Hypothermia: a cool intervention for hypoxic-ischemic encephalopathy: the window of time for diagnosis of hypoxic-ischemic insult is short. Quick recognition and fast referral ensure the best possible outcome for affected infants.(REVIEW ARTICLE)(Clinical report)

Publication: JAAPA-Journal of the American Academy of Physicians Assistants

Publication Date: 01-JUN-08

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Hypoxic-ischemic encephalopathy (HIE) is a serious condition that causes significant neonatal morbidity and mortality. The incidence of HIE is estimated at 2.8 cases per 1,000 live births. (13) Ten percent to 15% of affected infants die during the neonatal period, and 25% to 30% of the survivors will have permanent neurologic damage, typically manifesting as mental retardation, cerebral palsy, and/or epilepsy. (4,5) The timing of the injury remains controversial. HIE was believed to be caused by an intrapartum event such as cord prolapse, breech extraction, forceps delivery, abruptio placentae, or maternal pyrexia. (6,7) However, intrapamam factors have been found to account for only 4% of cases of neonatal encephalopathy, whereas 69% of cases had evidence of antepartum risk factors, (6,8) including maternal thyroid disease, severe preeclampsia, presumed viral infection, moderate-to-severe vaginal bleeding during pregnancy, and maternal hypertension. (9,10) Primary and secondary intrauterine growth restriction were also found to have a strong association with HIE. (9)

HIE is an evolving process. After the initial hypoxic-ischemic insult, the brain undergoes a reperfusion period during which cerebral blood flow is restored. (3,11) The restitudon of blood flow allows for a transient recovery period, the latent phase, that lasts 2 to 8 hours. (3,5,11) Oxidative cerebral metabolism is partially to completely restored during this phase. (3,5,11) However, a rapid decline in brain cell function, or secondary energy failure, caused by the lack of oxygen and nutrients during the insult typically follows the latent phase. (3,5,11,12) This final phase includes delayed seizure activity, cell edema, accumulation of cytotoxins, and, ultimately, brain cell demise. (3) The severity of the initial insult becomes a chief predictor of the infant's neurologic outcome.

MECHANISMS OF NEURONAL DEATH

Pathogenic mechanisms of action that follow a hypoxic-ischemic event include oxidative stress, excitotoxicity, and programmed cell death. How these processes relate to the developing brain explains the neuronal cell death that occurs.

Oxidative stress Byproducts of normal metabolism produce low concentrations of reactive oxygen species such as nitric oxide. In a healthy adult brain, enzymatic and nonenzymatic antioxidants help to neutralize the potentially toxic effects of these destructive species. (13) The immature brain has high concentrations of unsaturated fatty acids and redoxactive iron that potentiate the generation of free radicals, which are highly reactive and destructive to tissues; a high rate of oxygen consumption; and low concentrations of antioxidants. (10,13,14) These characteristics suggest that the neonatal brain is vulnerable to oxidative damage because it lacks sufficient antioxidant reserves.

Excitotoxicity Cell death mediated by excessive activation of excitatory neurotransmitter receptors is one of the primary processes involved in hypoxic-ischemic brain injury. (15,16) Normally, glutamate is released from the synapse and briefly enters the extracellular space. Signal transduction pathways are achieved via activation of glutamate receptors and are quickly removed by the energy-dependent neuronal and glial reuptake pumps before toxicity occurs. (15) However, hypoxic ischemia results when neuronal release of glutamate increases and glutamate reuptake pump activity decreases. (16-18) Prolonged stimulation of glutamate receptors triggers a neurotoxic cascade of events. Excessive extracellular glutamate combined with membrane depolarization opens channels and floods cells with calcium. (16) Once through the channels, calcium activates the enzyme nitric oxide synthase and free radicals form. Nitric oxide alone can cause cell demise, but when combined with a superoxide ion, it has an even more devastating effect on brain cell membranes. (16) This process becomes a self-propagating cascade of neuronal damage that persists for days to weeks, depending on the degree and location of the initial insult.

Programmed cell death (PCD) Apoptosis has a well-established, essential role in normal human growth and development. (19-22) Some laboratory data suggest up to 50% of the...

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