Stroke Treatment Advances

1
Stroke Treatment Advances

• Franz Chaves Sell
• Neurology, Hospital Clínica Bíblica, San José,
  Costa Rica
• Academia Nacional de Medicina
• SIECV

2
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

3
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

4
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

5
Stroke subtypes in Spain, Latin America and The
Caribbean
En asiáticos y en indígenas americanos lo q
predomina es enfermedad de pequeños
vasos Blancos, europeos, caucásicos predomina
enfermedad de grandes vasos, Cerebral media,
cerebral posterior.
Cerebral vein thrombosis, when included 4-8 of
all strokes
6
Days lived with disability from stroke in
different regions of the World and compared to
other diseases (from WHO 2002)
Cuadro 5. Años de vida vividos con discapacidad
(DALYs) por ECV en diferentes continentes y en
comparación con otras enfermedades comunes.
Adaptado en base a estimados de la Organización
Mundial de la Salud para el Año 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.
7
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.

8
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.

9
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.

10
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
11
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.

12
Fisiopatología
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 isquemia Hipocapnia
vasocontricción

• Circulación CerebralAutorregulada
• Incremento Presión Arterial
• Constricción Vascular Cerebral
• NOTA Presión de CO2 ------- afecta!!!

13
Fisiopatología

• CEREBRO 2 masa corporal
• consume 15 de gasto cardíaco
• Circulación Cerebral Normal
• 55ml / 100g / min
• lt 15 ml / 100g / min DAÑO

14
Flujo Vascular Cerebral

• lt 55 ml/100g/min Inhibe síntesis de proteínas
• lt 35 ml/100g/min Metabolismo anaerobio de la
  glucosa
• lt 25 ml-100g-min ATP, Lactato
• lt 15 ml-100g-min gradientes iónicos
• Despolarización y muerte por radicales libres
• AREA DE PENUMBRA ISQUÉMICA

15
Mecanismos de Lesión Celular
GLUCOPENIA Muerte Neuronal
3 min.
5 min.
40
9 min.
Cambios EEG (plano)
30
20
10 15 Síncope
0
O2
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17
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.
18
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).

• Shinton R, Beevers G. Metaanalysis of relation
  between cigarette smoking and stroke. BMJ 1989
  298 789-794.
• Wolf PA. Cigarettes, alcohol, and stroke. N Engl
  J Med 1986 315 1087-1089.
• 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.
• 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.

19
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!

• 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.
• 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.

20
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-e
   nzyme inhibitor, ramipril, on cardiovascular
   events in high-risk patients The Heart Outcomes
   Prevention Evaluation Study Investigators. N Engl
   J Med 2000 342 145-153.

21
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.

• 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.
• 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.

22
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!

• 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.
• 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.
• 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.
• 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.

23
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.
24
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 lt 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!

• 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.

25
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

26
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.

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

27
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.

28
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.

29
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.

• 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.

30
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.
31
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. .
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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

34
The North American Symptomatic Carotid
Endarterectomy Trial (NASCET)

• NASCET demonstrated the superiority of
  endarterectomy over medical treatment for
  symptomatic carotid stenosis gt/ 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 gt/ 60.
• Prevención 1 y 2 intervenir caróticas
  directamente, Qx. La endarterectomia de las
  carótidas debe realizarse con oclusión de 70 o
  más del lumen

35
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.
• gt/ 50 stenosis in the common or internal
  carotid artery, assessed by ultrasound or
  angiography in symptomatic patients, and gt/ 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.

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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.

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38
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 gt/ 1 established stroke
  warning sign (up from 57 in 1995 P lt .001).
• Subpopulations at the highest stroke risk (eg,
  elderly, African-Americans, men) were the least
  knowledgeable about risk factors and stroke
  warning signs.

• Schneider AT, Pancioli AM, Khoury JC, et al.
  Trends in community knowledge of the warning
  signs and risk factors for stroke. JAMA.
  2003289343-346.

39
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.

40
Urgency Room

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

41
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)

42
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

43
Stroke CT scan after 3 hours
Parece normal!
44
Stroke CT scan after 72 hours
45
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

• 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. 19953331581-1587
• 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. 19993401781-1787.

46
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)

• Lisboa RC, Jovanovic BD, Alberts MJ. Analysis of
  the safety and efficacy of intra-arterial
  thrombolytic therapy in ischemic stroke. Stroke.
  2002332866-2871

47
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.

48
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

49
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.

50
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

51
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 35C
  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.

52
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

53
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.

• 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. 20002832395-2403

54
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.

• Gladstone DJ, Black SE, Hakim AM. Toward wisdom
  from failure lessons from neuroprotective stroke
  trials and new therapeutic directions. Stroke.
  2002332123-2136. Abstract
• Lees KR, Barer D, Ford GA, et al. Tolerability of
  NXY-059 at higher target concentrations in
  patients with acute stroke. Stroke.
  200334482-487. Abstract
• 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. 20003551949-1954

55
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, PhDJulio J. Secades, MD,
  PhD Joan Mercadal, BS Sonia López, BS Erik
  Cobo, MD, PhDSteven 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

56
Citicoline in Acute Stroke?

• MethodsA systematic search of all prospective,
  randomized, placebo-controlled, double-blind
  clinical trials with oral citicoline (MEDLINE,
  Cochrane, and Ferrer Group bibliographic
  databases)
• ResultsOf 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).
• ConclusionsTreatment 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. 2002332850-2857.)

57
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)

58
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.

59
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 P0.005), the
  odds of death or institutionalised care (0.80
  0.71 to 0.90 P0.0002) and death or dependency
  (0.78 0.68 to 0.89 P0.0003).
• 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!

60
La Consultation. JM Charcot