Background This 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.
Methods Twenty 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.
Results Differences 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.
Conclusion Our 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.
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NS and GAC are joint first authors.
Contributors NS and GAC contributed equally to this article and are joint first authors. NS: data collection, planning of the work, data collection, data analysis, approval of the version to be published. GAC: conception and design of the work, planning of the work, data collection, data analysis and interpretation, drafting the article, critical revision of the article, final approval of the version to be published. YIJ: data collection, data analysis, approval of the version to be published. ML: data collection, data analysis, approval of the version to be published. AD: data collection, data analysis, approval of the version to be published. SR: conception or design of the work, data analysis and interpretation, critical revision of the article, approval of the version to be published. MN: conception or design of the work, planning of the work, data collection, approval of the version to be published. SAA: planning of the work, approval of the version to be published.TC: conception and design of the work, planning of the work, data collection, data analysis and interpretation, critical revision of the article, final approval of the version to be published. There is no one else who fulfils the criteria by ICMJE recommendations that has been excluded as an author.
Funding This study was funded by National Institutes of Health (NIH R01-NS093908).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval The experimental protocol was approved by the University of Chicago Institutional Animal Care and Use Committee and is reported in compliance with Animal Research: Reporting of In Vivo Experiments guidelines. The University of Chicago is an Association for Assessment and Accreditation of Laboratory Animal Care International accredited institution adhering to the following guidelines, regulations and policies: (a) Guide for the Care and Use of Laboratory Animals (National Research Council), (b) USDA Animal Welfare Act and Animal Welfare Regulations, and (c) Public Health Service Policy on Humane Care and Use of Laboratory Animals.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. Data are available upon reasonable request.
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