This project represents a continuation of our efforts to assess the impact of cardiopulmonary resuscitation (CPR) on brain in both adult and pediatric animal models. Chest compression provides only partial restoration of cerebral blood flow (CBF) until the heart is defibrillated. Neurological deficit depends on duration of arrest, the delay of applying basic life support CPR, and the subsequent delay of applying advanced fife support CPR accompanied by epinephrine administration to raise perfusion pressure and cardiac defibrillation. In anesthetized adult dogs, we will use 31P magnetic resonance spectroscopy to investigate the effect of CPR on restoration of brain metabolism. By varying the delay in the onset of CPR and by precisely regulating cerebral perfusion pressure to mimic that expected in basic versus advanced life support CPR, we will determine under what circumstances application of CPR improves or worsens intracellular pH. We will demonstrate if the level of CBF required to restore ATP once depleted by cardiac arrest is greater than that required to maintain ATP without arrest. Furthermore, we will determine if the profound systemic acidemia that accompanies CPR impedes recovery of brain pH. Complete cerebral ischemia associated with cardiac arrest followed by incomplete cerebral ischemia during CPR can result in a prolonged period of tissue acidosis and may act to promote lipid peroxidation. We will test if treatment with deferoxamine, an iron chelator, and with tirilazad (U74006F), a 21-aminosteroid inhibitor of lipid peroxidation, improves recovery of brain ATP and pH during CPR associated with improved neuropathology and outcome. These studies will provide new insights on the impact of CPR on brain pH and the consequent effects on metabolism and neuronal injury. Pediatric cardiac arrest is often attributable to asphyxia and not necessarily accompanied by prolonged complete cerebral ischemia. Excitotoxicity may be a prominent mechanism of injury with periods of brief hypoxia/ischemia. Using a 7 minute period of asphyxic arrest followed by CPR and resuscitation in anesthetized one-week-old piglets, we will investigate the effect of treatment with MK-801 (an N-methyl-D-- aspartate antagonist), NBQX (a quisqualate/AMPA receptor antagonist), and tirilazad (an antioxidant known to inhibit excitotoxic injury in cell culture). Selective neuronal vulnerability will be evaluated by immunocytochemistry. These studies will demonstrate the contribution of excitotoxic mechanisms of injury in immature brain in a resuscitation model relevant to pediatric CPR.
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