acute ischemic stroke stroke therapeutic options in the thrombolytic era m. r. angle mnh april 1999

Acute Ischemic Stroke

StrokeStrokeTherapeutic Options in the

Thrombolytic Era

M. R. Angle

MNH

April 1999


ThrombolysisThrombolysis

rt-PA .9 mg/kg, max 90 mg

onset to treatment ‹ 180 min

usual exclusions (esp. elevated BP)

n = 624

NINDS rt-PA trial NEJM 1995


no/minimal disability at 3 months: rt-PA 50% vs control 38%odds ratio 1.7 (C.I. 1.2 to 2.6)

intra-cranial hemorrhage:rt-PA 6.4% vs control 0.6%

mortality:rt-PA 17% vs control 21%

benefit accrued independent of stroke sub-type and severity

8.8 patients treated to achieve one additional good outcome

NINDS ‘95: results NINDS ‘95: results

Acute Ischemic StrokeThe Brain AttackThe Brain Attack

Grond ‘98

City of Cologne, pop. 1,000,000

single stroke center

EMT triage stroke symptoms ‹ 3 hrs age ‹ 80 yrs reasonable level of consciousness

outcome results similar to/better than NINDS cohort


The Brain AttackThe Brain AttackGrond ‘98

recruitment

to all hospitals: to Stroke Center:

4032 453Patients with presumed stroke

final diagnosis of stroke

age ‹ 80 and duration ‹ 3hrs

received rt-PA

402

1950 245

149

100


ThrombolysisThrombolysisLessons:

the current therapeutic window is 3 hrs from symptom onset

most deaths occur amongst protocol violations

benefits are modest but real and enduring (5 yrs)

relatively few patients will actually benefit from this technology alone


ThrombolysisThrombolysis

increasing recruitment– public stroke awareness– systems improvement

expanding the therapeutic window– neuroprotective agents– individualized protocols

refining the target population– functional imaging (MRI, XeCT)

Future Directions:


NeuroprotectionNeuroprotection

Failed PCRT’s:

heparin

ASAtirilizadlubeluzole (‹ 6% benefit)eliprolil

selfotelenlimomabaptiganeldanaparoidpiracetam

Untested but exciting: melatonin

CASPase inhibitors

anti-adhesion molecule inhibitors


(Indredravik; Stroke ‘97)

stroke unit care vs. general ward care

relative risk of death and dependency decreased by 9%

relative risk of death and institutionalization decreased by 18%

accrued benefit related to staff interest and expertise, protocol

driven care, interdisciplinary coordination

cost-effective and enduring

Stroke UnitsStroke Units

Acute Ischemic StrokeNutritionNutrition

(Davalos, Stroke ‘96)

acute stroke patients demonstrate a stress-response

driven, catabolic state for 7-10 days

indices of ‘malnutrition’ at 7 days predict a poor outcome

(odds ratio 3.5, C.I. 1.2-10.2)

uncertain whether malnutrition is a marker of severity or

an independent contributor to poor outcome

no evidence that early feeding alters the catabolic course


Caloric RestrictionCaloric Restriction

shown to retard age-related neuropathic changes and

prolong life in a broad range of animal species

presumed to decrease the leak of oxyradicals from

mitochondria

significantly reduces injury in several models of excito-

toxicity

reduces post-ischemic gene expression and infarct

volume


HyperglycemiaHyperglycemia

extensive laboratory data shows increasing injury with hyperglycemia, pre-, during and post-ischemia, focal and global

extensive epidemiological data shows outcome inversely related to blood glucose in non-lacunar stroke

no demonstrable threshold value - mild hypoglycemia may be beneficial


HyperglycemiaHyperglycemiaBruno, Neurology ‘99

post-hoc analysis 1259 patients from TOAST study

odds ratio .82/100 mg % for good outcome

deleterious in all non-lacunar strokes

deleterious in treated lacunar strokes


HyperglycemiaHyperglycemiaPotential mechanisms of injury:

1. increased penumbral acidosis

2. increased BBB injury on reperfusion

3. dysregulated post-ischemia gene expression

4. impaired vascular responses to flow and pressure

5. upregulated NMDA receptor activity


HyperthermiaHyperthermia

experimentally, enhances injury and worsens outcome

in trauma and both global and focal ischemia

threshold temperature (37.5 oC - ax) common post-

stroke - @ 60% over first 72 hours

hyperthermia during first 24 hours strongly associated

with mortality and poor outcome

odds ratio 3.2, [C.I. 1.7 - 5.5]


HyperthermiaHyperthermiaPotential mechanisms of injury:

1. enhanced penumbral metabolic rate

2. increased BBB injury post-reperfusion

3. enhanced ischemia-induced expression of

excitotoxic amino-acids

4. vascular dysregulation


HypertensionHypertension

common and self-limited

no current treatment recommendations below

threshold value 210/120

strongly associated with poor outcome in thrombolytic

trials

NINDS ‘95: no adverse outcome of conservative

treatment at 185/110 mmHg


HemisphericHemisphericInfarctionInfarction

younger cohort, › 50% mca hypodensity

80% mortality with conservative treatment

predicted by deteriorating level of consciousness,

nausea and vomiting, › 3mm midline shift at 36 hours

early signs related to distortion, late signs to ICP and

herniation


HemicraniectomyHemicraniectomy

strong experimental support for early decompression

preliminary human data (n = 63) confirming @ 80%

survival and generally good outcome

(Shwab, Stroke ‘98)


Hemispheric Hemispheric InfarctionInfarction

Treatment Options:

1. no intervention

2. hyperosmolar agents (Shwartz, Stroke ‘98)

3. hypothermia (Shwab, Stroke ‘98)

4. barbiturate coma (Shwab, Neurology, ‘97)

5. hemicraniectomy +/- debulking


Adjunctive TherapiesAdjunctive Therapies

1. Steroids deleterious

2. Hemodilution no effect

3. O2 therapy untested but deleterious in vitro

4. Albumin decreased oedema and infarct volume in animals

5. Hyperosmolar untested; hypertonic saline agents possibly more effective

6. Naloxone uncorroborated report of benefit in early stroke


ConclusionsConclusions19991999

meticulously controlled thrombolysis programs offer

real benefit to relatively few,

extending the benefit of thrombolysis will involve

considerable investment in public education and the

development of neuroprotective agents,

stroke units, and careful avoidance of well

documented co-morbid factors, offer immediate

benefit to the many.

acute ischemic stroke stroke therapeutic options in the thrombolytic era m. r. angle mnh april 1999

Documents