Studies of isolated global brain ischaemia: I. Overview of irreversible brain injury and evolution of a new concept - redefining the time of brain death

Abstract

Despite advanced cardiac life support (ACLS), the mortality from sudden death after cardiac arrest is 85-95%, and becomes nearly 100% if ischaemia is prolonged, as occurs following unwitnessed arrest. Moreover, 33-50% of survivors following ACLS after witnessed arrest develop significant neurological dysfunction, and this rises to nearly 100% in the rare survivors of unwitnessed arrest. Although, whole body (cardiac) survival improves to 30% following recent use of emergency cardiopulmonary bypass, sustained neurological dysfunction remains a devastating and unresolved problem. Our studies suggest that both brain and whole body damage reflect an ischaemic/reperfusion injury that follows the present reperfusion methods that use normal blood, which we term 'uncontrolled reperfusion'. In contrast, we have previously introduced the term 'controlled reperfusion', which denotes controlling both the conditions (pressure, flow and temperature) as well as the composition (solution) of the reperfusate. Following prolonged ischaemia of the heart, lung and lower extremity, controlled reperfusion resulted in tissue recovery after ischaemic intervals previously thought to produce irreversible cellular injury. These observations underlie the current hypothesis that controlled reperfusion will become an effective treatment of the otherwise lethal injury of prolonged brain ischaemia, such as with unwitnessed arrest, and we tested this after 30 min of normothermic global brain ischaemia. This review, and the subsequent three studies will describe the evolution of the concept that controlled reperfusion will restore neurological function to the brain following prolonged (30 min) ischaemia. To provide a familiarity and rationale for these studies, this overview reviews the background and current treatment of sudden death, the concepts of controlled reperfusion, recent studies in the brain during whole body ischaemia, and then summarizes the three papers in this series on a new brain ischaemia model that endorses our hypothesis that controlled reperfusion allows complete neurological recovery following 30 min of normothermic global brain ischaemia. These findings may introduce innovative management approaches for sudden death, and perhaps stroke, because the brain is completely salvageable following ischaemic times thought previously to produce infarction.