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   Table of Contents      
COMMENTARY
Year : 2019  |  Volume : 5  |  Issue : 4  |  Page : 241-243

Regional cerebral infusion for acute ischemic stroke


1 Department of Neurosurgery, Xuanwu Hospital Capital Medical University, Beijing, China
2 Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA

Date of Submission06-Dec-2019
Date of Decision09-Dec-2019
Date of Acceptance17-Dec-2019
Date of Web Publication27-Dec-2019

Correspondence Address:
Dr. Xunming Ji
Department of Neurosurgery, Xuanwu Hospital Capital Medical University, Beijing
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bc.bc_61_19

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How to cite this article:
Wu C, Huber C, Huber M, Xu S, Ji X. Regional cerebral infusion for acute ischemic stroke. Brain Circ 2019;5:241-3

How to cite this URL:
Wu C, Huber C, Huber M, Xu S, Ji X. Regional cerebral infusion for acute ischemic stroke. Brain Circ [serial online] 2019 [cited 2022 Jul 5];5:241-3. Available from: http://www.braincirculation.org/text.asp?2019/5/4/241/274167



Acute ischemic stroke (AIS) is a leading cause of death and disability, worldwide. Clinical investigation has yielded promising treatment options for AIS, but the transition from benchtop to bedside has proven difficult. At present, recanalization using recombinant tissue plasminogen activator (tPA) is the best accepted and most widely available reperfusion method. However, a therapeutic window of 4.5 h from symptom onset prevents the vast majority of AIS patients from receiving thrombolytic recanalization; recent evidence suggests that only 6%–8% of AIS patients actually receive tPA.[1] As an alternative to tPA, mechanical thrombectomy (MT) has gained popularity in recent years but is typically only beneficial in patients with a large-vessel occlusion, and surgical candidacy requires perfusion imaging indicating a sufficiently large mismatch.[2] In response to this lack of therapeutic options, hundreds of neuroprotective strategies have been investigated in the preclinical setting in hopes of finding new ways to improve outcomes in stroke patients to whom tPA or thrombectomy is not an option. After a half century of work, one neuroprotective strategy has separated itself from the rest, therapeutic hypothermia. Here, we introduce regional cerebral infusion (RCI), the most advanced and promising therapeutic hypothermia induction method.

RCI is a method of targeted cerebral hypothermia, wherein the ischemic region of the brain is cooled by perfusing chilled saline directly to the infarct site using an endovascular catheter. By isolating hypothermic efforts to the ischemic region, the brain can be cooled in a matter of minutes, and since RCI avoids cooling the whole body, the metabolic and hematologic drawbacks of hypothermia are avoided. In addition, since AIS is increasingly treated using endovascular techniques, RCI could be administered through the same catheter used for thrombectomy, making clinical implementation relatively simple and cost-effective.

Over the past 20 years, RCI has been extensively investigated in the preclinical and clinical settings. Ding et al. first described prereperfusion RCI in a landmark 2002 study.[3] Before reperfusion, this group infused isotonic saline at 23°C or 37°C into the ischemic territory of rats with a transient middle cerebral artery occlusion. The rats receiving prereperfusion RCI demonstrated significantly increased cerebral blood flow, decreased infarct volumes, and improved neurologic outcomes. In a follow-up comparative analysis, Ding et al. demonstrated that prereperfusion RCI allowed achievement of cerebral target temperatures much more effectively than systemic infusion was able to, and that this cooling translated to significantly smaller infarct volumes and augmented functional recovery.[4] Then two other studies came to the same conclusion.[5],[6] Another study by Chen et al also demonstrated a synergistic effect of regional cerebral infusion and low-dose Alb infusion in acute ischemic stroke.[7] Through these experiments, the neuroprotective efficacy of RCI was established.

Following the success in rat models, the safety and efficacy of the RCI concept were evaluated in larger mammals. In a 2016 study, cold lactated Ringer's solution was infused into the middle cerebral artery of healthy Rhesus monkeys via RCI.[8] Target temperatures were achieved within minutes, and no cerebral edema, vasospasm, or cerebrovascular reactivity were observed, thereby establishing RCI as a safe, effective cooling method in models more similar to humans [Table 1].
Table 1: The effect of regional cerebral infusion in preclinical experiments

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The next step toward clinical implementation of RCI was taken by our group in a 2016 pilot study.[9] In this clinical trial of 26 patients with AIS, a microcatheter was advanced through the thrombus and ice-cold saline was perfused before stent retrieval and continued for several minutes following recanalization [Figure 1]. The local temperature of ischemic cerebral tissue decreased by an estimated 2°C or greater, and there were no appreciated side effects of cold infusion. In this way, we established the safety of RCI in humans. We then set out to investigate its cooling efficacy; in a 2018 trial, 45/113 patients received RCI plus MT, while remaining subjects received MT alone.[10] In patients who received RCI and MT, infarct volumes were significantly reduced compared to MT alone, and the rate of complications was no different between the groups; the cooling efficacy of RCI in humans is now established as well. To our knowledge, these studies are the first to establish an effective neuroprotective adjunct to recanalization in humans, which represents a massive step forward in stroke care [Table 2]. Based on these encouraging results of these studies, a randomized clinical trial is ongoing to further assess the efficacy of the RIC plus MT for AIS patients with large-vessel occlusion (ClinicalTrials.gov number: NCT03163459). As of November 30, 2019, 46 patients have been randomly assigned.
Figure 1: Sketch map of the regional cerebral infusion procedure in patients

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Table 2: The effect of regional cerebral infusion in aforementioned clinical trials

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Although RCI has made great strides over the past two decades, there is still a long way to go. Previous investigations have utilized a wide variety of target temperatures, durations of hypothermia, and induction times, which make it difficult to meaningfully compare data from different studies. In addition, there is a potential for harm if hypothermia is too deep or if infusion volumes are too large, so the depth, duration, and therapeutic window all require optimization if RCI is to gain clinical acceptance going forward.[11] Future investigations should focus on optimization of these variables as they likely play a significant role in the degree of benefit that RCI would provide to patients.

Another potential avenue of investigation is the combination of RCI with other neuroprotective strategies. In particular, RCI allows for co-administration of neuroprotective drugs directly to the infarct site, which maximizes local drug concentrations while avoiding their dose-dependent systemic side effects. Indeed, several recent investigations have demonstrated a synergistic neuroprotection when RCI is co-administered with magnesium sulfate[12] or a human albumin solution.[7] This concept provides a multitude of new therapeutic opportunities and opens up a world of possibilities for stroke clinicians.

The neuroprotective benefits of RCI have been well established in preclinical models, and clinical trials have recently demonstrated to safety and feasibility of RCI in an ischemic stroke patient. Thus, RCI holds significant promise for future stroke treatment and rehabilitation. Moreover, the technical skills and equipment required for the procedure are no different from that of a thrombectomy; cost and training are not hurdles to clinical implementation. We sincerely appreciate the benchtop and clinical work that has been done so far, but future investigations are warranted; large, randomized clinical trials are required for any widespread clinical acceptance to occur. Given the cost-effective and robust neuroprotective efficacy that RCI provides, it may fill the void of recommended neuroprotective methods in AIS and benefit patients all over the world.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, et al. 2018 guidelines for the early management of patients with acute ischemic stroke: A guideline for healthcare professionals from the American heart association/American stroke association. Stroke 2018;49:e46-110.  Back to cited text no. 1
    
2.
Albers GW, Marks MP, Kemp S, Christensen S, Tsai JP, Ortega-Gutierrez S, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med 2018;378:708-18.  Back to cited text no. 2
    
3.
Ding Y, Li J, Rafols JA, Phillis JW, Diaz FG. Prereperfusion saline infusion into ischemic territory reduces inflammatory injury after transient middle cerebral artery occlusion in rats. Stroke 2002;33:2492-8.  Back to cited text no. 3
    
4.
Ding Y, Li J, Luan X, Lai Q, McAllister JP 2nd, Phillis JW, et al. Local saline infusion into ischemic territory induces regional brain cooling and neuroprotection in rats with transient middle cerebral artery occlusion. Neurosurgery 2004;54:956-64.  Back to cited text no. 4
    
5.
Ji Y, Hu Y, Wu Y, Ji Z, Song W, Wang S, et al. Therapeutic time window of hypothermia is broader than cerebral artery flushing in carotid saline infusion after transient focal ischemic stroke in rats. Neurological research. 2012;34:657-63.  Back to cited text no. 5
    
6.
Ji YB, Wu YM, Ji Z, Song W, Xu SY, Wang Y, et al. Interrupted intracarotid artery cold saline infusion as an alternative method for neuroprotection after ischemic stroke. Neurosurgical focus. 2012;33:E10.  Back to cited text no. 6
    
7.
Chen J, Fredrickson V, Ding Y, Cheng H, Wang N, Ling F, et al. Enhanced neuroprotection by local intra-arterial infusion of human albumin solution and local hypothermia. Stroke; a journal of cerebral circulation. 2013;44:260-2.  Back to cited text no. 7
    
8.
Wang B, Wu D, Dornbos Iii D, Shi J, Ma Y, Zhang M, et al. Local cerebral hypothermia induced by selective infusion of cold lactated ringer's: A feasibility study in rhesus monkeys. Neurol Res 2016;38:545-52.  Back to cited text no. 8
    
9.
Chen J, Liu L, Zhang H, Geng X, Jiao L, Li G, et al. Endovascular hypothermia in acute ischemic stroke: Pilot study of selective intra-arterial cold saline infusion. Stroke 2016;47:1933-5.  Back to cited text no. 9
    
10.
Wu C, Zhao W, An H, Wu L, Chen J, Hussain M, et al. Safety, feasibility, and potential efficacy of intraarterial selective cooling infusion for stroke patients treated with mechanical thrombectomy. J Cereb Blood Flow Metab 2018;38:2251-60.  Back to cited text no. 10
    
11.
Huber M, Duan H, Chandra A, Li F, Wu L, Geng X, et al. Hypothermia in stroke therapy: Systemic versus local application. In: Zheng J, Zhou, C, editor. Hypoxia and Human Disease. London: InTech; 2017.  Back to cited text no. 11
    
12.
Song W, Wu YM, Ji Z, Ji YB, Wang SN, Pan SY. Intra-carotid cold magnesium sulfate infusion induces selective cerebral hypothermia and neuroprotection in rats with transient middle cerebral artery occlusion. Neurol Sci 2013;34:479-86.  Back to cited text no. 12
    


    Figures

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    Tables

  [Table 1], [Table 2]


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