Elsevier

The Lancet Neurology

Volume 10, Issue 4, April 2011, Pages 372-382
The Lancet Neurology

Review
Treatment advances in neonatal neuroprotection and neurointensive care

https://doi.org/10.1016/S1474-4422(11)70016-3Get rights and content

Summary

Knowledge of the nature, prognosis, and ways to treat brain lesions in neonatal infants has increased remarkably. Neonatal hypoxic-ischaemic encephalopathy (HIE) in term infants, mirrors a progressive cascade of excito-oxidative events that unfold in the brain after an asphyxial insult. In the laboratory, this cascade can be blocked to protect brain tissue through the process of neuroprotection. However, proof of a clinical effect was lacking until the publication of three positive randomised controlled trials of moderate hypothermia for term infants with HIE. These results have greatly improved treatment prospects for babies with asphyxia and altered understanding of the theory of neuroprotection. The studies show that moderate hypothermia within 6 h of asphyxia improves survival without cerebral palsy or other disability by about 40% and reduces death or neurological disability by nearly 30%. The search is on to discover adjuvant treatments that can further enhance the effects of hypothermia.

Introduction

Disorders that damage the developing brain are a substantial cause of death or permanent disability such as cerebral palsy. Hypoxic-ischaemic encephalopathy (HIE) in term infants occurs at a rate of about three per thousand live-born infants in developed countries, but the rate is estimated to be higher in the developing world.1, 2 As many as a million deaths worldwide might be caused by perinatal asphyxia.3 Less common but no less important causes of brain injury in neonates are ischaemic strokes, including venous sinus thrombosis, encephalopathy associated with severe congenital heart disease, intraventricular haemorrhages, and periventricular leukomalacia (PVL) in premature infants.4, 5, 6 Infants with encephalopathy secondary to rare metabolic disorders such as urea-cycle disorders should also be included in this group.7 Physicians who care for these children in the period after injury have traditionally provided supportive care with little expectation that their interventions would salvage brain tissue or have an effect on the final outcome. However, this situation has changed over the past 5 years with the publication of positive results from several controlled trials of therapeutic moderate hypothermia for term infants with neonatal HIE.8 Publication of these results has led to wider clinical application of therapeutic hypothermia for neonatal encephalopathy. This new therapy is increasingly being given to babies in special neurointensive care nursery units where they can be monitored with amplitude integrated electroencephalography (aEEG) and continuous conventional electroencephalography (EEG) by specially trained nurses.9 Time to recovery of a normal background pattern on aEEG seems to be a better predictor of outcome in infants treated with therapeutic hypothermia than in normothermic infants with HIE.10

These advances in treatment are based on knowledge gained from clinical observation of babies with asphyxia and extensive laboratory research with experimental models.11, 12 Data from these experiments led to a heuristic model in which hypoxia-ischaemia triggers a delayed series of events that lead to cell death in the brain.13 This period of delay, or latent interval, suggested that post-insult interventions could be protective if started in time. Discoveries of the role of glutamate-mediated excitotoxicity, oxidative stress, and cell-death signalling pathways in perinatal brain injuries have provided a foundation for these trials in humans, and continuing research on basic mechansisms of cell death is important to improve treatment and identify new treatment targets. These basic studies suggest that combination of hypothermia with adjuvant treatments, including the anaesthetic gas xenon, erythropoietin, or anticonvulsants, might improve outcome.14 In this Review we discuss three advances: progress in understanding the cascade of neurochemical events that mediate brain damage after a hypoxic-ischaemic insult in term infants; data from clinical trials that show benefit of therapeutic hypothermia for term infants with HIE; and early clinical results of trials of erythropoietin and other adjuvant drugs that might enhance neuroprotection.

Section snippets

Neonatal encephalopathy in term infants

Signs of encephalopathy in newborn babies older than 34 weeks' gestation can include hyperalertness, lethargy, somnolence or coma, seizures, poor feeding, hypotonia, and respiratory problems that might need mechanical ventilation.11 Sarnat and Sarnat15 were the first to define this syndrome as neonatal encephalopathy following foetal distress in 21 infants older than 36 weeks' gestation.15 They distinguished three stages of encephalopathy: stage 1, or mild encephalopathy associated with

The excito-oxidative cascade

Implicit in the early descriptions of the syndrome of neonatal HIE was the notion that its clinical signs progress after a latent period of hours to days and then resolve within several weeks.15 Recognition of this concept led to clinical and basic research aimed at understanding the cascade of neurochemical processes responsible for brain injury to improve intervention and salvage brain tissue.20, 21, 22 An important early discovery made by Reynolds and colleagues23, 24 was termed “secondary

Neuroprotection mediated by hypothermia

Hypothermia has been used successfully since the 1950s as a protective measure to allow babies with complex congenital heart disease to undergo circulatory arrest for corrective surgery,102 but its use in neonatological settings was impeded by data showing that it increased the death rate in premature infants.103 However, interest in this technique was renewed with the publication of data on the pathogenesis of HIE reviewed above, especially that which showed the importance of delayed secondary

Conclusions

Over the past decade, substantial progress has been made in neuroprotection and neurointensive care for neonates. Decades of clinical and basic science research into the pathogenesis of HIE in term infants have been translated into the use of moderate hypothermia for infants with mild or moderate HIE, and much evidence shows that this therapy substantially, although incompletely, reduces neurological disability. This therapy is increasingly being given to babies in special neurointensive care

Search strategy and selection criteria

We searched all articles listed in PubMed published from 1906, to January, 2011, in English, Japanese, and Chinese using the phrases “neonatal asphyxia”, “neonatal hypoxic-ischemic encephalopathy”, “neonatal encephalopathy”, “neonatal therapeutic hypothermia”, “neonatal excitotoxicity”, “neonatal neuroprotection”, “neonatal neuroinflammation”, “neonatal brain oxidative stress”, “amplitude integrated EEG”, and “neonatal neurointensive care”. Articles reporting controlled clinical trials

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