Comparisons of pre-lethal neurochemical alterations to neurologic outcome and neuropathology following cardiac arrest (CA) and resuscitation in animals using hyperoxic and normoxic ventilation strongly implicate early, oxidative modification to mitochrondial proteins and associated metabolic dysfunction in the etiology of delayed neural cell death and permanent brain injury. To expedite progress in improving neurologic outcome following human CA, we propose a change in standard resuscitative protocols that dramatically lowers the concentration of inspired 02 (Fi02) to a level that sufficiently oxygenates the brain and other tissues but that minimizes oxidative stress, cell death, and neurologic impairment.
Our specific aims test the hypothesis that neuronal cell death and both short- and long-term neurologic impairment following CA and resuscitation are minimized by maintaining normal post-ischemic PaO2, as guided by oximetry-based measurements of hemoglobin 02 saturation (SpO2) that are practical for use in the field.
Aim 1. Compare neurologic outcome following canine cardiac arrest and resuscitation using:* Hyperoxic Resuscitation - 100% FiO2 for 1 hr then adjust FiO2 to maintain normal PaO2 * Normoxic Resuscitation - 21% FiO2 for 1 hr then adjust FiO2 to maintain normal PaO2 * Oximetry-Based Resuscitation - Adjust FiO2 to maintain SpO2 at 94% to 96% *Aim 2. Establish relationships between resuscitative FiO2 and neuronal cell death using the canine model and three resuscitation protocols.
Aim 3. Extend the results obtained with the short-term canine CA model using a transient global cerebral ischemia model with long-term outcome measures performed on mature and aged rats. We will compare both neurologic outcome and neuronal cell death using different protocols in a clinically very relevant canine model of cardiac arrest. In addition, a rat model of transient global cerebral ischemia is utilized to measure long-term outcome and to test different protocols on aged animals, representing the typical CA patient age-group. Within the first two - three years of this project, our results could be used to design clinical trials to improve neurologic outcome following cardiac arrest and resuscitation. With over 250,000 cardiac arrest victims resuscitated each year in the U.S. alone, and over half of these suffering from neurological morbidity and mortality, the potential impact of the proposed translational research project is highly significant.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01NS049425-01
Application #
6817717
Study Section
Special Emphasis Panel (ZNS1-SRB-M (07))
Program Officer
Pancrazio, Joseph J
Project Start
2004-07-01
Project End
2007-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
1
Fiscal Year
2004
Total Cost
$353,451
Indirect Cost
Name
University of Maryland Baltimore
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Hazelton, Julie L; Balan, Irina; Elmer, Greg I et al. (2010) Hyperoxic reperfusion after global cerebral ischemia promotes inflammation and long-term hippocampal neuronal death. J Neurotrauma 27:753-62
Richards, Erica M; Fiskum, Gary; Rosenthal, Robert E et al. (2007) Hyperoxic reperfusion after global ischemia decreases hippocampal energy metabolism. Stroke 38:1578-84
Vereczki, Viktoria; Martin, Erica; Rosenthal, Robert E et al. (2006) Normoxic resuscitation after cardiac arrest protects against hippocampal oxidative stress, metabolic dysfunction, and neuronal death. J Cereb Blood Flow Metab 26:821-35
Richards, Erica M; Rosenthal, Robert E; Kristian, Tibor et al. (2006) Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity. Free Radic Biol Med 40:1960-70
Balan, Irina S; Fiskum, Gary; Hazelton, Julie et al. (2006) Oximetry-guided reoxygenation improves neurological outcome after experimental cardiac arrest. Stroke 37:3008-13
Chandrasekaran, Krish; Hazelton, Julie L; Wang, Yu et al. (2006) Neuron-specific conditional expression of a mitochondrially targeted fluorescent protein in mice. J Neurosci 26:13123-7