Stroke Treatment Advances

Franz Chaves SellNeurology, Hospital Clínica Bíblica, San José, Costa Rica

Academia Nacional de MedicinaSIECV

Ictus

• Los Ictus Vasculares Cerebrales (AccidenteVascularCerebral.) son todos aquellos trastornos en los cuales se daña un área del cerebro en forma permanente o transitoria, a causa de isquemia o hemorragia y/o también los padecimientos en los cuáles uno o más vasos sanguíneos presentan una alteración primaria por algún proceso patológico.

• Isquémicos: 85%• Hemorragicos 15%

Ictus• Existen diferentes tipos de ictus vascular cerebral siendo sin duda

alguna los eventos isquémicos la gran mayoría ya que representan el 90%:– Aterotrombosis a nivel de las bifurcaciones de los grandes vasos– Embolias arterio-arteriales– Embolias de origen cardíaco. – Vasoespasmo

• Los más frecuentes de los isquémicos son emobolias arterio-arteriales

• Vasoespasmo: casi siempre x vasculitis

Ictus

• Factores de riesgo:– Hipertensión Arterial que aumenta el riesgo 5 veces y es el

factor más importante que puede ser controlado– Diabetes Mellitus factor de riesgo independiente y también

controlable– Tabaquismo que aumenta el riesgo 4 veces– Dislipidemias que incrementan el riesgo 5 veces– Edad ya que la incidencia de Ictus aumenta un 10% por año

después de los 45 años.• Son los mismos factores de riesgo que los del corazón. Los ictus

cerebrales son más frecuentes que los IAM. Genética, factores raciales

Stroke subtypes in Spain, Latin America and The Caribbean

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Isquémicos Hemorrágicos No bien clasificado o AIT

*Cerebral vein thrombosis, when included= 4-8% of all strokes

En asiáticos y en indígenas americanos lo q predomina es enfermedad de pequeños vasosBlancos, europeos, caucásicos predomina enfermedad de grandes vasos, Cerebral media, cerebral posterior.

Days lived with disability from stroke in different regions of the World and compared to other diseases

(from WHO 2002)

La ECV es más frecuente q la enfermedad coronaria y en el mundo, cuando se habla de discapacidad el ECV es solo superado x SIDA y cáncer. Entonces cuando se habla de prevención de hacer campañas de aterosclerosis, controlando Hta, en realidad se trabaja mucho con el ECV.

Epidemiología• Estados Unidos:

– prevalencia 1.200 por 100.000 habitantes– Incidencia de 200 por 100.000 habitantes por año– Stroke is the third leading cause of death in USA – American Heart Association y NIH han estimado que 550.000 nuevos casos

de ictus ocurren por año, basándose en poblaciones de raza blanca (Ej: Framingham)

– Al analizar los índices entre población negra en Cincinatti, Kentucky y Rochester 730.000 nuevos casos por año.

Epidemiología

• Mortalidad:– Indices de muerte por 100.000 habitantes por Ictus: – 26.5% para hombres blancos– 52.2 para hombres negros– 21. 3 % para mujeres blancas– 39.6% para mujeres negras– En 1995 las mujeres norteamericanas representaron el 61% de las

muertes por Ictus.– Hay mayor mortalidad en pacientes de raza negra que en blancos, xq:

• Hta es más prevalente yd e dificil control en los negros• En USA estas poblaciones tienen menos educación para reconocer en forma

temprana los signos, síntomas y además acceso a servicios de salud.

Epidemiología• América Latina:• Meta-análisis de 18 estudios (7 estudios de población y 11 registros hospitalarios)

realizado por Saposnick y Del Bruto.– Prevalencia del ictus en Sudamérica de 1.74 a 6.51 x1000– Incidencia de 0.35 a 1.83 x1000, sugiriendo que el problema se presenta en menor

medida que en los países desarrollados– También el patrón de los subtipos de Ictus fue diferente, con una mayor presencia de las

hemorragias, de la enfermedad de pequeños vasos y de lesiones arterioescleróticas intracraneales.

Region of the Cerebrum Damaged by Stroke

Signs and Symptoms

Wernicke's area (central language area)

Difficulty speaking understandably and comprehending speech; confusion between left and right; difficulty reading, writing, naming objects, and calculating

Broca's area (speech) Difficulty speaking and, sometimes, writing

Parietal lobe on the left side of the brain

Loss of coordination of the right arm and leg

Facial and limb areas of the motor cortex on the left side of the brain

Paralysis of the right arm and leg and the right side of the face

Facial and arm areas of the sensory cortex

Absence of sensation in the right arm and the right side of the face Optic radiation Loss of the right half of the visual field of both eyes

Apuntes Diapositiva anterior!• Depende de donde se de la lesión va a ser la manifestación clínica• Isquémicos: no duelen

– Wernicke: afasia receptiva (no entiende pero si puede hablar)– Broca: afasia expresiva (entiende)– Parietal: sensitivos contralaterales afectados– Prerolandica: hemiplejia contralateral.

• Hemorrágicos: duelen• Tipos de Hemiplejia: infarto de la cerebral media (la mayoría de los de grandes vasos). Dos territorios: uno

muy cortical (irriga mano, brazo cara), hemiparesia contralateral de predominio fasciobraquial (más afección de cara brazo que de pierna) y uno muy profundo, las ramas talamoestriadas irrigan toda la cápsula interna, x lo tanto si una rama profunda se tapa, la hemiparesia contralateral densa y proporcionada: brazo pierna y cara parejo.

• Infarto de cerebral anterior: hemiparesia crural contralateral. • Cerebral posterior: hemianopsia lateral homónima contralateral. • Infarto en tallo: dan síndromes alteronos: pares craneales del mismo lado pero hemiparesias

contralaterales.

Fisiopatología

Circulación Cerebral====Autorregulada

Incremento Presión Arterial

Constricción Vascular Cerebral

NOTA: Presión de CO2 ------- afecta!!!

La ciruculación cerebral autorregulada, entonces aun cuando hay isquemia se da una señal de que igualmente llegue sangre hacia él.Si hay incremento de la presión arterial se cierra, pero eso tamb puede provocar isquemiaHipocapnia: vasocontricción

Fisiopatología

CEREBRO == 2% masa corporal

consume 15% de gasto cardíaco

Circulación Cerebral Normal

= 55ml / 100g / min

< 15 ml / 100g / min DAÑO

Flujo Vascular Cerebral

• < 55 ml/100g/min: Inhibe síntesis de proteínas

• < 35 ml/100g/min: Metabolismo anaerobio de la glucosa

• < 25 ml-100g-min: ATP, Lactato

• < 15 ml-100g-min: gradientes iónicos

Despolarización y muerte por radicales libres AREA DE PENUMBRA ISQUÉMICA

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40Cambios EEG (plano)

GLUCOPENIAMuerte Neuronal

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Mecanismos de Lesión Celular

Lifestyle factors

The Nurses' Health Study: nurses who ate fish containing -3 fatty acids had a lower risk of stroke, by as much as 52%,compared with those who did not eat fish. Intake of fruits, folic acid, potassium, and low levels of homocysteine have also been associated with lower incidence of stroke. It also found a specific reduction in women who exercise

One study reported an association between whole grain intake and reduced stroke incidence.

Specific evidence for prevention of stroke with dietary manipulations, however, has not been established. Much previous evidence has favored exercise for the prevention of both heart attack and stroke.

• Demostró: que comer pescados ricos en Omega 3, eran personas de hasta 50% menos probabilidad de Ictus que las personas q no comen pescado.

• Frutas ac fólico, potasio, y bajos niveles de homocisteina: menos ictus. • Ingesta de granos: reduce

1. Iso H, Rexrode KM, Stampfer MJ, Manson JE, Colditz GA, Speizer FE, et al. Intake of fish and    -3 fatty acids and risk of stroke in women. JAMA 2001; 285: 304-312. 2.Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: Probable benefits of increasing folic acid intakes. JAMA 1995; 274: 1049-1057. 3. Liu S, Manson JE, Stampfer MJ, Rexrode KM, Hu FB, Rimm EB, et al. Whole grain consumption and risk of ischemic stroke in women. A prospective study. JAMA 2000; 284: 1534-1540.

Lifestyle factors

• Smoking clearly increases stroke risk, by as much as 1.5- to 2-fold

• Alcohol may be protective of ischemic stroke in moderate drinkers (vinos), but hemorrhages are more likely with any intake of alcohol. Se comprobó el año pasado q estos se mueren menos de ECV pero se mueren x accidentes en la casa, caídas, etc.

• The Caerphilly Study in Wales reported a specific association between life stresses and incidence of stroke, particularly fatal stroke (risk ratio [RR], 3.36).

1.Shinton R, Beevers G. Metaanalysis of relation between cigarette smoking and stroke. BMJ 1989; 298: 789-794. 2.Wolf PA. Cigarettes, alcohol, and stroke. N Engl J Med 1986; 315: 1087-1089. 3.Sacco RL, Elkind M, Boden-Albala B, Lin IF, Kargman DE, Hauser WA, et al. The protective effect of moderate alcohol consumption on ischemic stroke. JAMA 1999; 281: 53-60. 4.May M, McCarron P, Stansfeld S, Ben-Shlomo Y, Gallacher J, Yarnell J, et al. Does psychological distress predict the risk of ischemic stroke and transient ischemic attack? The Caerphilly Study. Stroke 2002; 33: 7-12.

Hypertension and Stroke

• A meta-analysis of studies of antihypertensive therapy reported that a modest, 5 to 6 mm Hg blood pressure reduction resulted in a 42% reduction in stroke incidence

• The Systolic Hypertension in the Elderly Program (SHEP) showed a 37% reduction in ischemic stroke in elderly patients treated with one of three antihypertensive regimens.

• Reducciones aún leves de hipertensión, producen reducciones de hasta 40% de ECV. Sin importar que antihipertensivo se use!

1.Collins R, Peto R, MacMahon S, Hebert P, Fiebach NH, Eberlein KA, et al. Blood pressure, stroke, and coronary heart disease. Part 2. Short-term reductions in blood pressure: Overview of randomized drug trials in their epidemiological context. Lancet 1990; 335: 827-838. 2.The Systolic Hypertension in the Elderly Program (SHEP). Effect of treating isolated systolic hypertension on the risk of developing various types and subtypes of stroke. JAMA 2000; 284: 465-471.

Hypertension and Stroke

• In the HOPE trial of high-risk patients older than 55 years of age, the ACE inhibitor ramipril reduced the incidence of stroke, myocardial infarction (MI), and vascular death by 22% more than placebo

• Strokes were 32% less frequent in ramipril-treated patients. Cualquier antihipertensivo va a tener buen impacto!

1. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients: The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000; 342: 145-153.

Hypertension and Stroke

• The LIFE trial, also a primary stroke prevention study in high-risk patients, found better stroke prevention with the ACE receptor blocker losartan than the beta-blocker atenolol.

• Secondary prevention of stroke has been studied in the PROGRESS trial. 6,105 patients were randomized to active treatment with the ACE inhibitor perindopril, with or without the diuretic indapamide, versus placebo. – The "active treatment" arm had a 28% reduction in stroke

compared with the placebo arm.

1.PROGRESS Collaborative Group. Randomized trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischemic attack. Lancet 2001; 358: 1033-1041. 2.Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, Faire U, et al. Cardiovascular morbidity and mortality in the Losartan Intervention for End point reduction in hypertension (LIFE): A randomized trial against atenolol. Lancet 2002; 359: 995-1003.

Lipid Lowering in Stroke Prevention

• The "MRFIT" analysis of serum cholesterol levels and stroke found increases in stroke mainly with severely elevated low-density lipoprotein (LDL) cholesterol levels

• Scandinavian 4S study: 30% reduction in TIA and stroke was found with simvastatin.

• Aumento de ECV asociado a niveles elevados de LDL, q disminuye riesgo con estatinas!

1.Iso H, Jacobs DR Jr, Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and 6-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. New Engl J Med 1989; 320: 904-910. 2.The West of Scotland Coronary Prevention Study Group. A coronary primary prevention study of Scottish men aged 45-64 years: Trial design. J Clin Epidemiol 1992; 45: 849-860. 3.Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383-1389. 4.Pedersen TR, Kjekshus J, Pyorala K, Olsson AG, Cook TJ, Musliner TA, et al. Effect of simvastatin on ischemic signs and symptoms in the Scandinavian Simvastatin Survival Study (4S). Am J Cardiol 1998; 81: 333-335.

Lipid Lowering in Stroke Prevention

• CARE trial: patients with MI, many of whom had normal plasma lipids, showed a similar degree of stroke preventive effect with pravastatin.

• The FDA has included stroke prevention as an indication for the use of both simvastatin and pravastatin.

• LIPID trial reported a 19% stroke reduction with pravastatin.

1. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996; 335: 1001-1009.

Lipid Lowering in Stroke Prevention

• The National Cholesterol Education Program (NCEP): Adult Treatment Program (ATP III), 2001.

– Diabetes is equal to that of coronary artery or peripheral vascular disease in indicating lowering of the LDL level below 100 mg/dl.

– Symptomatic carotid artery disease is also an indication.– Patients with two or more risk factors should have a goal of less than 130 mg/dl;

these risk factors include age greater than 45 in men and 55 in women, hypertension, smoking, family history of early coronary disease, and low high-density lipoprotein (HDL < 40 mg/dl).

– LDL por debajo de 100 pero en diabéticos se buscan LDL debajo de 70 pero para eso solo se puede lograr con estatina!

1.Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285: 2486-2495.

Antiplatelet Therapy

• Aspirin exerts an effect by irreversibly acetylating and deactivating cyclooxygenase, halting production of thromboxane A2.

• 100-mg dose irreversibly inhibits this mechanism of platelet activation, and the effect persists for the life of the platelets. It does not inhibit platelet aggregation directly.

• The Chinese Acute Stroke Trial assessed low-dose aspirin versus placebo in acute ischemic stroke. This trial only tested aspirin versus placebo, and found a similar benefit to the International Stroke Trial.

• When the results of the International Stroke Trial and the Chinese Acute Stroke Trial are taken together, low-dose aspirin improved the outcomes in approximately 13 per 1,000 patients treated.

• Nota: hay prevención primaria y secundaria. 1: no hay evento previo pero si factores de riesgo. Todo lo q hemos mencionado hasta ahora es de prevención primaria y secundaria, pero los antiagregantes plaquetarios, generalmente son de prevención secundaria! La FDA como antiagregantes plaquetarios son la aspirina, plavix o clopidurel, y la combinacion de dipiradol + aspirina, q es superior a aspirina

Antiplatelet Therapy

• The CAPRIE trial studied 19,000 patients with stroke, MI, or peripheral vascular disease and showed a 8.7% relative risk reduction of clopidogrel over aspirin. The group with stroke showed a 7.4% relative risk reduction, not statistically significant.

• The CURE trial in acute coronary syndrome suggested greater efficacy of Plavix when combined with aspirin, though with an increased bleeding risk.

• MATCH trial, compares clopidogrel plus aspirin against clopidogrel alone in secondary stroke prevention.

1. CAPRIE Steering Committee. A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE). Lancet 1996; 348: 1329-1336.

2. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494-502.

Match

• Is the largest secondary prevention trial to date to investigate combination antiplatelet therapy vs monotherapy in the secondary prevention of vascular events in patients with symptomatic cerebrovascular disease.

• It is an international, randomized, double-blind, placebo-controlled, parallel-group trial designed to determine whether the combination of clopidogrel plus ASA is superior to clopidogrel alone in high-risk patients with recently symptomatic ischemic cerebrovascular disease.

Match results

• There is no advantage to adding ASA to clopidogrel for preventing a second stroke in patients who have already experienced a TIA or IS

• The combination significantly increases their risk of serious and life-threatening hemorrhage.

– Reported for the first time on May 13th at the 13th European Stroke Conference. Hans-Christoph Diener, MD, Professor of Neurology, Universitat Essen, Germany, and principal

investigator of the MATCH trial.

Antiplatelet Therapy

• In the European Stroke Prevention Study II, aspirin plus dipyridamole (Aggrenox 25/200 mg bid) prevented 19% more strokes than aspirin alone, 37% more than placebo.

1. Diener H, Cunha L, Forbes , Sivenius J, Smets P, Lowenthal A. European stroke prevention study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996; 143: 1-13.

Antiplatelet Therapy

• The Warfarin Aspirin Recurrent Stroke Study: – No significant difference between aspirin and warfarin in the

secondary prevention of stroke in patients who have had an ischemic stroke without evidence of either significant carotid stenosis or a definite cardiac source of embolus.

• Only atrial fibrillation in primary and secondary prevention has been adequately tested to prove a benefit of warfarin.

• Solo hay una condición donde es indicación absoluta de anticoagular: ACFA, todas las demás son indicaciones relativas

1.Mohr JP, Thompson JLP, Lazar RM, Levin B, Sacco RL, Furie KL, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001; 345: 1444-1451.

2. European Atrial Fibrillation Trial Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischemic attack or minor stroke. Lancet 1993; 342: 1255-1262.

Antiplatelet Therapy

• Patients with carotid dissections, venous sinus thrombosis, intracranial vascular stenosis, low cardiac ejection fraction, and hypercoagulable states may benefit from warfarin

• Large trials have not addressed these relatively uncommon indications for warfarin.

• Estas son relativas! Solo ACFA es absoluta xq las probabilidades de ictus isquémico son 7 veces más altas comparada con grupo control

1.Mohr JP, Thompson JLP, Lazar RM, Levin B, Sacco RL, Furie KL, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001; 345: 1444-1451. .

Arteriosclerosis

• Modelo de remodelacion de Glagov: la visión típica es q el vaso se va tapando hacia adentro, concentricamente. Se hace un cateterismo se ve que el flujo no pasa, pero tambien tenemos arterias que hacen la placa hacia adentro pero hay pacientes que hacen placa hacia afuera y llega un momento donde esa palca rompe y proboca embolias arterio-arteriales. Si uno hace un cateterismo a este el pte se va a ver normal.

• IVUS: Intravascular US. Se introduce cateter, pero con el US uno ve el lumen y las placas de las periferia

• IVUS Modelo• IVUS Angiografia

The North American Symptomatic Carotid Endarterectomy Trial (NASCET)

NASCET demonstrated the superiority of endarterectomy over medical treatment for symptomatic carotid stenosis >/= 70%.

The Asymptomatic Carotid Atherosclerosis Study (ACAS) showed a statistically significant reduction in stroke incidence after carotid endarterectomy in asymptomatic patients with a carotid stenosis of >/= 60%.

• Prevención 1 y 2: intervenir caróticas directamente, Qx. La endarterectomia de las carótidas debe realizarse con oclusión de 70% o más del lumen

1.Clinical alert: benefit of carotid endarterectomy for patients with high-grade stenosis of the internal carotid artery. National Institute of Neurological Disorders and Stroke and Trauma Division. North American Symptomatic Carotid Endarterectomy Trial (NASCET) investigators. Stroke. 1991;22:816-817. 2.Carotid endarterectomy for patients with asymptomatic internal carotid artery stenosis. National Institute of Neurological Disorders and Stroke. J Neurol Sci. 1995;129:76-77. Abstract

SAPPHIRE: Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy

• A randomized, multicenter (29 sites) trial that compared carotid artery

stenting with distal protection (Precise nitinol self-expanding stent and the AngioGuard distal protection device) to CEA in patients at high risk for surgical treatment.

• >/= 50% stenosis in the common or internal carotid artery, assessed by ultrasound or angiography in symptomatic patients, and >/= 80% in asymptomatic patients with 1 or more comorbidity criteria.

• 723 patients enrolled. Consensus was achieved in 307 patients who were randomized to either stenting (n = 156) or CEA (n = 151). Patients who did not undergo randomization entered a stent or surgical registry.

• Stent en carótida: se desprendian fragmentos de placas, entonces no eran mejores que Qx. Ahora estudio nuevo demostró que Angioplastía con stent pero usando protección distal si estan a la altura de Qx. Entra el cateter con el balón pero antes de inflarlo se abre un filtro entonces cuando el balón dilta, si se desprende algo el filtro lo atrapa. Eso redujo los ECV q se daban.

SAPPHIRE

– Interdisciplinary approach to determine eligible (or ineligible) candidates for therapy, and surgical ineligibility based specifically on the judgment of the surgeon.

– Patients randomized to carotid stenting with embolic protection had a significantly lower 30-day rate of major adverse cardiac events (death/stroke/MI) compared with patients randomized to CEA

– There was a favorable trend for stenting in all individual endpoints in both symptomatic and asymptomatic patients and in the stent registry.

Prehospital Care

• A coordinated response that emphasizes the importance of early treatment of persons with suspected stroke is needed.

• At present, many people are not aware of the symptons of stroke. • In a recently reported US survey, 70% of respondents could name

>/= 1 established stroke warning sign (up from 57% in 1995; P < .001).

• Subpopulations at the highest stroke risk (eg, elderly, African-Americans, men) were the least knowledgeable about risk factors and stroke warning signs.

1.Schneider AT, Pancioli AM, Khoury JC, et al. Trends in community knowledge of the warning signs and risk factors for stroke. JAMA. 2003;289:343-346.

Pre-Hospital Care• 1995 en una encuesta se encontró que solo el 57%

podía mencionar aunque fuera solo un síntoma o signo del stroke.

• Las personas mayores que son los q tienen más riesgo aún tenían menos información.

• Hace 4 años, se hizo un nuevo estudio y paso de 57 a 70%.

• Si se hace “fast” puede revertirse el problema pero no se está haciendo. Lo q hay son solo 4 horas y media para realizar la reperfusión, para trombolisis con ERTPA.

Urgency Room

• Vital signs• Airway• IV’s• EKG, Echocardiogram• Chest X rays• Laboratory testing: glicemia, electrolitos, etc• Brain CT Scan• Neurologist, ICU, Internal Medicine.

Apuntes Diapositiva Anterior!

• Sistema de respuesta de alemania de ambulancias: del momento de llamada a llegada de ambulancia en 7 minutos. EEUU menos de un 5% en CR muy pocos.

• ABCD de paciente agudamente enfermo. Minimo un TAC. Se pide inmediatamente un TAC de cerebro SIN contraste para ver si es isquemico o hemorragico. Si es isquemico el tac es normal, los cambios se ven horas despues, si TAC es normal se descarta hemorragia y se tromboliza.

• Si es hemorragico cambia el panorama (rputura de aneurisma)

Penumbra

• Within minutes after an ischemic insult, there is a region of irreversibly damaged tissue. This is named the "necrotic core."

• Surrounding this necrotic core is a region of tissue that undergoes a series of preprogrammed biologic steps called the ischemic cascade that will eventually lead to death of the cells within the "ischemic penumbra." Specific actions can be taken to minimize damage to the penumbra.

• Trombolisis es para que la parte de penumbra no se muera

Stroke: CT scan after 3 hours

Parece normal!

Stroke: CT scan after 72 hours

Emergent Pharmacotherapy (Hour 0-3)

• Intravenous Thrombolysis (IVT)

– The central aim of acute stroke treatment is to restore cerebral perfusion and conserve the ischemic penumbra. Proof-of-concept for the use of reperfusion approaches in acutely ischemic cerebrovascular vascular beds derives largely from the NINDS trial.

– Intravenous thrombolysis with rtPA is the only FDA-approved regimen for patients with acute ischemic stroke seen within 3 hours of symptom onset.

– Trombolisis: se dice 0-3 horas, xq eso es lo q dice FDA pero muchos estudios han demostrado q 4,5 después todavía es benefico

1. NINDS Study Group. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333:1581-1587

2. Kwiatkowski TG, Libman RB, Frankel M, et al. Effects of tissue plasminogen activator for acute ischemic stroke at one year. National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator Stroke Study Group. N Engl J Med. 1999;340:1781-1787.

Investigational Pharmacologic Approaches (Hour 3-8)

• Intra-arterial Thrombolysis (IAT)– Certain patients with MCA occlusions may be candidates for

IAT, and multimodal MRI has shown some pathophysiologic evidence of MCA recanalization with reduced infarct volumes and enhanced clinical outcomes.

– IAT uses lower overall doses of fibrinolytic agent than IVT and thus may incur a lower risk of inter- or postictal hemorrhage.

– Prolyse in Acute Cerebral Thromboembolism (PROACT)

1.Lisboa RC, Jovanovic BD, Alberts MJ. Analysis of the safety and efficacy of intra-arterial thrombolytic therapy in ischemic stroke. Stroke. 2002;33:2866-2871

Experience in a general hospital in Costa Rica with Thrombolysis in Acute Ischemic Stroke (AIS). F Chaves-Sell; M Moreira;

R Sánchez et al.

• Since the FDA approved thrombolysis with r-TPA in AIS, we decided to develop our

own experience in a general hospital following the AAN and the AHA inclusion and exclusion criteria.

• We describe the first 7 patients treated with r-TPA and the outcome and complications that seen at onset, 24 hours and 3 months later.

• It was clear how difficult was to treat patients during the first 3 hours of stroke onset, since most of the general population and sometimes even physicians, lack information regarding the modern and right management of acute stroke.

• However we demonstrated, it is possible to use trombolysis in almost every hospital in the country with nearly the same resources we already have, promoting the creation of stroke units.

• ERTA, para trombolisis! Es el único que sirve, los otros trombolíticos más bien causan más sangrado. Con ERTA hay q poner 0,9mg/Kg. 10% en bolo y el restante en una hora.

• De los strokes isquémicos 0,6% pasan a ser hemorrágicos, pero de los iquémicos q se trombolizan 6% pasan a ser hemorráigos, pero igual se tormbolizan xq aumenta px en un 30%.

• Revneurol, in press.

Perfusion and Blood Pressure• Because of a loss of autoregulation, brain perfusion is strongly affected by

changes in systemic blood pressure.

• Hypotension and dehydration should be avoided

• No todo es trombolizar, sino que se deben dejar en UCI. Como hay perdida de autorregulación se afecta la perfusión cerebral x eso se debe evitar la hipotensión y la deshidratación

• Si un pte esta teniendo un ictus isquémicos, llega a emergencias, como va a tener la PA? alta! X el fenómeno de Cushing, si hay oclusión arriba, hay aumento de presión para que llegue sangre arriba. JAMAS se les debe bajar la presión en forma abrupta y solo se baja (despacio) si es una crisis hipertensiva Sistolicas arriba de 180-200, diastólicas arriba de 120! No es derrame x presión alta, el presión alta x derrame

Perfusion and Blood Pressure

• Hypertension, in the form of the Cushing response, is a normal response to cerebral ischemia.

• Blood pressure should not be lowered in acute stroke, except in the setting of thrombolysis or end-organ damage.

• Gravity also can have an effect on perfusion.

Normoglycemia

• Maintenance of normoglycemia is important beyond the increased risk of stroke in general in patients with diabetes. The mechanism is believed to be related to anaerobic metabolism and increased lactic acid production; the acidosis is toxic and promotes neuronal cell death.

• Hyperglycemia itself may be caused by the stress response of the event.

• In the Trial of ORG 10172 in Acute Stroke Treatment, hyperglycemia predicted worse outcome in all strokes in general and especially in non-lacunar stroke.

• Among patients treated with t-PA, absence of diabetes and admission normoglycemia predict good outcome as well.

• Evitar hipoglicemia! Hay q tenerlo normoglicemio, y es mejor un poco hiperglicémico que hipoglicemico

Fever

• Fever has been shown to be associated with worse outcome and lowering body temperature may lead to neuronal salvage by a variety of mechanisms.

• Treatment with antipyretic medications is standard. Induced hypothermia is labor intensive and costly. Cooling patients below 34° to 35°C requires intubation, sedation, and intravenous infusion of ice-cold saline.

• A recent trial failed to show lower body temperatures with cooling blankets as opposed to acetaminophen alone.

• Hipotermia protege las neuronas! El Ictus x si solo puede dar fiebre x la respuesta inflamatoria, x eso hay q tratar de bajarla. Más temperatura, se aumenta el metabolismo, de las neuronas.

Glycoprotein IIb/IIa (GP IIb/IIIa) Receptor Antagonists

Abciximab and/or other GP IIb/IIIa receptor antagonists may:

Improve microcirculation and collateral circulation in experimental stroke models.

Promote or enhance thrombolysis by downregulating platelet aggregation and thrombin generation (impeding rethrombosis)

Attenuate inflammation, dampening the cascade of reperfusion injury and limiting the "no-reflow" phenomenon.

• GP IIb/IIIa receptor blockers are currently approved to reduce ischemic and other complications (and improve outcomes) following percutaneous coronary interventions (eg, coronary angioplasty, stenting).

• Pontentes antiagregantes plquetarios que per se no han mostrado mucho avance, pero hay q ver la combinación de esto con tromboliticos

Defibrinogenating Agents

• Promising results involving a defibrinogenating agent for acute ischemic stroke:

• Stroke Treatment With Ancrod (STAT) trial involving 500 patients (mean age, ~73 years) seen within 3 hours of stroke onset (median, 2.7 hours; range, 1.5-4.0 hours).

• At 90 days, about 42% of ancrod-treated patients and 34% of controls had favorable outcomes.11.8% of patients receiving ancrod were severely disabled at 3 months, compared with 19.8% of controls (P = .01). Mortality rates in the 2 treatment arms were also similar. Infusions of ancrod, which splits fibrinopeptide A from fibrinogen, was individualized according to baseline fibrinogen levels in order to reduce plasma fibrinogen levels to 1.18-2.03 mcM.

1.Sherman DG, Atkinson RP, Chippendale T, et al. Intravenous ancrod for treatment of acute ischemic stroke: the STAT study: a randomized controlled trial. Stroke Treatment with Ancrod Trial. JAMA. 2000;283:2395-2403

Neuroprotection

• Agents designed to salvage the ischemic penumbra and prevent neuronal apoptosis-necrosis have largely failed.

• Clinical trials in which putative neuroprotective benefits conferred neither benefit nor harm have included free-radical scavengers (eg, NXY-059), the neuronal NMDA receptor antagonists gavestinel, aptiganel, and YM-90K, and agents designed to limit neuronal excitability (lubeluzole).

• Why have most clinical trials failed? – Basic study design defects: lack of statistical power and the use of unfavorable

treatment time windows and behavioral efficacy outcomes. It may not be possible to extrapolate favorable data from in vivo stroke models to the clinical setting with its heterogeneity of stroke subtypes, territories, and degrees of collateral circulation.

1.Gladstone DJ, Black SE, Hakim AM. Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions. Stroke. 2002;33:2123-2136. Abstract 2.Lees KR, Barer D, Ford GA, et al. Tolerability of NXY-059 at higher target concentrations in patients with acute stroke. Stroke. 2003;34:482-487. Abstract 3.Lees KR, Asplund K, Carolei A, et al. Glycine antagonist (gavestinel) in neuroprotection (GAIN International) in patients with acute stroke: a randomised controlled trial. GAIN International Investigators. Lancet. 2000;355:1949-1954

Oral Citicoline in Acute Ischemic Stroke

• An Individual Patient Data Pooling Analysis of Clinical Trials• Antoni Dávalos, MD, PhD; José Castillo, MD, PhD; José Álvarez-Sabín, MD,

PhD;Julio J. Secades, MD, PhD; Joan Mercadal, BS; Sonia López, BS; Erik Cobo, MD, PhD;Steven Warach, MD, PhD; David Sherman, MD; Wayne M. Clark, MD; Rafael Lozano, MD

• Background and Purpose: the objective was to evaluate the effects of oral citicoline in patients with acute ischemic stroke by a data pooling analysis of clinical trials.

• Evaluation of recovery: National Institutes of Health Stroke Scale 1, modified Rankin Scale score1, and Barthel Index 95 at 3 months.

• Medicamentos neuroprotectores: no se ha logrado mayor cosa. La citicolina, muestra evidencia DEBIL de ptes agudos tratados con citicolina tienen mejor px pero es evidencia debil

Citicoline in Acute Stroke?

• Methods—A systematic search of all prospective, randomized, placebo-controlled, double-blind clinical trials with oral citicoline (MEDLINE, Cochrane, and Ferrer Group bibliographic databases)

• Results—Of 1652 randomized patients, 1372 fulfilled the inclusion criteria (583 received placebo, 789 received citicoline).

• Recovery at 3 months was 25.2% in citicoline-treated patients and 20.2% in placebo-treated patients (odds ratio [OR], 1.33; 95% CI, 1.10 to 1.62; P0.0034).

• Conclusions—Treatment with oral citicoline within the first 24 hours after onset in patients with moderate to severe stroke increases the probability of complete recovery at 3 months. (Stroke. 2002;33:2850-2857.)

Preventing Complications

• Hospital-acquired infections are frequent complications. Aspiration pneumonia is usually caused by inability to protect the airway in combination with atelectasis from immobility. Before feeding, patients should be screened for swallowing risks and a speech pathologist should be consulted.

• Urinary tract infections are usually caused by indwelling catheters. These catheters are often unnecessary and should be removed as soon as possible. A rapid urinary catheter protocol can be useful in this regard.

• Constipation leading to gastrointestinal distress is also a frequent occurrence.

• Prevent Brain Edema!• Trombos, broncoaspiración, infecciones (princaalmente pulmonar y

renal)

Investigational Nonpharmacologic Interventions

• Extracranial-intracranial (EC-IC) bypass or embolectomy (eg, for a limited number of patients with MCA emboli)

• Endovascular treatments:– Mechanical clot disruption or removal (MCA occlusions)– Direct balloon angioplasty of thrombus– Stenting– Suction thrombectomy– Laser or Doppler-assisted thrombolysis.

Stroke Units

• Twenty three trials were included. Compared with alternative services, stroke unit care showed reductions in the odds of death recorded at final (median one year) followup (odds ratio 0.86; 95% confidence interval 0.71 to 0.94; P=0.005), the odds of death or institutionalised care (0.80; 0.71 to 0.90; P=0.0002) and death or dependency (0.78; 0.68 to 0.89; P=0.0003).

• Stroke patients who receive organised inpatient care in a stroke unit are more likely to be alive, independent, and living at home one year after the stroke. The benefits were most apparent in units based in a discrete ward. No systematic increase was observed in the length of inpatient stay.

• Ptes de ictus en mejores unidades evolucionan mejor que tratados en salones generales!

Cochrane Rev Abstract 2004. © 2004 The Cochrane Collaboration

La Consultation. JM Charcot