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The potential of erythropoietin to treat asphyxia in newborns

Sandra Juul, Gillian Pet
2014 Research and Reports in Neonatology  
Perinatal asphyxia is a cause of significant neonatal morbidity worldwide. Lack of oxygenation and perfusion to the neonatal brain leads to energy failure and cell death. Currently, therapeutic hypothermia is the standard of care for term infants with hypoxicischemic encephalopathy, but as it has shown only modest effects on survival and morbidity, additional neuroprotective agents are needed. Erythropoietin has been extensively studied as a neuroprotective agent for infants who suffer a
more » ... who suffer a hypoxic-ischemic brain injury. It has multiple mechanisms of action, in both preventing cell death and promoting tissue repair. Studies have progressed over time from in vitro to in vivo studies, first in animals and now in humans, with several Phase I/II trials completed and Phase III trials underway. As therapeutic hypothermia has become the standard of care in treating term infants with hypoxic-ischemic encephalopathy, studies must now evaluate other neuroprotective agents, including erythropoietin, used in concert with therapeutic hypothermia. Erythropoietin has shown promise as a neuroprotective agent in animal and human models, both alone and together with hypothermia. Perinatal asphyxia Lack of oxygen and tissue perfusion in the perinatal period can lead to neonatal hypoxic-ischemic encephalopathy (HIE), which occurs in one to three/1,000 live births in developed countries. 1 In 2008, it was estimated that birth asphyxia caused between 563,000 and 997,000 deaths worldwide, 9% of all deaths in children younger than 5 years of age. 2 Recently, therapeutic hypothermia has proven to be effective at improving mortality and neurodevelopmental outcomes in infants with moderate-tosevere HIE. 3,4 However, even with therapeutic hypothermia, HIE still causes significant morbidity and mortality, with approximately 48% of infants dying or having major neurodevelopmental disability at 18 months of age. 4 Additional interventions are clearly needed to further improve outcomes, and these must be tested in the context of therapeutic hypothermia. Mechanisms of brain injury Perinatal asphyxia results from disruption in cerebral perfusion and oxygenation, often caused by an interruption in blood flow and gas exchange across the placenta. The resulting brain injury is characterized by an evolving process, which spans the period of initial interruption of blood flow through the period of recovery after reperfusion. The first phase occurs during the period of decreased oxygen delivery to the infant. The body must switch to anaerobic metabolism, resulting in significantly less adenosine Research and Reports in Neonatology downloaded from https://www.dovepress.com/ by 207.241.231.83 on 23-Jul-2018 For personal use only. submit your manuscript | www.dovepress.com Dovepress Dovepress 196 Pet and Juul triphosphate (ATP) being generated for each molecule of glucose metabolized. The decreased availability of ATP causes failure of the ATP-dependent Na+/K+ pump, leading to a sodium influx into cells. The sodium influx is followed by chloride and water influx, leading to cellular swelling and, eventually, lysis with cell death by necrosis. 5 The failure of the ATP-dependent Na+/K+ pump also causes membrane depolarization, leading to increased glutamate release and decreased glutamate uptake. The increased concentration of extracellular glutamate, along with activation of ion-gated calcium channels and failure of energy-dependent processes of calcium removal from the cell, causes accumulation of calcium in the cytosol, which has significant negative effects including membrane injury, generation of free radicals and nitric oxide, and further decreases in ATP production. 5,6 The number of cells that die during this initial phase is related to the severity of the insult, with a higher number of cells dying in the initial phase after a more severe insult. 6 The next phase consists of secondary energy failure that occurs 6 to 48+ hours after the original injury and involves inflammation, cytotoxic edema, nitric oxide synthesis, mitochondrial dysfunction, and further accumulation of excitotoxins. 6,7 This phase correlates best with neurodevelopmental outcomes and has the potential to be affected by neuroprotective interventions. 3,6,8 Hypoxia and ischemia can cause injury to both white and gray matter regions, depending on the type, duration, timing, and other circumstances of the injury. In term infants, the most common patterns of injury include watershed injury (plus cortical gray matter injury when severe), deep gray matter injury (involving deep grey nuclei, hippocampi, and perirolandic cortex, with additional cortical damage when severe), and multicystic encephalopathy in infants who experience an acute event superimposed on more chronic mild-to-moderate hypoxia. 9 Research and Reports in Neonatology downloaded from https: //www.dovepress.com/ by 207.241.231.83 on 23-Jul-2018 For personal use only. Powered by TCPDF (www.tcpdf.org)
doi:10.2147/rrn.s52375 fatcat:jvdrnvbpaze6vgr7py7frr56hy