Michael Katsnelson

Remote Ischemic Limb Preconditioning After Subarachnoid Hemorrhage A Phase Ib Study of Safety and Feasibility

Background and Purpose— Making a limb transiently ischemic has been shown to induce ischemic tolerance in a distant organ. This phenomenon is known as remote ischemic limb preconditioning. We conducted a Phase IB study of remote ischemic limb preconditioning to determine the safety and feasibility of increasing durations of limb ischemia in patients with subarachnoid hemorrhage. Methods— Patients with aneurysmal subarachnoid hemorrhage underwent limb preconditioning every 24 to 48 hours for 14 days. Limb preconditioning consisted of 3 5-minute inflations of a blood pressure cuff to 200 mm Hg around a limb followed by 5 minutes of reperfusion. In the lead-in phase, we preconditioned the upper extremities, but this proved impractical and we began preconditioning the leg in a similar manner. Ischemia times were then escalated to 7.5 and 10 minutes. After each session, a visual analog scale was obtained and the extremity examined for neurovascular complications. Results— A total of 33 patients completed the study. Mean age was 53±12 years and mean Hunt Hess score was 2.4±0.9. In the lead-in phase, an average of 7.7±2.4 preconditioning sessions was completed with mean visual analog scale 3.6±3.4. In the dose escalation phase, an average of 8.6±2.1 preconditioning sessions was done with mean visual analog scale 1.8±2.2 and 2.5±2.9 for the 7.5- and 10-minute cohorts, respectively. No session was prematurely terminated due to subject discomfort. No objective signs of neurovascular injury were observed. Conclusions— We found limb preconditioning to be safe and well tolerated, even at ischemia times of 10 minutes, in critically ill patients with subarachnoid hemorrhage.

Transcranial Doppler Velocities in a Large, Healthy Population

Transcranial Doppler (TCD) ultrasonography has been extensively used in the evaluation and management of patients with cerebrovascular disease since the clinical application was first described in 1982 by Aaslid and colleagues TCD is a painless, safe, and noninvasive diagnostic technique that measures blood flow velocity in various cerebral arteries. Numerous commercially available TCD devices are currently approved for use worldwide, and TCD is recognized to have an established clinical value for a variety of clinical indications and settings. Although many studies have reported normal values, there have been few recently, and none to include a large cohort of healthy subjects across age, race, and gender. As more objective, automated processes are being developed to assist with the performance and interpretation of TCD studies, and with the potential to easily compare results against a reference population, it is important to define stable normal values and variances across age, race, and gender, with clear understanding of variability of the measurements, as well as the yield from various anatomic segments.

Agreement between TOAST and CCS ischemic stroke classification: The NINDS SiGN Study

Objective: The objective of this study was to assess the level of agreement between stroke subtype classifications made using the Trial of Org 10172 Acute Stroke Treatment (TOAST) and Causative Classification of Stroke (CCS) systems. Methods: Study subjects included 13,596 adult men and women accrued from 20 US and European genetic research centers participating in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN). All cases had independently classified TOAST and CCS stroke subtypes. Kappa statistics were calculated for the 5 major ischemic stroke subtypes common to both systems. Results: The overall agreement between TOAST and CCS was moderate (agreement rate, 70%; κ = 0.59, 95% confidence interval [CI] 0.58–0.60). Agreement varied widely across study sites, ranging from 28% to 90%. Agreement on specific subtypes was highest for large-artery atherosclerosis (κ = 0.71, 95% CI 0.69–0.73) and lowest for small-artery occlusion (κ = 0.56, 95% CI 0.54–0.58). Conclusion: Agreement between TOAST and CCS diagnoses was moderate. Caution is warranted when comparing or combining results based on the 2 systems. Replication of study results, for example, genome-wide association studies, should utilize phenotypes determined by the same classification system, ideally applied in the same manner.

Pathogenic ischemic stroke phenotypes in the NINDS-stroke genetics network.

Background and Purpose— NINDS (National Institute of Neurological Disorders and Stroke)-SiGN (Stroke Genetics Network) is an international consortium of ischemic stroke studies that aims to generate high-quality phenotype data to identify the genetic basis of pathogenic stroke subtypes. This analysis characterizes the etiopathogenetic basis of ischemic stroke and reliability of stroke classification in the consortium. Methods— Fifty-two trained and certified adjudicators determined both phenotypic (abnormal test findings categorized in major pathogenic groups without weighting toward the most likely cause) and causative ischemic stroke subtypes in 16 954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries using the web-based Causative Classification of Stroke System. Classification reliability was assessed with blinded readjudication of 1509 randomly selected cases. Results— The distribution of pathogenic categories varied by study, age, sex, and race (P<0.001 for each). Overall, only 40% to 54% of cases with a given major ischemic stroke pathogenesis (phenotypic subtype) were classified into the same final causative category with high confidence. There was good agreement for both causative (&kgr; 0.72; 95% confidence interval, 0.69–0.75) and phenotypic classifications (&kgr; 0.73; 95% confidence interval, 0.70–0.75). Conclusions— This study demonstrates that pathogenic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes highlights the fact that the presence of an abnormality in a patient with stroke does not necessarily mean that it is the cause of stroke.

Effects of Remote Ischemic Preconditioning on the Coagulation Profile of Patients With Aneurysmal Subarachnoid Hemorrhage: A Case-Control Study

BACKGROUND Animal studies suggest that ischemic preconditioning prolongs coagulation times. OBJECTIVE Because coagulation changes could hinder the translation of preconditioning into clinical settings where hemorrhage may be an issue, such as ischemic or hemorrhagic stroke, we evaluated the effects of remote ischemic preconditioning (RIPC) on coagulation in patients undergoing RIPC after aneurysmal subarachnoid hemorrhage (SAH). METHODS Twenty-one patients with SAH (mean age, 56.3 years) underwent 137 RIPC sessions 2 to 12 days after SAH, each consisting of 3 to 4 cycles of 5 to 10 minutes of lower limb ischemia followed by reperfusion. Partial thromboplastin time (PTT), prothrombin time (PT), and international normalized ratio (INR) were analyzed before and after sessions. Patients were followed for hemorrhagic complications. RESULTS No immediate effect was identified on PTT (mean pre-RIPC, 27.62 s; post-RIPC, 27.54 s; P = .82), PT (pre-RIPC, 10.77 s; post-RIPC, 10.81 s; P = .59), or INR (pre-RIPC, 1.030; post-RIPC, 1.034; P = .57) after each session. However, statistically significant increases in PT and INR were identified after exposure to at least 4 sessions (mean PT pre-RIPC, 11.33 s; post-RIPC, 12.1 s; P = .01; INR pre-RIPC, 1.02; post-RIPC, 1.09; P = .014, PTT pre-RIPC, 27.4 s; post-RIPC, 27.85 s; P = .092) with a direct correlation between the number of sessions and the degree of increase in PT (Pearson correlation coefficient = 0.59, P = .007) and INR (Pearson correlation coefficient = 0.57, P = .010). Prolonged coagulation times were not observed in controls. No hemorrhagic complications were associated with the procedure. CONCLUSION RIPC by limb ischemia appears to prolong the PT and INR in human subjects with SAH after at least 4 sessions, correlating with the number of sessions. However, values remained within normal range and there were no hemorrhagic complications.

Recommendations for management of patients with carotid stenosis.

Stroke is a one of the leading causes of morbidity and mortality in the world. Carotid atherosclerosis is recognized as an important factor in stroke pathophysiology and represents a key target in stroke prevention; multiple treatment modalities have been developed to battle this disease. Multiple randomized trials have shown the efficacy of carotid endarterectomy in secondary stroke prevention. Carotid stenting, a newer treatment option, presents a less invasive alternative to the surgical intervention on carotid arteries. Advances in medical therapy have also enabled further risk reduction in the overall incidence of stroke. Despite numerous trials and decades of clinical research, the optimal management of symptomatic and asymptomatic carotid disease remains controversial. We will attempt to highlight some of the pivotal trials already completed, discuss the current controversies and complexities in the treatment decision-making, and postulate on what likely lies ahead. This paper will highlight the complexities of decision-making optimal treatment recommendations for patients with symptomatic and asymptomatic carotid stenosis.

Progress for Stroke Prevention With Atrial Fibrillation Emergence of Alternative Oral Anticoagulants

Atrial fibrillation (AF) is both a common cardiac arrhythmia and a frequent cause of cardioembolic strokes. The prevalence of AF markedly increases with age and with the current population trends, the number of patients with AF is expected to continue to grow and may reach 12 million in the United States by 2050.1 AF accounts for up to 20% of all ischemic strokes and independently increases the risk of these events by up to 5-fold.2,3 Various cardiovascular risk factors do increase the risk of AF and given the continuing rise of obesity and resultant hypertension and diabetes, the future healthcare burden of AF-related strokes is likely to greatly increase. AF is arguably 1 of the best-studied causes of stroke with dozens of randomized trials that have led to well-established evidence-based recommendations regarding effective treatment modalities. Warfarin, a vitamin K antagonist, is currently the most commonly used oral anticoagulant. It has been used for decades, is inexpensive, and has standardized laboratory monitoring and reversal protocols. Warfarin is also exceedingly effective; a recent meta-analysis has shown it to reduce stroke by almost two thirds compared with placebo and to provide an almost 40% relative risk reduction compared with antiplatelet therapy.4 Warfarin, however, has several limitations that have led to underuse in the community. It has a very narrow therapeutic window with potentially life-threatening consequences from both under- and overdosing the medication. Bleeding, either systemically or intracranially, is the most feared complication; it has hindered a more wide-scale acceptance of this therapy, particularly among elderly patients. Maintaining most patients within that therapeutic window is challenging due to numerous drug and diet interactions and requires frequent and inconvenient blood testing and monitoring. Due to these difficulties, a portion of patients and physicians has never adequately adopted this therapy, which …

Differences in lipid profiles in two Hispanic ischemic stroke populations

Background and Purpose The study aims to compare lipid profiles among ischemic stroke patients in a predominantly Caribbean-Hispanic population in Miami and a Mestizo Hispanic population in Mexico City. Methods We analyzed ischemic stroke Hispanic patients with complete baseline fasting lipid profile enrolled contemporaneously in the prospective registries of two tertiary care teaching hospitals in Mexico City and Miami. Demographic characteristics, risk factors, medications, ischemic stroke subtype, and first fasting lipid profile were compared. Vascular risk factor definitions were standardized. Multiple linear regression analysis was performed to compare lipid fractions. Results A total of 324 patients from Mexico and 236 from Miami were analyzed. Mexicans were significantly younger (58·1 vs. 67·4 years), had a lower frequency of hypertension (53·4% vs. 79·7%), and lower body mass index (27 vs. 28·5). There was a trend toward greater prevalence of diabetes in Mexicans (31·5 vs. 24·6%, P = 0·07). Statin use at the time of ischemic stroke was more common in Miami Hispanics (18·6 vs. 9·4%). Mexicans had lower total cholesterol levels (169·9 ± 46·1 vs. 179·9 ± 48·4 mg/dl), lower low-density lipoprotein (92·3 ± 37·1 vs. 108·2 ± 40·8 mg/dl), and higher triglyceride levels (166·9 ± 123·9 vs. 149·2 ± 115·2 mg/dl). These differences remained significant after adjusting for age, gender, hypertension, diabetes, body mass index, smoking, ischemic stroke subtype, and statin use. Conclusion We found significant differences in lipid fractions in Hispanic ischemic stroke patients, with lower total cholesterol and low-density lipoprotein, and higher triglyceride levels in Mexicans. These findings highlight the heterogeneity of dyslipidemia among the Hispanic race-ethnic group and may lead to different secondary prevention strategies.

Moderate correlation between breath-holding and CO(2) inhalation/hyperventilation methods for transcranial doppler evaluation of cerebral vasoreactivity.

Both CO2 inhalation followed by hyperventilation and breath‐holding have been utilized to measure cerebral vasomotor reactivity (VMR) but their correlation has been poorly studied and understood.

Stroke Patients With Suspected Atrial Fibrillation Should NOT Be Started on Anticoagulation WHILE AWAITING the Results of Long-Term Cardiac Monitoring

Cryptogenic stroke is a frustrating diagnosis. For the patient who is looking for explanations, for the family members worrying and caring for their loved one, and, perhaps most of all, for the physician trained to localize, identify, and prevent a recurrent stroke. With a large proportion of ischemic strokes (20–30%) still classified as having no definite cause, this diagnostic scenario happens all too often at the bedside. Atrial fibrillation (AF) is a well-established cause of many cardioembolic strokes, but may not always be readily detectable and frequently goes under-recognized by the patient. Occult AF could also explain a proportion of cryptogenic infarcts. However, initiating a treatment before knowing the diagnosis is much like putting the cart ahead of the horse. The case in point describes a 76-year old woman who suffered a recent embolic-looking occipital stroke with intermittent palpitations and other vascular risk factors. Potential causes of her stroke other than cardioembolic also need to be strongly considered. We are assuming that vertebral artery origins were carefully studied, as they do …