Hypoxia-Ischemic Brain Injury in Term Infants: Is a Treatment in Sight?
Hypoxic ischemic encephalopathy (HIE) affects 1-2/1000 live born infants and is a devastating event. Fifteen to twenty percent of the infants die and 20-25% of the survivors are permanently disabled with neurodevelopmental impairment. There has been no change in these statistics over the past 20 years. Until recently, HIE has been managed by supportive care. Significant advances in our understanding of the pathophysiology of neonatal brain injury, however, have led to novel intervention strategies aimed at improving neuroprotection and recovery.
Neonatal HIE etiology is multifactorial, but impaired cerebral blood flow is the primary insult. Post-HI brain injury is an evolving process. Reduction in cerebral blood flow and oxygen delivery causes rapid high-energy-phosphate-reserve depletion and lactic acid accumulation. Cellular energy failure initiates cascades of deleterious biochemical events leading to excitatory neurotransmitter release, intracellular Ca++ accumulation, lipid peroxidation and free-radical formation, as well as inflammatory responses. Insult nature and severity dictates the magnitude of initial necrotic cell death. After resuscitation, cerebral perfusion is restored and intracellular pH return to baseline. In many cases, however, HI-induced biochemical events trigger apoptotic pathways causing continued neuronal and oligodendroglia injury and death, over a period of hours, days, or even weeks. They also activate brain expression of prosurvival-factor genes such as neural growth factors and erythropoietin, critical for neuronal survival and function recovery.
The clinical presentation of neonate HIE evolves over a period of days to weeks. Within the first hours after an insult, predominant symptoms are cortical depression and hypotonia. Bradycardia, periodic breathing and apnea may occur, but cranial nerve functions are often spared. Severely injured infants die of cardiorespiratory failure. After the initial phase of depression, surviving infants often become hyperactive, characterized by a transient increase in level of alertness, jitteriness and exaggerated reflexes but no signs of improvement in neurological functions. Seizures may occur in moderately to severely affected infants within the first hours of injury and can persist for months or years.
Early diagnosis of neonatal HIE is critical for intervention and outcome. Neuroimaging studies are invaluable in evaluating encephalopathic newborns. Head ultrasound is useful in detecting and following intracranial bleeding but is limited for diagnosing other causes of encephalopathy. Early head CT scans may be used to rule out stroke and intracranial hemorrhage requiring immediate medical or surgical intervention. Brain MRI is the study choice of assessing brain parenchymal injury. It provides specific information regarding the injury pattern, severity and evolution. Perinatally acquired HI brain injuries are usually most obvious by MRI between 1 and 2 weeks of age. Diffusion-weighted imaging is useful for early white-matter ischemic change identification. MR spectroscopy can reveal metabolic changes such as lactate accumulation,
relatively specific to post-HI brain injury. In term infants, deep gray nuclei and perirolandic cortex are the most vulnerable regions to HI insults. Significant injuries in either area may lead to spastic cerebral palsy. Intellectual, visuospatial and language impairments and epilepsy are often seen in children who have sustained severe neonatal cortical injury. Electroencephalogram (EEG) is helpful in identifying seizures, determining encephalopathy severity, and predicting outcome following neonatal HIE. Recently introduced amplitude-integrated EEG (aEEG) monitors, that record 2- to 4- channel EEGs, are useful tools for early and continuously (hour to days) bedside assessment of brain activity. Severely abnormal aEEG patterns recorded at 6 hours of life have been shown to predict a poor outcome with >80% accuracy.
Development of specific interventions to ameliorate ongoing injury and enhance neuroprotection is the focus of recent experimental and clinical studies. Animal data have demonstrated that modest hypothermia initiated within hours of HI brain injury and continued for a sufficient duration, reduces cellular metabolic demands and suppresses pathways leading to delayed cell death and, therefore, provides potent, long-lasting neuroprotection. To date, three large randomized controlled trials in newborn infants have been completed to evaluate modest hypothermia (33.5–35 oC), achieved by either selective head or whole-body cooling, as a neuroprotective treatment for HIE in term infants. No significant adverse effects were observed during these studies. The whole-body cooling trial showed a significant reduction in incidence of death and /or moderate-to-severe disability at 18 months of age in the hypothermic group compared with the control group. Although the head cooling study did not exhibit an overall reduction in death and/or severe disability, a predetermined subgroup analysis showed a significant improved outcome for infants with less severe changes on prerandomization aEEG. More data, from three ongoing hypothermia clinical trials, will be available within the next 2-3 years. Based on a review of the published studies, the NICHD hypothermia workshop has concluded that “therapeutic hypothermia is a promising therapy that should be considered investigational until the short-term safety and efficacy have been confirmed in the additional human trails underway. Long-term safety and efficacy remain to be established.”
Specific agents, such as glutamate receptor antagonists, free radical scavengers, metal chelators and erythropoietin, have shown promising therapeutic potential in animal studies. Hypothermia therapy has the potential benefit of extending the therapeutic window and efficacy of other treatments. Given the evolving complex biochemical processes underlying HI brain injury, combination therapy aimed at particular phases of the injury cascade is needed to achieve effective neuroprotection and repair. These therapies all offer some hope that the long term damage from prenatal and perinatal hypoxia may be decreased.
This information provided by Dong-Li Song, M.D., Neonatologist, California Pacific Medical Center Department of Pediatrics.