Stroke

1
Stroke

• Therapeutic Options in the Thrombolytic Era

M. R. Angle MNH April 1999
2
Thrombolysis
NINDS rt-PA trial NEJM 1995

• rt-PA .9 mg/kg, max 90 mg
• onset to treatment 180 min
• usual exclusions (esp. elevated BP)
• n 624

3
NINDS 95 results

• 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

4
The Brain AttackGrond 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

5
The Brain AttackGrond 98

• recruitment
• to all hospitals to Stroke Center

453
Patients with presumed stroke final diagnosis of
stroke age 80 and duration 3hrs received rt-PA
4032
1950
245
402
149
100
6
Thrombolysis

• Lessons
• 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

7
Thrombolysis
Future Directions

• increasing recruitment
• public stroke awareness
• systems improvement
• expanding the therapeutic window
• neuroprotective agents
• individualized protocols
• refining the target population
• functional imaging (MRI, XeCT)

8
Neuroprotection

• Failed PCRTs
• heparin
• ASA
• tirilizad
• lubeluzole ( 6 benefit)
• eliprolil

selfotel enlimomab aptiganel danaparoid piracetam
Untested but exciting melatonin CASPase
inhibitors anti-adhesion molecule inhibitors
9
Stroke Units

• (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

10
Nutrition

• (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

11
Caloric 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

12
Hyperglycemia

• 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

13

• Hyperglycemia
• Bruno, 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

14
Hyperglycemia

• Potential 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

15
Hyperthermia

• experimentally, enhances injury and worsens
  outcome in trauma and both global and focal
  ischemia
• threshold temperature (37.5 oC - ax) common
  post-stroke - _at_ 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

16
Hyperthermia

• Potential 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

17
Hypertension

• 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

18
HemisphericInfarction

• 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

19
Hemicraniectomy

• strong experimental support for early
  decompression
• preliminary human data (n 63) confirming _at_ 80
  survival and generally good outcome (Shwab,
  Stroke 98)

20
Hemispheric Infarction

• 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

21
Adjunctive 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
22
Conclusions1999

• 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.