A new neurological focus in neonatal intensive care

Department of Pediatrics, UCSF School of Medicine, UCSF Benioff Children's Hospital, Box 0410, 513 Parnassus Avenue, S211, San Francisco, CA 94143-0410, USA.
Nature Reviews Neurology (Impact Factor: 15.36). 08/2011; 7(9):485-94. DOI: 10.1038/nrneurol.2011.119
Source: PubMed

ABSTRACT Advances in the care of high-risk newborn babies have contributed to reduced mortality rates for premature and term births, but the surviving neonates often have increased neurological morbidity. Therapies aimed at reducing the neurological sequelae of birth asphyxia at term have brought hypothermia treatment into the realm of standard care. However, this therapy does not provide complete protection from neurological complications and a need to develop adjunctive therapies for improved neurological outcomes remains. In addition, the care of neurologically impaired neonates, regardless of their gestational age, clearly requires a focused approach to avoid further injury to the brain and to optimize the neurodevelopmental status of the newborn baby at discharge from hospital. This focused approach includes, but is not limited to, monitoring of the patient's brain with amplitude-integrated and continuous video EEG, prevention of infection, developmentally appropriate care, and family support. Provision of dedicated neurocritical care to newborn babies requires a collaborative effort between neonatologists and neurologists, training in neonatal neurology for nurses and future generations of care providers, and the recognition that common neonatal medical problems and intensive care have an effect on the developing brain.

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Available from: Hannah C Glass, Feb 20, 2015
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    • "The treatment considerations for hypothermia in addition to combining other therapies are based on the evolving pathophysiology of neonatal brain injury, discussed by Ferriero et al. (133, 134). Using a combination of therapies may be more beneficial to tackle the activated cell death pathways; moreover, detecting it early in at-risk newborns may help prevent or reduce the disabilities following neonatal brain injury (133, 134). "
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    ABSTRACT: Treatments for neonatal hypoxic-ischemic encephalopathy (HIE) have been limited. The aim of this paper is to offer translational research guidance on stem cell therapy for neonatal HIE by examining clinically relevant animal models, practical stem cell sources, safety and efficacy of endpoint assays, as well as a general understanding of modes of action of this cellular therapy. In order to do so, we discuss the clinical manifestations of HIE, highlighting its overlapping pathologies with stroke and providing insights on the potential of cell therapy currently investigated in stroke, for HIE. To this end, we draw guidance from recommendations outlined in stem cell therapeutics as an emerging paradigm for stroke or STEPS, which have been recently modified to Baby STEPS to cater for the "neonatal" symptoms of HIE. These guidelines recognized that neonatal HIE exhibit distinct disease symptoms from adult stroke in need of an innovative translational approach that facilitates the entry of cell therapy in the clinic. Finally, new information about recent clinical trials and insights into combination therapy are provided with the vision that stem cell therapy may benefit from available treatments, such as hypothermia, already being tested in children diagnosed with HIE.
    Frontiers in Neurology 08/2014; 5:147. DOI:10.3389/fneur.2014.00147
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    • "Our results raise the important and worrying question whether resuscitation paradigms where normocapnic conditions established in a fast manner will, in fact, lead to the promotion of birth-asphyxia seizures. Graded restoration of normocapnia and/or drugs targeting the Na/H exchange in the blood–brain barrier offer an effective and straightforward means to functionally suppress seizures and ameliorate other neurological sequela after birth asphyxia (Rakhade and Jensen, 2009; Bonifacio et al., 2011), and can be readily used in conjunction with other treatment modalities, such as hypothermia (Johnston et al., 2011) and optimization of blood oxygenation levels (Saugstad, 2010). "
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    ABSTRACT: Birth asphyxia is often associated with a high seizure burden that is predictive of poor neurodevelopmental outcome. The mechanisms underlying birth asphyxia seizures are unknown. Using an animal model of birth asphyxia based on 6-day-old rat pups, we have recently shown that the seizure burden is linked to an increase in brain extracellular pH that consists of the recovery from the asphyxia-induced acidosis, and of a subsequent plateau level well above normal extracellular pH. In the present study, two-photon imaging of intracellular pH in neocortical neurons in vivo showed that pH changes also underwent a biphasic acid-alkaline response, resulting in an alkaline plateau level. The mean alkaline overshoot was strongly suppressed by a graded restoration of normocapnia after asphyxia. The parallel post-asphyxia increase in extra- and intracellular pH levels indicated a net loss of acid equivalents from brain tissue that was not attributable to a disruption of the blood-brain barrier, as demonstrated by a lack of increased sodium fluorescein extravasation into the brain, and by the electrophysiological characteristics of the blood-brain barrier. Indeed, electrode recordings of pH in the brain and trunk demonstrated a net efflux of acid equivalents from the brain across the blood-brain barrier, which was abolished by the Na/H exchange inhibitor, N-methyl-isobutyl amiloride. Pharmacological inhibition of Na/H exchange also suppressed the seizure activity associated with the brain-specific alkalosis. Our findings show that the post-asphyxia seizures are attributable to an enhanced Na/H exchange-dependent net extrusion of acid equivalents across the blood-brain barrier and to consequent brain alkalosis. These results suggest targeting of blood-brain barrier-mediated pH regulation as a novel approach in the prevention and therapy of neonatal seizures.
    Brain 11/2012; 135(Pt 11). DOI:10.1093/brain/aws257 · 9.20 Impact Factor
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    • ", and ( ii ) Zeynalov and colleagues report that low doses of exogenous CO protect against transient or permanent focal ischemia in adult mice [ 23 , 24 ] . Perinatal HI can be partially predicted based on the presence of several risk factors : signals of distress during intrauterine life and hypoxic - ischemic insults at birth ( Bonifacio et al . 2011 ) . Also , preterm newborns represent a high - risk population for brain injury due to HI [ 44 ] . Therefore , preconditioning - based strategies can become potential therapies for perinatal HI , and CO is a promising candidate . Other preconditioning - based strategies have also been developed for perinatal cerebral ischemia . In pigle"
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    ABSTRACT: Perinatal hypoxia-ischemia is a major cause of acute mortality in newborns and cognitive and motor impairments in children. Cerebral hypoxia-ischemia leads to excitotoxicity and necrotic and apoptotic cell death, in which mitochondria play a major role. Increased resistance against major damage can be achieved by preconditioning triggered by subtle insults. CO, a toxic molecule that is also generated endogenously, may have a role in preconditioning as low doses can protect against inflammation and apoptosis. In this study, the role of CO-induced preconditioning on neurons was addressed in vitro and in vivo. The effect of 1 h of CO treatment on neuronal death (plasmatic membrane permeabilization and chromatin condensation) and bcl-2 expression was studied in cerebellar granule cells undergoing to glutamate-induced apoptosis. CO's role was studied in vivo in the Rice-Vannucci model of neonatal hypoxia-ischemia (common carotid artery ligature +75 min at 8% oxygen). Apoptotic cells, assessed by Nissl staining were counted with a stereological approach and cleaved caspase 3-positive profiles in the hippocampus were assessed. Apoptotic hallmarks were analyzed in hippocampal extracts by Western Blot. CO inhibited excitotoxicity-induced cell death and increased Bcl-2 mRNA in primary cultures of neurons. In vivo, CO prevented hypoxia-ischemia induced apoptosis in the hippocampus, limited cytochrome c released from mitochondria and reduced activation of caspase-3. Still, Bcl-2 protein levels were higher in hippocampus of CO pre-treated rat pups. Our results show that CO preconditioning elicits a molecular cascade that limits neuronal apoptosis. This could represent an innovative therapeutic strategy for high-risk cerebral hypoxia-ischemia patients, in particular neonates.
    PLoS ONE 08/2012; 7(8):e42632. DOI:10.1371/journal.pone.0042632 · 3.23 Impact Factor
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