The role of the microcirculation in delayed cerebral ischemia and chronic degenerative changes after subarachnoid hemorrhage

Abstract

The mortality after aneurysmal subarachnoid hemorrhage (SAH) is 50%, and most survivors suffer severe functional and cognitive deficits. Half of SAH patients deteriorate 5 to 14 days after the initial bleeding, so-called delayed cerebral ischemia (DCI). Although often attributed to vasospasms, DCI may develop in the absence of angiographic vasospasms, and therapeutic reversal of angiographic vasospasms fails to improve patient outcome. The etiology of chronic neurodegenerative changes after SAH remains poorly understood. Brain oxygenation depends on both cerebral blood flow (CBF) and its microscopic distribution, the so-called capillary transit time heterogeneity (CTH). In theory, increased CTH can therefore lead to tissue hypoxia in the absence of severe CBF reductions, whereas reductions in CBF, paradoxically, improve brain oxygenation if CTH is critically elevated. We review potential sources of elevated CTH after SAH. Pericyte constrictions in relation to the initial ischemic episode and subsequent oxidative stress, nitric oxide depletion during the pericapillary clearance of oxyhemoglobin, vasogenic edema, leukocytosis, and astrocytic endfeet swelling are identified as potential sources of elevated CTH, and hence of metabolic derangement, after SAH. Irreversible changes in capillary morphology and function are predicted to contribute to long-term relative tissue hypoxia, inflammation, and neurodegeneration. We discuss diagnostic and therapeutic implications of these predictions.

Figure 1

Changes in the capillary morphology after subarachnoid hemorrhage (SAH), ischemia, and hypotonic hyponatremia. Panels A and B show swelling of astrocytic endfeet (*) and endothelial protrusions (arrows) after SAH. Scale bars indicate 5 μm in panel A and 2 μm in panel B, respectively. Reproduced from ref. with permission from the publisher. Panel C shows segmental narrowing of capillaries due to capillary constrictions after ischemia and reperfusion (bottom) compared with slender, thread-like, horseradish peroxidase-filled capillaries in the normal hemisphere (top). Reproduced from ref. with permission from the publisher. Panels D and E show tangential sections through capillaries in sham-operated brain (D) and in a hypotonic hyponatremic edema model (E) in rabbit. The distended astrocytic endfeet (OL), the membranes of which are marked by arrows, clearly compress the capillary lumen, as shown in the transverse section (F). Other astrocytic membranes are labeled ‘A', and axons ‘AX'. The magnifications were × 6500 (D and E) and × 5000 (F), respectively. Reproduced from ref. with permission from the publisher.

Figure 2

The relation between blood flow and net oxygen extraction in single capillaries. The curve in plot C shows the so-called flow–diffusion equation for oxygen, that is, shows the maximum amount of oxygen that can diffuse from a single capillary into tissue, for a given perfusion rate. The curve shape predicts three important properties of parallel-coupled capillaries: First, the curve slope decreases towards high-perfusion values, making vasodilation increasingly inefficient as a means of improving tissue oxygenation towards high-perfusion rates. Second, if erythrocyte flows differ among capillary paths (case B) instead of being equal (case A), then net tissue oxygen availability declines. This can be observed by using the curve to determine the net tissue oxygen availability resulting from the individual flows in case B. The resulting net tissue oxygen availability is the weighted average of the oxygen availabilities for the two flows, labeled b in the plot. Note that the resulting tissue oxygen availability will always be less than that of the homogenous case, labeled a. Conversely, homogenization of capillary flows during hyperemia has the opposite effect, and serves to compensate for the first property. By a similar argument, insert D disproves the traditional assumption that increased perfusion always results in improved tissue oxygenation: By increasing tissue perfusion from F_hom to F_het, and again subdividing capillary flows in the latter case into f₁ and f₂, tissue oxygen availability in fact decreases in response to a flow increase, as indicated by the double asterisk. Note that, if erythrocyte flows are hindered (rather than continuously redistributed) along single capillary paths (as indicated by slow-passing white blood cell (WBC) and/or rugged capillary walls), upstream vasodilation is likely to amplify the redistribution losses, as erythrocytes are forced through other branches at very high speeds, with negligible net oxygenation gains. Reproduced from refs. and .

Figure 3

Metabolic thresholds. The green iso-contour surface corresponds to the metabolic rate of contralateral tissue in patients with focal ischemia. The red plane marks the boundary, left of which vasodilation fails to increase tissue oxygen availability (malignant capillary transit time heterogeneity (CTH)). The maximum value that CTH can attain at a tissue oxygen tension (P_tO₂) of 25 mm Hg, if oxygen availability is to remain above that of resting tissue, is indicated by the label A. As CTH increases further, a critical limit is reached as P_tO₂ approaches 0—label B. At this stage, the metabolic needs of tissue cannot be supported unless mean transit time (MTT) is prolonged to a threshold of approximately 4 seconds, corresponding to cerebral blood flow (CBF)=21 mL/100 mL/minute. Modified from ref. .

Figure 4

The subarachnoid hemorrhage (SAH) stages. The yellow arrows indicate flow with different velocities through the capillary system. The color within the vessels indicates oxygen saturation, and the background color outside the tissue oxygen tension. (A) The normal state, (B) the hyperemic state, where slight capillary transit time heterogeneity (CTH) increases lead to increased cerebral blood flow (CBF). (C) The flow suppression state. (D) Tissue hypoxia. OEF, oxygen extraction fraction.

Figure 5

The figure summarizes the pathways from the acute subarachnoid hemorrhage to early brain injury (EBI), delayed cerebral ischemia (DCI), and the long-term degenerative changes that are hypothesized to be the result of irreversible increases in capillary transit time heterogeneity (CTH). Nitric oxide synthetase (NOS) dysfunction refers to the loss of neuronal nitric oxide synthetase (nNOS) from nerve fibers in the arterial adventitia, and the inhibition of endothelial NOS (eNOS) by asymmetric dimethyl arginine (ADMA)—see text. The blue arrows indicate ‘vicious cycles' through which low oxygen tension exacerbates blood–brain barrier (BBB) disruption and capillary flow disturbances. The green text boxes indicate possible sites of therapeutic intervention discussed in the text. HgbO, oxyhemoglobin; NO, nitric oxide; ROS, reactive oxygen species; SD, spreading depolarizations.

Figure 6

Panel A summarizes the sources of capillary flow disturbances as identified in this review, and their estimated duration. They include the oxidative stress and nitric oxide (NO) depletion caused by pericapillary oxyhemoglobin, structural damage to the capillary wall (including endothelial cells, basement membranes, pericytes, and astrocytic endfeet), leukocytosis, and compression by pericapillary edema. The extent to which the structural damage to the capillary wall is permanent remains crucial in that permanent changes in capillary transit time heterogeneity (CTH) are potential sources of long-term, neurodegenerative changes. Panel B indicates the added effect of the changes in panel A in terms of the resulting change in CTH over time. The time of the peak CTH change is likely to coincide with the peak pericapillary oxyhemoglobin HgbO concentration, whereas the height of the peak is likely to correlate with the size of the hematoma. The extent to which one observes flow increases by transcranial Doppler sonography (TCD), angiographic vasospasm, or tissue lesions by computed tomography (CT) or magnetic resonance imaging (MRI), is predicted to depend on the individual sizes of the factors in panel A. Note that large hematomas are likely to generate large net CTH increases owing to their larger, net capillary NO depletion, and thus to result in both angiographic vasospasm and hypoxic lesions.