This is the first detailed spatiotemporal investigation of the hemodynamic and metabolic impact of pharmacologically increased systemic blood pressure on the ischemic core and penumbra. Using high spatiotemporal resolution laser speckle flowmetry and multispectral reflectance imaging simultaneously, we found that increasing MAP by 30% 10 minutes after dMCAO improved CBF, oxygenation, and CMRO2 in both the core and penumbra; delayed intervention 60 minutes after dMCAO was equally efficacious. Consistent with a marked hemodynamic and metabolic improvement during induced hypertension, infarct volume was reduced by almost 50% without significantly exacerbating ischemic swelling. The concentric improvement in CBF and infarct volume suggested that raising MAP augments pial collateral flow from all 3 divisions of internal carotid artery, including the MCA branches proximal to the occlusion.
Although increased morbidity and mortality due to prolonged phenylephrine infusions in mice precluded testing longer treatment times in this study, prolonged vasopressor infusions are feasible and part of standard care in the clinical setting, for example, in neurocritical care of patients with subarachnoid hemorrhage-induced delayed vasospasm. Several anecdotal reports and small nonrandomized series have suggested that induced hypertension may improve cerebral perfusion and neurological deficits in acute stroke. For example, MAP elevation by 50% using phenylephrine acutely improved mean transit time on perfusion-weighted MRI and neurological deficits in a patient with embolic anterior cerebral artery A2 branch occlusion19
; cerebral blood volume was not altered by this treatment, which is consistent with our findings. In a study of 19 patients with acute large MCA strokes, a 30% elevation of MAP caused a 35% increase in mean ipsilateral MCA flow velocities; the contralateral increase was only 17%, presumably due to intact cerebral autoregulation.20
In another small, randomized study, the volume of perfusion deficit on MRI significantly decreased from day 1 to 3 in patients who received induced hypertension treatment.26
Our understanding of the mechanisms by which hypertension improved tissue outcome has been limited. Although induced hypertension has reduced infarct size in several studies,1-3,12,43
its impact on cerebral perfusion has been assessed in only a few studies.1,2,4,16
-chloralose-anesthetized baboons, a 30% increase in blood pressure enhanced CBF by almost 60% when measured by hydrogen clearance method and partially restored cortical somatosensory evoked potentials.4
In pentobarbital-anesthetized dogs, induced hypertension augmented CBF in all animals studied.16
When measured using [14
C]-iodoantipyrine autoradiography 15 minutes after proximal MCAO in rats, the volume of severely ischemic tissue (CBF ≤15 mL/100 g per minute) was decreased by a 30% increase in MAP.1
Our 2-dimensional analysis of CBF deficit using laser speckle flowmetry showed that the area of CBF deficit shrinks in a concentric manner on induced hypertension (). We, therefore, hypothesized that hypertension increases perfusion in the ischemic cortex through pial collaterals from ACA and PCA branches and confirmed this by making selective measurements from these collaterals; MCA flow immediately distal to the occlusion did not significantly increase, confirming complete occlusion. These data suggest that pial collaterals are the major source of CBF augmentation by induced hypertension in this dMCAO model.
The multispectral reflectance imaging demonstrated in real-time that improved CBF translates into increased oxygen delivery and higher CMRO2
, 2 critical determinants of tissue viability. Moreover, oxygen metabolism progressively increases in penumbra over time and is improved even in the severely ischemic core. It should be noted, however, that the relative increase in CBF exceeded the increase in CMRO2
, perhaps suggesting irreversible impairment in oxygen utilization in a subset of cells. Induced hypertension has previously been reported to reduce tissue lactate levels in focal ischemia,44
providing indirect evidence for utilization of increased oxygen delivery by ischemic brain metabolism. Consistent with this observation, induced hypertension decreased infarct volume by almost 50%. The volume of ischemic tissue swelling was not increased by hypertension, suggesting that any potential increase in edema formation by induced hypertension was offset by a net reduction in infarct volume. Consistent with these findings, published experimental data suggest that induced hypertension does not increase ischemic brain edema or intrainfarct hematoma formation and may be safe even when administered after reperfusion.12-15,45-48
We also found that the deleterious effect of PIDs on CBF and oxygenation were ameliorated by induced hypertension, providing an additional mechanism for metabolic improvement.
Although observational studies and small clinical trials in carefully selected patients suggest that induced hypertension is feasible and probably safe and effective, larger studies of unselected patients indicate that high blood pressure during acute ischemic stroke is associated with poor outcome,49-51
higher risk of early recurrence,49
and malignant brain swelling53
in acute stroke. Clearly not all patients will benefit from induced hypertension. Patients with stroke with an identifiable blood pressure threshold above which neurological deficits improve19
are likely to benefit as may patients with significant diffusion–perfusion MRI mismatch. Our data suggest that improved cerebral perfusion and metabolism (eg, perfusion-weighted MRI and MR spectroscopy for tissue lactate) may provide a more sensitive measure than acute improvement in neurological examination for patient selection.
Our data strongly suggest that when instituted early after vascular occlusion, mild pharmacologically induced hypertension increases cerebral perfusion and oxygen delivery, improves CMRO2, and reduces infarct volume in this distal cortical branch occlusion model; the efficacy of induced hypertension in more proximal arterial occlusions (eg, filament MCAO) or when collateral channels are limited (eg, contralateral stenosis or occlusion), however, needs further testing. Improved understanding of the dynamics of collateral perfusion and risk factors for edema and hemorrhage will be critical to determine the usefulness of induced hypertension in acute stroke management.