OBJECTIVE: Manual CPR improves the likelihood of neurologically intact survival following cardiac arrest. The mechanism of this benefit is not completely understood. We propose a mechanism whereby manual CPR simultaneously limits ischemia and specifically protects against reperfusion injury. We derive a conceptual framework that describes cell survival as it relates to the ischemic and reperfusion stages and CPR effects. RESULTS: Based on a synthesis of basic science and clinical information, we propose that the benefit of the subnormal circulation produced by manual CPR is multifaceted and specifically includes attenuating reperfusion injury by providing graded blood flow to the heart and brain. Although manual CPR produces reperfusion pathophysiology, the low flow from CPR limits reperfusion injury specifically through mechanisms of post-ischemic conditioning which include attenuating peak levels of oxidative substrate and activating pathways that protect against oxidative stress. CONCLUSIONS: If such a hypothesis of post-ischemic conditioning is borne out, CPR may be considered a dose-sensitive therapy whereby certain physiologic states would be best served by different levels of circulation and hence distinct grades of CPR.