Influence of simultaneous pressor and vasodilatory agents on the evolution of infarct growth in experimental acute middle cerebral artery occlusion

Abstract

BackgroundThis study sought to test the hypothesis that simultaneous central blood pressure elevation and potent vasodilation can mitigate pial collateral-dependent infarct growth in acute ischemic stroke.MethodsTwenty mongrel canines (20–30 kg) underwent permanent middle cerebral artery occlusion (MCAO). Eight subjects received continuous infusion of norepinephrine (0.1–1.5200 µg/kg/min; titrated to a median of 34 mmHg above baseline mean arterial pressure) and hydralazine (20 mg) starting 30 min following MCAO. Pial collateral recruitment was scored prior to treatment and used to predict infarct volume based on a previously reported parameterization. Serial diffusion magnetic resonance imaging (MRI) acquisitions tracked infarct volumes over a 4-hour time frame. Infarct volumes and infarct volume growth between treatment and control groups were compared with each other and to predicted values. Fluid-attenuated inversion recovery (FLAIR) MRI, susceptibility weighted imaging (SWI), and necropsy findings were included in the evaluation.ResultsDifferences between treatment and control group varied by pial collateral recruitment based on indicator-variable regression effects analysis with interaction confirmed by regression model fit. Benefit in treatment group was only in subjects with poor collaterals which had 35.7% less infarct volume growth (P=0.0008; ANOVA) relative to controls. Measured infarct growth was significantly lower than predicted by the model (linear regression partial F-test, slope P<0.001, intercept=0.003). There was no evidence for cerebral hemorrhage or posterior reversible encephalopathy syndrome.ConclusionOur results indicate that a combination of norepinephrine and hydralazine administered in the acute phase of ischemic stroke mitigates infarct evolution in subjects with poor but not good collateral recruitment.

Quantitative perfusion and water transport time model from multi b-value diffusion magnetic resonance imaging validated against neutron capture microspheres

“…Note that values are considerably higher in the MCAO model due to the use of aggressive flow augmentation. 21,22 4 Discussion…”

“…The canine model has several advantages compared to rodents as a model for assessment of infarct progression using perfusion and diffusion imaging studies. Canines have a gyrencephalic neocortex with similar ratio of white to gray matter 17 – 19 as well as comparable pial arteriolar network organization, 20 critical in modeling collateral arterial blood supply and predicting infarct evolution, 21 to humans. In addition, the canine model provides tissue volumes necessary to evaluate both core and penumbra during ischemia using microsphere deposition.…”

“…In each animal, two experiments were performed on consecutive days to validate our algorithm in a setting of cerebrovascular response to hypercapnia and MCAO and the effect of flow augmentation on collateral arterial networks after MCAO 15 , 21 . We present an analysis of these experiments in which neutron capture microspheres and IVIM were acquired during quiescent physiologic conditions.…”

“…In each animal, two experiments were performed on consecutive days to validate our algorithm in a setting of cerebrovascular response to hypercapnia and MCAO and the effect of flow augmentation on collateral arterial networks after MCAO. 15,21 We present an analysis of these experiments in which neutron capture microspheres and IVIM were acquired during quiescent physiologic conditions. On the first day, canines were imaged at baseline (i.e., normocapnia) (target PaCO 2 ¼ 30 to 35 mmHg) and hypercapnia (5% to 7% carbogen respiration, target PaCO 2 60 to 70 mmHg) induced by carbogen gas inhalation (5% to 7% CO 2 95% O 2 ).…”

Effect of early Sanguinate (PEGylated carboxyhemoglobin bovine) infusion on cerebral blood flow to the ischemic core in experimental middle cerebral artery occlusion

“…To account for this, we also compared differences in the measured infarct volume relative to the predicted infarct volume (estimate) between the two groups. The equation for predicted infarct volume was V(t)=V f (1 − e (-Gt) ) as previously described and validated,7 8 where G=−0.0013*PCS + 0.0179, Vf=−2,472.7*PCS + 34,2 97, t is time interval between imaging onset and MCAO (in minutes) and PCS is pial collateral score.…”