Gary S. Krause Blaine C. White
Early ..Reperfusion Late.Ëyents.Durinfl, Reperfusion Therapy
Cerebral resuscitation continues to affect a substantial portion of the population of the United States. Data from the ARIC (Atherosclerotic Risk in Communities), CHS (Cardiovascular Health Study), and the NHLBI (National Heart, Lung, and Blood Institute) show that about 600,000 people suffer a new or recurrent stroke each year. Furthermore, stroke is the leading cause of serious, long-term disability in the United States. Three million Americans are currently permanently disabled because of stroke, and 31 percent of stroke survivors need help caring for themselves, 20 percent need help walking, 71 percent have an impaired vocational capacity when examined an average of 7 years later, and 16 percent have to be institutionalized. The direct and indirect cost of stroke in 1998 was estimated at over $40 billion. In addition, cardiopulmonary resuscitation for victims of cardiac arrest, both within and outside of the hospital, succeeds in restoring spontaneous circulation in about 70,000 patients a year in the United States. At least 60 percent of these patients subsequently die in the hospital as a result of extensive brain damage; only 3 to 10 percent of resuscitated patients are finally able to resume their former lifestyles. Clearly, the development of effective interventions to prevent these sequela of brain ischemia and reperfusion would enormously enhance the value of the investment already made and would return thousands of now lost patients to renewed vigorous and productive time with their families and in our society.
There are two important issues involved in the ongoing effort to reduce this neurologic morbidity. One is discovery of the mechanisms involved in tissue injury and repair, and the other is the identification of clinically effective therapy. Clinical trials conducted more than a decade ago utilizing postresuscitation treatment with barbiturates1 or calcium antagonists2 were disappointing. More recently, clinical treatment of stroke with the radical scavenger tirilazad was found ineffective, 3 and laboratory investigations of treatment with glutamate receptor antagonists after resuscitation from cardiac arrest produced disappointing results. 4 The wide variety of therapeutic agents now in single-drug clinical trials (e.g., involving thrombolysis, glutamate release inhibition, M-methyl-D-aspartate receptor antagonism, opioid antagonism, calcium channel blockade, free radical scavenging, membrane stabilization, intercellular adhesion molecule-1 antagonism, ganglioside administration, and growth factor administration) suggests that understanding of the mechanisms involved in damage and repair in neurons remains incomplete.
Four major observations have provided the foundation for investigation of brain injury by ischemia and reperfusion: 5 (1) rapid loss of high-energy phosphate compounds during ischemia followed by their recovery within the first 15 min of reperfusion, (2) morphologic evidence that most structural damage occurs during reperfusion, especially in selectively vulnerable zones, (3) progressive brain hypoperfusion during postischemic reperfusion, and (4) prolonged suppression of protein synthesis in selectively vulnerable neurons.
Cardiac arrest resulting in ischemic-anoxic brain injury is characterized by three phases: ischemia, early reperfusion, and late reperfusion. We have published extensive reviews of our theoretical model of the causal interactions of neuronal injury and repair mechanisms during ischemia and reperfusion. 56 Briefly, primary injury mechanisms include, at a minimum, activation of phospholipases and proteolytic enzymes (calpain) during ischemia and generation of radicals accompanied by lipid peroxidation during reperfusion. This chapter outlines the crucial role of calcium and iron in these injury mechanisms and suggests possible therapies to ameliorate brain injury following an ischemic insult.
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