The Massachusetts General Hospital Neuroradiology Division employed an experience and evidence based approach to develop a neuroimaging algorithm to best select patients with severe ischemic strokes caused by anterior circulation occlusions (ACOs) for intravenous tissue plasminogen activator and endovascular treatment.

Methods found to be of value included the National Institutes of Health Stroke Scale (NIHSS), non-contrast CT, CT angiography (CTA) and diffusion MRI. Perfusion imaging by CT and MRI were found to be unnecessary for safe and effective triage of patients with severe ACOs. An algorithm was adopted that includes: non-contrast CT to identify hemorrhage and large hypodensity followed by CTA to identify the ACO; diffusion MRI to estimate the core infarct; and NIHSS in conjunction with diffusion data to estimate the clinical penumbra.

Read full article: The Massachusetts General Hospital acute stroke imaging algorithm (PDF)

• Superior reduction of ischemic and hemorrhagic stroke vs warfarin
• Similar rate of major bleeds^‡ with PRADAXA vs warfarin
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• PRADAXA also demonstrated a lower rate of intracranial bleeding vs warfarin

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In a randomized, double-blind, placebo-controlled trial conducted at 114 centers in China, we randomly assigned 5170 patients within 24 hours after the onset of minor ischemic stroke or high-risk TIA to combination therapy with clopidogrel and aspirin (clopidogrel at an initial dose of 300 mg, followed by 75 mg per day for 90 days, plus aspirin at a dose of 75 mg per day for the first 21 days) or to placebo plus aspirin (75 mg per day for 90 days). All participants received open-label aspirin at a clinician-determined dose of 75 to 300 mg on day 1. The primary outcome was stroke (ischemic or hemorrhagic) during 90 days of follow-up in an intention-totreat analysis. Treatment differences were assessed with the use of a Cox proportional- hazards model, with study center as a random effect.

Stroke occurred in 8.2% of patients in the clopidogrel–aspirin group, as compared with 11.7% of those in the aspirin group (hazard ratio, 0.68; 95% confidence interval, 0.57 to 0.81; P<0.001). Moderate or severe hemorrhage occurred in seven patients (0.3%) in the clopidogrel–aspirin group and in eight (0.3%) in the aspirin group (P = 0.73); the rate of hemorrhagic stroke was 0.3% in each group.

Among patients with TIA or minor stroke who can be treated within 24 hours after the onset of symptoms, the combination of clopidogrel and aspirin is superior to aspirin alone for reducing the risk of stroke in the first 90 days and does not increase the risk of hemorrhage.

Original Article

Stroke is a major cause of death and disability worldwide, and the third or fourth most common cause of death in the USA.^[1] Therefore, stroke is an extremely common and potentially devastating disease. Acute recognition is critical to timely therapeutic intervention, which has evolved over time due to research including intravenous recombinant tissue plasminogen activator for ischemic stroke.^[2] However, the management of the stroke patient after the initial few hours and over the next few days – including blood pressure management, development of raised intracranial pressure (ICP) and management of seizures, fever and medical complications – are critical to patient outcomes.^[3] The evolution of bedside intensive care unit (ICU) techniques to monitor unstable brain tissue has developed in parallel to the ongoing research in acute stroke therapeutics.^[4] For example, the avoidance of hypoglycemia or hypotension after acute ischemic stroke might improve patient outcomes.^[5] However, after acute stroke, long-term hypertension control is important to preventing secondary stroke.^[6,7] Prevention and treatment of fever after stroke can also potentially improve outcome.^[5] This article briefly describes standard ICU bedside stroke monitoring techniques and expands upon them with newer ICU stroke monitoring techniques.

Perhaps one of the oldest methods of monitoring the acute stroke patient is the measurement of ICP. Since cerebral perfusion pressure (CPP) = mean arterial pressure – ICP, the measurement and management of ICP has profound cerebral physiology management implications.^[8] Without detection of raised ICP, CPP will be compromised and can cause secondary focal or global ischemia. The Monroe–Kellie hypothesis explains how three volumes of brain, blood and cerebrospinal fluid relate to intracranial pressure–volume relationship. The adult skull contains a finite volume, as compared with pediatric populations (<2 years of age), which contain a soft, expansive fontanel. Since the skull is a closed intracranial vault in adults, an increased ‘total’ intracranial volume such as adding a hematoma must be reciprocally compensated by a decrease in cerebral blood volume (e.g., more venous outflow) or decreased cerebrospinal fluid volume in order to maintain normal ICP and preserve CPP. When intracranial compensatory mechanisms can no longer accommodate additional increases in intracranial volume, ICP rises precipitously and CPP trends towards 0. Normal ICP values are defined as <20 mmHg.^[9–14] CPP in a normal ‘autoregulated’ state varies across a range of mean arterial pressure values to maintain a constant cerebral blood flow (CBF) (Figure 1). Injury to brain tissue results in disturbed pressure autoregulation, meaning CBF becomes linearly dependent upon CPP. Therefore, ICP monitoring is often necessary to first measure ICP, and secondarily calculate CPP. CBF can be assumed but not directly measured from ICP alone, which is problematic, especially if it is not known whether autoregulation is present or absent. However, newer complex ‘multimodal monitoring’ (MMM) computers can calculate via a Pearson moving correlation coefficient method,^[9] whether pressure autoregulation is present or absent, which adds value to the bedside management of critical patients.

External ventricular drain (EVD) is perhaps one of the most common methods to invasively measure ICP via an intraventricular catheter, which allows for diagnosis and treatment of raised ICP. Ventricular ICP measurement is considered a ‘gold-standard’ means for assessing elevations in global ICP,^[4,11] but it is invasive. EVDs also carry the risk of CNS infection such as meningitis/ventriculitis, like any other invasive brain probe, as well as risk of brain hemorrhage with EVD placement within the parenchyma. Antibiotic and silver-coated catheters are now in clinical use and may reduce the risk of infection.

Over the last 100 years, an ever-increasing number of ICU bedside monitoring techniques have been discovered and researched to aid the stroke patient. Newer and noninvasive methods are emerging such as NIRS, nICP and MMM computer help provide a ‘unified’ graphical display to help manage complex physiological relationships. Such MMM ability, while it remains mostly at advanced or academic neuroscience ICUs across the world, may prove in future research to derive specific physiological parameters for intervention, similar to directed therapy targets in sepsis.

Key Issues

• Stroke is a devastating disease, ranking fourth among leading causes of death in the USA, and is a global disease with similar mortality and morbidity.
• Management of blood pressure, intracranial pressure, fever and seizures in critical care patients after the onset of a stroke is vital to patient outcomes.
• The recent advancements in neuromonitoring and interventional therapy have been linked to an overall decrease in the rates of morbidity and mortality among patients suffering from stroke-related illnesses.
• Monitoring of intracranial pressure (ICP) has profound implications to the status of a patient’s cerebral autoregulation, and the direction of necessary neurotherapeutics.
• Understanding the mixed venous O₂saturation provided by jugular venous oxygen saturation and near-infrared spectroscopy (NIRS) offers insights into the ‘supply and demand’ physiology of the injured brain, and may help detect previously undiagnosed ‘cerebral desaturations’ and secondary ischemia.
• Currently, invasive methods of ICP measurement such as the external ventricular drain are seen as the gold standard for assessing elevations in ICP, but may place the patient at risk of infection, especially with prolonged monitoring.
• Noninvasive monitoring devices such as EEG, transcranial Doppler and NIRS provide alternative methods for indirectly measuring cerebral metabolic function without the risks of invasive probes and devices (e.g., Licox^TM).
• Newer modalities such as NIRS and cerebral Hemedex^TM require validation against gold-standard methods of brain oxygenation and blood flow, respectively, before they receive widespread implementation.

Full Article at Medscape Neurology

These guidelines were put together by an expert panel and touch on many aspects of acute stroke care, with a focus on ischemic stroke. The guidelines include dozens of recommendations. I am not going to talk about all of them today, but I would like to highlight some that are particularly important to treating clinicians.

First, the guidelines come out very strongly in favor of transporting patients with acute stroke to the nearest primary or comprehensive stroke center. This is a great idea because we know from numerous studies and analyses that care at these certified stroke centers really does make a difference in terms of improving outcomes and reducing complications. That is a very strong positive recommendation. In addition, the guidelines now say that these stroke centers should be certified by an independent body or agency, so we are moving away from the paradigm of self-certification [toward independent, objective certification], which is also a positive move.

Next is a curious recommendation about patients with intracranial stenosis: If you want to confirm that someone has an intracranial stenosis, the guidelines now recommend catheter angiography rather than noninvasive studies such as CTA (computerized tomographic angiography) or MRA (magnetic resonance angiography). That is curious, because I think a lot of folks have moved away from doing catheter angiography, but in these recommendations they really come down in favor of doing a catheter angiogram to confirm an intracranial stenosis. We will have to see where that goes in terms of altering routine care.

As you might imagine, a fairly extensive section [is dedicated to] using IV tPA (tissue plasminogen activator), and the recommendations come down very strongly in favor of a door-to-needle time of 60 minutes, which is emerging as a national quality metric by the National Quality Forum. This is a good timeframe to aim for, although, again, in a clinical context I think we have all had the experience or occasion when we do have to delay giving the IV tPA as we try to get more clinical information. I think we need to have some flexibility here. The new guidelines do recommend treatment up to the 4.5-hour time window, with exclusion criteria in terms of age, oral anticoagulation, diabetes, and stroke, similar to [the criteria in] the ECASS 3 study. What is curious is that if you talk to our stroke colleagues in Europe who actually conducted ECASS 3, they do not follow their own exclusion criteria. They treat everybody [with IV tPA] up to 4.5 hours except those who have had a massive stroke with significant early changes. Our new guidelines, the 2013 guidelines, do have the ECASS 3 exclusion criteria similar to what the scientific statement said several years ago. However, these new guidelines now say that it is reasonable to treat people with mild strokes, or improving symptoms, if the benefits outweigh the risks. They also say that it may be reasonable to treat patients even if they had surgery within the past 3 months, assuming that there is no active bleeding and the benefits outweigh the risks.

Finally, on the vexing issue of using IV tPA in patients taking [one of the] new oral anticoagulants, the guidelines say do not treat these patients with IV tPA unless you are sure that their clotting studies are normal or you are certain that they have not taken any of these oral anticoagulants for the past 2 days.

Dr. Mark Alberts is a Vice-Chair of Clinical Affairs in the Department of Neurology at University of Texas Southwestern Medical Center in Dallas.

“The findings of this study suggest that the blood pressure lowering and lipid effects of plain dark chocolate could represent an effective and cost effective strategy for the prevention of cardiovascular disease in people with metabolic syndrome (and no diabetes),” the researchers, with senior author Christopher M. Reid, PhD, CCRE Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, The Alfred Centre, Melbourne, Victoria, Australia, conclude.

“Chocolate benefits from being by and large a pleasant and, hence sustainable, treatment option,” they write. “Evidence to date suggests that the chocolate would need to be dark and of at least 60-70% cocoa, or formulated to be enriched with polyphenols.”

Dark chocolate, derived from coca beans, is rich in polyphenols, specifically flavonoids that exhibit antihypertensive, anti-inflammatory, antithrombotic, and metabolic effects, all of which may contribute to cardio-protection.

Long-Term Effects

Previous studies have shown that dark chocolate consumption may lower blood pressure, but they have been relatively short, only up to a maximum of 18 weeks. Studies have also shown that dark chocolate may decrease total and low-density lipoprotein cholesterol and increase high-density lipoprotein cholesterol, but again, these changes have been explored only in short-term trials.

To determine potential long-term effects of consuming dark chocolate every day, as well as the cost-effectiveness of this strategy, Australian researchers used statistical modeling techniques, particularly a Markov model to which health states (“alive without cardiovascular disease,” “alive with cardiovascular disease,” “dead from cardiovascular disease,” “dead from other causes”) and decision analysis (no dark chocolate [control], or with dark chocolate [treatment]) were added.

With each annual cycle, the researchers used risk prediction algorithms and population life tables to estimate how eating dark chocolate every day for 10 years would affect patients with metabolic syndrome.

The study used data on 2013 participants from the Australian Diabetes Obesity and Lifestyles study who had metabolic syndrome, did not have a diagnosis of cardiovascular disease or frank diabetes, and who were not receiving antihypertensive medications.

The patients were relatively young (mean age, 53.6 years) and considered at high risk: They had a mean systolic blood pressure of 141.1 mmHg, mean total cholesterol level of 6.1 mmol/L, mean hemoglobin A1c of 34.4 mmol/mol, and mean waist circumference of 100.4 cm.

The researchers concluded that under the best-case scenario, in which all these patients ate dark chocolate daily for a decade, 70 nonfatal cardiovascular events, including nonfatal stroke and nonfatal myocardial infarction per 10,000 population, as well as 15 cardiovascular related deaths per 10,000 population, could be prevented.

The estimated incremental cost-effectiveness ratio was $52,500 per years of life saved when $42 per person per year was assumed to have been spent on a prevention strategy using dark chocolate.

Even if only 80% of individuals with metabolic syndrome adhered to daily consumption of dark chocolate over 10 years, preventing only 55 nonfatal and 10 fatal events per 10,000, it would still be considered an effective and cost-effective intervention strategy, the authors write.

Prevention Strategy

A dark chocolate prevention strategy of $42 per person per year in a high-risk population would be cost-effective “based on the commonly accepted, albeit arbitrary, threshold of $50,000 per years of life saved,” said the authors.

The $42 per person per year could be devoted to advertising, education campaigns, or, potentially, subsidization of dark chocolate in this high-risk population, they said.

The authors point out that they did not assess the potential effectiveness of dark chocolate consumption on cardiovascular events other than nonfatal stroke and nonfatal myocardial infarction, such as heart failure.

They also stressed that the effects of dark chocolate consumption on blood pressure and total cholesterol, although beneficial, are not as profound as those of drug interventions.

The authors have disclosed no relevant financial relationships.

BMJ. Published online May 31, 2012.