Oxidative stress in regional cerebral blood flow alterations after cardiac arrest

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DESCRIPTION (provided by applicant): Pediatric cardiac arrest remains a significant cause of mortality and morbidity and thus it is an important public health problem. In the United States, it is estimated that 16,000 children die annually of cardiac arrest. Asphyxia is the cause of cardiac arrest in the majority of pediatric victims. Most survivors have severe neurological impairment. Cerebral blood flow (CBF) disturbances after resuscitation may further contribute to neuropathological damage after cardiac arrest. Reactive oxygen and nitrogen species play an important role in regulating CBF, and are generated during and after resuscitation from cardiac arrest. CBF, cerebral metabolism, oxidative stress, nitrative stress and the interaction of these factors remain to be defined in pediatric cardiac arrest, and may represent an important therapeutic target toward improving outcome of this debilitating condition. The candidate recently has developed a protocol for serial and regional assessment of CBF in developing postnatal day 17 rats via arterial spin label MRI and found insult duration dependency of CBF after asphyxial cardiac arrest. The candidate will (i) determine the relationship between CBF, cerebral metabolism and neuropathological damage and (ii) quantify production of nitric oxide, reactive oxygen species and other reactive nitrogen species after two durations of asphyxial cardiac arrest (8.5 min and 12 min). The candidate will also (iii) determine if scavenging ROS and RNS in either vascular or parenchyma! compartments will prevent pathological CBF alterations and reduce neuropathological damage after asphyxial cardiac arrest. Regional CBF will be measured serially via arterial spin label MRI. Cerebral metabolic rate for glucose will be measured with autoradiography. Nitric oxide will be measured in vivo serially with tissue minisensors and ex vivo with electron paramagnetic resonance spectroscopy. Oxidative and nitrosative stress will also be quantified: we will measure 3-nitrotyrosine by ELISA and immunofluorescence, ascorbic acid by high liquid field chromatography, and reduced glutathione by fluorescence. The candidate is a pediatric emergency physician at Children's Hospital of Pittsburgh. There is a need for training pediatric emergency clinician-scientists, as interventions likely to impact outcome after pediatric cardiac arrest should ideally be started at the arrest scene or in the Emergency Department. This Mentored Career Development Award will allow the candidate to pursue a unique and highly integrated mentored program in resuscitation medicine. To assure success in becoming an independent clinician-scientist, the candidate assembled a multidisciplinary and multi-institutional advisory committee that includes senior mentors with special expertise in 1) resuscitation research, 2) vascular biology, 3) oxidative stress, 4) MRI and 5) pediatric clinical resuscitation guidelines development and implementation.