Pathophysiologic Processes and Factors Influencing the Patterns of Injury in HII

Pathophysiologic Processes and Factors Influencing the Patterns of Injury in HII
Regardless of the specific cause of injury, the common underlying physiologic processes that
result in HII are diminished cerebral blood flow (ischemia) and reduced blood oxygenation (hypoxemia). In general, infants and children are more likely to suffer asphyxial events, which result
in hypoxemia and brain hypoxia. With prolonged hypoxemia, cardiac hypoxia occurs, leading to
diminished cardiac output and, ultimately, to brain ischemia. Thus, brain injury resulting from
asphyxia is the consequence of ischemia superimposed on hypoxia. In fact, acute hypoxemia without superimposed ischemia is less likely to cause injury, unless the hypoxic state is prolonged (7,8).
On the other hand, adults more frequently suffer brain ischemia as a result of cardiac arrest or cerebrovascular disease, with secondary hypoxia due to reduced blood flow (8). It is well known that global hypoxic-ischemic insults do not affect all brain structures uniformly. Rather, certain tissues in the brain are more likely to be injured and are injured earlier than others, a concept known as selective vulnerability. Evidence suggests that the observed patterns of injury reflect dysfunction of selected excitatory neuronal circuits, which causes a complex cascade of deleterious biochemical events and,ultimately, selective neuronal death (7). Brain ischemia results in a switch from oxidative phosphorylation to anaerobic metabolism, which is
highly inefficient. This change causes rapid depletion of adenosine triphosphate (ATP), lactate accumulation within cells, and eventual loss of normal cellular membrane function. Depolarization of presynaptic neuronal cell membranes causes a massive release of excitatory neurotransmitters—in particular, glutamate. In immature brains, glutamate binds predominantly to N-methyld-aspartate (NMDA) receptor–mediated calcium
(Ca2) channels. Activation of NMDA receptors results in an influx of Ca2 into postsynaptic neurons, which triggers a number of cytotoxic processes, including activation of membrane phospholipases and production of the oxygen free radicals (such as nitric oxide) that damage cell membranes and internal constituents. Damage to mitochondria may ensue, causing further loss of ATP production and, ultimately, energy depletion. Severe energy depletion results in rapid cell death from necrosis. With lesser degrees of energy
depletion, neurons may survive the initial insult, only to undergo a delayed form of programmed
cell death known as apoptosis (Fig 1) (1,7–9). Apoptosis appears to play a significant role in injury to the immature brain. From the model just described, we can draw the following conclusions: (a) the areas of the
brain with the highest concentrations of gluta mate or other excitatory amino acid receptors
(primarily located in gray matter) are more susceptible to excitotoxic injury that occurs as a result of hypoxia-ischemia; (b) the areas of the brain with the greatest energy demands become
energy depleted most rapidly during hypoxiaischemia, and are therefore injured early on; and
© because of delayed cell death from apoptosis, some injuries may not be evident until days after
the initial insult has occurred. These factors help to explain the relatively specific patterns of injury
that can be observed in patients with HII. In any given patient, the sites in the brain that
tend to be most vulnerable to hypoxic injury will be determined largely by the maturity of the
brain, which, in turn, is a function of patient age and, in infants, gestational age at birth. This is
why HII in the perinatal period (up to 1 month of age) differs from HII in adults or even in older
infants and why the imaging appearance of HII differs between term and preterm neonates. One
must be cognizant of the degree of brain maturity at the time of the insult when interpreting studies
for suspected HII. The severity of a hypoxic-ischemic insult also plays an important role in determining the distribution of injuries in the brain. Episodes of severe hypoxia-ischemia result in a different injury pattern compared with less severe insults. Duration of insult also seems to be a key determinant of the
pattern of injury in HII, since insults of short duration usually do not result in brain injury. It has
been suggested that, in the pediatric population, an arrest must typically last at least 15 minutes for
brain injury to occur (10).