Role Of Cerebral Blood Flow Changes

The association of cerebral ischemia and edema formation has been well studied. Although, based on experimental animal models, ischemia was initially thought to contribute to edema in ICH (44-48). This theory is currently controversial, and it is becoming more and more evident that ischemia does not play a role in edema formation in ICH.

No good test exists by which to measure the cerebral response at the cellular level in ICH, but emergent technology, such as MRI, single-photon emission computerized tomography

(SPECT), and positron emission tomography (PET), is being used indirectly to help determine the CBF changes during ICH.

On MRI studies, an initial increase in diffusion that affects both hemispheres diffusely appears to occur as early as 6 hr after hemorrhage onset. These changes reflect a rise in water content that may be attributed to the increased hydrostatic pressure that maintains cerebral perfusion. Vasogenic edema also occurs secondary to a diffuse cerebral inflammatory reaction. This global reaction may represent an adaptive process to a new steady state (49). A prospective study, in which perfusion-weighted MRI and diffusion-weighted MRI was used to asses perihematomal blood flow and edema in ICH, showed a reduction in blood flow in the perihema-toma region, but this was self-limited, and normalization occurred between days 3 and 5 after onset. No MRI markers of ischemia were associated with high-signal in diffusion-weighted images or apparent diffusion coefficient (ADC), suggesting that early perihematoma edema is plasma derived (50).

SPECT was also used to study the flow in the perihematoma region and showed decreased CBF that peaked at 24 hr and normalized as edema formed during the first 3 days after ICH; the extent of edema correlated with the size of the initial deficit (51), suggesting that hypo-perfusion was present and was highest in the early hours following ICH (52,53). PET studies also reported perihematomal CBF reductions, mainly diffuse and in the ipsilateral hemisphere, without evidence of ischemia (54-56). Although evidence of hypoperfusion has been shown in the perihematoma area or in the ipsilateral hemisphere, it seems to be self-limited and without ischemia (50,52,57,58). The mechanism for transient hypoperfusion may be related to a hydrostatic mechanism with normalization of perfusion as elevated tissue pressure normalizes (49 ), or it may be due to a transient reduction in metabolic rate of oxygen, suggesting that flow changes may represent hypoactive tissue rather than ischemia (59 ).

Upon resolution of hypoperfusion, vasodilation induced by inflammatory mediators from the blood clot could follow (60), which, although desired to reduce primary injury, could be implicated in the pathogenesis of secondary damage in ICH (Fig. 1) (52,61 ).Three phases of CBF and metabolism changes can be identified (Fig. 2) (60). First, a hibernation phase, an acute period of concomitant hypoperfusion and hypometabolism, predominantly involving the peri-hematoma region, is identified within 48 hr of hemorrhage onset. Reductions in CBF and cerebral oxygen consumption in both affected and contralateral cerebral hemispheres have been shown by PET scanning. Second, a reperfusion phase is observed between 48 hr and 14 days, with a heterogeneous pattern of CBF consisting of areas of relatively normal flow, persistent hypo-perfusion, and hyperperfusion. Third, a normalization phase is observed after 14 days, with normal CBF reestablished in all regions except those with nonviable tissue. Despite low CBF, the low metabolism in the acute hibernation phase probably prevents development of ischemia in the perihematoma region.

Figure 1 Pathophysiology of neuronal injury in the perihematoma region. Abbreviations: BBB, blood-brain barrier; RBCs, red blood cells; AAs, amino acids; MMPs, matrix metalloproteinases.

Figure 2 Schematic representation of the evolution of CBF and cellular metabolism (M) in intracranial hemorrhage; hematoma (H) in intracranial hemorrhage. (A) Hibernation, (B) reperfusion, (C) normalization. Abbreviation: CBF, cerebral blood flow.

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