Hypoxic–ischemic brain injury in the term infant-current concepts

doi:10.1016/j.earlhumdev.2004.06.003

Early Human Development

Volume 80, Issue 2, November 2004, Pages 125-141

https://doi.org/10.1016/j.earlhumdev.2004.06.003 Get rights and content

Abstract

An enhanced understanding of the cellular characteristics contributing to ongoing brain injury following intrapartum hypoxia-ischemia has resulted in the implementation of targeted neuroprotective strategies in the newborn period. This review briefly covers the pathogenesis of hypoxic-ischemic injury with an emphasis on reperfusion injury; the role of magnetic resonance imaging in the detection of such injury, and focuses on potential strategies both supportive and neuroprotective to prevent ongoing injury with a specific emphasis on modest hypothermia.

Section snippets

Background

Hypoxic–ischemic cerebral injury that occurs during the perinatal period is one of the most commonly recognized causes of severe, long-term neurological deficits in children, often referred to as cerebral palsy (CP) [1], [2]. The brain injury that develops is an evolving process initiated during the insult and extends into a recovery period, the latter referred to as the “reperfusion phase” of injury. Clinically, it is the latter phase that is amendable to potential intervention(s). Until

Pathogenesis of hypoxic–ischemic cerebral injury

The principal pathogenetic mechanism underlying most of the neuropathology attributed to intrapartum hypoxia–ischemia is impaired cerebral blood flow (CBF). This is most likely to occur as a consequence of interruption in placental blood flow and gas exchange, often referred to as “asphyxia” or severe fetal acidemia. The latter is defined as a fetal umbilical arterial pH≤7.00 [1].

At the cellular level, the reduction in cerebral blood flow and oxygen delivery initiates a cascade of deleterious

Delayed (secondary) brain damage

Following resuscitation, which may occur in utero or postnatally in the delivery room, cerebral oxygenation and perfusion is restored. During this recovery phase, the concentrations of phosphorus metabolites and the intracellular pH return to baseline. However, the process of cerebral energy failure recurs from 6 to 48 h later in a second phase of injury. This phase is characterized by a decrease in the ratio of phosphocreatine/inorganic phosphate, with an unchanged intracellular pH, stable

Mechanisms of neuronal cell death following hypoxia–ischemia

The mechanism of neuronal cell death in animals and human following hypoxia–ischemia includes neuronal necrosis and apoptosis. The intensity of the initial insult may determine the mode of death with severe injury resulting in necrosis, while milder insults result in apoptosis [16]. Necrosis is a passive process of cell swelling, disrupted cytoplasmic organelles, loss of membrane integrity and eventual lysis of neuronal cells and activation of an inflammatory process. By contrast, apoptosis is

Detection of neuronal injury following hypoxia–ischemia with magnetic resonance (MR) imaging

MR techniques have become very important in delineating evolving structural, metabolic and functional changes following intrapartum hypoxia–ischemia [18]. Thus, using conventional MR, three patterns of signal abnormalities can be identified including injury to the thalami and/or posterior–lateral putamen with involvement of the subcortical white matter in the most severe cases; injury to the parasagittal gray matter and subcortical white matter, posterior usually more than anterior; and focal

Strategies to prevent ongoing injury following hypoxia–ischemia

The goals of management of a newborn infant who has sustained a hypoxic–ischemic insult and is at risk for evolving injury should include: (1) early identification of the infant at highest risk for evolving injury, (2) supportive care to facilitate adequate perfusion and nutrients to the brain and (3) consideration of interventions to ameliorate the processes of ongoing brain injury.

Each of these approaches is briefly discussed next.

Early identification of high risk infants

The initial step in management is early identification of those infants at greatest risk for evolving to the syndrome of hypoxic–ischemic encephalopathy (HIE). This is a highly relevant issue because the therapeutic window, i.e., the time interval following hypoxia–ischemia during which interventions might be efficacious in reducing the severity of ultimate brain injury, is likely to be short. Based on experimental studies, it is estimated to vary from 2 to 6 h. Given this presumed short window

Supportive care

Supportive care should be directed towards the maintenance of adequate ventilation, avoidance of hypotension, judicious fluid management, avoidance of hypoglycemia and treatment of seizures. For this review, we will focus on the avoidance of hypoglycemia and the judicious treatment of seizures (Table 1).

Control of blood glucose concentrations

In the context of cerebral hypoxia–ischemia, experimental studies suggest that both hyperglycemia and hypoglycemia may accentuate brain damage. Regarding hyperglycemia, in adult experimental models as well as in humans, brain damage is accentuated. However, in immature animals subjected to cerebral hypoxia–ischemia, hyperglycemia to blood glucose concentration of 600 mg/dl entirely prevents the occurrence of brain damage [28]. Regarding hypoglycemia, the effects in experimental animals vary and

Hypothermia

Modest systemic or selective cooling of the brain by as little as 2–4 °C has been shown to reduce the extent of tissue injury in experimental studies as well as human following events such as stroke, trauma or cardiac arrest [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53]. Potential mechanisms of neuroprotection with hypothermia include inhibition of glutamate release, reduction of cerebral metabolism which in turn preserves high energy

Conclusions

Much progress has been made toward understanding the mechanisms contributing to ongoing brain injury following hypoxia–ischemia. This should facilitate more specific pharmacologic intervention strategies that might provide neuroprotection during the reperfusion phase of injury. Early identification of infants at highest risk for brain injury is critical if such interventions are to be successful. Moreover, given the small number of asphyxiated full-term infants that are likely to be admitted to

References (74)

J. Grow et al.
Pathogenesis of hypoxic–ischemic cerebral injury in the term infant: current concepts
Clin. Perinatol.
(2002)
C. Palmer
Hypoxic–ischemic encephalopathy. Therapeutic approaches against microvascular injury, and role of neutrophils, PAF, and free radicals
Clin. Perinatol.
(1995)
P. Hagan et al.
Adenovirus mediated overexpression of IL1 receptor antagonist reduces susceptibility to excitotoxic brain injury in perinatal rats
Neuroscience
(1996)
P.S. Huppi
Advances in postnatal neuroimaging:relevance to pathogenesis and treatment of brain injury
Clin. Perinatol.
(2002)
J.Y. Yager
Hypoglycemic injury to the immature brain
Clin. Perinatol.
(2002)
E.M. Mizrahi
Consensus and controversy in the clinical management of neonatal seizures
Clin. Perinatol.
(1989)
R.N. Goldberg et al.
Use of barbiturate therapy in severe perinatal asphyxia: a randomized controlled trial
J. Pediatr.
(1986)
R.T. Hall et al.
High-dose phenobarbital therapy in term newborn infants with severe perinatal asphyxia: a randomized prospective study with three-year follow-up
J. Pediatr.
(1998)
K. Shimizu et al.
Neuroprotection against hypoxia–ischemia in neonatal rat brain by novel superoxide dismutase mimetics
Neuroscience Letters
(2003)
H.H. de Haan et al.
Magnesium sulfate therapy during asphyxia in near-term fetal lambs does not compromise the fetus but does not reduce cerebral injury
Am. J. Obstet. Gynecol.
(1997)

J.N. Halle et al.

Enhancing adenosine A1 receptor binding reduces hypoxic–ischemic brain injury in newborn rats

Brain Res.

(1997)

A. Aydin

Erythropoietin exerts neuroprotective effect in neonatal rat model of hypoxic–ischemic brain injury

Brain and Development

(2003)

J.M. Perlman

Intrapartum hypoxic–ischemic cerebral injury and subsequent cerebral palsy: medico-legal issues

Pediatrics

(1997)

J.J. Volpe

Hypoxic–ischemic encephalopathy

R.C. Vannucci et al.

Interventions for perinatal hypoxic–ischemic encephalopathy

Pediatrics

(1997)

J.S. Wyatt et al.

Magnetic resonance and near infrared spectroscopy for investigation of perinatal hypoxic–ischemic brain injury

Arch. Dis. Child

(1989)

A. Lorek et al.

Delayed (“secondary”) cerebral energy failure after acute hypoxia–ischemia in the newborn piglet: continuous 48-hour studies by phosphorus magnetic resonance spectroscopy

Pediatr. Res.

(1994)

S.C. Roth et al.

Relation of deranged neonatal cerebral oxidative metabolism with neurodevelopmental outcome and head circumference at four years

Dev. Med. Child. Neurol.

(1997)

H. Hagberg et al.

Enhanced expression of IL1 and IL6 m-RNA and bioactive proteins after hypoxia ischemia in neonatal rats

Pediatr. Research

(1996)

E. Bona et al.

Chemokines and inflammatory cell response to hypoxia ischemia in immature rats

Pediatr. Research

(1999)

S. Eklind et al.

Bacterial endotoxin sensitizes the immature brain to hypoxic ischemic injury

Europ. J. Neuroscience

(2001)

Y. Yanasaki et al.

Blocking of IL-1 activity is a beneficial approach to ischemia and brain edema formation

Acta Neurochir.

(1995)

A.J. Bruce et al.

Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors

Nature Med.

(1996)

S.A. Loddick et al.

Cerebral interleukin 1 is neuroprotective against permanent focal ischemia in the rat

J. Cerebral Blood Flow and Metabolism

(1998)

E. Bonfold et al.

Apoptosis and necrosis: two distinct events, induced respectively by mild and intense insults with N methyl-dospartate or nitric oxide/superoxide in cortical cell cultures

Proc. Natl. Acad. Sci. U. S. A.

(1995)

A.D. Edwards et al.

Apoptosis in perinatal hypoxic–ischemic cerebral damage

Neuropathol. Appl. Neurobiol.

(1996)

L.R. Ment et al.

Practice parameter: neuroimaging of the neonate: report of the quality standards subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society

Neurology

(2002)

F.M. Cowan et al.

Early detection of cerebral infarction and hypoxic ischemic encephalopathy in neonates using diffusion-weighted magnetic resonance imaging

Neuropediatrics

(1994)

G.W. Albers et al.

Yield of diffusion-weighted MRI for detection of potentially relevant findings in stroke patients

Neurology

(2000)

F. Groenendaal et al.

Cerebral lactate and N-acetyl-aspartate/choline ratios in asphyxiated full-term neonates demonstrated in vivo using proton magnetic resonance spectroscopy

Pediatr. Res.

(1994)

J.D. Hanrahan et al.

Persistent increases in cerebral lactate concentration after birth asphyxia

Pediatr. Res.

(1998)

J.M. Risser et al.

Can asphyxiated infants at risk for neonatal seizures be rapidly identified by current high-risk markers?

Pediatrics

(1996)

L. Hellstrom-Westas et al.

Predictive value of early continuous amplitude integrated EEG recordings on outcome after severe birth asphyxia in full term infants

Arch. Dis. Child

(1995)

N. al Naqeeb et al.

Assessment of neonatal encephalopathy by amplitude-integrated electroencephalography

Pediatrics

(1999)

L. Shalak et al.

Amplitude-integrated electroencephalography coupled with an early neurologic examination enhances prediction of term infants at risk for persistent encephalopathy

Pediatrics

(2003)

R.C. Vannucci et al.

Effect of glucose on perinatal hypoxic–ischemic brain damage

Biol. Neonate

(1992)

W. Salhab et al.

Initial hypoglycemia and neonatal brain injury in term infants with severe fetal acidemia

Pediatrics

(2004)

Cited by (146)

Exogenous lactate administration: A potential novel therapeutic approach for neonatal hypoxia-ischemia
2023, Experimental Neurology
Neonatal hypoxic-ischemic encephalopathy (HIE) is the primary reason for neonatal mortality and prolonged disablement. Currently, hypothermia is the only approved clinical treatment available for HIE. However, hypothermia's limited therapeutic efficacy and adverse effects suggest an urgent need to advance our knowledge of its molecular pathogenesis and develop novel therapies. The leading cause of HIE is impaired cerebral blood flow and oxygen deprivation-initiated primary and secondary energy failure. Lactate was traditionally regarded as a marker of energy failure or a waste product of anaerobic glycolysis. Recently, the beneficial aspects of lactate as supplementary energy for neurons have been demonstrated. Under the conditions of HI, lactate supports various functions of neuronal cells, including learning and memory formation, motor coordination, and somatosensory. Furthermore, lactate contributes to the regeneration of blood vessels and has shown its beneficial effects on the immune system. This review first introduces the hypoxic or ischemic events-induced fundamental pathophysiological changes in HIE and then discusses the potential neuroprotective properties of lactate for the treatment and prevention of HIE. Finally, we discuss the possible protective mechanisms of lactate in the context of the pathological features of perinatal HIE. We conclude that exogenous and endogenous lactate exert neuroprotective effects in HIE. Lactate administration may be a potential approach to treating HIE injury.
Effects of prenatal hypoxia-ischemia on male rat periaqueductal gray matter: Hyperalgesia, astrogliosis and nitrergic system impairment
2023, Neurochemistry International
Prenatal hypoxic-ischemic insult (HI) may lead to a variety of neurological consequences that may persist throughout adulthood. In the most severe cases, HI is known to increase pain sensitivity which profoundly impacts quality of life. Periaqueductal gray matter (PAG) is a relevant region of the descending pain pathway and its function may be modulated by a complex network that includes nitrergic neurons and glial response, among other factors. Astrocytes, central players in pain modulation, are known to respond to HI by inducing hyperplasia, hypertrophy and increasing the number of their processes and the staining of glial fibrillary acidic protein (GFAP). In this work we investigated the effects of prenatal HI on touch and pain sensitivity, besides the distribution of the neuronal isoform of Nitric Oxide Synthase (nNOS) and GFAP in the PAG of young and adult male rats. At 18 days of gestation, rats had their uterine arteries clamped for 45 min (HI group). SHAM-operated animals were also generated (SHAM group). At post-natal day 30 (P30) or 90 (P90), the offspring was submitted to the behavioral tests of Von Frey and formalin or histological processing to perform immunohistochemistry for nNOS and GFAP. Although there was no significant difference between the groups concerning touch sensitivity, we observed an increase in pain sensitivity in HI P30 and HI P90. The number of nNOS + cells was reduced in HI adult animals in dlPAG and vlPAG. GFAP immunostaining was increased in HI P90 in dlPAG and dmPAG. Our results demonstrated for the first time an increase in pain sensitivity as a consequence of prenatal HI in an animal model. It reinforces the relevance of this model to mimic the effects of prenatal HI, as hyperalgesia.
Ordered iterative colour channel selection enhances segmentation of brain slice image neurons of the sham fetal sheep model
2022, Intelligent Systems with Applications
Hypoxic Ischemia (HI) accounts for 23% of annual worldwide neonatal death, brain damage and long-term disability. Histopathological studies of infants with HI are rare, so the assessment of neuronal survival in HI animal models compared to the neuronal survival of their sham control, such as the term in utero fetal sheep model, is pivotal to increasing our understanding of HI at the cellular level and for the development of novel therapeutics and treatments.
Histopathological studies of the in utero fetal sheep model rely heavily on the manual identification of neurons in histological brain slice images. However, manual identification is prone to being highly subjective, costly and time-consuming. Thus, there is an urgent need to automate the segmentation process, which is complicated by the existence of densely populated overlapping cells with no prior information of shape or size, resulting in images of high complexity.
In this article, we propose an ‘Ordered Iterative Colour Channel Selection (OICCS) method. Such that, when applied to the standard ‘Marker Controlled Watershed k-means segmentation’ (MCW k-means) method, serves to effectively segment cortical neurons from the background in brain slice images of the term equivalent sham control in utero fetal sheep model. Thus, tackling the over-segmentation issue that was encountered by MCW k-means alone. In the OICCS model, we determine that by iteratively applying MCW k-means segmentation: firstly, to the blue channel image; then again on the green channel image for cortical neurons that remained unsegmented from the blue channel segmentation; and finally again on the red channel image for cortical neurons that remained unsegmented from the green channel segmentation that optimal performance results could be achieved of 97.98% ± 0.97% over 90.65 ± 3.32% achieved by the standard MCW k-means applied to the R, G, B channel alone or other permutations of the colour channels.
The new OICCS enhanced MCW k-means segmentation method presented here is a significant step in automating the segmentation process of cortical brain cells from brain slice images of the sham control fetal sheep model. This will serve to accelerate the histological segmentation process over the manually intensive identification process that is currently employed.
Periventricular- intraventricular hemorrhage in the premature infant- A historical perspective
2022, Seminars in Perinatology
The objective of this chapter is to trace the evolution of intraventricular hemorrhage in the premature infant highlighting the importance of the germinal matrix, a critical role for cerebral blood flow changes in the genesis of hemorrhage, clinical factors that increase the bleeding risk, and potential preventative strategies. In 1976, neuropathological studies demonstrated capillary rupture within the germinal matrix as the precursor of hemorrhage. In 1980, introduction of cranial ultrasound facilitated diagnosis of intraventricular hemorrhage. In 1979, loss of cerebral autoregulation in sick newborn infants was demonstrated. In the 1980’s, studies demonstrated the importance of intravascular factors in provoking hemorrhage. In 1983, the association of cerebral blood flow velocity fluctuations and subsequent hemorrhage was demonstrated. In 1994, antenatal steroids use to accelerate lung development was recommended. This was associated with an unanticipated reduction in hemorrhage. In the mid 1990’s early indomethacin administration was associated with a reduction of severe hemorrhage.
Maternal depression during pregnancy alters infant subcortical and midbrain volumes.
2021, Journal of Affective Disorders
Maternal depression in pregnancy increases the risk for adverse neurodevelopmental outcomes in the offspring. The reason for this is unknown, however, one plausible mechanism may include the impact of maternal antenatal depression on infant brain. Nevertheless, relatively few studies have examined the brain anatomy of infants born to clinically diagnosed mothers.
A legacy magnetic resonance imaging (MRI) dataset was used to compare regional brain volumes in 3-to-6-month-old infants born to women with a clinically confirmed diagnosis of major depressive disorder (MDD) during pregnancy (n = 31) and a reference sample of infants born to women without a current or past psychiatric diagnosis (n = 33). A method designed for analysis of low-resolution scans enabled examination of subcortical and midbrain regions previously found to be sensitive to the parent-child environment.
Compared with infants of non-depressed mothers, infants exposed to maternal antenatal depression had significantly larger subcortical grey matter volumes and smaller midbrain volumes. There was no association between gestational medication exposure and the infant regional brain volumes examined in our sample.
Our scanning approach did not allow for an examination of fine-grained structural differences, and without repeated measures of brain volume, it is unknown whether the direction of reported associations are dependent on developmental stage.
Maternal antenatal depression is associated with an alteration in infant brain anatomy in early postnatal life; and that this is not accounted for by medication exposure. However, our study cannot address whether anatomical differences impact on future outcomes of the offspring.
Lactate Administration Reduces Brain Injury and Ameliorates Behavioral Outcomes Following Neonatal Hypoxia–Ischemia
2020, Neuroscience
Neonatal hypoxic–ischemic encephalopathy is a major cause of mortality and disability in newborns and the only standard approach for treating this condition is therapeutic hypothermia, which shows some limitations. Thus, putative neuroprotective agents have been tested in animal models. The present study evaluated the administration of lactate, a potential energy substrate of the central nervous system (CNS) in an animal model of hypoxia–ischemia (HI), that mimics in neonatal rats the brain damage observed in human newborns. Seven-day-old (P7) male and female Wistar rats underwent permanent common right carotid occlusion combined with an exposition to a hypoxic atmosphere (8% oxygen) for 60 min. Animals were assigned to four experimental groups: HI, HI + LAC, SHAM, SHAM + LAC. Lactate was administered intraperitoneally 30 min and 2 h after hypoxia in HI + LAC and SHAM + LAC groups. HI and SHAM groups received vehicle at the same time points. The volume of brain lesion was evaluated in P9. Animals underwent behavioral assessments: negative geotaxis, righting reflex (P8 and P14), and cylinder test (P20). Lactate administration reduced the volume of brain lesion and improved behavioral parameters after HI in both sexes. Thus, lactate administration could be a neuroprotective strategy for the treatment of neonatal HI, a disorder still affecting a significant percentage of human newborns.

View all citing articles on Scopus

View full text

Hypoxic–ischemic brain injury in the term infant-current concepts

Abstract

Section snippets

Background

Pathogenesis of hypoxic–ischemic cerebral injury

Delayed (secondary) brain damage

Mechanisms of neuronal cell death following hypoxia–ischemia

Detection of neuronal injury following hypoxia–ischemia with magnetic resonance (MR) imaging

Strategies to prevent ongoing injury following hypoxia–ischemia

Early identification of high risk infants

Supportive care

Control of blood glucose concentrations

Hypothermia

Conclusions

Clin. Perinatol.

Clin. Perinatol.

Neuroscience

Clin. Perinatol.

Clin. Perinatol.

Clin. Perinatol.

J. Pediatr.

J. Pediatr.

Neuroscience Letters

Am. J. Obstet. Gynecol.

Brain Res.

Brain and Development

Intrapartum hypoxic–ischemic cerebral injury and subsequent cerebral palsy: medico-legal issues

Pediatrics

Hypoxic–ischemic encephalopathy

Interventions for perinatal hypoxic–ischemic encephalopathy

Pediatrics

Magnetic resonance and near infrared spectroscopy for investigation of perinatal hypoxic–ischemic brain injury

Arch. Dis. Child

Delayed (“secondary”) cerebral energy failure after acute hypoxia–ischemia in the newborn piglet: continuous 48-hour studies by phosphorus magnetic resonance spectroscopy

Pediatr. Res.

Relation of deranged neonatal cerebral oxidative metabolism with neurodevelopmental outcome and head circumference at four years

Dev. Med. Child. Neurol.

Enhanced expression of IL1 and IL6 m-RNA and bioactive proteins after hypoxia ischemia in neonatal rats

Pediatr. Research

Chemokines and inflammatory cell response to hypoxia ischemia in immature rats

Pediatr. Research

Bacterial endotoxin sensitizes the immature brain to hypoxic ischemic injury

Europ. J. Neuroscience

Blocking of IL-1 activity is a beneficial approach to ischemia and brain edema formation

Acta Neurochir.

Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors

Nature Med.

Cerebral interleukin 1 is neuroprotective against permanent focal ischemia in the rat

J. Cerebral Blood Flow and Metabolism

Apoptosis and necrosis: two distinct events, induced respectively by mild and intense insults with N methyl-dospartate or nitric oxide/superoxide in cortical cell cultures

Proc. Natl. Acad. Sci. U. S. A.

Apoptosis in perinatal hypoxic–ischemic cerebral damage

Neuropathol. Appl. Neurobiol.

Practice parameter: neuroimaging of the neonate: report of the quality standards subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society

Neurology

Early detection of cerebral infarction and hypoxic ischemic encephalopathy in neonates using diffusion-weighted magnetic resonance imaging

Neuropediatrics

Yield of diffusion-weighted MRI for detection of potentially relevant findings in stroke patients

Neurology

Cerebral lactate and N-acetyl-aspartate/choline ratios in asphyxiated full-term neonates demonstrated in vivo using proton magnetic resonance spectroscopy

Pediatr. Res.

Persistent increases in cerebral lactate concentration after birth asphyxia

Pediatr. Res.

Can asphyxiated infants at risk for neonatal seizures be rapidly identified by current high-risk markers?

Pediatrics

Predictive value of early continuous amplitude integrated EEG recordings on outcome after severe birth asphyxia in full term infants

Arch. Dis. Child

Assessment of neonatal encephalopathy by amplitude-integrated electroencephalography

Pediatrics

Amplitude-integrated electroencephalography coupled with an early neurologic examination enhances prediction of term infants at risk for persistent encephalopathy

Pediatrics

Effect of glucose on perinatal hypoxic–ischemic brain damage

Biol. Neonate

Initial hypoglycemia and neonatal brain injury in term infants with severe fetal acidemia

Pediatrics