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TREATMENT
Approach Considerations
The central goal of therapy in acute ischemic stroke is to preserve tissue in the
ischemic penumbra, where perfusion is decreased but sufficient to stave off
infarction. Tissue in this area of oligemia can be preserved by restoring blood flow to
the compromised area and optimizing collateral flow.
Many surgical and endovascular techniques have been studied in the treatment of
acute ischemic stroke. Carotid endarterectomy has been used with some success in
the acute management of internal carotid artery occlusions, but no evidence
supports its use acutely in ischemic stroke.
Palliative care
Palliative care is an important component of comprehensive stroke care. Some
patients with severe strokes die during the initial hospitalization, others will be
severely disabled and palliative care can begin to address the patient's and family's
short- and long-term needs. Some patients have advance directives providing
instructions for medical providers in the event of severe medical illness or injury.
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Clinical education
Prehospital care providers are essential to timely stroke care. Course curricula for
prehospital care providers are beginning to include more information on stroke than
ever before. Through certification and Acute Cardiac Life Support (ACLS)
instruction, as well as continuing medical education classes, prehospital care
providers can remain current on stroke warning signs, prehospital stroke tools, and
triage protocols in their region, and can promote stroke awareness in their own
communities.
Physician and nursing staff involved in the care of stroke patients, in the Emergency
Department (ED) and in the hospital, should participate in scheduled stroke
education. This will help them to maintain the skills required to treat stroke patients
effectively and to remain current on medical advances for all stroke types.
Most of the patients who call EMS are those who present within 3 hours of symptom
onset. Calls to 911 and the use of EMS are associated with shorter time periods
from symptom onset to hospital arrival. [76, 77]
Stroke should be a priority dispatch with prompt EMS response. EMS responders
should perform a brief H&P, obtain time of symptom onset or last known normal,
perform a prehospital stroke assessment, determine blood glucose levels, and
provide advance notice to their ED destination in as timely a manner as possible so
as to allow preparation and marshalling of personnel and resources. With the
development of stroke center designation, which is currently in progress, such
centers would then become the preferred destination for patients with acute stroke
symptoms who utilize EMS.
Data supporting the use of emergency air transport for patients with acute stroke
symptoms are limited. Further evaluation of this transportation modality is necessary
to minimize the potentially high number of stroke mimics and to maximize the
appropriate use of transport resources. Telemedicine is also a technology that can
provide timely expert advice to rural and underserved clinics and hospitals. [1]
with fibrinolytics can be decreased with changes in EMS and ED coordination and in
ED procedures for treating acute stroke patients. [78]
Comorbidities
Comorbid medical conditions also need to be addressed. Hyperthermia is
infrequently associated with stroke but can increase morbidity. Administration of
acetaminophen, by mouth or per rectum, is indicated in the presence of fever
(temperature >100.4°F).
Oxygen supplementation
Fibrinolytic Therapy
The only fibrinolytic agent that has been shown to benefit selected patients with
acute ischemic stroke is alteplase (rt-PA). While streptokinase may benefit patients
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with acute MI, in patients with acute ischemic stroke it has been shown to increase
the risk of intracranial hemorrhage and death.
Fibrinolytics (ie, rt-PA) restore cerebral blood flow in some patients with acute
ischemic stroke and may lead to improvement or resolution of neurologic deficits.
Unfortunately, fibrinolytics may also cause symptomatic intracranial hemorrhage.
Other complications include potentially extracranial hemorrhage and angioedema or
allergic reactions. [1]
Inclusion/exclusion criteria
Therefore, if the patient is a candidate for fibrinolytic therapy, a thorough review of
the inclusion and exclusion criteria must be performed. The exclusion criteria largely
focus on identifying risk of hemorrhagic complications associated with fibrinolytic
use. The American Heart Association/American Stroke Association (AHA/ASA)
inclusion guidelines for the administration of rt-PA are as follows [1] :
Whereas these inclusion/exclusion criteria are from the original FDA approval, a
more recent revision by the FDA of the product insert has reclassified many prevous
absolute contraindications to now relative contraindications. Furthermore,
subsequent data and experience have allowed some patients with what were
previously considered relative contraindications to be safely treated. Involvement of
a physician with stroke expertise is critical for assessing the risk/benefit
consideration for these groups of patients.
Time to therapy
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An rt-PA stroke study group from the National Institute of Neurologic Disorders and
Stroke (NINDS) first reported that the early administration of rt-PA benefited
carefully selected patients with acute ischemic stroke. [3] The FDA subsequently
approved the use of rt-PA in patients who met NINDS criteria. In particular, rt-PA had
to be given within 3 hours of stroke onset and only after CT scanning had ruled out
hemorrhagic stroke.
Eligibility criteria for treatment during this later period are similar to those for earlier
treatment but are more stringent, with any 1 of the following serving as an additional
exclusion criterion:
Hemorrhage risk
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Although antiplatelet therapy may increase the risk for symptomatic intracerebral
hemorrhage with fibrinolysis, a study by Diedler et al that included 3782 patients
who had received 1 or 2 antiplatelet drugs found that the risk of intracerebral
hemorrhage was small compared with the documented benefit of fibrinolysis. [90]
These researchers concluded that antiplatelet treatment should not be considered a
contraindication to fibrinolysis, although caution is warranted in patients receiving
the combination of aspirin and clopidogrel.
A 2015 study, the largest of its kind, provides data supporting the use of fibrinolysis
for stroke in patients taking antiplatelet therapy. Researchers analyzed a cohort of
more than 85,000 stroke patients who had received tPA, approximately half of whom
were taking antiplatelet medication at the time of their stroke. Results show that
among patients with an acute ischemic stroke treated with intravenous tPA, those
receiving antiplatelet therapy before the stroke had a higher risk for hemorrhage but
better functional outcomes than those who were not receiving antiplatelet therapy.
[91]
Ultrasound therapy
Researchers have studied the use of transcranial ultrasound as a means of
assisting rt-PA in fibrinolysis. [92, 93] By delivering mechanical pressure waves to the
thrombus, ultrasound can theoretically expose more of the thrombus’s surface to the
circulating fibrinolytic agent. Further research is necessary to determine the exact
role of transcranial Doppler ultrasound in assisting fibrinolytics in acute ischemic
stroke.
For more information, see Thrombolytic Therapy in Stroke and Reperfusion Injury in
Stroke.
Intra-arterial Reperfusion
Theoretically, intra-arterial delivery may produce higher local concentrations of the
fibrinolytic agent at lower total doses (and thus possibly lower the risk of a systemic
bleed) and allow a longer therapeutic window. However, the longer time for initiating
intra-arterial administration may mitigate some of this advantage and earlier phase II
studies did not show a statistically significant difference in clinical outcomes. [1]
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The Interventional Management of Acute Stroke Study (IMS-III) was halted for futility
after showing no additional benefit from intra-arterial therapies (rt-PA, mechanical
thrombectomy with mostly first-generation devices, or both) compared with
intravenous rt-PA in patients with large-vessel occlusions. Additional analyses of the
IMS III data are under way to better understand the results and potentially identity
subsets of patients who may benefit from the combined approach. [94]
Intra-arterial fibrinolysis has been the traditional approach for patients with stroke
from basilar artery occlusion. However, results of the Basilar Artery International
Cooperation Study (BASICS), a prospective registry study in 592 patients, did not
support unequivocal superiority of intra-arterial fibrinolysis over intravenous
fibrinolysis. [95]
A meta-analysis of case studies involving a total of 420 patients with basilar artery
occlusion did indicate that recanalization was achieved more frequently with intra-
arterial fibrinolysis than with intravenous fibrinolysis (65% vs 53%), but the report
also found that death and long-term disability were equally common with the 2
techniques. [96] These researchers concluded that intravenous fibrinolysis
represents probably the best treatment that can be offered to these patients in
hospitals without a 24-hour interventional neuroradiologic service. [96]
Antiplatelet Agents
AHA/ASA guidelines recommend giving aspirin, 325 mg orally, within 24-48 hours of
ischemic stroke onset. The benefit of aspirin is modest but statistically significant
and appears principally to involve the reduction of recurrent stroke. [85]
The International Stroke Trial and the Chinese Acute Stroke Trial (CAST)
demonstrated modest benefit from the use of aspirin in the setting of acute ischemic
stroke. The International Stroke Trial randomized 19,435 patients within 48 hours of
stroke onset to treatment with aspirin 325 mg, subcutaneous heparin in 2 different
dose regimens, aspirin with heparin, and a placebo. The study found that aspirin
therapy reduced the risk of stroke recurrence within 14 days (2.8% vs 3.9%), with no
significant excess of hemorrhagic strokes. [97, 98]
In CAST, which included 21,106 patients, aspirin treatment (160 mg/day) that was
started within 48 hours of the onset of suspected acute ischemic stroke and was
continued in hospital for up to 4 weeks reduced mortality to 3.3%, compared with
3.9% with placebo. A separate study also found that the combination of aspirin and
low–molecular-weight heparin did not significantly improve outcomes. [97]
Other antiplatelet agents have also been under evaluation for use in the acute
presentation of ischemic stroke. In a preliminary pilot study, abciximab given within 6
hours showed a trend toward improved outcome at 3 months. [99] However, the
phase 3 Abciximab in Emergency Treatment of Stroke Trial (AbESTT-II) was
terminated prematurely after 808 patients because of lack of efficacy and an
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Calcium channel blockers did not alter outcome after ischemic stroke in some trials.
Possible adverse effects of antihypertensive treatment have been reported in certain
trials, especially those using intravenous calcium channel blockers or oral beta
blockers. In the Controlling Hypertension and Hypotension Immediately Post-Stroke
(CHHIPS) trial, early lowering of blood pressure with labetalol and lisinopril slightly
improved outcome and did not increase serious adverse events. However, CHHIPS
had a small sample size. [102]
A study in 339 patients with ischemic stroke found that oral candesartan reduced
combined vascular events but had no effect on disability. [101] However, the
Scandinavian Candesartan Acute Stroke Trial (SCAST), a randomized, placebo-
controlled, double-blind study involving 2029 patients, found no indication of benefit
from candesartan but did find some suggestion of harm. [103]
Among the 2,038 patients who received antihypertensive treatment, 683 reached
the primary endpoint of death or major disability at 14 days or hospital discharge,
compared with 681 of the 2,033 patients who received no antihypertensive
treatment. At 3-month follow-up, 500 patients in the antihypertensive treatment
group and 502 patients in the control group reached the secondary endpoint of
death or major disability. [104, 105]
For patients who are not candidates for fibrinolytic therapy, current guidelines
recommend permitting moderate hypertension in most patients with acute ischemic
stroke. Most patients will experience spontaneous reduction in blood pressure over
the first 24 hours without treatment. [85] The exceptions would be patients who have
active comorbidities (eg, aortic dissection, acute myocardial infarction [MI],
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Thresholds for antihypertensive treatment in acute ischemic stroke patients who are
not fibrinolysis candidates, according to the 2013 ASA guidelines, are systolic blood
pressure higher than 220 mm Hg or diastolic blood pressure above 120 mm Hg. [85]
In those patients, a reasonable goal is to lower blood pressure by 15% during the
first 24 hours after onset of stroke. Care must be taken to not lower blood pressure
too quickly or aggressively, since this could worsen perfusion in the penumbra.
Mechanical Thrombectomy
Mechanical clot disruption is an alternative for patients in whom fibrinolysis is
ineffective or contraindicated.
The Multi MERCI trial used the newer-generation Concentric retrieval device (L5).
Recanalization was demonstrated in approximately 55% of patients who did not
receive t-PA and in 68% of those to whom t-PA was given. Seventy-three percent of
patients who failed intravenous t-PA therapy had recanalization following
mechanical embolectomy. [109] On the basis of these results, the FDA cleared the
use of the MERCI device in patients who are either ineligible for or who have failed
intravenous fibrinolytics.
Fever Control
Antipyretics are indicated for febrile stroke patients, since hyperthermia accelerates
ischemic neuronal injury. Substantial experimental evidence suggests that mild brain
hypothermia is neuroprotective. The use of induced hypothermia is currently being
evaluated in phase II clinical trials. [113, 114, 115]
High body temperature in the first 12-24 hours after stroke onset has been
associated with poor functional outcome. However, results from the Paracetamol
(Acetaminophen) in Stroke (PAIS) trial did not support the routine use of high-dose
acetaminophen (6 g daily) in patients with acute stroke, although post-hoc analysis
suggested a possible beneficial effect on functional outcome in patients admitted
with a body temperature of 37-39° C. [116]
The American Heart Association and the American Stroke Association have
released a guideline for the management of cerebral and cerebellar infarction with
brain swelling; recommendations include the following [121, 122] :
Seizure Control
Seizures occur in 2-23% of patients within the first days after ischemic stroke. These
seizures are usually focal, but they may be generalized. Although primary
prophylaxis for poststroke seizures is not indicated, secondary prevention of
subsequent seizures with standard antiepileptic therapy is recommended. [1]
Acute Decompensation
In the case of the rapidly decompensating patient or the patient with deteriorating
neurologic status, reassessment of the ABCs as well as hemodynamics and
reimaging are indicated. Many patients who develop hemorrhagic transformation or
progressive cerebral edema will demonstrate acute clinical decline. Rarely, a patient
may have escalation of symptoms secondary to increased size of the ischemic
penumbra. Careful observation for hemorrhagic transformation (especially in the first
24 hours postreperfusion) and cerebral edema in patients with hemispheric or
posterior fossa strokes in the first 24-36 hours is warranted.
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Neuroprotective Agents
The rationale for the use of neuroprotective agents is that reducing the release of
excitatory neurotransmitters by neurons in the ischemic penumbra may enhance the
survival or these neurons. Despite very promising results in several animal studies,
however, no single neuroprotective agent in ischemic stroke has as yet been
supported by randomized, placebo-controlled human studies. Nevertheless,
substantial research is under way evaluating different neuroprotective strategies.
Hypothermia was very promising for the ongoing treatment of patients surviving
cardiac arrest from ventricular tachycardia or ventricular fibrillation. However, no
major clinical study has demonstrated a role for hypothermia in the early treatment
of ischemic stroke. [1]
Stroke Prevention
Primary prevention refers to the management of individuals with no history of stroke.
Preventative measures may include the use of antiplatelet agents, statins, smoking
cessation and exercise. The 2011 AHA/ASA guidelines for the primary prevention of
stroke emphasize the importance of lifestyle changes to reduce well-documented
modifiable risk factors, citing an 80% lower risk of a first stroke in people who follow
a healthy lifestyle compared with those who do not. [22]
Secondary prevention refers to the treatment of individuals who have already had a
stroke. Measures may include the use of anitplatelet agents, [125] anticoagulants
(warfarin or newer novel oral anticoagulants) antihypertensives, statins, [126] and
lifestyle interventions. A study by the Warfarin-Aspirin Symptomatic Intracranial
Disease Trial Investigators concluded that in stroke patients who have significant
intracranial arterial stenosis, aspirin should be used in preference to warfarin for
secondary prevention. [127]
Smoking cessation, blood pressure control, diabetes control, a low-fat low-salt diet,
weight loss, and regular exercise should be encouraged as strongly as the
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Written prescriptions for exercise and medications for smoking cessation (ie,
nicotine patch, bupropion, varenicline) increase the likelihood of success with these
interventions. In addition, the 2011 AHA/ASA guidelines for primary stroke
prevention indicate that it is reasonable to avoid exposure to environmental tobacco
smoke, despite a lack of stroke-specific data.
Overall, the value of aspirin in primary prevention appears uncertain, [128] and its
use for this purpose is not recommended for patients at low risk. Aspirin is
recommended for primary prevention only in persons with at least a 6-10% risk of
cardiovascular events over 10 years. [22]
On the other hand, low-dose aspirin may be beneficial for primary prevention of
stroke in women. A randomized, placebo-controlled trial in 39,876 initially healthy
women aged 45 years or older demonstrated that 100 mg of aspirin on alternate
days resulted in a 24% reduction in the risk of ischemic stroke, with a nonsignificant
increase in the risk of hemorrhagic stroke. [129]
Patients who have had a stroke or transient ischemic attack (TIA) should be
screened for diabetes and obesity
Patients should possibly be screened for sleep apnea
Patients should possibly undergo a nutritional assessment and be advised to
follow a Mediterranean-type diet
Patients who have had a stroke of unknown cause should undergo long-term
monitoring for atrial fibrillation (AF)
The new oral anticoagulants dabigatran (class I, level of evidence [LOE] A),
apixaban (class I, LOE B), and rivaroxaban (class IIa, LOE B) are among the
drugs recommended for patients with nonvalvular AF
Based on research results, the guidelines also recommend that, in patients without
deep venous thrombosis (DVT), a patent foramen ovale not be closed. In addition,
because there is little data to suggest that niacin or fibrate drugs, as a means to
raise high-density lipoprotein (HDL) cholesterol, reduce secondary stroke risk, the
guidelines no longer recommend their use.
Atrial fibrillation
Atrial fibrillation (AF) is a major risk factor for stroke. The 2011 AHA/ASA primary
stroke prevention guideline recommends that EDs screen for AF and assess
patients for anticoagulation therapy if AF is found. [22]
In the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular
Events (ACTIVE W), oral anticoagulation with warfarin proved superior to
clopidogrel plus aspirin for prevention of vascular events in patients with AF who
were at high risk of stroke. [136] The study was stopped early because of clear
evidence of superiority of oral anticoagulation therapy.
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ASRH: Designed to address the lack of hospitals typically in rural areas that
have the resources to achieve PSC or CSC certification and yet serve as a
critical access point for healthcare. Typically they have all the elements of a
PSC but lack a physician with stroke expertise and often a dedicated stroke
unit. Through the use of telemedicine and teleradiology these centers can
evaluate patients for the potential use of fibrinloytics. Key to the optimal
function of these stroke centers is their interactions within a regional stroke
system of care.
PSC: Designed to maximize the timely provision of stroke-specific therapy,
including the administration of rt-PA; the center is also capable of providing
care to patients with uncomplicated stroke
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CSC: Shares the commitment that the PSC has to acute delivery of rt-PA and
also provides care to patients with hemorrhagic stroke and intracranial
hemorrhage, as well as to all patients with stroke who require emergent
advanced imaging, intra-arterial therapies, neurosurgical interventions, and
management in a neurosurgical intensive care unit (NSICU)
ASRHs, PSCs, and CSCs work most effectively when integrated into a regional
stroke system of care so that patients are treated at the most appropriate hospital
based on factors such as severity, comorbidities, and timing. Integrating regional
prehospital services (911 and EMS) into this system of care ensures the most
appropriate triage from the field.
Coordination of care
Once patients have been identified as potential stroke patients, their ED evaluation
must be fast-tracked to allow for the completion of required laboratory tests and
requisite noncontrast head CT scanning, as well as for the notification and
involvement of neurologic consultants. These requirements have led to the
development of "code stroke" protocols for the ED. In addition, EMS personnel are
trained to identify possible stroke patients and arrange for their speedy, preferential
transport to a PSC or CSC. [79]
A stroke system should ensure effective interaction and collaboration among the
agencies, services, and people involved in providing prevention and the timely
identification, triage to the most appropriate hospital, rapid transport, treatment, and
rehabilitation of stroke patients. For more information, see Stroke Team Creation
and Primary Stroke Center Certification.
Consultations
A stroke team or an experienced professional who is sufficiently familiar with stroke
should be available within 15 minutes of the patient's arrival in the ED. Other
consultations are tailored to individual patient needs. Often, occupational therapy,
physical therapy, speech therapy, and physical medicine and rehabilitation experts
are consulted within the first day of hospitalization.
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Medication
References
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