Experimental treatments for hypoxic ischaemic encephalopathy

https://doi.org/10.1016/j.earlhumdev.2010.05.011Get rights and content

Abstract

Hypoxic ischaemic encephalopathy continues to be a significant cause of death and disability worldwide. In the last 1–2 years, therapeutic hypothermia has entered clinical practice in industrialized countries and neuroprotection of the newborn has become a reality. The benefits and safety of cooling under intensive care settings have been shown consistently in trials; therapeutic hypothermia reduces death and neurological impairment at 18 months with a number needed to treat of approximately nine. Unfortunately, around half the infants who receive therapeutic hypothermia still have abnormal outcomes. Recent experimental data suggest that the addition of another agent to cooling may enhance overall protection either additively or synergistically. This review discusses agents such as inhaled xenon, N-acetylcysteine, melatonin, erythropoietin and anticonvulsants. The role of biomarkers to speed up clinical translation is discussed, in particular, the use of the cerebral magnetic resonance spectroscopy lactate/N-acetyl aspartate peak area ratios to provide early prognostic information. Finally, potential future therapies such as regeneration/repair and postconditioning are discussed.

Introduction

Neonatal encephalopathy remains a significant problem worldwide. An estimated 4 million babies die every year during the neonatal period, and one quarter of these deaths are attributed to neonatal asphyxia [1]. Even in the developed world, neonatal encephalopathy is a common clinical condition affecting approximately 2 per 1000 neonates [2] and accounts for a substantial proportion of admissions to neonatal intensive care; 10–15% of cases will die in the neonatal unit, 10–15% will develop cerebral palsy and up to 40% will have other significant disabilities including blindness, deafness, autism, epilepsy, global developmental delay, and problems with cognition, memory, fine motor skills and behaviour [3], [4], [5].

Within the last decade, therapeutic hypothermia for infants with hypoxic ischaemic encephalopathy has been studied in pre-clinical models [6] and several major randomized clinical trials in the developed world [7]. Despite the clinical heterogeneity of perinatal asphyxia and the use of different cooling methods there are consistent findings that hypothermia reduces the extent of neurological damage and improves survival without disability [8]. Therapeutic hypothermia is now widely offered to moderately and severely asphyxiated infants in countries and centers which participated in the trials [9].

Despite the promising outcome of these trials, the reduction in disability or death at 18 months with therapeutic hypothermia is modest — meta-analyses indicate that the composite adverse outcome reduces from 58% to 47% with cooling [5], [8]. Thus approximately half the infants who receive therapeutic hypothermia still have an abnormal outcome and some infants with the most severe injuries may not be rescued [7]. Recent experimental data suggest that hypothermia extends the duration of the therapeutic window [10], [11] and that certain drugs given during this time may augment neuroprotection [11], [12], [13]. Research is now being focused on pre-clinical studies of drugs, which act synergistically or additively with hypothermia with the hope that combination therapy might reduce the overall number of infants needed to treat to improve intact survival.

Section snippets

Overview of biomarkers

Biomarkers are critically needed in neonatal encephalopathy because the timing of brain injury is heterogeneous and difficult to identify. Biomarkers may have several roles, including: (a) the identification of who is injured, (b) the extent of injury, (c) the timing of injury, (d) identification of the most likely outcomes with and without therapy and (e) speeding up clinical translation of interventions. In a recent systematic review of studies where urine, serum and cerebrospinal fluid

Xenon

Xenon was discovered by Sir William Ramsay (together with his student Morris Travers) in 1898 while he was Professor of Chemistry at University College London; they found xenon in the residue left over from evaporating components of liquid air. Ramsay estimated the proportion of xenon in the earth's atmosphere as one part in 20 million [31]. Ramsay also discovered krypton and neon and received the Nobel Prize for Chemistry in 1904. Although the noble gas xenon is considered chemically inert, it

Postconditioning

The “ischaemic conditioning” phenomenon was first described in 1986 in the heart whereby brief non-lethal episodes of ischaemia and reperfusion in advance of prolonged lethal ischaemia boosted the intrinsic resistance of the myocardium to injury [121]. This was termed ischaemic preconditioning (IPC); such resistance has been reproduced in all species tested including humans and in a variety of organs including the heart, kidney and brain [122]. As perinatal hypoxia–ischaemia is unpredictable,

Regeneration and repair

During HI brain injury neurons, glia and endothelial cells are damaged and lose their function or die. Endogenous regeneration mechanisms have been shown to exist in the brain as ischemic brain injury stimulates neural stem cell proliferation and differentiation in cerebral neurogenic areas [131], [132], [133]. The capacity of the neonatal brain to respond with enhanced endogenous neurogenesis following neonatal HI may, however, depend on timing and severity of insult. In addition endogenous

Conclusion

Carefully conducted pre-clinical studies are needed to define the best combination of drugs and interventions that will optimize neuroprotection for hypoxic ischaemic encephalopathy. In many cases, neuroprotective agents have not been tested with therapeutic hypothermia and this is needed before clinical translation. It is important to make sure that the administration of individual drugs or combinations of drugs does not exacerbate neurodegeneration in the developing brain. Finally the use of

Role of funding source

This work was undertaken at UCLH/UCH who received a proportion of funding from the UK Department of Health's NIHR Biomedical Research Centres funding scheme.

References (135)

  • N. Jawad et al.

    Neuroprotection (and lack of neuroprotection) afforded by a series of noble gases in an in vitro model of neuronal injury

    Neurosci Lett

    (2009)
  • G.D. Williams et al.

    Allopurinol preserves cerebral energy metabolism during perinatal hypoxia-ischemia: a 31p nmr study in unanesthetized immature rats

    Neurosci Lett

    (1992)
  • W.D. Johnson et al.

    A randomized controlled trial of allopurinol in coronary bypass surgery

    Am Heart J

    (1991)
  • T. Gunes et al.

    Effect of allopurinol supplementation on nitric oxide levels in asphyxiated newborns

    Pediatr Neurol

    (2007)
  • O. Cakir et al.

    Neuroprotective effect of n-acetylcysteine and hypothermia on the spinal cord ischemia-reperfusion injury

    Cardiovasc Surg

    (2003)
  • M. Bouslama et al.

    Melatonin prevents learning disorders in brain-lesioned newborn mice

    Neuroscience

    (2007)
  • V. Ruth et al.

    Postnatal changes in serum immunoreactive erythropoietin in relation to hypoxia before and after birth

    J Pediatr

    (1990)
  • A. Cariou et al.

    Early high-dose erythropoietin therapy and hypothermia after out-of-hospital cardiac arrest: a matched control study

    Resuscitation

    (2008)
  • J.M. Dean et al.

    Partial neuroprotection with low-dose infusion of the alpha2-adrenergic receptor agonist clonidine after severe hypoxia in preterm fetal sheep

    Neuropharmacology

    (2008)
  • D. Ma et al.

    Dexmedetomidine produces its neuroprotective effect via the alpha 2a-adrenoceptor subtype

    Eur J Pharmacol

    (2004)
  • M. Matsumoto et al.

    The alpha 2 adrenergic agonist, dexmedetomidine, selectively attenuates ischemia-induced increases in striatal norepinephrine concentrations

    Brain Res

    (1993)
  • N. Rajakumaraswamy et al.

    Neuroprotective interaction produced by xenon and dexmedetomidine on in vitro and in vivo neuronal injury models

    Neurosci Lett

    (2006)
  • V.H.N. Pierrat et al.

    Groupe d'Etudes en Epidemiologie Perinatale. Prevalence, causes, and outcome at 2 years of age of newborn encephalopathy: population based study

    Arch Dis Child Fetal Neonatal Ed

    (2005)
  • N. Marlow et al.

    Prevalence, causes, and outcome at 2 years of age of newborn encephalopathy

    Arch Dis Child Fetal Neonatal Ed

    (2005)
  • E. Bona et al.

    Protective effects of moderate hypothermia after neonatal hypoxia-ischemia: short- and long-term outcome

    Pediatr Res

    (1998)
  • A. Edwards et al.

    Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data

    BMJ

    (2010)
  • A. Kapetanakis et al.

    Therapeutic hypothermia for neonatal encephalopathy: a UK survey of opinion, practice and neuro-investigation at the end of 2007

    Acta Paediatr

    (2009)
  • F. O'Brien et al.

    Delayed whole-body cooling to 33 or 35 degrees c and the development of impaired energy generation consequential to transient cerebral hypoxia-ischemia in the newborn piglet

    Pediatrics

    (2006)
  • Y. Liu et al.

    Topiramate extends the therapeutic window for hypothermia-mediated neuroprotection after stroke in neonatal rats

    Stroke

    (2004)
  • D. Ma et al.

    Xenon and hypothermia combine to provide neuroprotection from neonatal asphyxia

    Ann Neurol

    (2005)
  • M. Jatana et al.

    Combination of systemic hypothermia and n-acetylcysteine attenuates hypoxic-ischemic brain injury in neonatal rats

    Pediatr Res

    (2006)
  • M. Thoresen et al.

    Mild hypothermia after severe transient hypoxia-ischemia ameliorates delayed cerebral energy failure in the newborn piglet

    Pediatr Res

    (1995)
  • N. Robertson et al.

    Cerebral intracellular lactic alkalosis persisting months after neonatal encephalopathy measured by magnetic resonance spectroscopy

    Pediatr Res

    (1999)
  • S. Thayyil et al.

    Cerebral magnetic resonance biomarkers in neonatal encephalopathy: a meta-analysis

    Pediatrics

    (2010)
  • M.W. Parsons et al.

    Combined (1)h mr spectroscopy and diffusion-weighted mri improves the prediction of stroke outcome

    Neurology

    (2000)
  • M. Chandrasekaran et al.

    Xenon combined with hypothermia reduces cerebral Lactate/Cr on 1H MRS, markers of cell death and phagocytosis at 48 hours in a perinatal asphyxia piglet model

    EPAS

    (2010)
  • D. Azzopardi et al.

    Prognosis of newborn infants with hypoxic-ischemic brain injury assessed by phosphorus magnetic resonance spectroscopy

    Pediatr Res

    (1989)
  • H. Lei et al.

    Effect of temperature on the kinetics of lactate production and clearance in a rat model of forebrain ischemia

    Biochem Cell Biol

    (1998)
  • J. Penrice et al.

    Proton magnetic resonance spectroscopy of the brain during acute hypoxia-ischemia and delayed cerebral energy failure in the newborn piglet

    Pediatr Res

    (1997)
  • H. Lei et al.

    Evolution of the neurochemical profile after transient focal cerebral ischemia in the mouse brain

    J Cereb Blood Flow Metab

    (2009)
  • D.L. Rothman et al.

    Localized proton nmr observation of [3-13c]lactate in stroke after [1-13c]glucose infusion

    Magn Reson Med

    (1991)
  • J.D. Hanrahan et al.

    Persistent increases in cerebral lactate concentration after birth asphyxia

    Pediatr Res

    (1998)
  • N. Robertson et al.

    Brain alkaline intracellular ph after neonatal encephalopathy

    Ann Neurol

    (2002)
  • H. Mehmet et al.

    Relation of impaired energy metabolism to apoptosis and necrosis following transient cerebral hypoxia-ischaemia

    Cell Death Differ

    (1998)
  • J.H. Garcia

    Cerebral infarction. Evolution of histopathological changes after occlusion of a middle cerebral artery in primates

    J nNeuropathol Exp Neurol

    (1974)
  • W. Ramsay

    An attempt to estimate the relative amounts of krypton and of xenon in atmospheric ai

    Proc R Soc Lond

    (1902)
  • S. Cullen et al.

    The anesthetic properties of xenon in animals and human beings, with additional observations on krypton

    Science

    (1951)
  • N. Franks et al.

    How does xenon produce anaesthesia?

    Nature

    (1998)
  • G.A. Lane et al.

    Anesthetics as teratogens: nitrous oxide is fetotoxic, xenon is not

    Science

    (1980)
  • D. Ma et al.

    Xenon mitigates isoflurane-induced neuronal apoptosis in the developing rodent brain

    Anaesthesiology

    (2007)
  • Cited by (67)

    • Xenon detection in human blood: Analytical validation by accuracy profile and identification of critical storage parameters

      2018, Journal of Forensic and Legal Medicine
      Citation Excerpt :

      In 1939, it was discovered that xenon can act as an anesthetic agent, and in 1951, the first surgery with xenon was performed.2,3 Since then, much research has been conducted on this gas to better understand its mechanism of action in the body.4–7 In addition to its anesthetic properties, xenon has organ-protective properties that may be based on its interaction with the hypoxia-inducible factor HIF-1α.8,9

    • Xenon Combined With Hypothermia in Perinatal Hypoxic-Ischemic Encephalopathy: A Noble Gas, a Noble Mission

      2018, Pediatric Neurology
      Citation Excerpt :

      Renal function is not harmed, and xenon has myocardial protective properties as well.54 It is not fetotoxic55 and is not teratogenic.56 Added to this safety profile, xenon has no negative environmental effects.48

    • Xenon: From medical applications to doping uses

      2017, Toxicologie Analytique et Clinique
      Citation Excerpt :

      The anaesthetic property of xenon has then been confirmed on mice in 1946; and lately in 1951 [3] for the first surgery with xenon anaesthesia. Xenon was considered as an effective anaesthetic with its low blood-gas partition coefficient, safe cardiovascular profile and ability to penetrate through blood brain barrier without extensive effort [4,33,34]. These advantageous properties enable xenon to have a rapid induction, which is a key element in anaesthesia.

    View all citing articles on Scopus
    View full text