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Project Title:
Gender-Specific Treatment of Pediatric Cardiac Arrest
Funding Agency:
NIH
Total Project Period:
May 1, 2005 - Feb 28, 2010
Principal Investigator:
Robert Clark, MD
Co-Investigator(s):
Hulya Bayir, MD; Robert Hickey, MD; Larry Jenkins, MD; C Edward Dixon, MD; Patrick Kochanek, MD.
Project Summary:
The primary objective of this project is to identify efficacious and perhaps gender-specific therapeutic strategies, to serve as the foundation for clinical trials designed to improve outcome in infants and children after cardiopulmonary arrest. Hypoxic-ischemic encephalopathy (HIE) remains an incurable disease. The most common cause of HIE in infants and children is as a consequence of cardiopulmonary arrest. In the United States, it is estimated that 16,000 children die of unexpected cardiopulmonary arrest per year. This mortality rate is ~87%, and is related to the degree of brain damage, with unfavorable neurological outcome seen in ~50% of the survivors. These dismal outcomes reflect the fact that, to date, there are no interventions to reverse the cellular consequences of HIE. Recent clinical trials in adult patients suggest that some degree of HIE can be prevented if hypothermia is initiated early after cardiac arrest. However, cardiopulmonary arrest in infants and children differs from adults in both primary etiology and therefore mechanism. Whereas a cardiac etiology is the principle cause of cardiopulmonary arrest in adults, asphyxia is the principle cause of cardiopulmonary arrest in infants and children, resulting in systemic hypoxemia in and of itself producing cardiac failure. Despite the importance of this clinical entity and the lack of a specific therapy, there is no contemporary age-appropriate pediatric model of HIE for the evaluation of prolonged neuro-degeneration and long-term neurological outcome. We have developed a model of pediatric asphyxial cardiac arrest (PACA) in post-natal day (PND) 17 rats that produces transient coma, region specific to the duration of asphyxia. Preliminary data confirm that these deficits can be attenuated by treatment with post-resuscitative hypothermia. Thus, this model has the capacity for 1) invasive physiologic monitoring and acute resuscitation that closely mimics guidelines used in humans; 2) acute and long-term biochemical and cellular assessment utilizing currently available molecular tools tested in rodents; and 3) acute and long-term functional outcome assessment utilizing standardized behavioral tools developed in rodents with the potential for the investigation of either acute therapies or chronic rehabilitation strategies.
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