The search continues: neuroprotection for all neonates with hypoxic-ischemic encephalopathy

Abstract

Hypoxic-ischemic encephalopathy (HIE) from peripartum complications is a leading cause of neonatal brain injury. Inducing therapeutic hypothermia within 6 hours of birth to 33.0-34.0 ℃ for 72 hours is the standard of care for moderate to severe encephalopathy in many developed countries. The protection afforded by hypothermia is incomplete, however, as nearly half of hypothermia-treated survivors suffer persistent moderate to severe neurologic disabilities (1,2). Therefore, we continue to search for therapeutic strategies that can provide full neuroprotection in all neonates with HIE.Dr. Shankaran et al. report their findings from a multicenter randomized trial to test deeper, longer, or deeper and longer cooling for neonates with HIE in "Effect of Depth and Duration of Cooling on Death or Disability at Age 18 Months Among Neonates with HIE: A Randomized Clinical Trial". After determining that the predicted probability of detecting a decrease in in-hospital mortality was less than 2% with longer or deeper cooling, the study was stopped for safety and futility. Bradycardia, inhaled nitric oxide use, extracorporeal membrane oxygenation use, and longer duration of oxygen therapy were more common in neonates cooled to 32.0 ℃ than in those cooled to 33.0-34.0 ℃. The risks of arrhythmia, anuria, and longer hospital stay were also greater in neonates cooled for 120 hours than in those cooled for 72 hours (3). In the more recent report of outcomes at 18 months, deeper cooling to 32.0 ℃ or longer cooling for 120 hours did not reduce rates of death or disability. Additionally, a significant interaction between cooling depth and cooling duration raised concerns about increased mortality when these interventions were combined (4). Preclinical studies also have shown that cooling to lower temperatures does not provide additional neuroprotection (5) and might be detrimental (6).Hypothermia is the primary and most widely available brain-focused treatment for HIE. Until the advent of hypothermia, no other targeted therapies for HIE reached wide-scale clinical investigation. Hypothermia opened the door for neurotherapeutic clinical trials and stimulated the development of modern neonatal neurocritical care. Though we do not know precisely how hypothermia protects the brain, decades of preclinical studies have demonstrated that it reduces hypoxia-induced inflammation, oxidative stress, cytotoxic edema, excitotoxicity, energy failure, and the resulting neural cell death. The rationale for clinically testing hypothermia depth and duration was based on data from small and large-animal studies (7) coupled with the incomplete neuroprotection observed in a high proportion of infants cooled for HIE. Dr. Shankaran's study (4) suggests that improving neurologic outcomes after HIE will require approaches beyond hypothermia.Limited evidence suggests that hypothermia's failure to EditorialThe search continues: neuroprotection for all neonates with hypoxic-ischemic encephalopathy

Oxytocin protects neurons from hypoxic-ischemic brain injury by enhancing inhibitory neurotransmission in neonatal rats

“…About 20 % of the affected neonates die during the perinatal period, while the survivors suffer neurodevelopmental disorders, epilepsy and learning disabilities, all of which seriously endanger the physical and mental health of children [8]. The pathogenesis of HIBD is not yet fully understood, although it is generally believed to be related to calcium overload, disorders in energy metabolism, and oxygen free radicalinduced damage [9,10]. Therefore, there is need to understand the mechanism involved in the occurrence and development of HIBD, and to evolve a safe and effective treatment strategy for it.…”