Cardiac arrest is a major public health concern affecting over half a million people per year in the US. Furthermore, many survivors have brain injury that worsen their quality of life and increases mortality in the long term. However, medical advances have failed to develop good treatments to improve outcome and survival rates in the recent decades. The pathophysiology of cardiac arrest is very complex, involving multi-system processes, that makes it difficult to find a single simple treatment. In this dissertation, we split the process of cardiac arrest and resuscitation into two parts to better understand the pathophysiological process of cardiac arrest and recovery: Induction of cardiac arrest and reperfusion. Chapter 2 describes the role of spreading depolarizations in the induction of cardiac arrest. Cardiac arrest induces global ischemia that produces cortical spreading depolarizations SD, self-propagating waves of neuronal and glial depolarizations, that is traditionally thought to be harmful and worsens ischemic injury. While asphyxia-induced cardiac arrest leading to a severe drop in blood pressure may affect cerebral hemodynamics and is widely known to cause anoxic SD, the effect of anoxic SD on peripheral blood pressure in the extremities has not been investigated. This relationship is especially important to understand for conditions such as circulatory shock and cardiac arrest that directly affect both peripheral and cerebral perfusion in addition to producing anoxic SD in the brain. In this study, we used a rat model of asphyxial cardiac arrest to investigate the role of anoxic SD on cerebral hemodynamics and metabolism, peripheral blood pressure, and the relationship between these variables in 8-12 weeks old male rats. We incorporated a multimodal monitoring platform measuring cortical DC current simultaneously with optical imaging. We found that during anoxic SD there is decoupling of peripheral BP from cerebral blood flow and metabolism. We also observed that anoxic SD may modify cerebrovascular resistance. Furthermore, shorter time difference between anoxic SDs measured at different locations in the same rat was associated with better neurological outcome based on the recovery of electrocorticography activity (bursting) immediately post-resuscitation and neurological deficit scale 24 hours post-resuscitation. To our knowledge, this is the first study to quantify the relationship between peripheral blood pressure, cerebral hemodynamics and metabolism, and neurological outcome in anoxic SD. These results indicate that the characteristics of SD may not be limited to cerebral hemodynamics and metabolism but rather may also encompass changes in peripheral blood flow, possibly through a brain-heart connection, providing new insights into the role of anoxic SD in global ischemia and recovery.
Chapter 3 describes the role hyperemia in reperfusion injury post-CA. After resuscitation from cardiac arrest, patients often suffer from secondary injury of post-cardiac arrest syndrome, caused by the ischemic and reperfusion injury. Post cardiac arrest care focuses on minimizing this secondary injury, which has increasingly been shown to be a critical determinant of neurological outcome. In the first 30 min post resuscitation from cardiac arrest (CA), there is a brief hyperemia phase where blood pressure rises significantly, followed by a prolonged hypoperfusion phase in which blood pressure remains below baseline levels. Most of these studies focused on a broad time range in the span of hours post cardiac arrest and mainly treated the hypoperfusion phase. Because of this, the only current American Heart Association guideline for blood pressure is to simply treat hypotension, but states that there is no evidence for an optimal blood pressure target. However, the very dynamic hyperemia phase that occurs during the first 30 min post resuscitation has been neglected. It may be that hyperemia contributes to reperfusion injury, worsening neurological outcome. In this study, we analyzed the role of hyperemia in eventual neurological recovery using two different rodent models of cardiac arrest to investigate the role of hyperemia post-CA and the effects of using a cardioselective beta blocker to blunt hyperemia on neurological outcome. Overall, we found that a high hyperemia was associated with worse outcome which could be improved by blocking hyperemia with a cardio-selective beta blocker. In addition, we found that esmolol may be protective of vessels and maintain a certain level of cerebral autoregulation.
In Chapter 4, we followed up on possible mechanisms of hyperemia related reperfusion injury. As we saw injury could be reduced by blunting hyperemia, we specifically investigated the role of the concentration of oxygen inspired during hyperemia and how it may contribute to an increase in reactive oxygen species. Reactive oxygen species is a known contributor of reperfusion injury and so we tested the effects of 100% oxygen vs room air concentration of oxygen inspired during hyperemia and saw that reducing the inspired oxygen levels during hyperemia reduced oxidative injury and improved outcome. All of these studies provides support towards the injurious of role of hyperemia in reperfusion injury and warrants further investigation of hyperemia as a therapeutic target for improving recovery post-CA.
