Postconditioning and controlled reperfusion: the nerve of it all.

IT is being recognized that reperfusion is not only the definitive treatment for tissues undergoing arterial occlusions but also a major contributor to postischemic injury. This “reperfusion injury” has been observed in most organ systems, including the heart, brain and spinal cord, kidney, and skeletal muscle. Among these organ systems, there is a remarkable similarity in mediators, cellular victims, and physiologic manifestations of reperfusion injury. Infarct size and the extent of apoptosis have both been reported to increase after onset of reperfusion, suggesting that reperfusion may present a therapeutic window to mitigate tissue injury. Indeed, the existence of reperfusion injury has been demonstrated by indirect methods that are potentially therapeutic approaches, including drugs and mechanical interventions initiated before or at the onset of reperfusion. Low-pressure or “gentle” reperfusion and postconditioning (also called ischemic postconditioning, but we have dropped the restrictive term ischemic) are two such mechanical interventions that have been shown to reduce reperfusion injury in heart and neural tissue. Since the initial report by Zhao et al. in 2003, the question was raised early on whether postconditioning was an “old wine in an new bottle” of mechanical interventions in which gentle or low-pressure reperfusion was the prototype. Although the term postconditioning was originally limited to the application of serial intervals of reperfusion and ischemia or reoxygenation and hypoxia, the moniker has been expanded to include many interventions applied at the onset of reperfusion, including drugs, hypothermia, and now low-flow or lowpressure reperfusion. Indeed, several reports have shown that low-pressure reperfusion reduced postischemic myocardial injury, with one showing equivalence between low-pressure reperfusion and postconditioning in reducing irreversible injury and improving contractile recovery. In this issue of ANESTHESIOLOGY, Jiang et al. compare two modalities of postconditioning: conventional “ischemic” postconditioning and low-pressure reperfusion, both applied at the onset of reperfusion after spinal cord ischemia was imposed by a balloon placed in the abdominal aorta distal to the renal arteries in the in vivo rabbit model. In this study, the authors induced 25 min of spinal cord ischemia in anesthetized rabbits by inflating an infrarenal balloon catheter. Ischemic postconditioning was achieved by serial 1-min inflations and 1-min deflations of the balloon at the onset of reperfusion repeated for five cycles, while low-pressure reperfusion was achieved by partial deflation of the balloon to achieve a measured perfusion pressure of 45–55 mmHg for the first 10 min of reperfusion. The interventions lasted for a total of 10 min. They reported that both “postconditioning interventions” equally improved neuromotor function (Tarlov score) and increased the number of intact motor neurons 28 days after treatment compared with a control group with rapid-onset reperfusion. In addition, the two postconditioning methods involved increased phosphorylation of the reperfusion injury survival kinase pathway components extracellular signal–regulated protein kinase (ERK1/2) and phosphatidylinositol 3-kinase 2 h after reperfusion/treatment; intrathecal injection of inhibitors of extracellular signal–regulated protein kinase and phosphatidylinositol 3-kinase abrogated phosphorylation of extracellular signal–regulated protein kinase and the downstream target of phosphatidylinositol 3-kinase, serine/threonine protein kinase protein kinase B (also known as Akt), morphologic salvage of motor neurons, and increased Tarlov motor scores. Hence, this study showed that neuroprotection by postconditioning is equivalent to that of low-pressure reperfusion after transient ischemia in spinal cord. Now that the notion of equivalent tissue protection has been demonstrated for low-pressure reperfusion and postconditioning in both neural tissue and myocardium, it would be interesting to know whether the same physiologic and molecular mechanisms are engaged by the same triggers. The most obvious difference between the two maneuvers is transient periods of total ischemia in postconditioning, whereas low pressure presumes a continual blood flow that is lower than that required to fully meet energy demands. Hence, both methods may share some level of ischemia as a commonality. These periods of ischemia would maintain tissue acidosis and delay realkalinization. This “pH hypothesis” was introduced by Cohen et al., in which perfusion of isolated perfused rabbit hearts with an acidic buffer for the first 2 min of reperfusion reduced infarct size. Cardioprotection was abrogated by transient perfusion with alkalotic buffer, oxygen radical scavenger (N-2-mercaptopropionly glycine), protein kinase C inhibition (chelerythrine), or This Editorial View accompanies the following article: Jiang X, Ai C, Shi E, Nakajima Y, Ma H: Neuroprotection against spinal cord ischemia–reperfusion injury induced by different ischemic postconditioning methods: Role of phosphatidylinositol 3-kinase–Akt and extracellular signal–regulated kinase. ANESTHESIOLOGY 2009; 111:1197–1205.