Acute Stroke: Lecture Notes

Epidemiology

  • Stroke is the third commonest cause of death (11%), and the commonest cause of adult disability in western world.
  • 80-85% are ischaemic (thrombotic or embolic) and 15-20% the more lethal haemorrhagic stroke, of which over 50% will die.

Active Management

Early CT scan

  • Ideally within 1 hour ED arrival, if any of: indications for lysis or early anticoagulation; on warfarin; known bleeding tendency; depressed GCS <13; unexplained progressive or fluctuating symptoms; suspected meningitis; severe headache at onset.
  • Otherwise within 24 hours (see later).

General supportive (see under Stroke Units / Teams below)

  • Airway protection, correction of hypoxia, treatment of hypoglycaemia or hyperglycaemia, treatment of infection, maintenance of normothermia, avoidance of aspiration, and pressure area care if unconscious.
  • Consider BP control, though no agent significantly affects outcome.
  • Calcium channel blockers (nimodipine / nicardipine), ACEI, and GTN all have been used. Note thrombolysis requires SBP < 185/ DBP < 110 mmHg to qualify.
  • Avoidance of hypotension equally important.

Cochrane Database Syst Rev 2006 Issue 3 [Reference]

Antiplatelet treatment:

  • Aspirin 300 mg orally (or via NGT / PR) early and then daily if stroke is non-haemorrhagic on CT or for TIA, ideally within first 24 hours. Far greater benefit (15-fold) with less risk than use of lysis or anticoagulation (see later). Continue for at least 2 weeks.
  • Addition of dipyridamole 200 mg po bd for TIAs and minor ischaemic stroke preferred, but note more side effects including headache!

Sudlow C. Give dipyridamole with aspirin instead of aspirin alone to prevent vascular events after ischaemic stroke or TIA. BMJ 2007;334:901. [Reference]

Sudlow C. Preventing further vascular events after a stroke or transient ischaemic attack: an update on medical management. Practical Neurology 2008; 141-157 [Reference]

The ESPRIT Study Group. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 2006; 367:1665-73. [Reference]

Anticoagulant treatment:

  • No net advantages of heparin over antiplatelet agents. No clear advantages of LMWH / heparinoids over UFH. Need more data.
  • LMW or UF heparin reduce DVT/PE, but not stroke deaths or dependency. Glycoprotein IIb/IIIa antagonists have an unknown effect.

Sandercock P, Counsell C, Tseng M-C. Low-molecular weight heparins or heparinoids versus standard unfractionated heparin for acute ischaemic stroke. Cochrane Database Syst Rev 2007:3. CD000119. [Reference]

Thrombolysis:

  • Treatment with tPA within 3 hours of onset in adults > 18 and < 80 years most promising in overall reduction in death / disability, when given in experienced centres, in highly selected patients, where a licence for its use exists ie. not recommended for widespread clinical use. Also still not clear what the optimal adjunctive therapy is.

National Institute for Health and Clinical Excellence. Alteplase for the treatment of acute ischaemic stroke. NICE Technology Appraisal Guidance 122. June 2007. [Reference]

  • Safe and effective use of lysis within 3 hours of symptom onset in routine clinical use appears to have been validated by SITS-MOST post-marketing surveillance, rather than just in trial hospitals. However, note SITS-MOST excluded patients who were very elderly > 80 years, most severe with NIHSS scores > 25, hypertensive > 185/110 mmHg, and if treated outside of 3 hours.

Wahlgren N, Ahmed N, Davalos A et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation fo Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet 2007;369:275-82. [Reference] Editorial: Albers G, Olivot J-M. Lancet 2007;369:249- 50. [Reference]

  • Original Cochrane database report had 18 trials to 2003 using urokinase, streptokinase, recombinant tPA or recombinant pro-urokinase with 5727 patients studied (of which over 50 % received tPA), although very few patients over 80 years.
  • Overall significant net reduction in death or dependency (OR 0.84, or 0.80 for tPA). However, this was with an increase in death in first 7-10 days from ICH (4.34%, or 3.60% for tPA), and of symptomatic ICH (3.37%, or 3.13% for tPA). Also noted an increase in deaths at follow up at 3-6 months (OR 1.33, or 1.17 but non-significant for tPA).
  • Disagreement on lysis use between ‘antagonists’ who believe benefit of tPA is unproven, at best marginal with significant safety issues, and that ‘effectiveness’ in a community setting is far different from ‘efficacy’ in a trial situation.

Hurley J. MJA 188:488. [Reference] Toncich G. MJA 188:489. [Reference] Fatovich D MJA 188:489. [Reference]

Hoffman J. Thrombolysis for stroke: Policy should be based on science, and not on politics, money or fear of malpractice. Emerg Med Australas 2006; 18:215-218. [Reference]

  • And ‘protagonists’ who are dismayed that “a clear benefit” of tPA in trials and in routine practice …” with an absolute benefit that exceeds lysis in AMI“… has not translated into more enthusiastic adoption of this therapy, that is underused.

Davis S, Hand P, Donnan G. Tissue plasminogen activator for ischaemic stroke: highly effective, reasonably safe and grossly underused. MJA 2007;187:548-9. [Reference] [Reference]

Levi C. Tissue plasminogen activator (tPA) in acute ischaemic stroke: time for collegiate communication and consensus. MJA 2004; 180: 634-5. [Reference]

  • National Institute of Neurological Disorders and Stroke (NINDS) study 1995 is traditionally the main positive outcome trial, using tPa (note MRIs were not utilised). NINDS results included:
    • 12 % additional patients improved neurological outcome at 3 months over placebo.
    • 6 % additional symptomatic intracerebral haemorrhage, of which half died, although no overall mortality difference versus placebo at 3 months.
    • Majority (> 80%) no difference.

Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. NEJM 1995; 333: 1581-7 [Reference]

  • However, ultimately still less than 5% of all stroke patients will be eligible, as need to:
    • present and have CT demonstrating absence of intracerebral haemorrhage ie. an ischaemic stroke, within 3 hours of onset of symptoms. MRI may become the standard imaging necessary…
    • have no contraindications to lysis. These include minor symptoms only (ie. ataxia, minor sensory loss, dysarthria alone); major symptoms that are rapidly improving; SBP >185 / DBP >110 mmHg; previous ICH/SAH/neoplasm; seizure at stroke onset; recent trauma/surgery; bleeding diathesis/use of heparin or warfarin; other GI/urinary bleeding etc.
  • Dose is tPA 0.9 mg/kg IV (not to exceed a total 90mg dose, regardless of the patient’s weight). A 10% bolus is given intravenous push over one minute. The remaining 90% is infused over 60 minutes via an infusion pump.

Warlow C, Wardlaw J. Therapeutic thrombolysis for acute ischaemic stroke. BMJ 2003; 326: 233-4. [Reference]

Khaja A, Grotta J. Established treatments for acute ischemic stroke. Lancet 2007; 369: 319-30. (Good overview) [Reference]. Editorial. Albers G, Olivot J-M. Lancet 2007; 369: 249-50. [Reference]

Neuroprotective agents

  • Glutamate (excitatory amino acids) receptor antagonists or glutamate release inhibitors, magnesium as an NMDA blocker, other ion channel blockers, free radical scavengers, NO donors or NO synthase inhibitors, gangliosides, fibrinogen depleting agents, membrane stabilisers, monoclonal antibodies to adhesion molecules, statins.
  • No definitive success yet, but combination therapies may be shown to have greatest value.
  • Induced hypothermia is being investigated to ‘buy time’.

Sacco R, Prabhakaran S, Elkind M. Experimental treatments for acute ischemic stoke. Lancet 2007; 369:331-41. [Reference]

Other Considerations

Dedicated stroke unit +/- multidisciplinary stroke teams.

  • Streamlining of care, abandoning previous nihilistic approach to stroke. Stroke teams/unit reduce death or dependency at 1 year from 62% to 56.4% (NNT 18), with an absolute risk reduction for mortality of 3% and need for institutional care by 2%.
  • Features studied in trials include assessment and monitoring with protocols for medical, nursing and therapy; early management including physiological management, early mobilisation and nursing care; and multidisciplinary team rehabilitation.

Candelise L, Gattinoni M, Bersano A et al. Stroke-unit care for acute stroke patients: an observational follow-up study. Lancet 2007; 369: 299-305. Editorial Lancet 2007; 369: 254-5. [Reference]

Langhorne P, Dennis M. Stroke units: the next 10 years. Lancet 2004; 363: 834-5. [Reference]

  • Co-operation between emergency medicine, neurology, general and geriatric medicine, neuroradiology, neurosurgery, intensive care, as well as nursing, OT, physio, speech therapy, rehab plus public education programs ensuring rapid recognition, liaison with GPs and EMS are necessary.24 hour access to high resolution CT and/or MRI with experienced personnel reporting. Also availability of ECG, Doppler USS, echocardiography, ICP monitoring are ideal.

Primary prevention

  • Treatment of high risk patients with significant hypertension or AF, and by reducing risk factors in the general population such as smoking.
  • Non-valvular AF may be treated to reduce risk of stroke with aspirin (ARR 1.7%, NNT 59) or warfarin (ARR 3.1%, NNT 32), although warfarin causes over twice as many ICH, especially over age 75 years.
  • Interest in newer agents such as oral direct thrombin inhibitor ximelagatran, that is “non-inferior” to warfarin but fewer side effects.

Eikelboom J, Hankey G. The beginning of the end of warfarin? MJA 2004; 180: 549-51. [Reference]

Secondary prevention.

  • Transient ischaemic attack (TIA) with stroke symptoms and signs (numbness, weakness or paralysis, slurred speech, blurred vision, confusion) that resolve within 24 hours has forward risk of stroke of 3.9% at 2 days, 5.5% at 7 days and 9.2% at 90 days.

Hankey G. The ABCD, California and unified ABCD2 risk scores predicted stroke within 2, 7, and 90 days after TIA. Evid Based Med 2007;12:88. [Reference]

  • 15-30% patients presenting with ischaemic stroke recall a history of a preceding TIA, and in these 17% had the stroke on the same day, 9% the day after the TIA and 43% the stroke followed the TIA within 7 days.

Rothwell P, Warlow C. Timing of TIAs preceding stroke. Neurology 2005; 64:817-20. [Reference]

  • ABCD2 TIA Scoring Tool scores 2 for unilateral weakness, or duration of symptoms ≥ 60 mins; and 1 for each of age ≥ 60 yrs, SBP ≥140 mmHg or DBP ≥90 mmHg, speech disturbance without motor weakness, duration of symptoms 10-59 mins, or diabetes.

Johnston S, Rothwell P, Nguyen-Huynh M et al. Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack. Lancet 2007; 369: 283-92. Editorial Lancet 2007; 369: 251-2. [Reference]

  • ‘High risk’ ABCD2 Scoring Tool group with score 6-7 have 2-day stroke risk of 8.1%, ‘moderate risk’ with score 4-5 have 4.1% stroke risk, so ideally need immediate admission (ie. not sent home). Cost-utility of admission proven. Also admit patients with ‘crescendo TIAs’.
  • ‘Low risk’ have score 0-3 with a 1.0% 2-day stroke rate may be managed as an outpatient, ideally within one week.
  • These data have major implications for the timing of urgent out patient medical assessment including Doppler carotids +/- stroke clinic review.
  • Stop smoking, BP control, lipid lowering drugs (statins), antiplatelet drugs (aspirin plus dipyridamole), anticoagulation (warfarin), carotid endarterectomy etc.

The Lancet. Stroke – prevention is better than cure. Lancet 2007; 369:247. [Reference]

National Institute for Health and Clinical Excellence. Stroke. Diagnosis and initial management of acute stroke and transient ischaemic attack (TIA). Quick reference guide. NICE Clinical Guideline 68. July 2008 [Reference - PDF]

Lancet 2007; 369: January 27th www.thelancet.com Issue dedicated to stroke management with massive amount of data available (often interpreted in different ways!)

The Cochrane Collaboration. Currently there are 163 stroke guidelines or reviews listed [Reference] plus some new titles in preparation. All available at http://www.cochrane.org/reviews/en/topics/93.html.

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