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: Patients with presumed stroke final diagnosis of stroke age ‹ 80 and duration ‹ 3hrs received rt-PA 453 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 PCRT’s: 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 - @ 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 @ 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.