Peter Panagos

Review, Historical Context, and Clarifications of the NINDS rt-PA Stroke Trials Exclusion Criteria Part 1: Rapidly Improving Stroke Symptoms

Background and Purpose— Since Food and Drug Administration approval of intravenous tissue-type plasminogen activator (tPA) for treatment of acute ischemic stroke in 1996, it has become clear that several criteria used for exclusion from therapy were not based on actual data or operationally defined for use in clinical practice. All eligibility criteria from the National Institute of Neurological Disorders and Stroke (NINDS) recombinant tPA Stroke Study were adopted within the alteplase package insert as contraindications/warnings. Many clinicians have expressed the need for clarification and better definition of these treatment criteria. Methods— A group of investigators who also practice as stroke physicians convened a collaborative endeavor to work toward developing more clinically meaningful and consensus-driven exclusion criteria for intravenous tPA. The first of these exclusion criteria chosen was rapidly improving stroke symptoms (RISS). We reviewed and clarified the historical context and intention with the original investigators, held e-mail discussions, convened an in-person RISS Summit, and obtained the understanding of experienced stroke physicians broadly. Results— Historically, the intent of this exclusion criterion within the NINDS recombinant tPA Stroke Trial was to avoid treatment of transient ischemic attacks—who would have recovered completely without treatment. There was unanimous consensus that, in the absence of other contraindications, patients who experience improvement of any degree, but have a persisting neurological deficit that is potentially disabling, should be treated with intravenous tPA. This statement is supported from the methods established for the original NINDS trial, on the basis of detailed discussions and interviews with the former NINDS trialists. It was agreed that improvement should only be monitored for the extent of time needed to prepare and administer the intravenous tPA bolus/infusion. An explicit operational definition of RISS was developed by consensus to guide future decision making in acute stroke. There was unanimous agreement that all neurological deficits present at the time of the treatment decision should be considered in the context of individual risk and benefit, as well as the patient’s baseline functional status. Conclusions— A structured framework and quantitative approach toward defining RISS emerged through expert opinion and consensus. The term, RISS, should be reserved for those who improve to a mild deficit, specifically one which is perceived to be nondisabling. This is recommended to guide decision making on intravenous tPA eligibility going forward, including the design of future studies. An additional study of patients with rapid improvement to nonmild deficits is not justified because these patients should be treated.

Defining the Ischemic Penumbra Using Magnetic Resonance Oxygen Metabolic Index

Background and Purpose— Penumbral biomarkers promise to individualize treatment windows in acute ischemic stroke. We used a novel magnetic resonance imaging approach that measures oxygen metabolic index (OMI), a parameter closely related to positron emission tomography–derived cerebral metabolic rate of oxygen utilization (CMRO2), to derive a pair of ischemic thresholds: (1) an irreversible-injury threshold that differentiates ischemic core from penumbra and (2) a reversible-injury threshold that differentiates penumbra from tissue not-at-risk for infarction. Methods— Forty patients with acute ischemic stroke underwent magnetic resonance imaging at 3 time points after stroke onset: <4.5 hours (for OMI threshold derivation), 6 hours (to determine reperfusion status), and 1 month (for infarct probability determination). A dynamic susceptibility contrast method measured cerebral blood flow, and an asymmetrical spin echo sequence measured oxygen extraction fraction, to derive OMI (OMI=cerebral blood flow×oxygen extraction fraction). Putative ischemic threshold pairs were iteratively tested using a computation-intensive method to derive infarct probabilities in 3 tissue groups defined by the thresholds (core, penumbra, and not-at-risk tissue). An optimal threshold pair was chosen based on its ability to predict infarction in the core, reperfusion-dependent survival in the penumbra, and survival in not-at-risk tissue. The predictive abilities of the thresholds were then tested within the same cohort using a 10-fold cross-validation method. Results— The optimal OMI ischemic thresholds were found to be 0.28 and 0.42 of normal values in the contralateral hemisphere. Using the 10-fold cross-validation method, median infarct probabilities were 90.6% for core, 89.7% for nonreperfused penumbra, 9.95% for reperfused penumbra, and 6.28% for not-at-risk tissue. Conclusions— OMI thresholds, derived using voxel-based, reperfusion-dependent infarct probabilities, delineated the ischemic penumbra with high predictive ability. These thresholds will require confirmation in an independent patient sample.

Transient ischemic attack (TIA): the initial diagnostic and therapeutic dilemma

Many patients with transient ischemic attacks (TIA) are at high risk of stroke within the first few days of onset of symptoms. Emergency physicians and primary care physicians need to assess these patients quickly and initiate appropriate secondary stroke prevention strategies. Recent refinements in diagnostic imaging have produced valuable insight into risk stratification of patients with TIA. Clinical data regarding urgent initiation of antiplatelet therapy specifically in this patient population with non-cardioembolic TIA are limited but promising. This review outlines the diagnostic tools available for rapid assessment of patients presenting with symptoms of TIA and discusses clinical trials that apply to these vulnerable patients.

Accuracy of emergency medical services-reported last known normal times in patients suspected with acute stroke.

Background and Purpose— The last known normal (LKN) time is a critical determinant of IV tissue-type plasminogen activator (IV tPA) eligibility; however, the accuracy of emergency medical services (EMS)-reported LKN times is unknown. We determined the congruence between neurologist-determined and EMS-reported LKN times and identified predictors of incongruent LKN times. Methods— We prospectively collected EMS-reported LKN times for patients brought into the emergency department with suspected acute stroke and calculated the absolute difference between the neurologist-determined and EMS-reported LKN times (|&Dgr;LKN|). We determined the rate of inappropriate IV tPA use if EMS-reported times had been used in place of neurologist-determined times. Univariate and multivariable linear regression assessed for any predictors of prolonged |&Dgr;LKN|. Results— Of 251 patients, mean and median |&Dgr;LKN| were 28 and 0 minutes, respectively. |&Dgr;LKN| was <15 minutes in 91% of the entire cohort and <15 minutes in 80% of patients with a diagnosis of stroke (n=86). Of patients who received IV tPA, none would have been incorrectly excluded from IV tPA if the EMS LKN time had been used. Conversely, of patients who did not receive IV tPA, 6% would have been incorrectly included for IV tPA consideration had the EMS time been used. In patients with wake-up stroke symptoms, EMS underestimated LKN times: mean neurologist LKN time−EMS LKN time =208 minutes. The presence of wake-up stroke symptoms (P<0.0001) and older age (P=0.019) were independent predictors of prolonged |&Dgr;LKN|. Conclusions— EMS-reported LKN times were largely congruent with neurologist-determined times. Focused EMS training regarding wake-up stroke symptoms may further improve accuracy.

Treating the Elderly Stroke Patient: Complications, Controversies, and Best Care Metrics

Acute stroke is a devastating disease that affects almost 800,000 Americans annually. Worldwide, the incidence of stroke is rapidly increasing. Although stroke can affect all age groups, patients over age 80 are at much higher risk for ischemic stroke. Despite this, there are disparities in thrombolytic treatment rates, and as well as outcomes, between elderly stroke patients and their younger counterparts. This article discusses what is currently known about the elderly stroke patient for a greater understanding of the disease burden, research limitations and potential treatment options.

Stroke center certification: where are we in 2010?

Each year about 795 000 people in the USA will experience a new or recurrent stroke. About 600 000 of these events are first attacks, and 185 000 are recurrent attacks. Of all the strokes, 87% are ischemic, 10% are intracranial hemorrhage and 3% are subarachnoid hemorrhage. On average, every 40s someone in the USA has a stroke. Significant disparities exist within the US population: each year women have 55 000 more strokes than men, blacks have almost twice the risk of first-ever stroke compared with whites and Mexican Americans have an increased incidence of intracranial hemorrhage and subarachnoid hemorrhage compared with non-Hispanic whites, as well as increased incidence of stroke and transient ischemic attack (TIA) at younger ages. In 2005, stroke accounted for about one of every 17 deaths in the USA or 143 579 individuals. Stroke ranks at number three among all causes of death, behind cardiovascular disease and cancer and is the leading cause of serious, long-term disability in the USA. The estimated direct and indirect cost of stroke for 2009 is

Streamlined triage and transfer protocols improve door-to-puncture time for endovascular thrombectomy in acute ischemic stroke

68.9 billion.1 Since the approval of intravenous tPA in 1995, a number of key initiatives supported by evidence-based medicine have led to the national, regional and local organization of previously fragmented stroke care into more specialized hospital-based and stroke systems of care. These initiatives in organized stroke care have dramatically altered the landscape for stroke patients and providers. Many factors are driving the centralization of acute stroke care in the USA. The recent development of formal certification for stroke centers is both a cause and an effect of this push. The certification process is still in evolution, and many different organizations, including state legislatures, are involved. In addition, the relationship between primary stroke centers (PSCs, essentially intravenous tPA-capable facilities) and comprehensive stroke centers (CSCs, generally endovascularly capable facilities) is …

Four evolving strategies in the emergent treatment of acute ischemic stroke.

OBJECTIVE Shorter time from symptom onset to treatment is associated with improved outcomes in patients who undergo mechanical thrombectomy for treatment of acute ischemic stroke due to emergent large vessel occlusion. In this work, we detail pre-thrombectomy process improvements in a multi-hospital network and report the effect on door-to-puncture time in patients undergoing mechanical thrombectomy. PATIENTS AND METHODS A streamlined workflow was adopted to minimize door-to-puncture time. Key features of this workflow included rapid and concurrent clinical and radiological evaluation with point-of-care image interpretation, pre-transfer IV thrombolysis and CTA for transferred patients, immediate transport to the angiography suite potentially before neurointerventional radiology team arrival, and minimalist room setup. Door-to-puncture time was measured prospectively and analyzed retrospectively for 78 consecutive patients treated between January 2015 and December 2015. Statistical analysis was performed using the F-test on individual coefficients of a linear regression model. RESULTS From quarter 1 to quarter 4, the number of thrombectomies performed increased by 173% (11 patients to 30 patients, p = 0.002), and there was a significant increase in the proportion of transferred patients that underwent pre-transfer CTA (p = 0.04). During this interval, overall median door-to-puncture time decreased by 74% (147 min to 39 min, p < 0.001); this decrease was greatest in transferred patients with pre-transfer CTA (81% decrease, 129 min to 25 min, p < 0.001) and smallest in patients presenting directly to the emergency department (52% decrease, 167 min to 87 min, p < 0.001). CONCLUSION Simple workflow improvements to streamline in-hospital triage and perform critical workup at transferring hospitals can produce reductions in door-to-puncture time.