP generation is impaired energy flux is
maintained by the breakdown of PCr while Pi increases, so that
a decline in the ratio PCr/Pi is a precise indicator of impaired
energy metabolism (7).
Experimental studies of several species of mammals using
MRS and other methods have described a characteristic bipha-
sic pattern of cerebral metabolic abnormality after cerebral
hypoxia-ischemia (8 –10). During experimental hypoxia-
ischemia, intracerebral [PCr]/[Pi], and pHi fall, and lactate
increases. Eventually [ATP] declines, but even if this tran-
siently falls to undetectable levels, prompt resuscitation causes
all these metabolites to return rapidly to normal values. How-
ever, some hours later, a second phase of metabolic abnormal-
ity begins: [PCr]/[Pi] again declines and lactate increases,
although now pHi becomes alkaline. There is a dose-response
relationship between the severity of the hypoxic-ischemic in-
sult, the magnitude of the secondary changes in cerebral energy
metabolism, and the extent of histologic injury.
MRS of infants with neonatal encephalopathy shows iden-
tical abnormalities in cerebral energy metabolism. The primary
event cannot be observed, but cerebral energy metabolism is
frequently normal soon after resuscitation, while some hours
later a progressive decline in [PCr]/[Pi] and increase in pHi and
lactate begins. Infants with these changes develop neurodevel-
opmental impairment or die, and there is a close relationship
between the magnitude of the delayed disruption in energy
metabolism, reduced brain growth, and the severity of neuro-
developmental impairment 1 and 4 years later (11). These
findings led to the concept of “secondary energy failure,”
which has been developed and extended by several groups (6,
12–14).
It has not escaped wide recognition that the apparent delay
before secondary energy failure offers a rationale for develop-
ing therapies that may prevent neurologic impairment even
when administered after hypoxia-ischemia. The prospect of a
useful therapeutic intervention is a powerful stimulus to further
432 COMMENTARY
investigations, and a large number of diverse interventions
applied after hypoxia-ischemia have successfully reduced brain
damage in many experimental systems.
The development of neural rescue therapies requires a pre-
cise understanding of the mechanisms of damage. Cells die by
both apoptosis and necrosis and multiple cellular pathways are
involved. Excess excitatory amino acids, changed intracellular
calcium regulation, free radical generation, mitochondrial dys-
function, specific gene activation, changes in the availability of
trophic factors, and the immuno-inflammatory system are all
implicated. Few researchers have contributed as much to the
understanding of cerebral metabolism and brain injury as
Professor Siesjö, and the results presented by him and his
colleagues in this issue of Pediatric Research add further to our
understanding of secondary energy failure. They demonstrate
in an immature animal model that the delayed phase of injury
is not associated with a deficit in tissue oxygenation, but
nevertheless there is impaired mitochondrial function with the
production of damaging free radicals. They thus add further
weight to the view that transient hypoxia-ischemia to the
developing brain does not have to lead to a prolonged period of
critically reduced perfusion (the “no-reflow” phenomenon) in
order to cause persisting dysfunction of the energy-producing
systems, in particular the mitochondria.
Mitochondrial dysfunction has far-reaching effects, leading
not only to energy depletion and free radical generation, but
also may directly activate caspase-9 and trigger apoptotic
execution of the cell. Indeed there is evidence to suggest that
mitochondrial dysfunction may persist for many months after
hypoxia-ischemia (15). In children who develop neurodevel-
opmental impairment after perinatal hypoxia-ischemia, in-
creased lactate and pHi can be detected in the brain for many
months (16). It is not known if this is related to the very
prolonged period of increased apoptotic death seen after hy-
poxia-ischemia in adult rats (17).
Does this increasingly clear definition of the mechanisms of
hypoxic-ischemic injury conflict with epidemiological data
suggesting that other causal pathways are important in the
origins of neonatal encephalopathy and cerebral palsy? Prob-
ably not. The two approaches are internally consistent and
scientifically valid, and look at the problem from different
angles. Indeed, common ground is emerging; for example, both
epidemiological and laboratory studies emphasize the impor-
tance of inflammation in brain injury. There is much to be
learned from combining the two approaches. The broad vision
of an epidemiological approach allied to the precise phenotypic
definition available with modern neuroinvestigative techniques
would be powerful indeed, especially as studies will soon have
access to the huge resources of human genomics, which prom-
ises a revolution in this as in many other areas of research.
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