In the US, more than 1000 lives are lost each day due to sudden cardiac death. About 90% of these deaths follow """"""""successful"""""""" CPR and are due to postresuscitation organ injury. The PULSE Initiative defined research priorities for resuscitation research which included development of new animal models of cardiac arrest and pharmacologic interventions to minimize organ injury. The studies outlined in this proposal will utilize a new cardiac arrest animal model of enhanced clinical relevance, evaluate an alternative mechanism for postresuscitation cardiac dysfunction and the post-resuscitation syndrome, and test the effects of both unique and existing therapies on short and long-term outcome. Preliminary studies in a porcine model indicate that myocardial ischemia prior to the onset of spontaneous ventricular fibrillation (VF) dramatically increases defibrillation energy requirements and resuscitation time when compared to traditional electrically induced VF. Preliminary studies have also demonstrated a dramatic increase in tumor necrosis factor-alpha (TNF) following resuscitation and reperfusion that is inversely related to the degree of cardiac dysfunction and that monoclonal anti-TNF antibody attentuates this dysfunction. TNF is also known to be involved in the pathogenesis of ischemic neuronal injury.
The specific aims of the proposal are: 1. To demonstrate differences in the time course and severity of postresuscitation ventricular dysfunction following electrically- induced versus ischemically-induced VF in a porcine model, 2. To define the effects of administered anti- TNF drugs on post-resuscitation cardiac function and short-term survival (6 hours) in the ischemic VF model, and 3. To evaluate the effects of anti-TNF therapy on post-resuscitation cardiac function, long-term survival (72 hours), and neurologic function in the ischemic VF model. Ischemic VF will be produced by occlusion of a coronary artery.
In aim 1, transthoracic defibrillation intracardiac potential gradient, peak current, dose- response curves, serial indices of cardiac function, and blood cytokines and will be compared for ischemic and electrically induced VF.
In aim 2, the effect of anti-TNF therapy, namely, monoclonal anti-TNF antibody and soluble TNF receptors, on postresuscitation cardiac function and short-term survival will be evaluated.
In aim 3, the effect of anti-TNF therapy on long-term survival and neurologic outcome will be evaluated. ? ?
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