Repetitive apnea is commonly associated with the perinatal period. Apneic episodes longer than 15 s and accompanied by hypoxia or bradycardia have been reported to occur in all infants with gestational ages less than 34 weeks. Apneic episodes requiring ventilatory support or pharmacologic intervention occur in at feast 50% of surviving infants weighing less than 1500 g at birth. The cumulative effect of brief but repetitive apnea may have clinical significance for later neurological function. The physiological mechanisms of apneic spells, however, are still poorly understood, due in part to the lack of reliable measurements of oxygenation of the brain. In these studies, the oxygen dependent quenching of phosphorescence, a noninvasive optical method for measuring oxygen developed in our laboratory, will be used to measure the oxygen in the microvasculature of the brain tissue. This method will allow continuous evaluation of the status of tissue oxygenation during apnea and post-apneic recovery. Thus, it will be possible, for the first time, to comprehensively analyze the changes in oxygen pressure that occur in the brain during apnea and recovery. Our experimental model will be newborn piglets. The different levels of inspired oxygen used during apnea models and post-apnetic recovery will represent clinically relevant conditions. The oxygen measurements will be coupled with measurements of the status of brain metabolism and the extent of brain injury. The mechanism(s) of cellular dysfunction and/or injury induced by the apnea will be examined at both the cellular and molecular levels. Changes in extracellular levels of dopamine and hydroxyl radicals, measured by in vivo microdialysis, will be used as markers of tissue hypoxia and a cellular dysfunction. The role of dopamine and hydroxyl radicals in brain injury will be also determined. The amplified antisense RNA (aRNA) technique will be used to screen multiple genes that may be altered in expression level during apnea and recovery. The genes which were chosen are directly or indirectly associated with dopamine. The morphological, immunohistochemical, temporal patterns and the severity of damage will be determined using standard histologic staining with Fluoro-Jade, and antibodies against APP/APLP and GFAP. These studies will result in a better understanding of the mechanisms causing the brain injury in response to repetitive apnea and provide an approach to evaluating the efficacy of procedural alterations designed to minimize this injury.
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