Background This study tests the hypothesis that simultaneous cerebral blood pressure elevation and potent vasodilation augments perfusion to ischemic tissue in acute ischemic stroke and it varies by degree of pial collateral recruitment.
Methods Fifteen mongrel canines were included. Subjects underwent permanent middle cerebral artery occlusion; pial collateral recruitment was scored before treatment. Seven treatment subjects received a continuous infusion of norepinephrine (0.1–1.52 µg/kg/min; titrated 25–45 mmHg above baseline mean arterial pressure while keeping systolic blood pressure below 180 mmHg) and hydralazine (20 mg) starting 30 min post-occlusion. Perfusion (cerebral blood flow—CBF) was evaluated with quantitative dynamic susceptibility contrast MRI 2.5 hours post-occlusion to produce images in mL/100 g/min, and relative CBF measured as ratios. Mean region of interest (ROI) values were reported, and compared and subject to regression analysis to elucidate trends.
Results Differences in quantitative CBF (qCBF) between treatment and control group varied by degree of pial collateral recruitment, based on Wilcoxon rank sum scores and regression model fit. For poorly collateralized subjects, ipsilateral anatomic, core infarct, and penumbra regions showed treatment with higher qCBF, raised above the ischemic threshold, compared with the control, while well collateralized subjects showed a paradoxical decrease maintained above the ischemic threshold for neuronal death. qCBF on the contralateral side increased regardless of collateralization.
Conclusion Results suggest that perfusion can be augmented in ischemic stroke with norepinephrine and hydralazine. Perfusion augmentation depends on degree of collateralization and territory in question, with some evidence of vascular steal.
Data availability statement
Data are available upon reasonable request.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.
Contributors ML: post-processed and analyzed all the data from the experiments, contributed to hypothesis formations, did statistical analysis, drafted manuscript, critical revision, and final approval. NS: data handling, performing pathology as well as assisting GAC throughout the two-day experiments including X-ray angiograms, animal transport, maintaining anesthesia within physiologic limits, point of care blood work, administration of physiologic challenges and therapeutics, necropsy, preparation of samples. Prepared and published the companion to the current manuscript, and final approval. MN: veterinarian who implemented anesthesia protocols, maintaining physiology throughout the experiments. Assisted in animal transportation and handling throughout the 2-day data collection, euthanized the animals, and ensured all experiments were ethical, and within the regulations set forth. SR: designed the protocol to minimize the effect on brain physiology while ethically treating the test subjects, critical revision and met regularly with the team when statistical modeling and data interpretation were being developed. YIJ: derived and validated many of the advanced post-processing algorithms used in this work and final approval. TJC: was involved in all aspects of this work. He and YIJ derived and implemented the MRI scan protocol, wrote all post processing software. GAC: neurointerventionalist who performed all experiments and involved in all aspects of this work. He and TJC conceived the overall study, the imaging protocols, the post-processing, pathologic correlation, and analysis for hypothesis test, critical revision, and final approval. GAC and TJC are responsible for the overall content as the guarantors.
Funding This study was funded by National Institute of Neurological Disorders and Stroke (R01‐ NS093908), National Science Foundation (DGE-1746045), American Heart Association (GRNT‐20380798).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.