Time course of intracellular edema and epileptiform activity following prenatal cerebral ischemia in sheep.

Abstract

The role of edema in the pathogenesis of hypoxic-ischemic injury in the immature brain is controversial. We studied 15 chronically instrumented fetal sheep following transient cerebral ischemia, to estimate changes in extracellular space using an impedance technique, to quantify the electroencephalogram with real-time spectral analysis, and to assess histologic outcome 3 days after the insult These measurements were made in the parasagittal cortex. There was a rapid loss of extracellular space from 5±2 minutes after the onset of ischemia. Following 10 minutes of ischemia (n=7) the intracellular edema peaked but then quickly resolved (6±4 minutes), and mild selective ncuronal loss was seen. In contrast, the swelling was biphasic after 30-40 minutes of ischemia (n=8). The early edema resolved slowly (28±12 minutes) but incompletely, and secondary swelling began at 7±2 hours and peaked at 28±6 hours. The early swelling was the more severe. Postinsult epileptiform activity began at 8±2 hours and peaked at 10 ±3 hours; later there was laminar necrosis of the underlying cortex. The secondary decrease of extracellular space indicates that a progressive loss of membrane function started with the onset of postischemic epileptiform activity. The increased metabolic load of the epileptiform activity may have worsened this delayed deterioration. (Stroke 1991,22:516-521)

Hypothermic neuroprotection

“…During this phase there is rapid depletion of high energy metabolites, leading to progressive hypoxic depolarization of cells, with severe cytotoxic edema (cell swelling), excessive intracellular accumulation of calcium, and extracellular accumulation of excitatory amino acids (EAAs) due to both failure of reuptake and excessive release. 23 Following return of cerebral circulation and / or oxygenation, after the end of the insult, the initial hypoxia-induced cytotoxic edema and accumulation of EAAs typically resolve over approximately 30 to 60 minutes, 24,25 with at least partial recovery of cerebral oxidative metabolism, in a 'latent' phase. However, cerebral oxidative metabolism may then secondarily deteriorate many hours later (approximately 6 to 15 h), in a phase that may extend over many days.…”

“…However, cerebral oxidative metabolism may then secondarily deteriorate many hours later (approximately 6 to 15 h), in a phase that may extend over many days. 19,21 At term equivalent, this secondary deterioration is often marked by the onset of seizures (figure 2), 26,27 secondary cytotoxic edema, 24 accumulation of excitotoxins, 23 failure of cerebral mitochondrial activity 21 and ultimately, cell death. 27,28 Surprisingly, although there are extensive data describing the timing and development of the delayed failure of mitochondrial oxidative metabolism after acute insults, its precise pathogenic significance remains highly controversial.…”

Hipotermia Terapêutica Em Recém-Nascidos Com Diagnóstico De Encefalopatia Hipóxico Isquêmica: Revisão De Literatura

“…Se o insulto é severo, há imediatamente uma "morte neuronal primária", relacionada à hipóxia celular com exaustão dos estoques de energia celular ("primeira falha energética"). Após um período latente de pelo menos seis horas, inicia-se a chamada fase secundária de "morte celular tardia" 19 . Nesta fase, os mecanismos envolvidos na morte neuronal incluem edema citotóxico, falência mitocondrial, acúmulo de toxinas, ativação de morte celular (análoga ao desenvolvimento de apoptose), síntese de óxido nítrico, danos provocados por radicais livres e ação citotóxica por ativação da micróglia 20 .…”

“…Nesta fase, os mecanismos envolvidos na morte neuronal incluem edema citotóxico, falência mitocondrial, acúmulo de toxinas, ativação de morte celular (análoga ao desenvolvimento de apoptose), síntese de óxido nítrico, danos provocados por radicais livres e ação citotóxica por ativação da micróglia 20 . A fase tardia é associada com encefalopatia e aumenta a atividade epileptogênica, sendo responsável por uma proporção significante do total de células perdidas após insultos muito severos 4,19 . Em crianças com evidência de hipóxia intraparto e encefalopatia moderada a severa, estudos de ressonância magnética são consistentes com esse modelo bifásico de morte neuronal.…”

Hypothermia for the treatment of infants with hypoxic–ischemic encephalopathy

“…The secondary or delayed phase of injury (apoptosis) that subsequently follows extends over several days. 15 This degree of secondary phase of energy failure and apoptosis is proportional to adverse neurodevelopmental outcomes at 1 and 4 years of age. 16,17 It is this time during transition from the recovery period into the secondary phase of injury that allows for a potential window for neuroprotection or diminution of injury.…”