Pathophysiology of Perinatal Hypoxic-ischemic Brain Damage

Vannucci, Robert C.; Plum, Fred

doi:10.1007/978-1-4684-2673-1_1

Cited by 16 publications

(11 citation statements)

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“…Phosphocreatine concentrations were generally about one-third of previously reported adult values, while lactate was about twofold higher-a result also observed in fetal rats (Vannucci and Duffy, 1974). Brain glycogen concentrations in fetal sheep, as in neonatal dog, cat, and rabbit, are 30-40% of the adult values (Vannucci and Plum, 1975). Imma ture mammalian brain has lower rates of oxygen consumption and a low rate of glycolysis and gly cogenolysis due to reduced activities of hexoki nase, phosphofructokinase, and phosphorylase (Vannucci and Plum, 1975).…”

Section: Discussionsupporting

confidence: 55%

“…Brain glycogen concentrations in fetal sheep, as in neonatal dog, cat, and rabbit, are 30-40% of the adult values (Vannucci and Plum, 1975). Imma ture mammalian brain has lower rates of oxygen consumption and a low rate of glycolysis and gly cogenolysis due to reduced activities of hexoki nase, phosphofructokinase, and phosphorylase (Vannucci and Plum, 1975). Thus, our observations of lowered ATP and phosphocreatine and increased AMP in mid-gestational fetal sheep as compared with adults are most likely the result of the imma turity of the nervous system in these animals rather than relative hypoxia-ischemia during the period of in situ freezing.…”

Section: Discussionmentioning

confidence: 94%

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Brain Metabolic Correlates of Hypoxic-Ischemic Cerebral Necrosis in Mid-Gestational Sheep Fetuses: Significance of Hypotension

Wagner

Ting

Westfall

et al. 1986

J Cereb Blood Flow Metab

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Summary: Midgestational sheep fetuses exposed to marked hypoxia for 2 h remain brain intact if MABP is maintained above 30 mm Hg. On the other hand, simi larly hypoxic fetuses, if they experience reductions in MABP below 30 mm Hg, develop foci of necrosis that predominantly affect hemispheric white matter and neo striatum. Cortex damage is more restricted and is usually associated with more massive underlying white matter damage. The present study examines the brain metabolic basis for the important role of hypotension in brain injury development in marked hypoxia. Sheep fetuses rendered hypoxic by respiring their ewes with 11 % oxygen (fetal PaOZ = 8-12 mm Hg) in which MABP was maintained above 30 mm Hg showed increases in brain lactic acid concentrations to 7 -13 f,Lmollg but unaltered energy charge. In contrast, fetuses that sustained MABP reduc tions below 30 mm Hg showed increases in lactic acid Fetal or neonatal hypoxic-ischemic encephalo pathy is commonly thought to result from an im paired oxygen supply to brain due to a decreased oxygen content of arterial blood and/or a decrease in CBF. Such asphyxia in utero, in contrast to various postnatal insults, is the predominant cause of "cerebral palsy," a syndrome that encompasses a variety of motor deficits and in which mental re tardation and epilepsy may or may not be present (Volpe, 1981).The neuropathology of perinatal hypoxic-isch emic encephalopathy includes selective neuronal Received July 8, 1985; accepted March 25, 1986. Address correspondence and reprint requests to Dr. K. R. Wagner at Veterans Administration Medical Center, Medical Research Service/15I , 3200 Vine Street, Cincinnati, OH 45220, U. S. A. 425concentrations in vulnerable structures to 16-24 f,Lmol/g accompanied by marked decreases in energy charge. The vulnerable structures also showed reductions in fructose concentrations but a variable behavior of other brain me tabolites including phosphocreatine, glycogen, and glu cose. Thus, the present findings suggest a relation be tween hypotension during marked hypoxia, low energy charge, lactic acid accumulation in brain at high concen trations, and fetal brain injury. The ewes of hypoxic hy potensive fetuses received pentobarbital at lower doses than did those of fetuses that maintained blood pressure. This suggests that pentobarbital plays an important role in protecting the fetal brain from asphyxia by extending the hypoxic fetus's ability to maintain blood pressure in addition to reducing its brain metabolism.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 94%

Brain Metabolic Correlates of Hypoxic-Ischemic Cerebral Necrosis in Mid-Gestational Sheep Fetuses: Significance of Hypotension

Wagner

Ting

Westfall

et al. 1986

J Cereb Blood Flow Metab

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“…The findings implicate a disruption of intracellular calcium homeo stasis as a major factor in the evolution of perinatal hyp oxic-ischemic brain damage. Key Words: Calcium Perinatal-Hypoxia-ischemia-Brain damage.born infant, and the presence or absence of super imposed systemic stress, e. g. , hypoglycemia, sepsis, or undernutrition (Vannucci and Plum, 1975). Vascular and metabolic factors (intrinsic vul nerability) also play a critical role as is known to exist in adults (Brierley and Graham, 1984).…”

mentioning

confidence: 99%

“…born infant, and the presence or absence of super imposed systemic stress, e. g. , hypoglycemia, sepsis, or undernutrition (Vannucci and Plum, 1975). Vascular and metabolic factors (intrinsic vul nerability) also play a critical role as is known to exist in adults (Brierley and Graham, 1984).…”

mentioning

confidence: 99%

Calcium Accumulation during the Evolution of Hypoxic—Ischemic Brain Damage in the Immature Rat

Stein

Vannucci

1988

J Cereb Blood Flow Metab

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Summary: An excessive accumulation of calcium in neu ronal and other tissues has been postulated to represent a "final common pathway" for cell death arising from hyp oxia-ischemia. To clarify the role of altered calcium flux into and distribution within the perinatal brain under going hypoxic-ischemic injury, 7-day postnatal rats un derwent unilateral common carotid artery ligation fol lowed by 3 h of hypoxia with 8% oxygen. This insult is known to produce brain damage confined to the cerebral hemisphere ipsilateral to the arterial occlusion in >90% of the animals. Either before or after hypoxia-ischemia, the animals received a subcutaneous injection of [45Ca]CI2, and their brains were subjected to 45Ca autora diography at 0-1, 5, 24, and 72 h, 7 or 15 days thereafter. During hypoxia-ischemia, calcium flux into the ipsilat eral cerebral hemisphere was prominent in 13 of 14 rat pups, especially in neocortex, hippocampus, striatum, and thalamus. Calcium accumulation also occurred to a variable degree (6 of 14 animals) in the contralateral cerePerinatal cerebral hypoxic-ischemic brain damage is characterized either by selective necrosis of vulnerable neurons or infarction (Rorke, 1982;Vannucci, 1985; Volpe, 1987). Regions of immature brain especially sensitive to hypoxic-ischemic in jury include the cerebral cortex, hippocampus, striatum, and thalamus as well as selected struc tures of the brainstem. Subcortical and periventri cular white matter also is vulnerable, especially in the premature infant. The severity and distribution of the neuropathologic lesions are dependent on several factors, including the nature and duration of the insult, the gestational age of the fetus or new- 834bral hemisphere. During recovery, radioactivity in the contralateral cerebral hemisphere was no longer ap parent, whereas in the ipsilateral hemisphere, the extent of calcium accumulation was mild in four of six at 1 h, moderate in three of six at 5 h, moderate to intense in six of seven and six of seven at 24 and 72 h, respectively, and intense in three of three and two of two animals at 7 and 15 days, respectively. As during hypoxia-ischemia, the distribution of the radioactivity was most prominent in those structures that are known to be vulnerable to hyp oxic-ischemic injury. Thus, hypoxia-ischemia is asso ciated with enhanced calcium uptake into the immature brain, which does not dissipate but rather progressively accumulates for up to 15 days of recovery. The findings implicate a disruption of intracellular calcium homeo stasis as a major factor in the evolution of perinatal hyp oxic-ischemic brain damage. Key Words: Calcium Perinatal-Hypoxia-ischemia-Brain damage.born infant, and the presence or absence of super imposed systemic stress, e. g. , hypoglycemia, sepsis, or undernutrition (Vannucci and Plum, 1975). Vascular and metabolic factors (intrinsic vul nerability) also play a critical role as is known to exist in adults (Brierley and Graham, 1984).The underlying pathogenetic mechanism(s) re sponsible for the brain damaging...

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“…Of necessity, a mismatch occurs between blood flow and metabolism during hypothermic circulatory arrest, because in the absence of cerebral perfusion, metabolism must continue at a basal rate to maintain ion gradients and structural integrity. Basal metabolism would be expected to continue for extended intervals in immature animals, owing to physiologically low rates of cerebral energy use combined with high endogenous stores of carbohydrates (glucose and glycogen), which serve as organic fuels for anaerobic glycolysis and energy production (37,38). Indeed, ATP concentrations in the brains of poikilothermic animals (e.g.…”

Section: Discussionmentioning

confidence: 99%

Physiologic and Neuropathologic Aspects of Hypothermic Circulatory Arrest in Newborn Dogs

1990

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ABSTRACT. A model of hypothermic circulatory arrest has been developed in the newborn dog. Ten puppies were anesthetized with halothane, paralyzed, and artificially ventilated with 70% nitrous oxide 30% oxygen to arterial oxygen pressure >8.0 kPa (60 mm Hg), arterial carbon dioxide pressure of 4.4-5.6 kPa (33-42 mm Hg), and arterial pH of 7. 35-7.42. Animals were surface cooled to 20°C, after which cardiac arrest was produced with i.v. KCI. Dogs remained asystolic without ventilation for 1.0 (n = 4), 1.5 (n = 3), or 2.0 (n = 3) h. Resuscitation was accomplished with closed-chest compression, mechanical ventilation, i.v. epinephrine and NaHC03, and rewarming to 37°C. Postarrest recovery was maintained for 3-4 h; thereafter, the puppies underwent perfusion-fixation of their brains for pathologic analysis. Plasma glucose (control = 8.3 mmol/L) increased slightly during hypothermic cardiac arrest (+36%) but was markedly elevated at 15 min postarrest (20 mmol/L). Blood lactate (control = 1.1 mmol/L) increased almost 200% during hypothermic circulatory arrest, with a further rise to 9.0 mmol/L at 15 min postarrest. Thereafter, lactate decreased in the 1-h arrested dogs but increased progressively in the other groups. Mean arterial blood pressure returned to baseline (73 mm Hg) by 15 min postarrest, remained stable in the 1-h dogs, but fell at 3 h to 62 and 34 mm Hg in the 1.5-and 2.0-h groups, respectively. No neuropathologic alterations were seen in puppies arrested for 1 h, whereas all puppies arrested for 1.5 or 2 h had varying degrees of cerebral cortical and hippocampal damage. Thus, newborn dogs tolerate 1 h of hypothermic circulatory arrest without brain damage, with graded neuronal injury thereafter. The experimental model has direct clinical relevance and can be used to study mechanisms of cellular injury in brain, heart, and other organs during prolonged ischemia. 3 5 in infants and children. The rationale for this surgical approach relates to the well-known observation that acute brain damage secondary to systemic hypoxia, hypotension, or cardiac arrest is prevented or at least substantially reduced by prior or concurrent hypothermia (1-5). It is the duration of cardiac arrest and its attendant total cerebral ischemia that is limiting for the prevention of brain damage. It is not known how long an infant can tolerate hypothermic circulatory arrest without sustaining ischemic brain injury, although clinical practice suggests a "safe" interval of 60-70 min (6-8). Unfortunately, infants occasionally sustain brain damage even when the duration of cardiac arrest is well within the "therapeutic window" (9, 10). It has not been established whether such brain damage arises as a silent complication of the surgical procedure itself (e.g. postoperative hypotension, air emboli, etc.) or as a result of cerebral ischemia beyond the safety margin for any specific individual infant. Given the fact that 0.5-1.0% of all infants are born with surgically correctable cardiac defects, it is surprising that little research has be...

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Pathophysiology of Perinatal Hypoxic-ischemic Brain Damage

Cited by 16 publications

References 150 publications

Brain Metabolic Correlates of Hypoxic-Ischemic Cerebral Necrosis in Mid-Gestational Sheep Fetuses: Significance of Hypotension

Brain Metabolic Correlates of Hypoxic-Ischemic Cerebral Necrosis in Mid-Gestational Sheep Fetuses: Significance of Hypotension

Calcium Accumulation during the Evolution of Hypoxic—Ischemic Brain Damage in the Immature Rat

Physiologic and Neuropathologic Aspects of Hypothermic Circulatory Arrest in Newborn Dogs

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