Hypothermia for hypoxic–ischemic encephalopathy

Abstract

Moderate to severe hypoxic-ischemic injury in newborn infants, manifested as encephalopathy immediately or within hours after birth, is associated with a high risk of either death or a lifetime with disability. In recent multicenter clinical trials, hypothermia initiated within the first 6 postnatal hours has emerged as a therapy that reduces the risk of death or impairment among infants with hypoxic-ischemic encephalopathy. Prior to hypothermia, no therapies directly targeting neonatal encephalopathy secondary to hypoxic-ischemic injury had convincing evidence of efficacy. Hypothermia therapy is now becoming increasingly available at tertiary centers. Despite the deserved enthusiasm for hypothermia, obstetric and neonatology caregivers, as well as society at large, must be reminded that in the clinical trials more than 40% of cooled infants died or survived with impairment. Although hypothermia is an evidence-based therapy, additional discoveries are needed to further improve outcome after HIE. In this article, we briefly present the epidemiology of neonatal encephalopathy due to hypoxic-ischemic injury, describe the rationale for the use of hypothermia therapy for hypoxic-ischemic encephalopathy, and present results of the clinical trials that have demonstrated the efficacy of hypothermia. We also present findings noted during and after these trials that will guide care and direct research for this devastating problem. KeywordsHIE; hyperthermia; hypothermia; hypoxic-ischemic encephalopathy; neonate; perinatal asphyxia What is hypoxic-ischemic encephalopathy & what is its impact on health outcomes?Neonatal encephalopathy, or a persistently abnormal neurologic examination that includes one or more of the following: altered consciousness, abnormal muscle tone or reflexes, altered respirations, and sometimes seizures in the first postnatal hours to days -can be caused by a number of etiologies, including acute perinatal asphyxia, intracranial bleeding and stroke, injuries secondary to birth trauma, infections, metabolic disorders including hypoglycemia, and congenital brain abnormalities. Encephalopathy due to hypoxic-ischemic injuryhypoxic-ischemic encephalopathy (HIE) -is defined as brain injury caused by the combination of inadequate blood flow and oxygen delivery to the brain. Attributing neonatal encephalopathy © 2010 Expert Reviews Ltd † Author for correspondence Duke University Medical Center, Box 2739 DUMC, Durham, NC 27710, USA, Tel.: +1 919 681 4844, Fax: +1 919 681 6065 cotte010@mc.duke.edu. NIH Public Access Author ManuscriptExpert Rev Obstet Gynecol. Author manuscript; available in PMC 2011 January 1. Published in final edited form as:Expert Rev Obstet Gynecol. 2010 March 1; 5(2): 227-239. doi:10.1586/eog.10.7. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript to perinatal hypoxic-ischemic injury requires combinations of parameters indicative of metabolic acidosis in the first postnatal hours with low cord pH (<7.0), base deficit of over 12, and evidence of a need for r...

Rescuing the neonatal brain from hypoxic injury with autologous cord blood

“…52 Four pivotal multicenter clinical trials of hypothermia for neonates with moderate-to-severe HIE (CoolCap, NICHD Neonatal Research Network, Total Body Hypothermia and Infant Cooling Evaluation) have led to widening adoption of cooling as a treatment of choice for term and near-term neonates with HIE. 9 Four published meta-analyses, including a Cochrane review, demonstrated a consistent beneficial effect for moderate hypothermia with reduction of risk of the combined outcome, death or neurodevelopmental impairment at B2 years ( Figure 3). All meta-analyses of several main trials and well-described phase I and II randomized studies, which included outcome information, demonstrate consistent relative risk of death or disability of B0.75 and a 95% confidence interval between 0.60 and 0.90.…”

“…7,8 However, in the clinical trials demonstrating benefit, a significant number of the HIE infants still died or survived with neurologic and functional impairment. 9 Stem cell regenerative therapies offer great promise in a variety of degenerative diseases including neurological disorders. Stem cells from different sources, such as neural stem/progenitor cells derived from either fetal tissue or embryonic stem-induced pluripotent stem cells, MSCs, human umbilical cord blood (HUCB)-derived stem cells or HUCB mononuclear cells, have been utilized in several animal models of neurological diseases.…”

Diffusion-Weighted MRI and Urinary Activin-A are Correlated with the Degree of Hypoxic Ischemic Encephalopathy in Neonates

“…During the last 2 decades, evidence from experimental and clinical studies proved that therapeutic hypothermia reduces cerebral injury and improves neurological outcome provided that cases of HIE are early diagnosed [15][16][17] . Many studies of perinatal asphyxia have measured several biologic markers (brain-specific creatine kinase, neurone specific enolase, S 100 B protein, Activin-A, hypoxanthine, erythropoietin, and lactate dehydrogenase in serum or cerebrospinal fluid), but the tests are usually performed late after birth, when the infants may already have HIE [18][19][20][21] .…”

Recent Information on the Pathogenesis and Treatment of Hypoxic-Ischemic Brain Lesions in Newborns

“…Фазы энергетической недостаточности Клинические и экспериментальные исследования пока-зывают, что ГИП развиваются через две фазы -первич-ную и вторичную энергетическую недостаточность [3][4][5][6].…”

“…Высокая степень первичной энер гетической недостаточности способствует дальней-шему повреждению [3][4][5][6]. Между первичной и вторичной фазой энергетической недостаточности есть короткий, так называемый латентный, период восстановления кровото-ка, который характеризуется нормальным церебральным метаболизмом.…”