Sequence Of Events During Complete And Incomplete Cerebral Ischemia

Complete global cerebral ischemia refers to situations in which cerebral blood flow (CBF) falls to zero, such as in the case of cardiac arrest. Incomplete global cerebral ischemia refers to situations in which CBF does not completely cease but falls sufficiently to impair cellular processes, metabolism, and function. Incomplete ischemia arises from various causes of arterial hypotension, shock, and intracranial hypertension. The brain requires a continuous supply of oxygen and glucose for normal function. With the sudden onset of complete cerebral ischemia, consciousness can be lost within 10 sec, and the electroencephalogram (EEG) can become isoelectric within 20 sec.The onset of isoelectric EEG is associated with (i) an efflux of potassium ions (K+) that increases the extracellular concentration from -3-12 mM, and (ii) a moderate increase in intracellular calcium ions (Ca2+) (1,2). Because of the high rate of oxidative metabolism in the brain, phosphocreatine becomes largely depleted within 1 min, and adenosine triphosphate (ATP) becomes depleted within 2 min of the onset of complete ischemia (3,4). When ATP falls to ~30% of normal levels, the cells depolarize, causing an additional large efflux of K++ an increase in extracellular K+ in excess of 60 mM, and a large influx of sodium (Na+), Ca2+, and water. Consequently, the extracellular space shrinks and the cells swell. The continued consumption of ATP and anaerobic glycolysis of glycogen and glucose stores generate a large proton load in the cell. The intracellular pH gradually falls from 7.1 to ~6.2 over the first 6 min of cardiac arrest (5). The lack of clearance of CO2 by blood flow contributes to the fall in pH. Therefore, complete lack of CBF initiates a rapid sequence of disturbances in cell homeostasis (Fig. 1).

For incomplete global cerebral ischemia, this sequence of events depends on reductions of CBF below a set of thresholds: inhibition of protein synthesis when CBF is below ~50% of normal, suppressed electrical activity and O2 consumption when CBF is below ~40% of normal, decreased ATP when CBF is below ~25% of normal, and anoxic depolarization when CBF is below ~20% of normal (6,7). The decrease in protein synthesis and electrical activity helps to conserve ATP for maintaining ionic homeostasis. This sequence of events is also time dependent and is delayed relative to that occurring with complete ischemia. Small, incremental improvements in CBF can forestall the loss of ATP. For example, with intracranial hypertension sufficient to reduce CBF to ~15% of baseline and O+ consumption to ~25% of baseline, ATP takes 12 min to fall to 35% of baseline and 30 min to fall to <10% (8). Thus, the time course of ATP loss can be delayed more than 10-fold compared to complete ischemia, even at "trickle" levels of blood flow. One concern is that "trickle" flow will worsen tissue acidosis by sustaining anaerobic glycolysis. However, after 30 min of CBF at 15% of baseline, intracellular pH falls to ~6.4 at 12 min and 6.2 at 30 min of normoglycemic ischemia. This fall in pH is slower than that observed during complete ischemia, where intracellular pH decreases from ~7.1 to 6.4 at 3 min and to 6.0 to 6.2 at 12 min (3,9). However, in the presence of acute or chronic hyperglycemia, the fall in intracellular pH during incomplete global ischemia is more rapid and can reach levels <6.0 by 30 min (8,10). This augmented acidosis is associated with poor metabolic, functional, and histologic outcome (8,10-12).

Figure 1 Schematic representation of the time course of relative changes in cerebral ATP concentration, [K+]o concentration, and pHi with the onset of cardiac arrest (time=0 min) and onset of full reperfusion (12 min). An initial, moderate increase in [K+]o is associated with EEG silence, and subsequent depletion of ATP <30% of normal is associated with anoxic depolarization. Increases in intracellular Na+ and Ca2+ tend to parallel changes in [K+]o, although compartmental changes in Ca2+ stores may persist for prolonged periods of reperfusion. Recovery of pHi lags behind recovery of [K+]o and ATP. Abbreviations: [K+]o, extracellular potassium concentration; pHi, intracellular pH; EEG, electroencephalogram; ATP, adenosine triphosphate.

Figure 1 Schematic representation of the time course of relative changes in cerebral ATP concentration, [K+]o concentration, and pHi with the onset of cardiac arrest (time=0 min) and onset of full reperfusion (12 min). An initial, moderate increase in [K+]o is associated with EEG silence, and subsequent depletion of ATP <30% of normal is associated with anoxic depolarization. Increases in intracellular Na+ and Ca2+ tend to parallel changes in [K+]o, although compartmental changes in Ca2+ stores may persist for prolonged periods of reperfusion. Recovery of pHi lags behind recovery of [K+]o and ATP. Abbreviations: [K+]o, extracellular potassium concentration; pHi, intracellular pH; EEG, electroencephalogram; ATP, adenosine triphosphate.

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