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Stroke is the second leading cause of death and a leading cause of disability worldwide. This invaluable reference provides clinicians caring for stroke patients with ready access to the optimal evidence for best practice in stroke prevention, acute stroke treatment, and stroke recovery. Now an edited volume, the editors and authors, many of whom are members of the Cochrane Stroke Review Group, describe all available medical, endovascular, and surgical treatments; the rationale for using them; and the strength of the evidence for their safety and effectiveness. New chapters cover key, rapidly advancing therapeutic topics, including prehospital stroke care and regionalized stroke systems, endovascular reperfusion therapy, and electrical and magnetic brain stimulation to enhance recovery. This is an essential resource for clinicians translating into practice the many dramatic advances that have been made in the treatment and prevention of stroke, and suggesting the most appropriate interventions.
Whereas only a minority of acute ischaemic stroke patients are eligible to reperfusion therapies, all can benefit from optimized supportive care to minimize acute stroke complications. Continuous pulse oximetry monitoring is recommended, and supplemental oxygen given as needed to maintain saturation>94%. During the first 24 hours after onset, when collateral dependence is greatest, blood pressure lowering may best be avoided, unless SBP >220 mm Hg, thrombolytics have been administered, or cardiac or other comorbidities are present; thereafter, gradual blood pressure lowering may safely be started. Initial fluid management should aim for normovolemia, using isotonic fluids; if substantial brain oedema develops, hypertonic fluids can be helpful. Electrolyte imbalances should be corrected and the underlying cause identified and treated. Extremely low and high blood glucose deviations should be avoided; if hyperglycaemia is present, treatment using a subcutaneous insulin sliding scale of moderate intensity is appropriate. Simple formal swallow screening should be performed early in all ischaemic stroke patients. When swallowing is impaired, initiating feeding via NG tube is reasonable within the first 2–3 days after onset. Temperature should be monitored and, if fever develops, antiyretic therapy started immediately and the cause identified and treated. For bladder dysfunction, an indwelling catheter should be avoided if possible to reduce infection rates. Hydration and passive/active movement of paretic extremities are important to prevent venous thromboembolism. In patients with reduced mobility, intermittent pneumatic compression devices should be employed. It is reasonable to use pharmacological thromboprophylaxis in patients at high risk of DVT (e.g. immobile, history of prior venous thromboembolism) and low risk of intracranial hemorrhage (e.g. small infarct less than 3 cm in diameter), and subcutaneous low-molecular-weight heparins are somewhat more effective than unfractionated heparin. Initial management of delirium should include non-pharmacological behavioral measures, including periodic verbal reassurances and reorientation, providing rooms with windows and clocks, facilitating sensory input with eyeglasses and hearing aids, and promoting a usual sleep-wake cycle.
Almost all efficacious stroke treatments confer moderate-to-large benefits, but not staggeringly huge benefits. However, moderate treatment effects can be clinically very worthwhile for the patient. To detect moderate-large treatment benefits, trials must avoid bias and random error. Studies with weak designs (personal experience, observational studies with historical controls, and observational studies with concurrent, non-randomized controls) will not sufficiently control bias and random error to enable reliable discrimination of a true moderate-to-large benefit from false positives and false negatives. Randomized clinical trials are required. 'Ingredients' for a good trial – Proper randomization and concealment of allocation (i.e. clinician cannot have foreknowledge of next treatment allocation)/Outcome evaluation blind to the allocated treatment/Analysis by allocated treatment (including all randomized patients: intention-to-treat)/Large numbers of major outcomes and correspondingly narrow CIs/Conclusion based on pre-specified primary hypothesis and outcome/Chief emphasis on findings in overall study population. Advantages of systematic reviews (over traditional unsystematic, narrative reviews) – Use explicit, well-developed methods to reduce bias/Summarize large amounts of data explicitly/Provide all available data/Increase statistical power and precision/Look for consistencies/inconsistencies/Improve generalizability. Cochrane Reviews – Generally higher quality than other systematic reviews/Periodically updated/Available over internet/Abstracts available free of charge/Full reviews available free of charge in over 100 low- and middle-income countries
More than 20,000 patients have participated in clinical trials of more than 100 neuroprotective therapies, but no study has provided convincing evidence of benefit. Several improvements to the rigor of preclinical agent qualification have been identified to increase the likelihood of success in human clinical trials: stringent randomization and blinding techniques to mitigate observer bias; assessment in in time periods achievable in the clinical setting; testing in older animals with comorbidities; and robust and reproducible benefit magnitudes. Human clinical trials should start agents hyperacutely, in the first minutes and hours after onset, when treatment effect would be maximal; target enrolment of patients likely to have transient rather than permanent ischaemic exposure; and use factorial and platform trial designs that would permit efficient testing of combinations of agents able to block multiple ischaemic injury-mediating pathways concurrently, including both anti-necrotic and anti-apoptotic interventions. For agents that allow cells to endure ischaemic stress, human trial delivery approaches include: prehospital initiation; initiation immediately upon brain imaging in patients destined for endovascular intervention; and initiation at outside hospitals in patients undergoing transfer to a neurothrombectomy center. For agents that mitigate reperfusion injury, treatment start before or concurrent with reperfusion, including intra-arterial administration via catheter immediately after endovascular thrombectomy, should be pursued.
Intravenous thrombolytic therapy (IV) with recombinant tissue-plasminogen activator (alteplase; 0.9 mg/kg over 1h) is beneficial for acute ischaemic stroke patients with potentially disabling neurological deficits, and without contraindications, when started =4.5h of onset. Benefit is time-dependent: among 1000 patients, IVT =3h lessen long-term disability in 178 patients, between 3-4.5h in 66. IVT under 4.5h is associated with an increase in symptomatic haemorrhage, but not an increase in death or severe disability. Based on trial evidence, IVT =3h is strongly endorsed, and between 3-4.5 hours moderately endorsed, by guidelines on 5 continents. Benefit is evident in patients under and over age 80, and in patients with up to moderate, but not extensive (more than 100 cc), early ischaemic changes on initial CT or MRI. IVT is also beneficial for patients =4.5h after onset with substantial salvageable tissue on penumbral CT or MR imaging. Systems of care should be optimized to start IVT =60m, and optimally =30m, after ED arrival. Large-scale trials are needed to further enhance IVT, testing: faster treatment start in mobile stroke units (mobile CT ambulances): fibrinolytic agent and concomitant lytic-enhancing combinations; bridging neuroprotection and collateral enhancement; and the optimal way to combine intravenous thrombolytic therapy and endovascular mechanical thrombectomy.
For hypertensive patients without prior stroke, TIA, or other symptomatic vascular disease, anti-hypertensive therapy reducing SBP by 10 mm Hg, is associated with reductions in recurrent stroke (by about one-quarter) and of combined stroke, MI, and vascular death (by about one-fifth). Benefit extends across all ages, race-ethnicities, and pathological stroke subtypes. Combined pharmacological and non-pharmacological therapy to lower blood pressure is indicated in all individuals with SBP> 140 or DBP> 90, and in individuals with SBP 130–139 or DBP 80–89 who have additional vascular risk factors. Non-pharmacological blood pressure lowering is indicated in individuals with SBP 130–139 or DBP 80–89 without important additional vascular risk factors. After an ischaemic stroke or TIA, treatment may be gradually started as early as 24–72 hours after onset. The absolute benefits of antihypertensive therapy increase with greater reductions in BP, and are higher for preventing recurrent stroke than for preventing MI, in both primary and secondary prevention. The degree of BP reduction more greatly influences vascular event prevention than does pharmacological agent class. Nonetheless, unless otherwise indicated, beta-blockers are not a preferred agent, as they show less efficacy for stroke prevention. Calcium channel antagonists, ACE inhibitors, and thiazide diuretics are particularly well-studied.
Among medical therapies, osmotherapy with colloidal agents (mannitol, glycerol) or crystalloid agents (hypertonic saline) is reasonable for patients whose condition is deteriorating due to mass effect and herniation from large anterior circulation hemispheric or cerebellar infarcts, especially as bridging therapies to definitive surgical intervention. Hyperventilation and hypothermia may also be reasonable, though are of less certain benefit. Corticosteroids have not been found helpful. Agents that block sulfonylurea receptor-mediated cellular swelling, such as intravenous glyburide, have shown promise but require pivotal trial testing. Ventriculostomy is useful to treat non-communicating hydrocephalus arising from obstruction of CSF flow pathways by swollen brain infarcts. But in select large cerebellar infarcts, ventricular drainage alone may exacerbate upward herniation of swollen cerebellar tissues, and suboccipital craniectomy along with ventricular drainage is preferred. Suboccipital craniectomy, often with resection of infarcted tissue, is recommended for massive cerebellar infarcts that may herniate directly into the brainstem, on the basis of observational evidence. Hemicraniectomy for brain oedema associated with large anterior circulation hemispheric infarction is life-saving, but survivors often have severe disability, especially when over age 60. If pursued, hemicraniectomy is generally best performed within 48 h of onset and before development of advanced herniation and neurological deterioration.
RCTs provide evidence that stroke risk is reduced by several risk factor control strategies reviewed in this chapter: adhering to a Mediterranean Diet , avoiding long-term estrogen hormone replacement, and treating severe obesity with gastric balloons or bariatric surgery. In addition, observational evidence suggests stroke risk is reduced by quitting smoking, controlling blood glucose, losing weight in moderately obese individuals, exercising regularly, abandoning heavy alcohol consumption, and improving diet (less salt and more unsaturated fats) via other approaches. Optimal goals for risk factor control are delineated in the American Heart Association Life’s Simple 7 ideal targets. The beneficial effects of these measures are likely largely mediated by amelioration of well-established risk factors such as blood pressure, cholesterol, diabetes, and coagulation status. To achieve these lifestyle changes, both the individual and the community must contribute. Governments have a responsibility to: improve public education; increase access to healthy foods and built environments with pedestrian, bicycle, and exercise infrastructure; and use regulation, legislation, and taxation to discourage hazardous lifestyle behaviours (e.g. smoking, alcohol, and perhaps salt or sugar in foods). Continued cultural change is also required among individuals and communities to promote regular physical activity, a healthy diet, and minimal exposure to smoking in everyday life.
Aspirin 160–300 mg daily started within 48 h of onset of acute ischaemic stroke is associated with a small beneficial reduction in recurrent ischaemic stroke (6 fewer per 1000 patients treated) and pulmonary embolism (1.5 fewer per 1000) that outweighs increased risk of bleeding (2 extra symptomatic ICHs and 4 extra major extracranial haemorrhages). The net effect is that, for every 1000 patients treated early with aspirin, 22 have reduced long-term disability, including 11 more achieving full recovery. Only two single antiplatelet regimens have been compared head to head against aspirin alone: cilostazol (a phosphodiesterase inhibitor) performed similarly to aspirin; ticagrelor (a GP IIa/IIIb receptor antagonist) showed tended to reduce ischaemic events but increased minor bleeding and dyspnea. In minor, non-cardioembolic ischaemic stroke or TIA, early dual antiplatelet therapy (DAPT) has shown advantages over early monotherapy. Most well-studied is clopidogrel and aspirin, with similar findings for dipyridamole and aspirin. DAPT reduces all-type (ischaemic and haemorrhagic) recurrent stroke (27 fewer per 1000 treated patients), but minimally increases major extracranial bleedings (3 more per 1000). Confining DAPT to the first 3 w maximizes the benefit to harm ratio. Anticoagulants alone and arterial-dose anticoagulants added to antiplatelet agents offer no net advantages over antiplatelet drugs alone. Venous prophylaxis-dose anticoagulants and aspirin, compared with aspirin alone, reduced recurrent ischaemic stroke more than it tend increased major extracranial haemorrhage.