Capillary Transit Time Heterogeneity and Flow-Metabolism Coupling after Traumatic Brain Injury

Abstract

Most patients who die after traumatic brain injury (TBI) show evidence of ischemic brain damage. Nevertheless, it has proven difficult to demonstrate cerebral ischemia in TBI patients. After TBI, both global and localized changes in cerebral blood flow (CBF) are observed, depending on the extent of diffuse brain swelling and the size and location of contusions and hematoma. These changes vary considerably over time, with most TBI patients showing reduced CBF during the first 12 hours after injury, then hyperperfusion, and in some patients vasospasms before CBF eventually normalizes. This apparent neurovascular uncoupling has been ascribed to mitochondrial dysfunction, hindered oxygen diffusion into tissue, or microthrombosis. Capillary compression by astrocytic endfeet swelling is observed in biopsies acquired from TBI patients. In animal models, elevated intracranial pressure compresses capillaries, causing redistribution of capillary flows into patterns argued to cause functional shunting of oxygenated blood through the capillary bed. We used a biophysical model of oxygen transport in tissue to examine how capillary flow disturbances may contribute to the profound changes in CBF after TBI. The analysis suggests that elevated capillary transit time heterogeneity can cause critical reductions in oxygen availability in the absence of ‘classic' ischemia. We discuss diagnostic and therapeutic consequences of these predictions.

Neurovascular coupling in humans: Physiology, methodological advances and clinical implications

“…52,[71][72][73] On the other hand, conditions such as stroke and traumatic brain injury are likely impaired due to alterations in hyperemic signalling from glutamate release secondary to neuronal death and astrocyte scarring. 67,[74][75][76][77][78] Furthermore, oxidative stress is suspected to play a particularly deleterious role in human neurovascular coupling and is implicated in the declines seen in hypertension (through angiotensin receptor type 1 agonism), Alzheimer's (through amyloid b accretion), diabetes (through chronic hyperglycemia), and healthy aging (Table 1). It may be that reducing oxidative stress is a viable therapeutic target for improving neurovascular coupling in humans, although this possibility needs to be clearly examined.…”

Neurovascular Coupling During Cortical Spreading Depolarization and –Depression

“…23,25,45 Flow suppression can only compensate for elevated CTH to a certain extent: We have demonstrated that a CTH threshold exists for which the metabolic needs of resting human brain are met at negligible tissue oxygen tension. Notably, the CBF value which optimizes oxygen extraction at this CTH threshold is approximately the classical ischemic threshold of 20 mL/100 mL/min.…”

“…Tissue injury is clearly imminent when spreading ischemia is observed, but in conditions where this devastating phenomenon occurs, it is unclear whether therapies that restore large vessel patency and normal CBF also improve clinical outcome if they fail to restore capillary flow patterns in parallel. 23,25,45 Therefore, we propose that both the proximal (resistance) and capillary vascular segments must be considered to understand the metabolic derangement in cortical spreading ischemia, for example, by parallel CTH, CBF, P t O 2 , and CSD recordings.…”

Traumatic Penumbra: Opportunities for Neuroprotective and Neurorestorative Processes

“…During this, time swelling of perivascular astrocytes is evident; their swollen endfeet constrict capillaries, which leads to a redistribution of capillary blood flow that can reduce oxygen availability to cerebral tissue even if ischemia is not obvious [122]. Data from experimental TBI models indicate that increased extravasation of the contents of blood vessels through microhemorrhages is evident between 3 and 12 hours after the injury [116].…”