Cyclooxygenase inhibition prior to ventricular fibrillation induced ischemia reperfusion injury impairs survival and outcomes.

Nonsteroidal anti-inflammatory medications (NSAIDs) are one of the most commonly used analgesics in the world. NSAIDs decrease prostaglandin synthesis through cyclooxygenase inhibition (COX-1 or COX-2). The effects of NSAIDs on survival and outcomes from global ischemia reperfusion events and specifically from cardiac arrest (CA) remain controversial. We hypothesized that NSAIDs prior to global whole-body ischemia reperfusion (I/R) injury impairs survival and outcomes. We explored this hypothesis in our swine model of Cardiac Arrest (CA) which involves global I/R with pretreatment using a predominantly COX-1 inhibitor (Indomethacin [COX-1/min COX-2 Inh], a COX-2 Inhibitor [COX-2-Inh, (Celecoxib)] or placebo control. We determined the effects of each inhibitor on a) survival, b) myocardial injury biomarker (Troponin 1), and c) Autonomic Nervous System (ANS) injury marker (heart rate variability [HRV]) up to 3 h after resuscitation. There were no survivals in COX-1/min COX-2-Inh pretreated animals and, 87% survived in both COX-2 Inhibited and control animals. COX-2 Inh pretreated animals had an 1800 fold increase of Troponin 1 compared to baseline whereas control animals had a 90 fold increase (p < 0.001). These results along with literature review of focal I/R in animal models with COX-2 overexpression, human studies of CA, and post myocardial infarction treatment with NSAIDs, support the hypothesis that NSAIDs prior to an I/R event impairs survival and outcomes. Specifically, predominantly COX-1 inhibition impairs survival, and COX-2 inhibition induces myocardial damage, autonomic nervous system dysfunction, and increases the risk for all-cause mortality and morbidity in humans post-MI which has significant implications for the nearly 10% of the population who are taking NSAIDs.