INTRODUCTION AND EPIDEMIOLOGY
Sudden cardiac arrest represents one of the most time-sensitive diseases in the practice of emergency medicine, requiring prompt recognition and rapid delivery of resuscitative care, including high-quality CPR, early defibrillation when appropriate, and appropriate airway management.1 Even with these interventions, aggregate survival to hospital discharge is less than 20% in most communities and hospital systems.2,3 Among survivors, neurologic injury is common (present in up to 50% of survivors) and widely varied, ranging from subtle memory deficits to persistent vegetative state.4,5 This chapter focuses on the pathophysiology of ischemia-reperfusion injury and the provision of targeted temperature management, also called therapeutic hypothermia.6
PATHOPHYSIOLOGY OF ISCHEMIA-REPERFUSION INJURY
The brain is exquisitely sensitive to ischemia, such that disruption of blood flow for several minutes is sufficient to initiate a set of injury mechanisms that may lead to irreversible disabilities.7,8 The complete loss of blood flow, followed by the abrupt return of spontaneous circulation, rapidly leads to a complex pathophysiologic process known as ischemia-reperfusion injury, also known specifically in the sudden cardiac arrest setting as postresuscitation syndrome.8,9
When blood flow is abruptly stopped and then restored, a number of overlapping mechanisms lead to clinical injury (Figure 26-1).
Schematic of postarrest pathophysiology, also called ischemia-reperfusion injury. The concepts shown here represent processes that occur at the subcellular, cellular, tissue, and organismal levels. The kinetics of these processes following cardiac arrest and the extent to which they affect clinical outcomes are still unclear.
CELLULAR RESPONSES TO RETURN OF SPONTANEOUS CIRCULATION
At the cellular level, mitochondrial integrity and function become damaged, with release of crucial enzymatic machinery such as cytochrome c and disruption of oxidative phosphorylation.9,10 Mitochondrial injury is implicated in the increased concentration of oxygen free radicals and downstream activation of programmed cell death pathways.10,11 At the humoral level, reperfusion triggers a broad array of immune activation, including increased blood levels of cytokines such as interleukin-6 and tumor necrosis factor-α.12 In addition, aberrant neutrophil and platelet activation can occur. These immune phenomena have led Adrie et al13 to describe the postresuscitation condition as a “sepsis-like syndrome,” in which inflammation plays a crucial role in injury. Immune activation, in turn, can lead to additional production of oxygen free radicals such as superoxide and hydrogen peroxide. These molecules, produced in small quantities during normal cellular function, are usually converted to oxygen and water by the enzymes catalase and superoxide dismutase. However, enzyme systems become overwhelmed with the dramatic increase of free radical species generated during postresuscitation syndrome. Different tissues exhibit varying sensitivity to ischemia-reperfusion processes, with brain tissue and vascular endothelium appearing to be particularly vulnerable.8,9