By Mohammad Binhussein & Ahmad Abolaban

2. Stroke Treatment By Mohammad Binhussein & Ahmad Abolaban

3. General Supportive Care and Treatment of Acute Complications • ABC: -Oxygen mask with a target oxygen saturation level 92% -endotrachealtube should be placed if the airway is threatened (e.g. decreasedconsciousness, who have bulbar dysfunction or GCS<8 )

4. General Supportive Care and Treatment of Acute Complications ABC: Nonhypoxic patients with acute ischemic stroke do not need supplementaloxygen therapy (Class III, Level of Evidence B) (5)

5. General Supportive Care and Treatment of Acute Complications • Hyperbaric oxygen ?? used to treat patients with ischemicneurological symptoms secondary to air embolism or caisson disease (5) A systematicreview found no evidence that hyperbaric oxygen improved outcomesafter stroke or brain injury (5)

6. General Supportive Care and Treatment of Acute Complications • Temperature : (hyperthermia increases ischaemic neuronal injury) sources ofinfection (pneumonia or urinary tract) should be treated withantibiotics, fever should be treatedand antipyretic medications should beadministered to lowertemperature in febrile patients with stroke (5)

7. General Supportive Care and Treatment of Acute Complications • Arterial hypertension : lowering BPs may cause under perfusion of ischaemic penumbra

8. General Supportive Care and Treatment of Acute Complications • Arterial hypertension : Only Patientswho have other medicalindications for aggressive treatmentof blood pressure shouldbe treated e.g. AMI

9. General Supportive Care and Treatment of Acute Complications • Arterial hypertension : medicationsshould be withheld unless the systolicblood pressure is >220mm Hg or the diastolic blood pressureis >120 mm Hg (5) A reasonablegoal would be tolower blood pressure by 15% during first24 hours afteronset of stroke (5)

10. General Supportive Care and Treatment of Acute Complications • Arterial hypotension : In exceptional cases, a physician may prescribe vasopressorsto improve cerebral blood flow. If drug-induced hypertensionis used, close neurological and cardiac monitoring is recommended (5) Causes include: 1-Hypovolemia 2-Cardiac arrhytmias decrese cardiac out put

11. General Supportive Care and Treatment of Acute Complications • Hyperglycemia and hypoglycemia • Hydration Dehydration is a potential cause ofdeep vein thrombosis (5) gives 50ml/hr’s NS.

12. General Supportive Care and Treatment of Acute Complications • Nutrition : An assessmentof the ability to swallow is important before the patient isallowed to eat or drink Patients who cannot take food and fluids orally should receivenasogastric, nasoduodenal, or PEG feedings to maintain hydrationand nutrition (5)

13. General Supportive Care and Treatment of Acute Complications • Nutrition : Early vs. delayrd enteral feeding for stroke patient with dysphagia ?? Food study included two randomized trials that answer this question and shows that : early feeding with enteral nutrition does not appear to improve outcomes . And the 5% increase in survival was offset by an increase in pt. with extremely poor functional outcomes (i.e. bedridden state or needs assistance with walking and bodily needs) (6)

14. General Supportive Care and Treatment of Acute Complications • Activity : Aspiration precaution , head of the bed elevation to 30̊ physical therapy (3) &Early mobilization of less severely affected patients (5) Subcutaneous administrationof anticoagulants is recommendedfor treatment of immobilizedpatients to prevent deep vein thrombosis

15. General Supportive Care and Treatment of Acute Complications • Activity : Theuse of intermittent external compression devices is recommendedfor treatment of patients who cannot receive anticoagulants (5)

17. Acute stroke treatment Aim : • 1- restore perfusion to ischemic tissue (Thrombolytic agent) • 2- limit the ischemic cascade of biochemical events (Neuroprotective agent)

18. Ischaemic Penumbra (3) • Acute occlusion causes heterogeneous regions of ischaemia. • Local flow depends on major arterial source and any collateral. • Region without flow is the CORE • Cells die within minutes. • Marginal perfusion = PENUMBRA. • Tissue can remain viable for hours. • Therapies targeted to protecting these tissues.

19. Acute stroke treatment • Thrombolytic agent: used within 3 hours from the onset of ischemic stroke Approved as a result of trial that use rt-PA on 625 patient and show 11% absolute increase in number of pt. with no or little deficits compared to placebo . (1) NINDS

20. Acute stroke treatment • Thrombolitic agent: Three trials (ECASS, ECASS ll and ATLANTIS) shows no benefit of IV rt-PA over placebo if received after 3 hr’s. (1) And shows higher incidence of parenchymal hemorrhage (19.8% vs 6.5% in ECASS) and (7% vs 1.1% in ATLANTIS study) . (1)

21. Acute stroke treatment • And also confirm the clinical benefit of rt-PA shown in the NINDS trial. • So, strict adherence to the guide line is essential for safety of patient. • But only a small fraction of patients meet the NINDS criteria • The new drug ( Desmoteplase ) in a trial shows a promising theraputic option.

22. Caution • The use of anticoagulantsand antiplatelet agents should be delayed for 24 hours aftertreatment • potential sideeffect of angioedema that may cause partialairway obstruction Careful systolic blood pressureis ≤185 mm Hg andtheir diastolic blood pressure is ≤ 110 mm Hg and maintained below 180/105mm Hg for atleast the first 24 hours (5)

23. Prognosis post Thrombolysis. Neurological deficit: post tPA : 30 % normal or minimal neurological problems. 30%mild to moderate deficit 20% moderate to severe problems 20 % mortality Functional disability: 3/12 post tPA : 50% with complete or almost complete independent functioning. 15% moderate dependence 15% complete dependence 20% mortality

24. Use of Streptokinase- MAST I, MAST E, ASK –increased mortality rate and ICH occurrence So the rt-PA is the only thrombolytic approved by FDA

27. Acute stroke treatment • Neuroprotective agent Free radical trapping agent NXY059,Cerovive Reduce the rate of symptomatic bleeding among patients given rtPA At present, no intervention with neuroprotective actionshas been established as effective in improving outcomes afterstroke, and therefore none currently can be recommended. (5)

28. Ischaemic Cascade. • Processes occurring at cellular level • Happens within seconds to minutes of loss of glucose and oxygen delivery to neurons. • Begins with loss of cellular electro- phsyiological function. • Cell metabolism changes: Aerobic Anaerobic Depletion of ATP stores Membrane Ion pumps fail Increased intracellular Na, Ca . Ca mediated cytotoxic reaction Release of excitatory neurotrans (glutamate) Protease, Endonuclease, Phospholipase, NO synthase activation= free radicals. Neuronal, Glial injury, plus oedema.

29. Anticoagulants in Stroke. • Heparin prevents recurrent cardioembolic strokes • No evidence it reduces brain injury in acute ischaemic stroke • Risk of haemorrhagic transformation – some advocate only after 48hrs. • Low molecular weight Heparin as prophylaxis of DVT.

30. Anticoagulants in Stroke. • Anticoagulants : - Does IV heparin prevent stroke progression or recurrence. (Is it effective/safe) ??

31. anticoagulant therapy vs. control acute ischemic stroke (4) • A systematic review of twenty-two trials involving 23,547 patients. The anticoagulants tested were standard (heparin, LMWH, heparinoids, oral anticoagulants, and thrombin inhibitors) and the major findings: • Based upon nine trials (22,570 patients), anticoagulant therapy didn’t reduce the no. of death from all causes . • Based upon six trials (21,966 patients), anticoagulants didn’t reduce the no. of being dead or dependent at the end of follow-up .

32. anticoagulant therapy associated with -9/1000 fewer recurrent ischemic strokes. -9/1000 increase in symptomatic intracranial hemorrhages. -avoided 4/1000 pulmonary emboli. -9/1000 major extracranial hemorrhages.

33. Conclusion • not recommend full-dose anticoagulation for treatment of unselected patients with ischemic stroke . • Early anticoagulation may be given if stroke due to cardioembolism (significant valvular disease, severe congestive heart failure, or mechanical heart valves), large artery atherosclerotic stenosis with documented intraluminal thrombus, dissection of a cervical or intracranial large artery, and progressing stroke. (4)

34. Conclusion • given after a brain imaging study has excluded hemorrhage and estimated the size of the infarct • contraindications to anticoagulation large infarction, uncontrolled hypertension, or other bleeding conditions.

35. Selection of Antithrombotic Therapy for Ischemic Stroke Secondary Prevention • Aspirin, clopidogrel, ticlopidine & dipyridamole are effective and safe therapy in reducing atherothrombotic stroke .

36. Antiplatelet Therapy • ASA • Clopidogrel (Plavix) • Dipyridamole + ASA (Aggrenox)

37. Two major clinical trials studied the benefits and risks of aspirin in the setting of acute ischemic stroke the IST and CAST trials demonstrated that aspirin therapy in acute ischemic stroke led to 9/1000 decrease in the nonfatal strokes and deaths if started within 48 hours (4) initial dose 325 mg, thereafter 160 to 325 mg/day (4),(5)

38. Monotherapy Choice Aspirin VS Clopidogrel Based on existing data no clear indication to prescribe clopidogrel over aspirin for prevention of recurrent atherothrombotic stroke unless pt. is aspirn-intolerance (1) CAPRIE trial

40. Combination of Antiplatelet • Aspirin and dipyridamole • 2. Aspirin and clopidogrel ? • MATCH trial: ASA 75mg + Plavix 75mg vs.Plavix 75mg Heart Center Online , http://www.heartcenteronline.com

41. Dipyridamole Endothelial Damage Platelet adhesion Aspirine TXA2/ADP Gpllb/llla expression

42. Study Discussed in 17th European Stroke Conference, Nice, France, May 14, 2008 The beneficial effects of aspirin and dipyridamole for secondary stroke prevention appear to be additive . the combination of aspirin and extended-release dipyridamole (ER-DP) is twice as effective as aspirin alone for stroke prevention after 2 year (1) , (2) the combination does not provide additional benefit or risk over aspirin alone for MI. (2) The most adverse effect was headache (39.2%) . (1) PRoFESS trial

43. Aspirin & Clopidogrel • Benefit vs. Risk (12562 patient) • Rate of recurrent stroke is the 1.2% in clopidogrel-aspirin group compared with 1.4% with aspirin-alone . (1) • rate of major bleeding in the clopidogrel-aspirin group 3.7% vs. 2.7% with aspirin-alone group. (1) • Rate of minor bleeding were twice in clopidogrel-aspirin group compared with aspirin-alone group ( 5.1% vs. 2.4% ). (1)

44. Aspirin & Clopidogrel • Benefit vs. Risk (7599 patients) Overall, treatment with aspirin and clopidogrel compared with clopidogrel alone might prevent 10 ischemic events per 1000 treated (not statistically significant) at the cost of 13 life-threatening hemorrhages per 1000 treated MATCH trial

46. Therapeutic approach to Stroke. • 4 phases : a)preventative measures in general b)supportative and medical mx in acute phase c)measures to mitigate the pathologic or atherothrombotic process. d)rehabilitative and physical therapy programmes in post stroke period. Therefore, classes of drugs used : Neuro protectants Anticoagulants Thrombolytics.

47. Thrombolysis :Where are we now ? • Collective results from trials show consistent pattern of results. • Tx within 3 hours benefit substantially • Within 3 to 6 hrs : modest benefit, but increased risk of bleed. • Intra arterial thrombolysis with pro Urokinase (PROACT II) 1999, good functional outcome after 90 days. • January 2003 :Actilyse launched as first and only tx for acute ischaemic stroke. • Only used in units registered with SITS-MOST – all patients treated form part of database. • Patients must be within 3 to 4 hrs of event.

48. Exclusion criteria: Stroke or serious HI in last 3 months Major surgery or body trauma in last 2 weeks. Prior ICH Intra cranial Neoplasm AV malformation or Aneurysm GI haem in last 21 days Arterial puncture at non compressible site or LP in last week. Oral anticoag, with INR >1.7 Complications: Intracerebral Haemmorhage NINDS trial 6.4% with tPA (24-36hrs) Signals= raised BP, headache, decreased neuro func, vomiting. Oozing from IV puncture sites (30% of cases). Angioedema (rare) The problems with Thrombolysis.