Acute Ischemic Stroke Therapeutic Options in the Thrombolytic

Acute Ischemic Stroke Therapeutic Options in the Thrombolytic Era M. R. Angle MNH April 1999

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 Acute Ischemic Stroke

NINDS ‘ 95: results Acute Ischemic Stroke ð no/minimal disability at 3 months: rt-PA 50% vs control 38% odds ratio 1. 7 (C. I. 1. 2 to 2. 6) ð intra-cranial hemorrhage: rt-PA 6. 4% vs control 0. 6% ð mortality: rt-PA 17% vs control 21% ð benefit accrued independent of stroke sub-type and severity ð 8. 8 patients treated to achieve one additional good outcome

The Brain Attack Acute Ischemic Stroke Grond ‘ 98 ¨ City of Cologne, pop. 1, 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

Acute Ischemic Stroke The Brain Attack Grond ‘ 98 recruitment to all hospitals: to Stroke Center: 4032 Patients with presumed stroke 453 1950 final diagnosis of stroke 245 age ‹ 80 and duration ‹ 3 hrs 149 received rt-PA 100 402

Acute Ischemic Stroke 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

Acute Ischemic Stroke Thrombolysis Future Directions: ¨ increasing recruitment – public stroke awareness – systems improvement ¨ expanding therapeutic window – neuroprotective agents – individualized protocols ¨ refining the target population – functional imaging (MRI, Xe. CT)

Acute Ischemic Stroke 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

Stroke Units Acute Ischemic Stroke (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

Nutrition Acute Ischemic Stroke (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 Restriction Acute Ischemic Stroke ¨ 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 excitotoxicity ¨ reduces post-ischemic gene expression and infarct volume

Hyperglycemia Acute Ischemic Stroke ¨ 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

Acute Ischemic Stroke 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

Acute Ischemic Stroke 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

Acute Ischemic Stroke Hyperthermia ¨ experimentally, enhances injury and worsens outcome in trauma and both global and focal ischemia ¨ threshold temperature (37. 5 o. C - ax) common poststroke - @ 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]

Acute Ischemic Stroke 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

Acute Ischemic Stroke 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 mm. Hg

Acute Ischemic Stroke Hemispheric Infarction ¨ younger cohort, › 50% mca hypodensity ¨ 80% mortality with conservative treatment ¨ predicted by deteriorating level of consciousness, nausea and vomiting, › 3 mm midline shift at 36 hours ¨ early signs related to distortion, late signs to ICP and herniation

Acute Ischemic Stroke Hemicraniectomy ¨ strong experimental support for early decompression ¨ preliminary human data (n = 63) confirming @ 80% survival and generally good outcome (Shwab, Stroke ‘ 98)

Hemispheric Infarction Acute Ischemic Stroke 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 Therapies Acute Ischemic Stroke 1. Steroids deleterious 2. Hemodilution no effect 3. O 2 therapy untested but deleterious in vitro 4. Albumin 5. Hyperosmolar agents 6. Naloxone decreased oedema and infarct volume in animals untested; hypertonic saline possibly more effective uncorroborated report of benefit in early stroke

Conclusions 1999 Acute Ischemic Stroke ¨ 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.