Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, Polin RA, Robertson CM, Thoresen M, Whitelaw A, Gunn AJSelective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 365:663-670

The Liggins Institute, University of Auckland, Auckland, New Zealand.
The Lancet (Impact Factor: 45.22). 02/2005; 365(9460):663-70. DOI: 10.1016/S0140-6736(05)17946-X
Source: PubMed

ABSTRACT Cerebral hypothermia can improve outcome of experimental perinatal hypoxia-ischaemia. We did a multicentre randomised controlled trial to find out if delayed head cooling can improve neurodevelopmental outcome in babies with neonatal encephalopathy.
234 term infants with moderate to severe neonatal encephalopathy and abnormal amplitude integrated electroencephalography (aEEG) were randomly assigned to either head cooling for 72 h, within 6 h of birth, with rectal temperature maintained at 34-35 degrees C (n=116), or conventional care (n=118). Primary outcome was death or severe disability at 18 months. Analysis was by intention to treat. We examined in two predefined subgroup analyses the effect of hypothermia in babies with the most severe aEEG changes before randomisation--ie, severe loss of background amplitude, and seizures--and those with less severe changes.
In 16 babies, follow-up data were not available. Thus in 218 infants (93%), 73/110 (66%) allocated conventional care and 59/108 (55%) assigned head cooling died or had severe disability at 18 months (odds ratio 0.61; 95% CI 0.34-1.09, p=0.1). After adjustment for the severity of aEEG changes with a logistic regression model, the odds ratio for hypothermia treatment was 0.57 (0.32-1.01, p=0.05). No difference was noted in the frequency of clinically important complications. Predefined subgroup analysis suggested that head cooling had no effect in infants with the most severe aEEG changes (n=46, 1.8; 0.49-6.4, p=0.51), but was beneficial in infants with less severe aEEG changes (n=172, 0.42; 0.22-0.80, p=0.009).
These data suggest that although induced head cooling is not protective in a mixed population of infants with neonatal encephalopathy, it could safely improve survival without severe neurodevelopmental disability in infants with less severe aEEG changes.

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Available from: Marianne Thoresen, Sep 26, 2015
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    • "Hypoxic–ischemic encephalopathy is the most common cause of brain injury in term newborns. Therapeutic hypothermia is currently the only existing treatment to minimize brain injury in these newborns, with decreased death and disability rates at 12–18 months and beyond (Azzopardi et al., 2009; Eicher et al., 2005a, b; Gluckman et al., 2005; Jacobs et al., 2007; Shankaran et al., 2005; Shankaran et al., 2012). However , some newborns still develop brain injury despite this treatment (Barks, 2008; Higgins et al., 2006; Higgins and Shankaran, 2009). "
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    ABSTRACT: Arterial spin labeling (ASL) perfusion-weighted imaging (PWI) by magnetic resonance imaging (MRI) has been shown to be useful for identifying asphyxiated newborns at risk of developing brain injury, whether or not therapeutic hypothermia was administered. However, this technique has been only rarely used in newborns until now, because of the challenges to obtain sufficient signal-to-noise ratio (SNR) and spatial resolution in newborns.
    Clinical neuroimaging 12/2014; 6. DOI:10.1016/j.nicl.2014.08.010 · 2.53 Impact Factor
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    • "Neonatal hypoxic–ischemic encephalopathy (HIE) remains a serious condition that causes significant mortality and morbidity in near-term and term newborns (Gluckman et al., 2005; Shankaran et al., 2005). Brain hypoxia and ischemia due to systemic hypoxemia and reduced cerebral blood flow (CBF) are the primary causes of neonatal HIE accompanied by gray and white matter injuries occurring in neonates (Ferriero, 2004; Grow and Barks, 2002). "
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    ABSTRACT: Estetrol (E4) is a recently described natural estrogen with four hydroxyl-groups that is synthesized exclusively during pregnancy by the human fetal liver. It has important antioxidative activity. The aim of the present study was to define the importance of E4 in the attenuation of neonatal hypoxic-ischemic encephalopathy. Antioxidative effect of 650 μM, 3.25 mM and 6.5 mM E4 on primary hippocampal cell cultures was studied before/after H202-induced oxidative stress. To examine the oxidative stress and the cell viability, lactate dehydrogenase activity and cell proliferation colorimetric assays were performed. To study the neuroprotective and therapeutic effects of E4 in vivo neonatal hypoxic-ischemic encephalopathy model of 7-day-old newborn rat pups was used. The neuroprotective and therapeutic effectst of estetrol before/after hypoxic-ischemic insult was studied in 1 mg/kg//day, 5 mg/kg/day, 10 mg/kg/day, 50 mg/kg/day E4 pretreated/treated groups and compared with the sham and the vehicle treated groups. The body temperature of the rat pups was examined along with their body and brain weights. Brains were studied at the level of the hippocampus and cortex. Intact cell counting and expressions of microtubule-associated protein-2, doublecortin and vascular-endothelial growth factor were evaluated by histo- and immunohistochemistry. ELISAs were performed on blood samples to detect concentrations of S100B and glial fibrillary acidic protein as brain damage markers. This work reveals for the first time that E4 significantly decreases LDH activity and enhances cell proliferation in primary hippocampal neuronal cell cultures in vitro, and decreases the early gray matter loss and promotes neuro- and angiogenesis in vivo.
    Experimental Neurology 11/2014; 261. DOI:10.1016/j.expneurol.2014.07.015 · 4.70 Impact Factor
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    • "Collectively, those structures help maintain brain temperature homeostasis by shielding the brain from external thermal challenges. Without these layers, the surgically exposed cerebral cortex can have temperatures 5–10 • C below core body temperatures (Gorbach et al., 2003; Kalmbach and Waters, 2012). The surgical removal of a large piece of skull, performed to relieve the intracranial pressure after brain injury, increased brain's thermal susceptibility to the external environment and resulted in lowered brain temperatures (Nakagawa et al., 2011; Suehiro et al., 2011). "
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    ABSTRACT: Brain temperature, as an independent therapeutic target variable, has received increasingly intense clinical attention. To date, brain hypothermia represents the most potent neuroprotectant in laboratory studies. Although the impact of brain temperature is prevalent in a number of common human diseases including: head trauma, stroke, multiple sclerosis, epilepsy, mood disorders, headaches, and neurodegenerative disorders, it is evident and well recognized that the therapeutic application of induced hypothermia is limited to a few highly selected clinical conditions such as cardiac arrest and hypoxic ischemic neonatal encephalopathy. Efforts to understand the fundamental aspects of brain temperature regulation are therefore critical for the development of safe, effective, and pragmatic clinical treatments for patients with brain injuries. Although centrally-mediated mechanisms to maintain a stable body temperature are relatively well established, very little is clinically known about brain temperature's spatial and temporal distribution, its physiological and pathological fluctuations, and the mechanism underlying brain thermal homeostasis. The human brain, a metabolically "expensive" organ with intense heat production, is sensitive to fluctuations in temperature with regards to its functional activity and energy efficiency. In this review, we discuss several critical aspects concerning the fundamental properties of brain temperature from a clinical perspective.
    Frontiers in Neuroscience 10/2014; 8(307). DOI:10.3389/fnins.2014.00307 · 3.66 Impact Factor
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