title: Intervention strategies for neonatal hypoxic-ischemic cerebral injury.
abstract: BACKGROUND
  Accumulating evidence points to an evolving process of brain injury after intrapartum hypoxia-ischemia that initiates in utero and extends into a recovery period. It is during this recovery period that the potential for neuroprotection exists.
  
  
  OBJECTIVE
  This discussion briefly reviews the cellular characteristics of hypoxic-ischemic cerebral injury and the current and future therapeutic strategies aimed at ameliorating ongoing brain injury after intrapartum hypoxia-ischemia.
  
  
  METHODS
  As part of the Newborn Drug Development Initiative, the National Institute of Child Health and Human Development and the US Food and Drug Administration cosponsored a workshop held March 29 and 30, 2004, in Baltimore, Maryland. Information for this article was gathered during that workshop. Literature searches of MEDLINE (Ovid) and EMBASE (1996-2005) were also conducted; search terms included newborn, infant, hypoxia-ischemia, hypoxic-ischemic encephalopathy, asphyxia, pathogenesis, treatment, reperfusion injury, and mechanisms, as well as numerous interventions (ie, therapeutic hypothermia, magnesium, and barbiturates).
  
  
  RESULTS
  The acute brain injury results from the combined effects of cellular energy failure, acidosis, glutamate release, intracellular calcium accumulation, lipid peroxidation, and nitric oxide neurotoxicity that serve to disrupt essential components of the cell, resulting in death. Many factors, including the duration or severity of the insult, influence the progression of cellular injury after hypoxia-ischemia. A secondary cerebral energy failure occurs from 6 to 48 hours after the primary event and may involve mitochondrial dysfunction secondary to extended reactions from primary insults (eg, calcium influx, excitatory neurotoxicity, oxygen free radicals, or nitric oxide formation). Some evidence suggests that circulatory and endogenous inflammatory cells/mediators also contribute to ongoing brain injury. The goals of management of a newborn infant who has sustained a hypoxic-ischemic insult and is at risk for injury should include early identification of the infant at highest risk for evolving injury, supportive care to facilitate adequate perfusion and nutrients to the brain, attempts to maintain glucose homeostasis, and consideration of interventions to ameliorate the processes of ongoing brain injury. Recent evidence suggests a potential role for modest hypothermia (ie, a reduction in core body temperature to -34 degrees C) administered to high-risk term infants within 6 hours of birth. Either selective (head) or systemic (body) cooling reduces the incidence of death and/or moderate to severe disability at 18-month follow-up. Additional strategies-including the use of oxygen free radical inhibitors and scavengers, excitatory amino acid antagonists, and growth factors; prevention of nitric oxide formation; and blockage of apoptotic pathways-have been evaluated experimentally but have not been replicated in a systematic manner in the human neonate. Other avenues of potential neuroprotection that have been studied in immature animals include platelet-activating factor antagonists, adenosinergic agents, monosialoganglioside GM1, insulin-like growth factor-1, and erythropoietin.
  
  
  CONCLUSIONS
  Much progress has been made toward understanding the mechanisms contributing to ongoing brain injury after intrapartum hypoxia-ischemia. This should facilitate more specific pharmacologic intervention strategies that might provide neuroprotection during the reperfusion phase of injury.
authors.affiliation: Weill Medical College of Cornell University, New York, New York 10021, USA. jmp2007@med.cornell.edu
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Perlman
mesh_terms: D003245:Consensus Statements as Topic; D006801:Humans; D007036:Hypothermia, Induced / Q000379:methods*; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000628:therapy*; D007231:Infant, Newborn; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D017410:Practice Guidelines as Topic; D011379:Prognosis; D012121:Respiration, Artificial / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D018696:Neuroprotective Agents