Nature, time-course, and extent of cerebral edema in perinatal hypoxic-ischemic brain damage

doi:10.1016/0887-8994(93)90006-X

Pediatric Neurology

Volume 9, Issue 1, January–February 1993, Pages 29-34

https://doi.org/10.1016/0887-8994(93)90006-X Get rights and content

Abstract

To ascertain the nature, time-course, and extent of the cerebral edema that accompanies perinatal hypoxic-ischemic brain damage, 7-day postnatal rats were subjected to unilateral right common carotid artery ligation followed by exposure to hypoxia with 8% oxygen for up to 3 hours. Some rat pups were sacrificed during hypoxia-ischemia or recovery for determination of cerebral hemispheric water content and percentage of brain swelling. Other animals were sacrificed and their brains processed either for determination of cerebral cortical edema and infarct volume or for horseradish peroxidase staining. The results indicated that cerebral edema occurs even during the course of hypoxia-ischemia and that the extent and duration of edema formation during the recovery period is dependent upon the severity of tissue injury. The data also disclosed a direct, linear correlation between infarct volume and the extent of cerebral edema. Accordingly, the greater the severity of cerebral edema, the proportionately greater the extent of infarction. Horseradish peroxidase staining, a reflection of vasogenic edema, occurred in 17 of 19 brains in a distribution which corresponded closely to the distribution of neuropathologic alterations observed histologically. The findings indicate that cerebral edema can occur in the absence of consequent infarction and that when infarction does occur, the associated edema contributes little or nothing to the severity of the ultimate brain damage.

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Cited by (76)

Hypoxic-Ischemic Injury in the Term Infant
2018, Volpe's Neurology of the Newborn
Hypoxic-ischemic brain injury is a very important neurological problem of the perinatal period. This importance of hypoxic-ischemic brain injury relates to the general gravity of the lesions and to the relatively large number of affected infants. In this chapter, we review the neuropathology and pathogenesis of neonatal hypoxic-ischemic encephalopathy. The major neuropathological varieties include selective neuronal necrosis, which is the necrosis of neurons in a characteristic, often widespread distribution; it is very unusual to observe this in isolation. The topography of the neuronal injury depends in part on the severity and temporal characteristics of the insult and on the gestational age of the infant. Basic patterns observed best in term infants are diffuse neuronal injury, cerebrocortical–deep nuclear neuronal necrosis, pontosubicular neuronal injury, and cerebellar injury. Parasagittal cerebral injury is a lesion of the cerebral cortex and subcortical white matter with a distribution comprising parasagittal and superomedial aspects of the cerebral convexities; it is characteristic of the full-term infant with perinatal asphyxia. The predominant lesion in infants with hypoxic-ischemic encephalopathy may involve primarily cerebral white matter. Approximately 15% of infants exhibit this pattern of injury as the dominant abnormality. The similarities with periventricular leukomalacia of very premature infants are apparent. Important contributing pathogenetic factors in infants with hypoxic-ischemic encephalopathy are late preterm gestational age, neonatal hypoglycemia, and often chronic hemodynamic instability. The majority of term infants with congenital heart disease dying days after cardiac surgery exhibit at autopsy periventricular leukomalacia as a prominent lesion. Involvement of cerebral white matter is also the dominant neuroimaging feature of infants with complex congenital heart disease both before and after cardiac surgery.
Hypoxic-Ischemic Injury in the Term Infant: Neuropathology. Neuropathology.
2018, Volpe's Neurology of the Newborn
Hypoxic-ischemic brain injury is a very important neurological problem of the perinatal period. This importance of hypoxic-ischemic brain injury relates to the general gravity of the lesions and to the relatively large number of affected infants. In this chapter, we review the neuropathology and pathogenesis of neonatal hypoxic-ischemic encephalopathy. The major neuropathological varieties include selective neuronal necrosis, which is the necrosis of neurons in a characteristic, often widespread distribution; it is very unusual to observe this in isolation. The topography of the neuronal injury depends in part on the severity and temporal characteristics of the insult and on the gestational age of the infant. Basic patterns observed best in term infants are diffuse neuronal injury, cerebrocortical–deep nuclear neuronal necrosis, pontosubicular neuronal injury, and cerebellar injury. Parasagittal cerebral injury is a lesion of the cerebral cortex and subcortical white matter with a distribution comprising parasagittal and superomedial aspects of the cerebral convexities; it is characteristic of the full-term infant with perinatal asphyxia. The predominant lesion in infants with hypoxic-ischemic encephalopathy may involve primarily cerebral white matter. Approximately 15% of infants exhibit this pattern of injury as the dominant abnormality. The similarities with periventricular leukomalacia of very premature infants are apparent. Important contributing pathogenetic factors in infants with hypoxic-ischemic encephalopathy are late preterm gestational age, neonatal hypoglycemia, and often chronic hemodynamic instability. The majority of term infants with congenital heart disease dying days after cardiac surgery exhibit at autopsy periventricular leukomalacia as a prominent lesion. Involvement of cerebral white matter is also the dominant neuroimaging feature of infants with complex congenital heart disease both before and after cardiac surgery.
Evidence for Therapeutic Intervention in the Prevention of Cerebral Palsy: Hope from Animal Model Research
2013, Seminars in Pediatric Neurology
Citation Excerpt :
The result is a focal area of injury ranging from selective neuronal necrosis to frank infarction in the area of the middle cerebral artery, its severity is dependent on the duration of accompanying hypoxia. Although appearing as a perinatal ischemic stroke, the pathophysiology of injury has been well defined, and as such, has been recognized as being strongly representative of the cellular mechanisms underlying perinatal hypoxic-ischemic brain injury.51-58 In recent years, several other models have been developed that more specifically depict a “global ischemic” insult and hence, presumably, are more representative of the diplegic and quadriplegic spastic cerebral palsies.
Knowledge translation, as defined by the Canadian Institute of Health Research, is defined as the exchange, synthesis, and ethically sound application of knowledge—within a complex system of interactions among researchers and users—to accelerate the capture of the benefits of research through improved health, more effective services and products, and a strengthened healthcare system. The requirement for this to occur lies in the ability to continue to determine mechanistic actions at the molecular level, to understand how they fit at the in vitro and in vivo levels, and for disease states, to determine their safety, efficacy, and long-term potential at the preclinical animal model level. In this regard, particularly as it relates to long-term disabilities such as cerebral palsy that begin in utero, but only express their full effect in adulthood, animal models must be used to understand and rapidly evaluate mechanisms of injury and therapeutic interventions. In this review, we hope to provide the reader with a background of animal data upon which therapeutic interventions for the prevention and treatment of cerebral palsy, benefit this community, and increasingly do so in the future.
Cerebral palsy and perinatal asphyxia (II - Medicolegal implications and prevention)
2011, Gynecologie Obstetrique et Fertilite
La constante augmentation de la pression médicolégale en obstétrique constitue un problème préoccupant dans les pays développés, du fait des indemnisations croissantes des paralysies cérébrales, avec comme conséquence une flambée des primes d’assurance professionnelle conduisant de nombreux obstétriciens à abandonner la pratique des accouchements. Cinquante-quatre à 74 % des plaintes en responsabilité concernent des anomalies des tracés cardiotocographiques (CTG), mal interprétées ou suivies de réactions inadéquates ou trop tardives. Une revue critique des neuf critères retenus par le Collège des obstétriciens et gynécologues américains et par l’Académie américaine de pédiatrie pour caractériser l’encéphalopathie néonatale et la paralysie cérébrale, est effectuée à propos des quatre paramètres essentiels définissant l’asphyxie chez le nouveau-né à terme et des cinq critères mineurs évoquant une atteinte intrapartum. La nécessité d’un examen anatomopathologique du placenta est soulignée afin de pouvoir rattacher une paralysie cérébrale à une asphyxie fœtale, grâce à la confirmation d’événements « sentinelles » survenus avant ou pendant le travail ou bien grâce à la découverte de lésions thrombotiques affectant la circulation fœtale, d’aspects évoquant une insuffisance placentaire ou de réponses circulatoires d’adaptation à une hypoxie chronique dans les villosités. L’histologie placentaire doit aussi permettre d’exclure l’origine asphyxique d’une paralysie cérébrale en révélant des réactions inflammatoires aiguës de chorioamniotite avec dissémination au fœtus ou des aspects compatibles avec une maladie métabolique. L’imagerie cérébrale par résonance magnétique (IRM) nucléaire est fondamentale pour élucider le mécanisme et la chronologie des atteintes tissulaires hypoxiques, en localisant préférentiellement les lésions sur la substance blanche ou sur la substance grise du cerveau. Certaines asphyxies intrapartum peuvent être prévenues en effectuant une césarienne programmée pour un fœtus fragile, en évitant la survenue de certains événements « sentinelles » et surtout en répondant de façon appropriée aux anomalies CTG et en procédant avec compétence à la réanimation néonatale. Au cours de la réunion d’expertise contradictoire, il est indispensable de disposer d’un CTG lisible, d’un partogramme bien documenté, d’une analyse des gaz du sang au cordon ombilical, d’un examen anatomopathologique du placenta et d’une évaluation complète du nouveau-né incluant une IRM cérébrale. Le risque médicolégal peut être réduit par une formation continue en CTG, en respectant les recommandations nationales concernant le rythme cardiaque fœtal (RCF), en utilisant des méthodes complémentaires comme le pH ou les lactates au scalp, en réalisant de régulières revues de mortalité et morbidité (RMM) des dossiers litigieux et en instaurant la pratique périodique d’audits ou d’évaluations de la pratique professionnelle (EPP) à propos des acidoses néonatales sévères, des transferts en réanimation néonatale, des ventilations assistées et des délais observés entre la décision et la réalisation des accouchements opératoires. Compte tenu de la rapidité d’installation des lésions cérébrales fœtales en cas d’asphyxie aiguë, il reste de nombreux dossiers où aucune faute ne peut être retenue contre l’accoucheur. Inversement, un épisode hypoxique anténatal bien documenté au niveau cérébral n’exclut pas automatiquement une aggravation par une prise en charge défaillante pendant l’accouchement.
Obstetric litigation is a growing problem in developed countries and its escalating cost together with increasing medical insurance premiums is a major concern for maternity service providers, leading to obstetric practice cessation by many practitioners. Fifty-four to 74 % of claims are based on cardiotocographic (CTG) abnormalities and their interpretation followed by inappropriate or delayed reactions. A critical analysis is performed about the nine criteria identified by the American College of Obstetricians and Gynecologists and the American Academy of Pediatrics in their task force on Neonatal Encephalopathy and Cerebral Palsy: four essential criteria defining neonatal asphyxia and five other suggesting an acute intrapartum event sufficient to cause cerebral palsy in term newborns. The importance of placental histologic examination is emphasized in order to confirm sudden catastrophic events occurring before or during labor or to detect occult thrombotic processes affecting the fetal circulation, patterns of decreased placenta reserve and adaptative responses to chronic hypoxia. It may also exclude intrapartum hypoxia by revealing some histologic patterns typical of acute chorioamnionitis and fetal inflammatory response or compatible with metabolic diseases. Magnetic resonance imaging (MRI) of the infant's damaged brain is very contributive to elucidate the mechanism and timing of asphyxia in conjunction with the clinical picture, by locating cerebral injuries predominantly in white or grey matter. Intrapartum asphyxia is sometimes preventable by delivering weak fetuses by cesarean sections before birth, by avoiding some “sentinel” events, and essentially by responding appropriately to CTG anomalies and performing an efficient neonatal resuscitation. During litigation procedures, it is necessary to have access to a readable CTG, a well-documented partogram, a complete analysis of umbilical cord gases, a placental pathology and an extensive clinical work-up of the newborn infant including cerebral MRI. Malpractice litigation in obstetric care can be reduced by permanent CTG education, respect of national CTG guidelines, use of adjuncts such as fetal blood sampling for pH or lactates, regular review of adverse events in Clinical Risk Management (CRM) groups and periodic audits about low arterial cord pH in newborns, admission to neonatal unit, the need for assisted ventilation and the decision-to-delivery interval for emergency operative deliveries. Considering the fast occurrence of fetal cerebral hypoxic injuries, and thus despite an adequate management, many intrapartum asphyxias will not be preventable. Conversely, well-documented hypoxic-ischemic brain insults during the antenatal period do not automatically exclude intrapartum suboptimal obstetric care.
Animal Models of Perinatal Hypoxic-Ischemic Brain Damage
2009, Pediatric Neurology
Citation Excerpt :
Others documented an increase, particularly in the striatum of excitatory amino-acid release [80], and an accumulation of intracellular calcium that arises during the terminus of the insult and into recovery [81]. Pathologically, cerebral edema evolves over a period of several days, peaking at 72 hours in those animals with the most significant damage [82]. Histologically, there is a gradation of injury that correlates in a linear fashion with the duration or severity of the insult [83,84].
Animal models are often presumably the first step in determining mechanisms underlying disease, and the approach and effectiveness of therapeutic interventions. Perinatal brain damage, however, evolves over months of gestation, during the rapid maturation of the fetal and newborn brain. Despite marked advances in our understanding of these processes and technologic advances providing an improved window on the timing and duration of injury, neonatal brain injury remains a “moving target” regarding our ability to “mimic” its processes in an animal model. Moreover, interfering with normal processes of development as part of a therapeutic intervention may do “more harm than good.” Hence, controversy continues over which animal model can reflect human disease states. Numerous models have provided information regarding the pathophysiology of brain damage in term and preterm infants. Our challenges consist of identifying infants at greatest risk for permanent injury, identifying the timing of injury, and adapting therapies that provide more benefit than harm. A combination of appropriately suitable animal models to conduct these studies will bring us closer to understanding human perinatal damage and the means to treat it.
Treatment of the Term Newborn With Brain Injury: Simplicity As the Mother of Invention
2009, Pediatric Neurology
Citation Excerpt :
Early approaches to glucose homeostasis in the asphyxiated newborn tended to avoid levels that exceeded normality, due to evidence in adult animal models and humans suggesting that hyperglycemia during or after stroke, lead to increased lactic acidosis and increased brain damage [30,31]. Work by Vannucci et al. [32,33], however, has repeatedly shown that hyperglycemia and lactic acidosis is not harmful to the immature brain and may indeed be beneficial. In this regard, Voorhies et al. [34] found that 7-day rat pups treated with high glucose concentrations had improved survival rates and reduced brain injury after a hypoxic-ischemic insult, compared with the controls.
Neonatal brain injury remains a common cause of developmental disability, despite tremendously enhanced obstetrical and neonatal care. The timing of brain injury occurs throughout gestation, labor, and delivery, providing an evolving form of brain injury and a moving target for therapeutic intervention. Nonetheless, markedly improved methods are available to identify those infants injured at birth, via clinical presentation with neonatal encephalopathy and neuroimaging techniques. Postischemic hypothermia has been shown to be of tremendous clinical promise in several completed and ongoing trials. As part of this approach to the treatment of the newborn, other parameters of physiologic homeostasis can and should be attended to, with strong animal and clinical evidence that their correction will have dramatic influence on the outcome of the newborn infant. This review addresses aspects of newborn care to which we can direct our attention currently, and which should result in a safe and efficacious improvement in the prognosis of the newborn with neonatal encephalopathy.

View all citing articles on Scopus

^☆: Supported by Grant HD-19913 from the National Institute of Child Health and Human Development. Dr. Yager is the recipient of a Medical Research Council of Canada Fellowship Award.

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Original articleNature, time-course, and extent of cerebral edema in perinatal hypoxic-ischemic brain damage☆

Abstract

J Pediatr

A necropsy study of brain swelling in the newborn with special reference to cerebellar herniation

J Pathol

Water and electrolyte abnormalities in the human brain after severe intrapartum asphyxia

J Neurol Neurosurg Psychiatry

Anoxic-ischemic encephalopathy in rats

Am J Pathol

The influence of immaturity on hypoxic-ischemic brain damage in the rat

Ann Neurol

Reduction of perinatal hypoxic-ischemic brain damage with allopurinol

Pediatr Res

Neuropathology of remote hypoxic-ischemic damage in the immature rat

Acta Neuropathol

Fine structural localization of a blood-brain barrier to exogenous peroxidase

J Cell Biol

Columnar alterations of NADH fluorescence during hypoxia-ischemia in immature rat brain

J Cereb Blood Flow Metab

Carbohydrate and energy metabolism during the evolution of hypoxic-ischemic brain damage in the immature rat

J Cereb Blood Flow Metab

Cerebral energy metabolism during hypoxia-ischemia and early recovery in the immature rat

Am J Physiol

Duration of ischemia influences the development and resolution of ischemic brain edema

Stroke

Changes in extracellular cation activity in cerebral ischemia

J Cereb Blood Flow Metab

Brain tissue osmolality following middle cerebral artery occlusion in cats

J Cereb Blood Flow Metab

Pathogenesis of brain edema and hemorrhage: Role of the brain capillary

Pediatrics

Mannitol therapy in perinatal hypoxic-ischemic brain damage

Stroke

Original article
Nature, time-course, and extent of cerebral edema in perinatal hypoxic-ischemic brain damage☆