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Hypoxic-Ischemic Encephalopathy A Review for the Clinician

Martha Douglas-Escobar, MD1; Michael D. Weiss, MD2
[+] Author Affiliations
1Department of Pediatrics, University of California, San Francisco
2Department of Pediatrics, University of Florida, Gainesville
JAMA Pediatr. 2015;169(4):397-403. doi:10.1001/jamapediatrics.2014.3269.
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Importance  Hypoxic-ischemic encephalopathy (HIE) occurs in 1 to 8 per 1000 live births in developed countries. Historically, the clinician has had little to offer neonates with HIE other than systemic supportive care. Recently, the neuroprotective therapy of hypothermia has emerged as the standard of care, and other complementary therapies are rapidly transitioning from the basic science to clinical care.

Objective  To examine the pathophysiology of HIE and the state of the art for the clinical care of neonates with HIE.

Evidence Review  We performed a literature review using the PubMed database. Results focused on reviews and articles published from January 1, 2004, through December 31, 2014. Articles published earlier than 2004 were included when appropriate for historical perspective. Our review emphasized evidence-based management practices for the clinician.

Findings  A total of 102 articles for critical review were selected based on their relevance to the incidence of HIE, pathophysiology, neuroimaging, placental pathology, biomarkers, current systemic supportive care, hypothermia, and emerging therapies for HIE and were reviewed by both of us. Seventy-five publications were selected for inclusion in this article based on their relevance to these topics. The publications highlight the emergence of serum-based biomarkers, placental pathology, and magnetic resonance imaging as useful tools to predict long-term outcomes. Hypothermia and systemic supportive care form the cornerstone of therapy for HIE.

Conclusions and Relevance  The pathophysiology of HIE is now better understood, and treatment with hypothermia has become the foundation of therapy. Several neuroprotective agents offer promise when combined with hypothermia and are entering clinical trials.

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Figure 1.
Schematic Overview of the Pathophysiological Features of Hypoxic-Ischemic Encephalopathy

ATP indicates adenosine triphosphate; O2, oxygen.

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Figure 2.
Complex Cascade of Events Producing Cellular Damage and Destruction After Hypoxia-Ischemia (HI)

During hypoxic-ischemic encephalopathy, an excessive amount of the excitatory amino acid glutamate is released from the presynaptic terminal. This excess glutamate leads to overstimulation of the glutamate receptors (2-(aminomethyl)phenylacetic acid [AMPA], kainite [KA], and N-methyl-d-aspartate [NMDA]) located on the postsynaptic neuron and leads to excitotoxicity. Overstimulation of the KA and AMPA receptors causes sodium (Na+) and chloride to enter the cell, which increases cell osmolality. Overstimulation of the NMDA receptor triggers the influx of calcium (Ca2+). The 3 aberrant cellular processes lead to apoptosis and necrosis. The various neuroprotective agents are illustrated at the points where they interfere with the pathophysiological cascade. Solid arrows represent the pathophysiological cascade that is unleashed as a result of HI injury; dashed arrows, interruption of the cascade by the various neuroprotective agents (circled numbers). As in Figure 1, the orange boxes represent excitotoxicity; blue boxes, oxidative stress; yellow box, repair; light green box, cell death; and dark blue box, HI. NO indicates nitric oxide; 1, magnesium; 2, xenon; 3, erythropoietin; 4, stem cells; 5, N-acetylcysteine; 6, melatonin; 7, anticonvulsants; 8, antioxidants; 8a, allopurinol sodium; 9, BH4 (tetrahydrobiopterin); and 10, hydrogen sulfide.

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