|Year : 2020 | Volume
| Issue : 1 | Page : 11-18
Multiphase adjuvant neuroprotection: A novel paradigm for improving acute ischemic stroke outcomes
Wenbo Zhao1, Chuanjie Wu2, David Dornbos III3, Sijie Li4, Haiqing Song2, Yuping Wang2, Yuchuan Ding5, Xunming Ji6
1 Department of Neurology; Beijing Key Laboratory of Hypoxia Conditioning Translational Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China
2 Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
3 Department of Neurological Surgery, Semmes-Murphey Clinic and University of Tennessee Health Science Center, Memphis, TN, USA
4 Beijing Key Laboratory of Hypoxia Conditioning Translational Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China
5 China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China
6 Beijing Key Laboratory of Hypoxia Conditioning Translational Medicine; China-America Institute of Neuroscience; Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
|Date of Submission||19-Oct-2019|
|Date of Decision||29-Nov-2019|
|Date of Acceptance||17-Jan-2020|
|Date of Web Publication||18-Feb-2020|
Dr. Xunming Ji
Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Changchun Street, No. 45, Xicheng District, Beijing 100053
Source of Support: None, Conflict of Interest: None
While several large pivotal clinical trials recently revealed a substantial benefit of endovascular thrombectomy for acute ischemic stroke (AIS) caused by large-vessel occlusion, many patients still experience mediocre prognosis. Enlargement of the ischemic core, failed revascularization, incomplete reperfusion, distal embolization, and secondary reperfusion injury substantially impact the salvaging of brain tissue and the functional outcomes of AIS. Here, we propose novel concept of “Multiphase Adjuvant Neuroprotection” as a new paradigm that may help guide our search for adjunctive treatments to be used together with thrombectomy. The premise of multiphase adjuvant neuroprotection is based on the diverse and potentially nonoverlapping pathophysiologic mechanisms that are triggered before, during, and after thrombectomy therapies. Before thrombectomy, strategies should focus on preventing the growth of the ischemic core; during thrombectomy, improving recanalization while reducing distal embolization and maximizing reperfusion are of significant importance; after reperfusion, strategies should focus on seeking targets to reduce secondary reperfusion injury. The concept of multiphase adjuvant neuroprotection, wherein different strategies are employed throughout the various phases of clinical care, might provide a paradigm to minimize the final infarct size and improve functional outcome in AIS patients treated with thrombectomy. With the success of thrombectomy in selected AIS patients, there is now an opportunity to revisit stroke neuroprotection. Notably, if the underlying mechanisms of these neuroprotective strategies are identified, their role in the distinct phases will provide further avenues to improve patient outcomes of AIS.
Keywords: Acute ischemic stroke, endovascular thrombectomy, neuroprotection, penumbra, reperfusion injury
|How to cite this article:|
Zhao W, Wu C, Dornbos III D, Li S, Song H, Wang Y, Ding Y, Ji X. Multiphase adjuvant neuroprotection: A novel paradigm for improving acute ischemic stroke outcomes. Brain Circ 2020;6:11-8
|How to cite this URL:|
Zhao W, Wu C, Dornbos III D, Li S, Song H, Wang Y, Ding Y, Ji X. Multiphase adjuvant neuroprotection: A novel paradigm for improving acute ischemic stroke outcomes. Brain Circ [serial online] 2020 [cited 2022 Jul 5];6:11-8. Available from: http://www.braincirculation.org/text.asp?2020/6/1/11/278542
| Introduction|| |
Reperfusion, whether by thrombolysis, endovascular therapy, or a combination of these two methods, is the most effective therapeutic strategy for acute ischemic stroke (AIS)., For two decades, intravenous thrombolysis was the only effective reperfusion therapy for AIS. More recently, several large pivotal clinical trials have demonstrated the superiority of endovascular thrombectomy (EVT) for patients with AIS caused by large-vessel occlusion when compared to medical management alone.,, Despite its efficacy, only a small portion (approximately 10%) of AIS patients with large-vessel occlusion are eligible for thrombectomy, as most patients have a completed infarction on arrival to a thrombectomy-capable stroke center.,
Even with highly successful recanalization rates approaching 88%,,, functional independence at 90 days is typically seen between 50% and 55% with mortality around 10%., This counterintuitive mismatch between successful revascularization and mediocre prognosis calls for further investigation into underlying mechanisms and elucidation of strategies to improve functional outcomes of AIS patients undergoing thrombectomy. This review discusses the key challenges of improving functional outcomes among AIS patients treated with EVT, presents the concept of “Multiphase Adjuvant Neuroprotection” as a new paradigm to elucidate novel therapies for this patient population, and highlights several cautions regarding its implementation.
| Key Issues Impacting the Final Infarct Volume|| |
The primary goal of reperfusion therapy is to reduce the final infarct volume, a strong independent predictor of functional outcomes in patients with AIS caused by large-vessel occlusion. The key issues that have a substantial impact on the final infarct volume, including further enlargement of the ischemic core, failed revascularization, incomplete reperfusion, distal embolization to new territories, and secondary reperfusion injury, are summarized.
Enlargement of the ischemic core
Arterial occlusion initiates the ischemic cascade ultimately leading to cellular death and tissue necrosis. It is now widely recognized that not all territorial tissue is lost following arterial occlusion, but ischemic penumbra surrounding the ischemic core consists of salvageable brain tissue, which gradually evolves into irreversibly damaged tissue. Collateral blood flow to the penumbral region is the key element setting the pace of the ischemic process and thus resulting in fast and slow infarction progressors. Several studies have identified that good collaterals on initial presentation are associated with large volumes of salvageable brain tissue and good functional outcomes in AIS patients treated with thrombectomy.,,
Due to these factors, reperfusion must be achieved as early as possible, especially in patients with poor collateral flow, to maximize penumbral salvage and minimize ischemic core. Unfortunately, even in developed countries, the time from symptom onset to eventual reperfusion frequently takes up to 4–5 h.,,, In addition, in the majority moderate- or low-income countries, large gaps remain between urban and rural emergency service systems, being particularly difficult for dispersed rural areas where there are limited health care resources, and long distance transport causes great delays in treatment.
Revascularization of the occluded vessel and restoration of cerebral blood flow is the most effective therapy to salvage penumbral brain tissue, and meaningful recanalization is the most powerful indicator of a good clinical outcome., Recombinant tissue plasminogen activator (rtPA) is the mainstay drug for reperfusion therapy. It can initiate local fibrinolysis, leading to artery recanalization and improvement in functional outcomes if given within 4.5 h of presentation.,, However, the current data indicates that only 30% of intracranial arterial occlusions can be recanalized by rtPA, and the ratio is much lower (approximately 10%) for large vessel occlusion.,
Recently, the superiority of EVT for AIS caused by proximal large vessel occlusion has been established, and a number of modern thrombectomy devices and techniques are currently available. Substantial recanalization following large-vessel occlusion can be achieved in up to 88% of patients immediately after thrombectomy procedures, significantly greater than traditional treatment.,,,,, However, there is still a large number of patients with a large-vessel occlusion that cannot achieve or maintain substantial recanalization, despite state-of-the-art approaches. Consequently, in these patients, salvageable brain tissue invariably progresses to irreversibly damaged tissue and infarction.
Although revascularization of occluded large vessels is of vital importance to AIS patients, studies have found that angiographic recanalization of proximal large vessels, even in patients who achieved modified Thrombolysis in Cerebral Infarction (mTICI) score of 2b or 3, does not necessarily lead to complete distal reperfusion.,, This phenomenon has been described as “no-reflow” or “incomplete microcirculatory reperfusion.” This incomplete reperfusion is seen secondary to underlying microcirculatory disorders caused by ischemic injuries, namely microvascular thrombosis, cerebral edema, and microemboli formation.,,
Additionally, studies have found that patients with TICI 2b reperfusion have a poorer outcome than those with complete (TICI 3) reperfusion, indicating that reperfusion is a more accurate predictor of final infarct volume and functional outcome than simple proximal vessel recanalization.,, Recent studies have proposed adding a new reperfusion grade of mTICI 2c (near complete perfusion except for slow flow in a few distal cortical vessels or presence of small distal cortical emboli). Studies have determined that mTICI 2c could further stratify subgroups of patients into mTICI 2b and mTICI2c/3 reperfusion, shifting the end goal of EVT.,
During thrombectomy procedures with a stent retriever or direct clot aspiration, clot disruption and fragmentation is inevitable. Clot debris may migrate downstream with antegrade blood flow and can cause distal embolization in previously affected or unaffected vascular territories, potentially blocking collateral flow to salvageable tissue., If thrombus fragments occlude large arterial branches, then remedial strategies such as further thrombectomy attempts or intra-arterial thrombolysis can be employed. However,in vitro studies show that the majority of clot fragments generated during thrombectomy are very small (<10 μm), occluding microvessels., Although not detectable on angiogram, these distal microemboli translate to enlargement of ischemic core and poor functional outcomes.,,
Generally, revascularization promptly restores blood flow to the ischemic brain tissue and reduces enlargement of the ischemic core. However, restoration of blood flow also causes secondary injury through oxidative damage, cell death, and aberrant immunoinflammatory responses,,, all of which can worsen the underlying ischemic injury. Consequently, reperfusion injury can result in brain edema, cell death, increased infarct volume, intracranial hemorrhage, headache, and seizure. Paradoxically, reperfusion in this way may aggravate neurological deficits and reduce its beneficial effects.,
| Multiphase Adjuvant Neuroprotection|| |
As mentioned previously, enlargement of the ischemic core, revascularization failure, incomplete reperfusion, distal embolization, and reperfusion injury substantially impact functional outcomes in AIS patients. Based on diverse and potentially nonoverlapping pathophysiologic mechanisms that are triggered before, during, and after thrombectomy, we propose the concept of “Multiphase Adjuvant Neuroprotection” to guide the search for adjunctive treatments aimed at minimizing deleterious ischemic injury. In the initial stages of ischemic stroke prior to thrombectomy, strategies should be used that enhance collaterals and block primary cell death mechanisms to prevent ischemic core enlargement. During thrombectomy, improving recanalization and maximizing reperfusion while reducing distal embolization is of primary importance. In the final phase, after reperfusion has been achieved, identifying targets within the cascades of secondary cell death mechanisms and inflammation can provide avenues to potentially ameliorate further reperfusion injury.
Based on previous studies investigating neuroprotection in AIS,,, certain neuroprotective strategies can attenuate the growth of the ischemic core and ameliorate reperfusion injury, although variable maneuvers are needed in the various stages of stroke management. Previous studies have also shown that multimodal revascularization approaches can improve the rate of recanalization and reperfusion and prevent or limit distal emboli through the use of one or more devices and techniques. The targets and approaches utilized during different phases of multiphase adjuvant neuroprotection are summarized and discussed in detail [Figure 1].
|Figure 1: Multiphase adjuvant neuroprotection. Before revascularization, strategies should be used to prevent the enlargement of the ischemic core and preserve more salvageable brain tissue for reperfusion therapy. During endovascular therapy, strategies should be used to improve recanalization while reducing distal emboli and maximizing microcirculatory reperfusion. After reperfusion has been achieved, strategies should be used to reduce reperfusion injuries|
Click here to view
Strategies for slowing the enlargement of the ischemic core should be used as early as possible, during the prehospital phase and throughout interhospital transfer, to maximize their ability to attenuate ischemic core growth. Ideally, they should meet the following requirements:
- Fast-acting: The ischemic cascade starts immediately after arterial occlusion, and the ischemic core progresses quickly in patients with poor collaterals. Therefore, ideal strategies should take effect as soon as possible to prevent enlargement of the ischemic core, especially for the fast progressors
- Simple and usable: These strategies need to be initiated in prehospital settings and often by nonphysicians. As such, strategies that require special storage methods or complex preparation may limit their use
- Safe and tolerable: Therapies employed in this phase must have a low risk profile, not only for AIS but also for hemorrhagic stroke and stroke mimics, given the difficulty distinguishing between these pathologies acutely
- Do no harm: Most importantly, these strategies should not interfere with the effects of subsequent therapies, such as intravenous thrombolysis and thrombectomy.
Generally, neuroprotective drugs act directly on neurons, and thus, their neuroprotective efficacy depend on the presence of collaterals in the penumbra. Therefore, neuroprotective agents are typically ineffective with insufficient collaterals. This may partially explain why few neuroprotective drugs have translated into the clinical setting from preclinical models with limited efficacy in improving functional outcomes in clinical trials. Fortunately, nonpharmacological approaches that meet the aforementioned requirements and have shown some success in preventing the enlargement of the ischemic core are available. Remote ischemic conditioning, a noninvasive and simple strategy, has been shown to be safe and feasible in AIS patients, reducing the risk of cerebral tissue infarction if applied during the prehospital phase., One ongoing trial investigating remote ischemic conditioning performed ahead of hospital in acute stroke patient is ongoing (clinicaltrials.gov NCT 03481777). In addition, another ongoing trial specially investigated remote ischemic conditioning in AIS patients treated with EVT (clinicaltrials.gov NCT03045055). Additionally, normobaric oxygen can slow the progression of cell death, extend the time window for revascularization therapy, and salvage ischemic brain tissue., Preliminary safety, feasibility, and efficacy of this strategy have been demonstrated in a recent clinical trial.
In clinical practice, many patients first arrive at primary hospitals that are not capable of thrombectomy or intravenous thrombolysis and are subsequently transferred to a comprehensive stroke center for reperfusion therapies. For these patients, the ischemic stroke and absence of intracranial hemorrhage is usually diagnosed by computed tomography in the initial hospital. Therefore, neuroprotective strategies, unsuitable for hemorrhagic stroke, can also be used. Induced hypertension with appropriate range (systolic pressure of 160 mmHg) can be used to assist in the maintenance of cerebral collaterals, which are of vital importance in supporting brain tissue in the penumbra. Furthermore, neuroprotective strategies not available in the prehospital phase due to special storage methods or complex preparation requirements may also be available in the primary hospital setting.
During endovascular therapy
Currently, stent retriever thrombectomy and direct clot aspiration are the two seminal thrombectomy techniques, and many modifications to these techniques have emerged. Novel approaches, devices, techniques, and strategies have been discussed in detail in other reviews.,,,, It should be note that achieving complete recanalization with the simplest techniques and the least manipulation should be the primary goal of EVT.,
Improving reperfusion and reducing distal embolization
As previously stated, ischemic injury, microvascular thrombosis, cerebral edema, and microemboli are the main causes of incomplete reperfusion. Ischemic injury causes cytotoxic edema, resulting in microcirculatory disturbances and microvascular thrombosis. Neuroprotective agents or other neuroprotective approaches that attenuate ischemic injury may be effective in preventing microcirculatory disturbances, enhancing complete reperfusion. Furthermore, distal emboli, most of which result from downstream migration of clot debris, also contribute to incomplete reperfusion, and efforts have been made to improve thrombectomy techniques to reduce this phenomenon. In addition, to identify microvascular hypoperfusion and its extent, perfusion imaging is also needed after successful revascularization on angiogram images.
Balloon guide catheters can be used to block antegrade blood flow during thrombus retrieval, significantly reducing distal emboli. Many thrombectomy techniques, with or without balloon guide catheters, use large-bore aspiration catheters that employ negative pressure to continually aspirate blood during thrombus retrieval, also reducing distal embolization., However, even using these techniques, distal emboli in the affected and previously unaffected vascular territory is still common.,, Therefore, technological innovations and development of novel devices and techniques to limit clot fragmentation and distal emboli are still needed.
If distal embolization does occur, appropriate therapeutic strategies are needed for remediation. As the majority of distal emboli are very small and cannot be detected by angiography, distal drug infusion may be an appropriate treatment. Studies have determined that tirofiban, a glycoprotein IIb/IIIa antagonist, is effective in preventing microvascular thrombosis and improving functional outcome in AIS, with no increase in intracerebral hemorrhage if administered at a low dose., Intravenous or intra-arterial administration of thrombolytic agents (such as rtPA and urokinase) has been reported as an effective remedial strategy for the treatment of distal emboli as well,, but safety and efficacy considerations necessitate further investigation.
In the past few decades, reperfusion injury has been extensively investigated with numerous neuroprotective strategies having been proposed. Despite promising results in preclinical models, few of them have translated to clinical benefit in human trials. Inappropriate selection and inclusion of patients with poor rates of meaningful recanalization may underlie the lack of clinical efficacy. Furthermore, most neuroprotective strategies generally target a single pathway in the complex ischemic cascade. With the substantial increase in AIS patients being treated with mechanical thrombectomy and higher rates of recanalization, several nonpharmacological approaches targeting multiple pathways of the ischemic cascade are now available. With the increased number of patients achieving recanalization, it is plausible that combining reperfusion therapies with adjunctive pharmacological and nonpharmacological approaches could have synergistic effects.
Numerous neuroprotective pharmacological approaches have been investigated, although few have shown clinical beneficial. NXY-059, a free radical-trapping agent, reduces infarct size and preserves neurologic function in animal models of AIS. Despite preclinical efficacy, results of large clinical trials showed that NXY-059 administered within 6 h after symptoms onset did not improve functional outcomes in AIS., Another agent, magnesium, exerts both neuroprotective, vasodilatory, and glioprotective effects. Magnesium is reliably neuroprotective in animal models of AIS, a good safety profile, widely available, inexpensive, and simple to administer. Unfortunately, a clinical trial with 1,700 subjects found that, while prehospital initiation of intravenous magnesium was safe and feasible, it did not improve clinical outcomes. Importantly, these clinical trials recruited patients who had not undergone endovascular therapies, achieving low rates of recanalization. The effect of NXY-059 and magnesium in patients with definitive revascularization remains uninvestigated.
Although neuroprotective drugs for clinical application are currently lacking, novel pharmacological approaches are emerging. For example, NA-1, a cell-permeant eicosapeptide, is a promising agent that inhibits the interactions of the synaptic scaffolding protein PSD95 with NMDA glutamate receptors. NA-1 has been found to reduce infarct size in both rat and primate model of AIS. Furthermore, clinical evaluation of NA-1 in patients undergoing endovascular aneurysm embolization found that it could reduce the incidence and size of iatrogenic infarct following treatment. Positive results have been seen in preclinical stroke models, including rodent and nonhuman primates, and two large clinical trials investigating NA-1 in AIS are ongoing. One trial, FRONTIER (Field Randomization of NA-1 Therapy in Early Responders trial, NCT02315443), is investigating the safety and efficacy of prehospital intravenous NA-1 in the field for AIS within 3 h of symptom onset. Another trial, ESCAPE-NA-1 (The Extension of Stroke Care by Adding neuroProtection to Endovascular treatment trial, NCT02930018), is evaluating the efficacy of NA-1 in AIS patients undergoing EVT.
In contrast to other patient populations, AIS patients treated with thrombectomy can receive neuroprotective agents delivered, not only through peripheral venous access, but also through arterial catheters that provide direct access to the ischemic tissue. This could easily be performed during EVT, increasing the drug concentration administered to the local cerebral tissue. Finally, intra-arterial selective cooling, a promising nonpharmacological treatment, can easily be performed shortly after thrombectomy to induce partial hypothermia in the ischemic area.,,, In previous pilot study, intra-arterial selective cooling has been performed in AIS undergoing EVT. Cold 0.9% sodium chloride (4°C) was infused to the ischemic territory before recanalization (10 ml/min for 5 min) through microcatheter and postrevascularization (30 ml/min for 10 min) through the guiding catheter. Currently, a phase II study is ongoing to investigate the efficacy of short-duration selective brain cooling in AIS treated with EVT (clinicaltrials.gov NCT 03163459).
| Distinct Neuroprotective Approaches in Different Phases of Care|| |
Prior to initiating neuroprotective strategies for AIS, caution should be taken as many molecular pathways in the ischemic cascade have biphasic natures. For example, overactivation of N-methyl-D-aspartate receptors is clearly detrimental in the early phase of stroke, but these same receptors may be required for recovery later in the process. Another example is matrix metalloproteinase, which damages the blood–brain barrier and causes edema, hemorrhage, and neuronal death in the early stage of stroke, but promotes neurovascular remodeling in the delayed stage. Unfortunately, it is not entirely clear when these molecular signals transition from injury to repair and what initiates or triggers these transitions. Considering the biphasic roles, neuroprotective strategies that target different molecular signals should be applied only in distinct phases of stroke management. Further elucidation of these pathways and biomolecular responses is of great significance for clinical trials, as they can guide the administration of neuroprotective strategies accurately and effectively. Given these concerns, it is advisable to use neuroprotective strategies that have proven efficacy in a certain phase of the stroke, to reduce the possibility of targeting molecular signals in a haphazard or counterproductive manner.
| Conclusion|| |
In an era where reperfusion is seen with increasing frequency, enlargement of the ischemic core, revascularization failure, incomplete reperfusion, distal embolization, and reperfusion injury represent potential factors that negatively impact outcome following AIS. Utilizing a concept of multiphase adjuvant neuroprotection, wherein different strategies are employed throughout the various phases of clinical care, provides a paradigm to minimize the final infarct size and improve functional outcome in AIS patients treated with thrombectomy by tailoring neuroprotective measures to all phases of stroke management. Many neuroprotective approaches still need to be tested, alongside development of new generations of reperfusion strategies. As the underlying mechanisms of these neuroprotective strategies are identified, their role in the distinct phases of ischemic stroke care may provide further avenues to improve patient outcomes in this debilitating disease.
Financial support and sponsorship
This point of view was supported by the National Key R&D Program of China (2016YFC1301502), Cheung Kong (Chang jiang) Scholars Program (T2014251), and Beijing Municipal Administration of Hospitals' Mission Plan (SML20150802).
Conflicts of interest
There are no conflicts of interest.
| References|| |
Leng T, Xiong ZG. Treatment for ischemic stroke: From thrombolysis to thrombectomy and remaining challenges. Brain Circ 2019;5:8-11.
] [Full text]
Shetty AK, Upadhya R, Madhu LN, Kodali M. Novel insights on systemic and brain aging, stroke, amyotrophic lateral sclerosis, and Alzheimer's disease. Aging Dis 2019;10:470-82.
National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N
Engl J Med 1995;333:1581-7.
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.
Goyal M, Menon BK, van Zwam WH, Dippel DW, Mitchell PJ, Demchuk AM, et al
. Endovascular thrombectomy after large-vessel ischaemic stroke: A meta-analysis of individual patient data from five randomised trials. Lancet 2016;387:1723-31.
Nogueira RG, Jadhav AP, Haussen DC, Bonafe A, Budzik RF, Bhuva P, et al
. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N
Engl J Med 2018;378:11-21.
Rai AT, Seldon AE, Boo S, Link PS, Domico JR, Tarabishy AR, et al
. A population-based incidence of acute large vessel occlusions and thrombectomy eligible patients indicates significant potential for growth of endovascular stroke therapy in the USA. J Neurointerv Surg 2017;9:722-6.
Rocha M, Jovin TG. Fast versus slow progressors of infarct growth in large vessel occlusion stroke: Clinical and research implications. Stroke 2017;48:2621-7.
Zhao W, Che R, Shang S, Wu C, Li C, Wu L, et al
. Low-dose tirofiban improves functional outcome in acute ischemic stroke patients treated with endovascular thrombectomy. Stroke 2017;48:3289-94.
Jovin TG, Chamorro A, Cobo E, de Miquel MA, Molina CA, Rovira A, et al
. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N
Engl J Med 2015;372:2296-306.
Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, et al
. Randomized assessment of rapid endovascular treatment of ischemic stroke. N
Engl J Med 2015;372:1019-30.
Campbell BC, Hill MD, Rubiera M, Menon BK, Demchuk A, Donnan GA, et al
. Safety and efficacy of solitaire stent thrombectomy: Individual patient data meta-analysis of randomized trials. Stroke 2016;47:798-806.
Boers AM, Jansen IG, Beenen LF, Devlin TG, San Roman L, Heo JH, et al
. Association of follow-up infarct volume with functional outcome in acute ischemic stroke: A pooled analysis of seven randomized trials. J Neurointerv Surg 2018;10:1137-42.
Xing C, Arai K, Lo EH, Hommel M. Pathophysiologic cascades in ischemic stroke. Int J Stroke 2012;7:378-85.
Astrup J, Siesjö BK, Symon L. Thresholds in cerebral ischemia – The ischemic penumbra. Stroke 1981;12:723-5.
Liebeskind DS. Collaterals in acute stroke: Beyond the clot. Neuroimaging Clin N
Am 2005;15:553-73, x.
Miteff F, Levi CR, Bateman GA, Spratt N, McElduff P, Parsons MW. The independent predictive utility of computed tomography angiographic collateral status in acute ischaemic stroke. Brain 2009;132:2231-8.
Liebeskind DS, Jahan R, Nogueira RG, Zaidat OO, Saver JL, SWIFT Investigators. Impact of collaterals on successful revascularization in Solitaire FR with the intention for thrombectomy. Stroke 2014;45:2036-40.
Menon BK, Qazi E, Nambiar V, Foster LD, Yeatts SD, Liebeskind D, et al
. Differential effect of baseline computed tomographic angiography collaterals on clinical outcome in patients enrolled in the interventional management of stroke III trial. Stroke 2015;46:1239-44.
Saver JL, Goyal M, Bonafe A, Diener HC, Levy EI, Pereira VM, et al
. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N
Engl J Med 2015;372:2285-95.
Liebeskind DS, Bracard S, Guillemin F, Jahan R, Jovin TG, Majoie CB, et al
. eTICI reperfusion: Defining success in endovascular stroke therapy. J Neurointerv Surg 2019;11:433-8.
Lees KR, Emberson J, Blackwell L, Bluhmki E, Davis SM, Donnan GA, et al
. Effects of alteplase for acute stroke on the distribution of functional outcomes: A pooled analysis of 9 trials. Stroke 2016;47:2373-9.
Prabhakaran S, Ruff I, Bernstein RA. Acute stroke intervention: A systematic review. JAMA 2015;313:1451-62.
Lees KR, Bluhmki E, von Kummer R, Brott TG, Toni D, Grotta JC, et al
. Time to treatment with intravenous alteplase and outcome in stroke: An updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 2010;375:1695-703.
Menon BK, Al-Ajlan FS, Najm M, Puig J, Castellanos M, Dowlatshahi D, et al
. Association of clinical, imaging, and thrombus characteristics with recanalization of visible intracranial occlusion in patients with acute ischemic stroke. JAMA 2018;320:1017-26.
Tsivgoulis G, Katsanos AH, Schellinger PD, Köhrmann M, Varelas P, Magoufis G, et al
. Successful reperfusion with intravenous thrombolysis preceding mechanical thrombectomy in large-vessel occlusions. Stroke 2018;49:232-5.
Campbell BC, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi N, et al
. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N
Engl J Med 2015;372:1009-18.
Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ, et al
. A randomized trial of intraarterial treatment for acute ischemic stroke. N
Engl J Med 2015;372:11-20.
Soares BP, Tong E, Hom J, Cheng SC, Bredno J, Boussel L, et al
. Reperfusion is a more accurate predictor of follow-up infarct volume than recanalization: A proof of concept using CT in acute ischemic stroke patients. Stroke 2010;41:e34-40.
Soares BP, Chien JD, Wintermark M. MR and CT monitoring of recanalization, reperfusion, and penumbra salvage: Everything that recanalizes does not necessarily reperfuse! Stroke 2009;40:S24-7.
Goyal M, Fargen KM, Turk AS, Mocco J, Liebeskind DS, Frei D, et al
. 2C or not 2C: Defining an improved revascularization grading scale and the need for standardization of angiography outcomes in stroke trials. J Neurointerv Surg 2014;6:83-6.
Dalkara T, Arsava EM. Can restoring incomplete microcirculatory reperfusion improve stroke outcome after thrombolysis? J Cereb Blood Flow Metab 2012;32:2091-9.
del Zoppo GJ, Mabuchi T. Cerebral microvessel responses to focal ischemia. J Cereb Blood Flow Metab 2003;23:879-94.
Babikian VL, Caplan LR. Brain embolism is a dynamic process with variable characteristics. Neurology 2000;54:797-801.
Arsava EM, Arat A, Topcuoglu MA, Peker A, Yemisci M, Dalkara T. Angiographic microcirculatory obstructions distal to occlusion signify poor outcome after endovascular treatment for acute ischemic stroke. Transl Stroke Res 2018;9:44-50.
Kleine JF, Wunderlich S, Zimmer C, Kaesmacher J. Time to redefine success? TICI 3 versus TICI 2b recanalization in middle cerebral artery occlusion treated with thrombectomy. J Neurointerv Surg 2017;9:117-21.
Dargazanli C, Consoli A, Barral M, Labreuche J, Redjem H, Ciccio G, et al
. Impact of modified TICI 3 versus modified TICI 2b reperfusion score to predict good outcome following endovascular therapy. AJNR Am J Neuroradiol 2017;38:90-6.
Almekhlafi MA, Mishra S, Desai JA, Nambiar V, Volny O, Goel A, et al
. Not all “successful” angiographic reperfusion patients are an equal validation of a modified TICI scoring system. Interv Neuroradiol 2014;20:21-7.
Dargazanli C, Fahed R, Blanc R, Gory B, Labreuche J, Duhamel A, et al
. Modified thrombolysis in cerebral infarction 2C/thrombolysis in cerebral infarction 3 reperfusion should be the aim of mechanical thrombectomy: Insights from the ASTER trial (contact aspiration versus stent retriever for successful revascularization). Stroke 2018;49:1189-96.
Kaesmacher J, Maegerlein C, Zibold F, Wunderlich S, Zimmer C, Friedrich B. Improving mTICI2b reperfusion to mTICI2c/3 reperfusions: A retrospective observational study assessing technical feasibility, safety and clinical efficacy. Eur Radiol 2018;28:274-82.
Chueh JY, Puri AS, Wakhloo AK, Gounis MJ. Risk of distal embolization with stent retriever thrombectomy and ADAPT. J Neurointerv Surg 2016;8:197-202.
Gascou G, Lobotesis K, Machi P, Maldonado I, Vendrell JF, Riquelme C, et al
. Stent retrievers in acute ischemic stroke: Complications and failures during the perioperative period. AJNR Am J Neuroradiol 2014;35:734-40.
Chalumeau V, Blanc R, Redjem H, Ciccio G, Smajda S, Desilles JP, et al
. Anterior cerebral artery embolism during thrombectomy increases disability and mortality. J Neurointerv Surg 2018;10:1057-62.
Chueh JY, Kühn AL, Puri AS, Wilson SD, Wakhloo AK, Gounis MJ. Reduction in distal emboli with proximal flow control during mechanical thrombectomy: A quantitativein vitro
study. Stroke 2013;44:1396-401.
Chueh JY, Wakhloo AK, Gounis MJ. Effectiveness of mechanical endovascular thrombectomy in a model system of cerebrovascular occlusion. AJNR Am J Neuroradiol 2012;33:1998-2003.
Mazur MD, Kilburg C, Park MS, Taussky P. Patterns and clinical impact of angiographically visible distal emboli during thrombectomy with solitaire for acute ischemic stroke. Neurosurgery 2016;78:242-50.
Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N
Engl J Med 2007;357:1121-35.
Eltzschig HK, Eckle T. Ischemia and reperfusion – From mechanism to translation. Nat Med 2011;17:1391-401.
Anzell AR, Maizy R, Przyklenk K, Sanderson TH. Mitochondrial quality control and disease: Insights into ischemia-reperfusion injury. Mol Neurobiol 2018;55:2547-64.
Pan J, Konstas AA, Bateman B, Ortolano GA, Pile-Spellman J. Reperfusion injury following cerebral ischemia: Pathophysiology, MR imaging, and potential therapies. Neuroradiology 2007;49:93-102.
Dornbos D 3rd
, Ding Y. Reperfusion injury in the age of revascularization. Brain Circ 2018;4:40-2.
Moretti A, Ferrari F, Villa RF. Neuroprotection for ischaemic stroke: Current status and challenges. Pharmacol Ther 2015;146:23-34.
Tymianski M. Novel approaches to neuroprotection trials in acute ischemic stroke. Stroke 2013;44:2942-50.
Savitz SI, Baron JC, Yenari MA, Sanossian N, Fisher M. Reconsidering neuroprotection in the reperfusion era. Stroke 2017;48:3413-9.
Ghobrial GM, Chalouhi N, Rivers L, Witte S, Davanzo J, Dalyai R, et al
. Multimodal endovascular management of acute ischemic stroke in patients over 75 years old is safe and effective. J Neurointerv Surg 2013;5 Suppl 1:i33-7.
O'Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW. 1,026 experimental treatments in acute stroke. Ann Neurol 2006;59:467-77.
Hougaard KD, Hjort N, Zeidler D, Sørensen L, Nørgaard A, Hansen TM, et al
. Remote ischemic perconditioning as an adjunct therapy to thrombolysis in patients with acute ischemic stroke: A randomized trial. Stroke 2014;45:159-67.
Zhao W, Che R, Li S, Ren C, Li C, Wu C, et al
. Remote ischemic conditioning for acute stroke patients treated with thrombectomy. Ann Clin Transl Neurol 2018;5:850-6.
Singhal AB, Dijkhuizen RM, Rosen BR, Lo EH. Normobaric hyperoxia reduces MRI diffusion abnormalities and infarct size in experimental stroke. Neurology 2002;58:945-52.
Ding J, Zhou D, Sui M, Meng R, Chandra A, Han J, et al
. The effect of normobaric oxygen in patients with acute stroke: A systematic review and meta-analysis. Neurol Res 2018;40:433-44.
Padma MV, Bhasin A, Bhatia R, Garg A, Singh MB, Tripathi M, et al
. Normobaric oxygen therapy in acute ischemic stroke: A pilot study in Indian patients. Ann Indian Acad Neurol 2010;13:284-8.
] [Full text]
Powers WJ. Acute hypertension after stroke: The scientific basis for treatment decisions. Neurology 1993;43:461-7.
Kim BM. Causes and solutions of endovascular treatment failure. J Stroke 2017;19:131-42.
Kang DH, Kim YW, Hwang YH, Park J, Hwang JH, Kim YS. Switching strategy for mechanical thrombectomy of acute large vessel occlusion in the anterior circulation. Stroke 2013;44:3577-9.
Kang DH, Park J. Endovascular stroke therapy focused on stent retriever thrombectomy and direct clot aspiration: Historical review and modern application. J Korean Neurosurg Soc 2017;60:335-47.
Zhao W, Shang S, Li C, Wu L, Wu C, Chen J, et al
. Long-term outcomes of acute ischemic stroke patients treated with endovascular thrombectomy: A real-world experience. J Neurol Sci 2018;390:77-83.
Zaidat OO, Castonguay AC, Linfante I, Gupta R, Martin CO, Holloway WE, et al
. First pass effect: A new measure for stroke thrombectomy devices. Stroke 2018;49:660-6.
Arai D, Ishii A, Chihara H, Ikeda H, Miyamoto S. Histological examination of vascular damage caused by stent retriever thrombectomy devices. J Neurointerv Surg 2016;8:992-5.
Linfante I, Cipolla MJ. Improving reperfusion therapies in the era of mechanical thrombectomy. Transl Stroke Res 2016;7:294-302.
Mueller-Kronast NH, Zaidat OO, Froehler MT, Jahan R, Aziz-Sultan MA, Klucznik RP, et al
. Systematic evaluation of patients treated with neurothrombectomy devices for acute ischemic stroke: Primary results of the STRATIS registry. Stroke 2017;48:2760-8.
Humphries W, Hoit D, Doss VT, Elijovich L, Frei D, Loy D, et al
. Distal aspiration with retrievable stent assisted thrombectomy for the treatment of acute ischemic stroke. J Neurointerv Surg 2015;7:90-4.
Turk AS, Frei D, Fiorella D, Mocco J, Baxter B, Siddiqui A, et al
. ADAPT FAST study: A direct aspiration first pass technique for acute stroke thrombectomy. J Neurointerv Surg 2014;6:260-4.
Chartrain AG, Awad AJ, Mascitelli JR, Shoirah H, Oxley TJ, Feng R, et al
. Novel and emerging technologies for endovascular thrombectomy. Neurosurg Focus 2017;42:E12.
Choudhri TF, Hoh BL, Zerwes HG, Prestigiacomo CJ, Kim SC, Connolly ES Jr, et al
. Reduced microvascular thrombosis and improved outcome in acute murine stroke by inhibiting GP IIb/IIIa receptor-mediated platelet aggregation. J Clin Invest 1998;102:1301-10.
Nakano S, Iseda T, Yoneyama T, Ikeda T, Wakisaka S. Intravenous low-dose native tissue plasminogen activator for distal embolism in the middle cerebral artery divisions or branches: A pilot study. Neurosurgery 2000;46:853-8.
Fisher M. The ischemic penumbra: Identification, evolution and treatment concepts. Cerebrovasc Dis 2004;17 Suppl 1:1-6.
Chen F, Qi Z, Luo Y, Hinchliffe T, Ding G, Xia Y, et al
. Non-pharmaceutical therapies for stroke: Mechanisms and clinical implications. Prog Neurobiol 2014;115:246-69.
Stroke Therapy Academic Industry Roundtable (STAIR). Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 1999;30:2752-8.
Diener HC, Lees KR, Lyden P, Grotta J, Davalos A, Davis SM, et al
. NXY-059 for the treatment of acute stroke: Pooled analysis of the SAINT I and II Trials. Stroke 2008;39:1751-8.
Shuaib A, Lees KR, Lyden P, Grotta J, Davalos A, Davis SM, et al
. NXY-059 for the treatment of acute ischemic stroke. N
Engl J Med 2007;357:562-71.
Muir KW. Magnesium for neuroprotection in ischaemic stroke: Rationale for use and evidence of effectiveness. CNS Drugs 2001;15:921-30.
Saver JL, Starkman S, Eckstein M, Stratton SJ, Pratt FD, Hamilton S, et al
. Prehospital use of magnesium sulfate as neuroprotection in acute stroke. N
Engl J Med 2015;372:528-36.
Aarts M, Liu Y, Liu L, Besshoh S, Arundine M, Gurd JW, et al
. Treatment of ischemic brain damage by perturbing NMDA receptor- PSD-95 protein interactions. Science 2002;298:846-50.
Sun HS, Doucette TA, Liu Y, Fang Y, Teves L, Aarts M, et al
. Effectiveness of PSD95 inhibitors in permanent and transient focal ischemia in the rat. Stroke 2008;39:2544-53.
Hill MD, Martin RH, Mikulis D, Wong JH, Silver FL, Terbrugge KG, et al
. Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): A phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol 2012;11:942-50.
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.
Han Y, Rajah GB, Hussain M, Geng X. Clinical potential of pre-reperfusion hypothermia in ischemic injury. Neurol Res 2019;41:697-703.
Mattingly TK, Lownie SP. Cold blood perfusion for selective hypothermia in acute ischemic stroke. Brain Circ 2019;5:187-94.
] [Full text]
Zhang Z, Zhang L, Ding Y, Han Z, Ji X. Effects of therapeutic hypothermia combined with other neuroprotective strategies on ischemic stroke: Review of evidence. Aging Dis 2018;9:507-22.
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.
Young D, Lawlor PA, Leone P, Dragunow M, During MJ. Environmental enrichment inhibits spontaneous apoptosis, prevents seizures and is neuroprotective. Nat Med 1999;5:448-53.
Cunningham LA, Wetzel M, Rosenberg GA. Multiple roles for MMPs and TIMPs in cerebral ischemia. Glia 2005;50:329-39.
Lo EH. A new penumbra: Transitioning from injury into repair after stroke. Nat Med 2008;14:497-500.
|This article has been cited by|
||Elevated pulsatility index is associated with poor functional outcome in stroke patients treated with thrombectomy: A retrospective cohort study
| ||Wenbo Zhao, Ran Liu, Wantong Yu, Longfei Wu, Chuanjie Wu, Chuanhui Li, Sijie Li, Jian Chen, Haiqing Song, Yang Hua, Qingfeng Ma, Xunming Ji |
| ||CNS Neuroscience & Therapeutics. 2022; |
|[Pubmed] | [DOI]|
||Systematic Understanding of Mechanism of Danggui Shaoyao San against Ischemic Stroke Using a Network Pharmacology Approach
| ||Sijie Li, Yong Yang, Wei Zhang, Haiyan Li, Wantong Yu, Chen Gao, Jiali Xu, Wenbo Zhao, Changhong Ren, Feng Zhang |
| ||Evidence-Based Complementary and Alternative Medicine. 2022; 2022: 1 |
|[Pubmed] | [DOI]|
||Association between systolic blood pressure parameters and unexplained early neurological deterioration (UnND) in acute ischemic stroke patients treated with mechanical thrombectomy
| ||Aleksandras Vilionskis, Virginija Gaigalaite, Lukas Salasevicius, Dalius Jatuzis |
| ||Therapeutic Advances in Neurological Disorders. 2022; 15: 1756286422 |
|[Pubmed] | [DOI]|
||A Dynamic Nomogram to Predict the 3-Month Unfavorable Outcome of Patients with Acute Ischemic Stroke
| ||Cheng Zhang, Wenli Zhang, Ying Huang, Jianxiang Qiu, Zhi-Xin Huang |
| ||Risk Management and Healthcare Policy. 2022; Volume 15: 923 |
|[Pubmed] | [DOI]|
||Detection, Diagnosis and Treatment of Acute Ischemic Stroke: Current and Future Perspectives
| ||Smita Patil, Rosanna Rossi, Duaa Jabrah, Karen Doyle |
| ||Frontiers in Medical Technology. 2022; 4 |
|[Pubmed] | [DOI]|
||Timely and Appropriate Administration of Inhaled Argon Provides Better Outcomes for tMCAO Mice: A Controlled, Randomized, and Double-Blind Animal Study
| ||Juan He, Ke Xue, Jiayi Liu, Jin-hua Gu, Bin Peng, Lihua Xu, Guohua Wang, Zhenglin Jiang, Xia Li, Yunfeng Zhang |
| ||Neurocritical Care. 2022; |
|[Pubmed] | [DOI]|
||High Level of the Fibrin Degradation Products at Admission Predicts Parenchymal Hematoma and Unfavorable Outcome of Ischemic Stroke After Intravenous Thrombolysis
| ||Chang Liu, Yun Zhang, Lingchuan Niu, Jiani Li |
| ||Frontiers in Neurology. 2022; 12 |
|[Pubmed] | [DOI]|
||Updates on Selective Brain Hypothermia: Studies From Bench Work to Clinical Trials
| ||Xiaoyu Wang, Alexandra Wehbe, Shawn Kaura, Naveed Chaudhry, Xiaokun Geng, Yuchuan Ding |
| ||Frontiers in Neurology. 2022; 13 |
|[Pubmed] | [DOI]|
||Preclinical evidence of remote ischemic conditioning in ischemic stroke, a metanalysis update
| ||Coral Torres-Querol, Manuel Quintana-Luque, Gloria Arque, Francisco Purroy |
| ||Scientific Reports. 2021; 11(1) |
|[Pubmed] | [DOI]|
||Enhanced Cerebral Microbleeds by Long-Term Air Pollution Exposure in Spontaneously Hypertensive Rats
| ||Lipeng Cai,Jianjie Yang,Eric Cosky,Ruiqiang Xin,Xiaokun Geng,Yuchuan Ding |
| ||Neurological Research. 2021; : 1 |
|[Pubmed] | [DOI]|
||Rapid Intervention of Chlorpromazine and Promethazine for Hibernation-Like Effect in Stroke: Rationale, Design, and Protocol for a Prospective Randomized Controlled Trial
| ||Shuyu Lv,Wenbo Zhao,Gary B. Rajah,Chaitu Dandu,Lipeng Cai,Zhe Cheng,Honglian Duan,Qingqing Dai,Xiaokun Geng,Yuchuan Ding |
| ||Frontiers in Neurology. 2021; 12 |
|[Pubmed] | [DOI]|
||Remote Ischemic Conditioning With Exercise (RICE)—Rehabilitative Strategy in Patients With Acute Ischemic Stroke: Rationale, Design, and Protocol for a Randomized Controlled Study
| ||Zhenzhen Han,Wenbo Zhao,Hangil Lee,Melissa Wills,Yanna Tong,Zhe Cheng,Qingqing Dai,Xiaohua Li,Qingzhu Wang,Xiaokun Geng,Xunming Ji,Yuchuan Ding |
| ||Frontiers in Neurology. 2021; 12 |
|[Pubmed] | [DOI]|
||Rapid Intravenous Glyceryl Trinitrate in Ischemic Damage (RIGID) After Stroke: Rationale, Design and Protocol for a Prospective Randomized Controlled Trial
| ||Lipeng Cai,Gary Rajah,Honglian Duan,Jie Gao,Zhe Cheng,Ruiqiang Xin,Shangqian Jiang,Peter Palmer,Xiaokun Geng,Yuchuan Ding |
| ||Frontiers in Neurology. 2021; 12 |
|[Pubmed] | [DOI]|
||The Role of Edema in Subacute Lesion Progression After Treatment of Acute Ischemic Stroke
| ||Praneeta Konduri,Katinka van Kranendonk,Anna Boers,Kilian Treurniet,Olvert Berkhemer,Albert J. Yoo,Wim van Zwam,Robert van Oostenbrugge,Aad van der Lugt,Diederik Dippel,Yvo Roos,Joost Bot,Charles Majoie,Henk Marquering |
| ||Frontiers in Neurology. 2021; 12 |
|[Pubmed] | [DOI]|
||Sertraline for Functional Recovery After Acute Ischemic Stroke: A Prospective Observational Study
| ||Isabella Stuckart,Timo Siepmann,Christian Hartmann,Lars-Peder Pallesen,Annahita Sedghi,Jessica Barlinn,Heinz Reichmann,Volker Puetz,Kristian Barlinn |
| ||Frontiers in Neurology. 2021; 12 |
|[Pubmed] | [DOI]|
||Treatment of intracerebral hemorrhage: Current approaches and future directions
| ||Wenbo Zhao,Chuanjie Wu,Christopher Stone,Yuchuan Ding,Xunming Ji |
| ||Journal of the Neurological Sciences. 2020; : 117020 |
|[Pubmed] | [DOI]|
||Remote Ischemic Perconditioning for the Treatment of Acute Ischemic Stroke
| ||Wenbo Zhao,Changhong Ren,Xunming Ji |
| ||JAMA Neurology. 2020; |
|[Pubmed] | [DOI]|