Introduction and pathophysiology

Resuscitation of the brain after temporary complete global brain ischemic anoxia, as produced by prolonged normothermic cardiac arrest, is crucial. Pathophysiology and therapy are similar for the temporary incomplete global ischemic anoxia of asphyxia or severe shock, but are different for the permanent incomplete focal brain ischemia of stroke or for traumatic brain injury which can be multifocal and followed by lethal brain swelling. Measures effective for protection (pretreatment) and preservation (intra-insult treatment) may not be effective for resuscitation (to reverse the insult and support recovery).

Modern external cardiopulmonary resuscitation was established in the 1950s. However, by 1961 it was clear that a more comprehensive approach to resuscitation was needed, and the concept of cardiopulmonary-cerebral resuscitation was introduced, with a continuum from basic via advanced to prolonged life support ( SafaL

and Bircher. ...198.8). Secondary postarrest derangements in the brain and extracerebral organs—the post-resuscitation disease ( Negoysky.ef a/ 1983)—are extremely complex and multifactorial. Unfortunately, except for brain-oriented general extracerebral life support ( Table 1), no treatment that prevents or reverses all the cascades involved in the development of postcardiac arrest brain damage has yet been statistically documented in humans. Since the 1970s, some potentially valuable therapeutic strategies have been reported in experimental animal models of cardiac arrest and other forms of cerebral ischemia by an increasing number of investigative groups (Koehlereia/: 1996; S§f§L1996). Until recently, documentation of benefit has been difficult because of a lack of reproducible large animal cardiac arrest outcome models. Translation into clinical practice has been problematic for many reasons, ncluding the difficulty, cost, and unreliability of randomized clinical trials. There are numerous unknown or uncontrollable variables that influence cerebral outcome in cardiac arrest patients. A single specific cerebral resuscitation drug with minimal risk and a breakthrough effect may never be found. The multifactorial pathogenesis of the secondary derangements calls for multifaceted treatments (Safar. ..1996).

Table 1 Brain-oriented prolonged life support throughout coma

Normothermic cardiac arrest followed by restoration of spontaneous circulation within about 4 min (before exhaustion of energy charge in the brain) generally results in complete recovery of cerebral function within 3 to 7 days. During normothermic cardiac arrest of duration 10 to 20 min (with no blood flow), a combination of intraneuronal calcium loading, lactic acidosis, glutamate rise, increase in free fatty acids, hyperosmolality, metabolic silence, and membrane leakage sets the stage for reoxygenation injury. After cardiac arrest of duration 10 to 20 min, during and after reperfusion-reoxygenation, normal brain ATP, ion pump, tissue pH, and glutamate concentration are quickly restored. However, a combination of delayed, prolonged, and inhomogeneous cerebral hypoperfusion during rising cerebral O 2 demands (supply-demand mismatching), reoxygenation injury cascades triggered by free iron and free radicals, secondary calcium loading and excitotoxicity, and transient or prolonged extracerebral organ malfunction cause potentially preventable or treatable secondary derangements. The immediate multifocal cerebral no-reflow phenomenon seen with hypotensive reperfusion does not occur with hypertensive or normotensive reperfusion. Intracranial pressure increase due to brain swelling is not a problem after survivable cardiac arrest (but can be a major problem after focal brain ischemia or traumatic brain injury). After restoration of spontaneous circulation following prolonged cardiac arrest and a latent period of several hours, selectively vulnerable neurons (in the hippocampus, cerebellum, and neocortex) die over a period of 24 to 72 h (perhaps even longer) alongside surviving neurons. Why and how these cells die is still unclear, although triggering of programmed cell death (apoptosis) is a possibility.

Persistent unresponsiveness at 3 to 7 days after cardiac arrest and cardiopulmonary-cerebral resuscitation has been predictably followed by permanent severe brain damage, and therefore justifies consideration of discontinuation of life support. However, unresponsiveness for months or even years after traumatic brain injury has occasionally been followed by conscious survival. The mechanisms of the cerebral post-resuscitation syndrome are under intensive investigation. This may soon lead to additional novel therapies which would make those listed below more effective ( Koehler.etal 1996; SMa.L1.996).

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