Interventions for Perinatal Hypoxic–Ischemic Encephalopathy

Abstract

Perinatal cerebral hypoxia–ischemia remains a frequent cause of the chronic handicapping conditions of cerebral palsy, mental retardation, learning disability, and epilepsy.1Estimates suggest that between 2 and 4/1000 full-term newborn infants suffer asphyxia at or shortly before birth. Approximately 15% to 20% of such asphyxiated infants who exhibit hypoxic–ischemic encephalopathy actually die during the newborn period, and of the survivors, 25% will exhibit permanent neuropsychologic deficits. Given these incidence figures, physicians have searched for strategies to prevent or minimize the long-term consequences of perinatal cerebral hypoxia–ischemia.In the past, therapeutic interventions for hypoxic–ischemic encephalopathy in full-term newborn infants consisted of those drugs that reduced the severity of cerebral edema arising from hypoxia–ischemia.2 Such agents included osmotic diuretics (mannitol, furosemide), glucocorticosteroids, and barbiturates. One by one, these drugs and other manipulations to treat brain swelling have been discarded, such that presently no agent has been proven useful to ameliorate perinatal hypoxic–ischemic brain damage in the clinical setting (but see below). Accordingly, there is no uniform standard of care in the brain-oriented therapy of full-term newborn infants sustaining cerebral hypoxia–ischemia, and it remains for future research to uncover new and effective strategies for the neurologically compromised infant.Hypoxic–ischemic brain damage is an evolving process, which begins during the insult and extends into the recovery period after resuscitation (reperfusion interval).3Tissue injury takes the form of either selective neuronal necrosis or infarction, the latter with destruction of all cellular elements including neurons, glia, and blood vessels. When infarction occurs, the immediate area surrounding the infarct (penumbra) consists of neurons undergoing either necrosis or apoptosis (programmed cell death).4-7 It is the penumbral area that appears most amenable to reversal of cellular injury through therapeutic intervention.At the cellular level, cerebral hypoxia–ischemia sets in motion a cascade of biochemical events commencing with a shift from oxidative to anaero-bic metabolism (glycolysis), which leads to an accumulation of nicotinamide-adenine-dinucleotide (NADH), flavin-adenine-dinucleotide (FADH), and lactic acid plus H+ions. Anaerobic glycolysis cannot keep pace with cellular energy demands, resulting in a depletion of high-energy phosphate reserves, including ATP. Transcellular ion pumping fails, leading to an accumulation of intracellular Na+, Ca++, Cl−, and water (cytotoxic edema). Hypoxia–ischemia also stimulates release of excitatory amino acids (glutamate) from axon terminals. The glutamate release, in turn, activates glutamate cell surface receptors, resulting in an influx of Na+ and Ca++ ions. Within the cytosol, free fatty acids accumulate from increased membrane phospholipid turnover and, thereafter, undergo peroxidation by oxygen-free radicals that arise from reductive processes within mitochondria and as by-products in the synthesis of prostaglandins, xanthine, and uric acid. Ca++ ions accumulate within the cytosol as a consequence of increased plasma (cellular) membrane influx via voltage-sensitive and agonist-operated calcium channels and of decreased efflux across the plasma membrane combined with release from mitochondria and the endoplasmic reticulum. Nitric oxide, a free-radical gas, is generated via Ca++activation in selected neurons and diffuses to adjacent cells that are susceptible to nitric oxide toxicity. The combined effects of cellular energy failure, acidosis, glutamate and nitric oxide neurotoxicity, free radical formation, Ca++ accumulation, and lipid peroxidation serve to disrupt structural components of the cell with its ultimate death (for review, Reference 3).The therapeutic window is that interval after resuscitation from hypoxia–ischemia, during which an intervention might be efficacious in reducing the severity of the ultimate brain damage. Because of the slow process of neuronal necrosis and apoptosis in adult experimental animals and humans, the therapeutic window in adults can extend for several hours to a day or more.48-10 Such is not the case in perinatal animals and presumably in human infants, in whom the process of cellular destruction is much more rapid than in adults.3 Accordingly, in the full-term infant, the therapeutic window would be short and possibly no longer than 1 to 2 hours. In this regard, no drug has been found efficacious in reducing the severity of hypoxic–ischemic brain damage in immature animals when given later than 2 hours after termination of the hypoxic–ischemic insult (see below).An additional issue that constantly arises regarding therapeutic intervention of the asphyxiated full-term newborn infant is the identification of those infants at highest risk for permanent brain damage. Given the pre