Ischemic Stroke Tissue-Window in the New Era of Endovascular Treatment
2015; Lippincott Williams & Wilkins; Volume: 46; Issue: 8 Linguagem: Inglês
10.1161/strokeaha.115.009688
ISSN1524-4628
AutoresMichael D. Hill, Mayank Goyal, Andrew M. Demchuk, Marc Fisher,
Tópico(s)Cerebrovascular and Carotid Artery Diseases
ResumoHomeStrokeVol. 46, No. 8Ischemic Stroke Tissue-Window in the New Era of Endovascular Treatment Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessResearch ArticlePDF/EPUBIschemic Stroke Tissue-Window in the New Era of Endovascular Treatment Michael D. Hill, MD, MSc, Mayank Goyal, MD, Andrew M. Demchuk, MD and Marc Fisher, MD, PhD Michael D. HillMichael D. Hill From the Calgary Stroke Program, Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada. , Mayank GoyalMayank Goyal From the Calgary Stroke Program, Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada. , Andrew M. DemchukAndrew M. Demchuk From the Calgary Stroke Program, Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada. and Marc FisherMarc Fisher From the Calgary Stroke Program, Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada. Originally published25 Jun 2015https://doi.org/10.1161/STROKEAHA.115.009688Stroke. 2015;46:2332–2334Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2015: Previous Version 1 Ischemic stroke is a dynamic process of infarct expansion that varies as a function of time, residual blood flow, and other factors. Time can be measured easily but is an imprecise surrogate marker for brain physiology after stroke onset. After sudden intracranial artery occlusion, progression to brain infarction occurs quickly and on average, reperfusion therapies are not effective after several hours.1–4 However, there is enough variance in the rate of infarct development that experienced stroke physicians can identify individual cases using brain imaging where reperfusion will be useful in later time windows after stroke onset. This imaging selective approach has proven effective in recent randomized controlled trials.5–7 Furthermore, the opposite situation also occurs, where the infarction is completed in a short time after stroke onset and reperfusion is futile despite early presentation to medical attention and rapid treatment. The use of time as a surrogate marker for brain physiology has historical precedent with a similar approach having been used in cardiology and in the trials of intravenous thrombolysis for stroke. Time's advantage is that it is easily and definitively measureable resulting in relative ease of widespread use for guidelines and performance measurement.Brain imaging has advanced and is the most readily available and valuable biomarker for stroke. We do not have additional tools akin to those available to our colleagues in Cardiology. The brain equivalents of the ECG and serum troponin levels have yet to be discovered. However, brain imaging in acute ischemic stroke has many advantages over serum markers because primary intracerebral hemorrhage can be readily identified and an estimation of the extent of the ischemic core and penumbra provided. Because the brain is immobile in real time, detailed noninvasive imaging of the brain parenchyma, neurovascular anatomy, and perfusion is possible and relatively easy to obtain.The recent endovascular treatment trials provide proof of efficacy of reperfusion.5,8–11 The principle of fast reperfusion is now firmly established. In each of these trials, eligibility criteria were deliberate and specific. This therapy only applies to an imaging-defined subset of patients with ischemic stroke; neurovascular imaging was the key physiological marker in each of these trials. In 3 of the 4 trials, a small ischemic core as identified by the Alberta Stroke Program Early CT Score (ASPECTS) on plain computed tomography (CT) or CT perfusion was required for inclusion after CT angiography (CTA) was used to demonstrate the presence of a large vessel occlusion amenable to endovascular therapy. In the Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trial, multiphase CTA was also used to evaluate the extent of collateral flow and only patients with good or excellent collaterals were included. In each case, the key time point is at imaging because for both medical and endovascular treatments, the decisions about treatment take place immediately after neurovascular imaging.We propose a new conception of interval times in stroke treatment with imaging at the center.The full treatment time window for stroke is defined by the stroke onset to successful reperfusion time, and not by an arbitrary 4.5-hour or 6-hour or even 12-hour time window after onset. We recommend dividing this time window into 2 epochs with imaging time as the dividing instrument. The first epoch is the stroke-onset-to-imaging time. Imaging time is defined as the time of the first slice of the noncontrast CT scan, or less commonly if magnetic resonance is used, the time of first slice of the localizer image (Figure). The stroke-onset-to-imaging time defines the probability of imaging-defined eligibility for endovascular or reperfusion therapies. The second epoch is the imaging-to-reperfusion time. Reperfusion time is defined as the time from the beginning of imaging to the first evidence of reflow into the affected vascular territory, with the presumption that good final reperfusion (Thrombolysis in Cerebral Ischemia 2b/3) will follow (Figure). The imaging-to-reperfusion time epoch only applies to eligible patients and will define the probability of a good outcome among treated patients who have evidence of an ischemic core that is not too large. The probability of successful treatment at any given time in each epoch will be modified by patient clinical/laboratory characteristics, imaging results, and reperfusion success.Download figureDownload PowerPointFigure. Interval times in acute ischemic stroke. Epoch 1 represents time from stroke onset to first imaging. As time elapses, the proportion of treatment-eligible patients will decline because irreversible brain infarction will occur. The actual shape of the line remains to be determined. Epoch 2 represents imaging to reperfusion time. Similarly, as time elapses, the proportion of patients who do well will decline asymptotically to zero. The shape of this relationship is better known and is relatively linear.3 We note that the shape of the curve in both Epoch 1 and Epoch 2 are likely to show high interindividual variance. This has important implications because if the initial slope in Epoch 1 for a specific group of patients is relatively shallow, this would identify a group that could be transported over longer distances and remain eligible for endovascular treatment. Research is strongly encouraged to define and better understand the shape of the curve in both time epochs.Conceptualizing the problem of acute ischemic stroke treatment in this manner is helpful because it immediately points toward solutions. From a population perspective, getting the right patient to the right hospital with the right team faster will result in a greater number of patients with a favorable imaging profile who are therefore eligible for treatment. Regional decisions to redefine the prehospital phase of triaging major ischemic stroke to the correct center will be facilitated by taking this perspective. The denominator fallacy, inherent in hospital- or center-based report cards on treatment success, is well explained epidemiologically by taking this perspective.12 By including the door-to-imaging time in this epoch, the solution of taking patients directly to CT by the paramedics and bypassing the Emergency room becomes self-evident. Similarly, the newer and more aggressive approach to early imaging is the availability of an ambulance equipped with a CT scanner, but this approach is currently only occurring in a few selected locales and will likely remain limited.13 The principle of merging the early in-hospital and prehospital phases of care into one that ends with the imaging time means rethinking the roles of healthcare providers and workflow. Finally, we can begin to consider patients with unwitnessed and therefore unknown onset or stroke-on-awakening as eligible for therapy, not based on their conservatively presumed onset time defined by the last time known well, but instead by the tissue-window defined by their brain imaging. Despite the potential of this approach, effective ischemic stroke treatment for the population is going to require the shortest possible onset-to-reperfusion time.Among imaging-defined patients eligible for treatment, a focus on shortening imaging-to-reperfusion time would increase the likelihood of good outcomes in these patients. Optimization strategies have been published.14 We recommend using the first slice of the imaging study as the starting point, because in doing so we encourage the use of fast imaging paradigms that provide the minimum discriminatory information necessary for decision-making. We encourage the development of parallel thinking in angiography suite processing and patient management and in the small proportion who need it, anesthesia management focusing on minimizing delays to reperfusion.Finally, we would like to emphasize that the key reason to split the stroke onset to reperfusion time into 2 epochs in this manner is that the clinical decision-making point is immediately after imaging, exactly because imaging is a useful biomarker in ischemic stroke as was documented in the recent endovascular trials. Imaging is the brain physiology snap shot in time that we can use to define eligibility for therapy. Time will always remain a reasonable surrogate for the pathophysiology because empirically, patients with acute ischemic stroke are statistically likely to have favorable imaging profiles at early time points and they will also do better if reperfusion is faster. As time elapses the proportion of eligible patients asymptotically approaches zero, but there will likely be subsets of patients that can be treated in late time windows extended out to 24 hours or longer. Imaging defines the tissue window by providing an in vivo assessment of the extent of irreversible ischemic tissue injury.Innovation to increase the proportion of eligibility patients could be defined by a surrogate outcome of imaging eligibility, meaning that the volume of penumbra could be used as outcome for early phase trials. Novel therapeutic agents—neuroprotectants—to freeze the core could be assessed for preliminary efficacy by imaging the penumbra.15,16 A successful agent would result in a smaller core at all times from onset to reperfusion, and theoretically minimize damage and aid recovery. Such an approach would be particularly relevant for patient who will have long transport times from their communities or from outlying hospitals to the tertiary center. Assessing these compounds or strategies using imaging would be natural evolution of this recognition of stroke imaging as the key determinant of eligibility for treatment.An immediate challenge for the stroke and imaging community is to work out how to draw the line on what imaging eligibility means. Much of this debate can be informed by the recent randomized trials. It is clear that we can select patients with high specificity for successful treatment using multimodal imaging. However, given the large effect size observed in recent trials, we may have been overly specific. We have to determine the best balance of sensitivity and specificity, whereas simultaneously maximizing speed. Assessment of the intracranial collaterals is similar to assessment of the perfusion abnormality. There is high concordance between the degree of the perfusion deficit and the status of collaterals on CTA.17 Thus, although some recent trials used CTA only to assess collaterals and others used CTP to assess for a penumbral pattern, fundamentally both techniques are measuring the underlying blood flow. A focus on the principles of blocked artery and adequate collaterals/penumbral tissue, knowing that each of these 3 are highly inter-related, will likely lead to the right imaging schema for determining treatment eligibility in the shortest amount of time.We can and should begin to move away from rigid decision-making based on time windows. In doing so, we must not dismiss the critically important clinical information that is obtained and observed in the onset-to-imaging epoch. This must be incorporated into the clinical decision-making paradigm that culminates with imaging interpretation. The prehospital arena is open for ideas on how to improve onset to imaging (at the mothership hospital capable of endovascular treatment) times and in hospital our stroke and neurointervention teams must move as one to improve imaging to reperfusion times. A new era of acute ischemic stroke therapy is dawning and to maximally benefit as many patients as possible time from onset-to-imaging and imaging-to-reperfusion must be as used as efficiently as possible.DisclosuresDr Hill, Dr Goyal, and Dr Demchuk were coprincipal investigators of the ESCAPE trial. The ESCAPE was sponsored in part by a grant to the University of Calgary from Covidien/Medtronic. Dr Fischer is the current editor of Stroke. Dr Demchuk has received honouraria from Medtronic. Dr Hill has an ownership position (stock) in Calgary Scientific Inc, an imaging software company.FootnotesThe opinions expressed in the article are not necessarily those of the editors or of the American Heart Association.Guest Editor for this article was Ralph L. Sacco, MD.Current address for M.D.H.: Departments of Clinical Neurosciences, Medicine, Radiology and Community Health Sciences, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.Current address for M.G.: Departments of Radiology and Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.Current address for A.M.D.: Departments of Clinical Neurosciences and Radiology, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.Current address for M.F.: Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA.Correspondence to Michael D. Hill, MD, MSc, Calgary Stroke Program, Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Foothills Hospital, Rm 1242A, 1403 29th St NW, Calgary, Alberta T2N 2T9, Canada. E-mail [email protected]References1. Emberson J, Lees KR, Lyden P, Blackwell L, Albers G, Bluhmki E, et al; Stroke Thrombolysis Trialists' Collaborative Group. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials.Lancet. 2014; 384:1929–1935. doi: 10.1016/S0140-6736(14)60584-5.CrossrefMedlineGoogle Scholar2. Khatri P, Abruzzo T, Yeatts SD, Nichols C, Broderick JP, Tomsick TA; IMS I and II Investigators. Good clinical outcome after ischemic stroke with successful revascularization is time-dependent.Neurology. 2009; 73:1066–1072. doi: 10.1212/WNL.0b013e3181b9c847.CrossrefMedlineGoogle Scholar3. 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August 2015Vol 46, Issue 8 Advertisement Article InformationMetrics © 2015 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.115.009688PMID: 26111893 Manuscript receivedApril 7, 2015Manuscript acceptedMay 29, 2015Originally publishedJune 25, 2015Manuscript revisedApril 7, 2015 Keywordsstrokebrain infarctionreperfusionthrombectomyneuroimagingPDF download Advertisement SubjectsAngiographyComputerized Tomography (CT)Percutaneous Coronary InterventionTreatment
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