CHAPTER I

PREFACE

Stroke are rapidly clinical sign of focal an global disturbance of cerebral function
lasting more than 24 hour or leading to death with no apparent cause other than
vascular origin ( WHO ). Also previously called cerebrovascular accident (CVA)
or stroke syndrome.

In stroke, there Strokes are broadly classified as either hemorrhagic or ischemic.

Acute ischemic stroke refers to stroke caused by thrombosis or embolism and is
more common than hemorrhagic stroke. Prior literature indicates that only 8-18%
of strokes were hemorrhagic. However, a recent retrospective review from a
stroke center found that 40.9% of 757 strokes were hemorrhagic. However, the
authors state that the increased percentage of hemorrhagic stroke may be due to
improvement of CT scan availability and implementation unmasking a previous
underestimation of the actual percentage, or it may be due to an increase in
therapeutic use of antiplatelet agents and warfarin causing an increase in the
incidence of hemorrhage1

Stroke should be considered in any patient presenting with an acute neurologic

deficit (focal or global) or altered level of consciousness. No historical feature
distinguishes ischemic from hemorrhagic stroke, although nausea, vomiting,
headache, and change in level of consciousness are more common in hemorrhagic
strokes. Common symptoms of stroke include abrupt onset of hemiparesis,
monoparesis, or quadriparesis; monocular or binocular visual loss; visual field
deficits; diplopia; dysarthria; ataxia; vertigo; aphasia; or sudden decrease in the
level of consciousness. Although such symptoms can occur alone, they are more
likely to occur in combination.

Multiple factors contribute to delays in seeking care for symptoms of stroke.

Many strokes occur while patients are sleeping (also known as "wake-up" stroke)
and are not discovered until the patient wakes. Stroke can leave some patients too
incapacitated to call for help. Occasionally, a stroke goes unrecognized by the
patient or their caregivers.1,2

Stroke mimics commonly confound the clinical diagnosis of stroke. One study
reported that 19% of patients diagnosed with acute ischemic stroke by
neurologists before cranial CT scanning actually had noncerebrovascular causes
for their symptoms. The most frequent stroke mimics include seizure (17%);
systemic infection (17%); brain tumor (15%); toxic-metabolic cause, such as
hyponatremia (13%); and positional vertigo (6%). Miscellaneous disorders
mimicking stroke include syncope, trauma, subdural hematoma, herpes

Stroke 1
encephalitis, transient global amnesia, dementia, demyelinating disease,
myasthenia gravis, parkinsonism, hypertensive encephalopathy, and conversion
disorders. A critical masquerading metabolic derangement not to be missed by
providers is hypoglycemia.3,4

CHAPTER II

Stroke 2
 ISCHEMIC STROKE

2.1 Epidemiology

Frequency

a. United States
Incidence for first-time stroke is more than 700,000 per year, of which
20% of these patients will die within the first year after stroke. At current
trends, this number is projected to jump to 1 million per year by the year
20501

b. International
Global incidence of stroke is unknown.

Mortality/Morbidity

Stroke is the third leading cause of death and the leading cause of disability in the
United States9. Cerebrovascular disease was the second leading cause of death
worldwide in 1990, killing more than 4.3 million people10. Cerebrovascular
disease was also the fifth leading cause of lost productivity, as measured by
disability-adjusted life years (DALYs).

Sex

Men are at higher risk for stroke than women. Additionally, women seem to
respond better than men to interventions such as rt-PA.

Age

Although stroke often is considered a disease of elderly persons, one third of

strokes occur in persons younger than 65 years.1

2.2 Physical examination

Stroke 3
The goals of the physical examination include (1) detecting extracranial causes of
stroke symptoms. (2) distinguishing stroke from stroke mimics, (3) determining
and documenting for future comparison the degree of deficit, and localizing the
lesion.(4) careful head and neck examination for signs of trauma, infection, and
meningeal irritation. (5) careful search for the cardiovascular causes of stroke
requires examination of the ocular fundi (retinopathy, emboli, hemorrhage), heart
(irregular rhythm, murmur, gallop), and peripheral vasculature (palpation of
carotid, radial, and femoral pulses, auscultation for carotid bruit). (6) patients with
a decreased level of consciousness should be assessed to ensure that they are able
to protect their airway.

2.3 Neurologic examination

The goals of the neurologic examination include (1) confirming the presence of a
stroke syndrome (to be defined further by cranial CT scanning), (2) distinguishing
stroke from stroke mimics, and (3) establishing a neurologic baseline should the
patient's condition improve or deteriorate.

Essential components of the neurologic examination include evaluation of mental

status and the level of consciousness, cranial nerves, motor function, sensory
function, cerebellar function, gait, and deep tendon reflexes. The skull and spine
also should be examined, and signs of meningismus should be sought.

Central facial weakness from a stroke should be differentiated from the peripheral
weakness of Bell palsy. With peripheral lesions (Bell palsy), the patient is unable
to lift the eyebrows or wrinkle the forehead.

The 4 principal neuroanatomic stroke syndromes are caused by disruption of their

respective cerebrovascular distributions. Correlating the patient's neurologic
deficits with the expected site of arterial compromise may assist in confirming the
diagnosis of stroke and interpreting the subsequent cranial CT scan.

Middle cerebral artery (MCA) occlusion commonly produces contralateral

hemiparesis, contralateral hypesthesia, ipsilateral hemianopsia, and gaze
preference toward the side of the lesion. Agnosia is common, and receptive or
expressive aphasia may result if the lesion occurs in the dominant hemisphere.
Neglect, inattention, and extinction of double simultaneous stimulation may occur
in nondominant hemisphere lesions. Since the MCA supplies the upper extremity

Stroke 4
motor strip, weakness of the arm and face is usually worse than that of the lower
limb.

Anterior cerebral artery occlusions primarily affect frontal lobe function and can
result in dis-inhibition and speech perseveration, producing primitive reflexes (eg,
grasping, sucking reflexes), altered mental status, impaired judgment,
contralateral weakness (greater in legs than arms), contralateral cortical sensory
deficits gait apraxia, and urinary incontinence.

Posterior cerebral artery occlusions affect vision and thought, producing

contralateral homonymous hemianopsia, cortical blindness, visual agnosia, altered
mental status, and impaired memory.

Vertebrobasilar artery occlusions are notoriously difficult to detect because they

cause a wide variety of cranial nerve, cerebellar, and brainstem deficits. These
include vertigo, nystagmus, diplopia, visual field deficits, dysphagia, dysarthria,
facial hypesthesia, syncope, and ataxia. A hallmark of posterior circulation stroke
is that there are crossed findings: ipsilateral cranial nerve deficits and contralateral
motor deficits. This is contrasted to anterior stroke, which produces only
unilateral findings.

Lacunar strokes result from occlusion of the small, perforating arteries of the deep
subcortical areas of the brain. The infarcts are generally from 2-20 mm in
diameter. The most common lacunar syndromes include pure motor, pure sensory,
and ataxic hemiparetic strokes. Lacunar infarcts are often associated with partial
or full occlusion of the parent feeding artery. Lacunar strokes account for 13-20%
of all cerebral infarctions. Lacunar infarcts commonly occur in patients with small
vessel disease, such as diabetes and hypertension. By virtue of their small size and
well-defined subcortical location, lacunar infarcts do not lead to impairments in
cognition, memory, speech, or level of consciousness.

2.4 Pathophysiology

On the macroscopic level, ischemic stroke most often is caused by extracranial

embolism or intracranial thrombosis, but it may also be caused by decreased
cerebral blood flow. On the cellular level, any process that disrupts blood flow to
a portion of the brain unleashes an ischemic cascade, leading to the death of
neurons and cerebral infarction. Understanding this chain of events is important
for understanding current therapeutic approaches.

Stroke 5
Embolism

Emboli may arise from the heart, the extracranial arteries or, rarely, the right-
sided circulation (paradoxical emboli) with subsequent passage through a patent
foramen ovale. The sources of cardiogenic emboli include valvular thrombi (eg, in
mitral stenosis, endocarditis, prosthetic valve), mural thrombi (eg, in myocardial
infarction [MI], atrial fibrillation [AF], dilated cardiomyopathy, severe congestive
heart failure [CHF]), and atrial myxoma. MI is associated with a 2-3% incidence
of embolic stroke, of which 85% occur in the first month after MI.5

Thrombosis

Thrombotic stroke can be divided into large vessel, including the carotid artery
system, or small vessel comprising the intracerebral arteries, including the
branches of the Circle of Willis and the posterior circulation. The most common
sites of thrombotic occlusion are cerebral artery branch points, especially in the
distribution of the internal carotid artery. Arterial stenosis can cause turbulent
blood flow, which can increase risk for thrombus formation, atherosclerosis (ie,
ulcerated plaques), and platelet adherence; all cause the formation of blood clots
that either embolize or occlude the artery.

Less common causes of thrombosis include polycythemia, sickle cell anemia,

protein C deficiency, fibromuscular dysplasia of the cerebral arteries, and
prolonged vasoconstriction from migraine headache disorders. Any process that
causes dissection of the cerebral arteries also can cause thrombotic stroke (eg,
trauma, thoracic aortic dissection, arteritis). Occasionally, hypoperfusion distal to
a stenotic or occluded artery or hypoperfusion of a vulnerable watershed region
between two cerebral arterial territories can cause ischemic stroke.

Flow disturbances

Stroke symptoms can result from inadequate cerebral blood flow due to decreased
blood pressure (and specifically decreased cerebral perfusion pressure) or due to
hematologic hyperviscosity due to sickle cell disease or other hematologic
illnesses such as multiple myeloma and polycythemia vera. In these instances,
cerebral injury may occur in the presence of damage to other organ systems.

Ischemic cascade

Within seconds to minutes of the loss of perfusion to a portion of the brain, an

ischemic cascade is unleashed that, if left unchecked, causes a central area of
irreversible infarction surrounded by an area of potentially reversible ischemic
penumbra.

Stroke 6
On the cellular level, the ischemic neuron becomes depolarized as ATP is
depleted and membrane ion-transport systems fail. The resulting influx of calcium
leads to the release of a number of neurotransmitters, including large quantities of
glutamate, which, in turn, activates N -methyl-D-aspartate (NMDA) and other
excitatory receptors on other neurons. These neurons then become depolarized,
causing further calcium influx, further glutamate release, and local amplification
of the initial ischemic insult. This massive calcium influx also activates various
degradative enzymes, leading to the destruction of the cell membrane and other
essential neuronal structures.6

Free radicals, arachidonic acid, and nitric oxide are generated by this process,
which leads to further neuronal damage. Within hours to days after a stroke,
specific genes are activated, leading to the formation of cytokines and other
factors that, in turn, cause further inflammation and microcirculatory
compromise.6 Ultimately, the ischemic penumbra is consumed by these
progressive insults, coalescing with the infarcted core, often within hours of the
onset of the stroke.

The central goal of therapy in acute ischemic stroke is to preserve the area of
oligemia in the ischemic penumbra. The area of oligemia can be preserved by
limiting the severity of ischemic injury (ie, neuronal protection) or by reducing
the duration of ischemia (ie, restoring blood flow to the compromised area).

The ischemic cascade offers many points at which such interventions could be
attempted. Multiple strategies and interventions for blocking this cascade are
currently under investigation. The timing of the restoration of cerebral blood flow
appears to be a critical factor. Time also may prove to be a key factor in neuronal
protection. Although still being studied, neuroprotective agents, which block the
earliest stages of the ischemic cascade (eg, glutamate receptor antagonists,
calcium channel blockers), are expected to be effective only in the proximal
phases of presentation.

2.5 Causes

Risk factors for ischemic stroke include advanced age (the risk doubles every
decade), hypertension, smoking, heart disease (coronary artery disease, left
ventricular hypertrophy, chronic atrial fibrillation), hypercholesterolemia,
hyperhomocysteinemia, increased blood viscosity and the use of oral
contraceptives, previous cerebrovascular disease, transient ischemic attack ( 10%
of patients with TIA suffer stroke within 90 days and half of these patients suffer
stroke within 2 days). 7,8

Stroke 7
2.6 Differential Diagnoses

(1) acute coronary syndrome (2 ) alcohol and substance abuse evaluation (3)
anemia, acute (3) atrial fibrillation (4) bell palsy (5) benign positional vertigo (6)
brain abscess (7) cbrne – botulism (8) delirium, dementia, and amnesia (9)
dissection, carotid artery (10) dissection, vertebral artery (11) epidural hematoma
(12) hypernatremia (13) hyperosmolar hyperglycemic nonketotic coma (14)
hypoglycemia (15 ) hyponatremia (16 ) hypothyroidism and myxedema coma (17)
labyrinthitis (18) myocardial infarction (19) neoplasms, brain (20) status
epilepticus (21) stroke, hemorrhagic (22) subarachnoid hemorrhage (23) subdural
hematoma (24) syncope (25) transient ischemic attack

2.7 Laboratory Studies

CBC, basic chemistry panel, coagulation studies, and cardiac biomarkers should
be obtained in most patients.

1. CBC serves as a baseline study and may reveal a cause for the stroke (eg,
polycythemia, thrombocytosis, thrombocytopenia, leukemia) or provide
evidence of concurrent illness (eg, anemia).
2. Chemistry panel serves as a baseline study and may reveal a stroke mimic
(eg, hypoglycemia, hyponatremia) or provide evidence of concurrent
illness (eg, diabetes, renal insufficiency).
3. Coagulation studies may reveal a coagulopathy and are useful when
thrombolytics or anticoagulants are to be used. In patients who are not
anticoagulated and in whom there is no suspicion for coagulation
abnormality, administration of rt-PA should not be delayed awaiting
laboratory studies.
4. Cardiac biomarkers are important because of the association of cerebral
vascular disease and coronary artery disease. Additionally, several studies
have indicated a link between elevations of cardiac enzyme levels and
poor outcome in ischemic stroke.
5. Toxicology screening may be useful in selected patients in order to assist
in identifying intoxicated patients with symptoms/behavior mimicking
stroke syndromes. Urine pregnancy test should be obtained for all women
of childbearing age with stroke symptoms. rt-PA is Pregnancy Class C.

Stroke 8
2.8 Imaging Studies

Noncontrast head CT scan

Emergent noncontrast head CT scanning is mandatory for rapidly distinguishing

ischemic from hemorrhagic infarction and may help determine the anatomic
distribution of stroke. CT scan may also rule out other life-threatening processes,
such as hematoma, neoplasm, and abscess.

The changes in CT scan over the time course of acute cerebral infarction must be
understood. The sensitivity of standard noncontrast head CT increases 24 hours
after ischemic event.9 After 6-12 hours, sufficient edema is recruited into the
stroke area to produce a regional hypodensity on CT scan.19 A large hypodense
area present on CT scan within the first 3 hours of reported symptom onset should
prompt careful review regarding the time of stroke symptom onset (eg,
determining when the patient was last seen in usual health). The presence of CT
evidence of infarction early in presentation has also been associated with poor
outcome and increased propensity for hemorrhagic transformation after
thrombolytics.10

Other radiologic clues to acute ischemic infarction include the insular ribbon sign,
the hyperdense MCA sign (MCA occlusion), obscuration of the lentiform nucleus,
sulcal asymmetry, and loss of gray-white matter differentiation.9

Unfortunately, as many as 5% of patients with subarachnoid hemorrhages also

have a normal CT scan, making lumbar puncture or other imaging (MR or CTA)
imperative when subarachnoid hemorrhage is suspected. CT scan may also fail to
demonstrate some parenchymal hemorrhages smaller than 1 cm.

CT perfusion

CT perfusion is a novel modality potentially useful in identifying early areas of

ischemia. By continuing to scan through the brain after an initial bolus of
intravenous contrast dye, perfusion of different brain regions can be measured.
Areas of hypoattenuation on CT perfusion imaging correspond well with ischemia
and allow some determination of viability and as a result the ischemic penumbra.11

CT angiography

Stroke 9
Noncontrast CT may be followed by a CT angiography (CTA) in certain centers.
CTA may identify a filling defect in a cerebral artery, thus localizing the lesion to
a specific portion of the causative vessel. In addition, CTA can provide an
estimation of perfusion because poorly perfused cerebral tissue appears as
hypodense areas of tissue. Noncontrast head CT in combination with CT
angiography and CT perfusion imaging has been shown to have increased
sensitivity for detecting small ischemic lesions when compared with any of the
individual imaging modalities alone. CTA also has a higher sensitivity than
standard noncontrast CT for detecting subarachnoid hemorrhage.12,13

CT scanning utilizing all 3 of these CT modalities (CT perfusion, angiography

and noncontrast CT) are being studied in acute stroke imaging. This technology
may offer improved detection of early stroke signs, small hemorrhagic strokes,
and subarachnoid hemorrhages and as well allow for calculation of perfusion.
These studies have the disadvantage of requiring further etrast CT scanning such
as the cerebellum and the brain stem.9

MRI

Acute stroke volume, as measured on DWI MRI, correlates well with final lesion
volume and clinical stroke severity scales, suggesting a possible role in
prognostication.14,15

PWI MRI directly measures perfused areas of brain in a manner similar to CT

perfusion. A contrast bolus is given, and multiple images over time are obtained,
providing a comparative measure of perfused versus nonperfused tissue regions.
PWI MRI may have utility in acute stroke patients.16

MR angiography (MRA) has also been shown to have efficacy in the early
identification of vascular lesions and blockages in acute stroke.17

Disadvantages of MRI imaging in acute stroke include its high cost, lack of ready
availability at most centers, complexity, time required for transport and obtaining
the study (15-20 minutes minimum with most scanners), and significant
contraindication in patients with metallic implants. Despite the significant
improvements in CT and MRI technology, differentiation and thus measurement
of infarcted core tissue and ischemic and potentially rescuable penumbra tissue is
still not possible acutely. It is likely that a combination of CT and/or MRI
modalities will be necessary to fully assess the patient with acute stroke for
hemorrhage and stroke mimics, and to quantify the area of infarcted versus
ischemic tissue. These data will be useful in allowing the extension of the
therapeutic window for thrombolysis in certain cases where large areas of

Stroke 10
rescuable tissue are identified and in preventing symptomatic intracranial
hemorrhage in those patients in whom bleeds are identified.

Ultrasonography

Carotid duplex scanning is reserved for patients with acute ischemic stroke in
whom carotid artery stenosis or occlusion is suspected.

Transcranial Doppler ultrasonography is useful for evaluating more proximal

vascular anatomy, including the MCA, intracranial carotid artery, and
vertebrobasilar artery.18

Echocardiography is obtained in all patients with acute ischemic stroke in whom

cardiogenic embolism is suspected. Transesophageal echocardiography is
necessary for detecting thoracic aortic dissection and more accurate for
identification of thrombi in the left atrial appendage from atrial fibrillation. A
certain proportion of patients with strokes may have underlying systolic
dysfunction, diastolic dysfunction, or concentric hypertrophy. Echocardiography
is also a modality to identify the presence of a patent foramen ovale.

Chest radiography

Chest radiography has potential utility for patients with acute stroke; however,
obtaining a chest radiograph should not delay the administration of rt-PA, and it
has not been shown to alter the clinical course or decision making in most cases.

Electrocardiography

ECG should be obtained for all patients with acute stroke because as many as 60%
of all cardiogenic emboli are associated with atrial fibrillation or acute MI.

Some reports have also recommended continuous cardiac monitoring for all
patients, since 4% of patients have a life-threatening arrhythmia during the course
of their illness and 3% have concurrent MI. Acute ischemic stroke has been
associated with acute cardiac dysfunction and arrhythmia, which then correlate
with worse functional outcome and morbidity at 3 months.19,20

Angiography

Stroke 11
Angiography is useful for patients with acute ischemic stroke in whom
characterization of the cerebrovascular anatomy might lead to change in medical
or surgical management, such as patients with subtle occlusive diseases (eg,
fibromuscular dysplasia, vasculitis) or arterial dissection.

Angiography continues to play an important role in the preoperative evaluation of

carotid artery disease.

2.9 Emergency Department Care

The goal for the acute management of patients with stroke is to stabilize the
patient and complete initial evaluation and assessment including imaging and
laboratory studies within 60 minutes of patient arrival. 12 Critical decisions focus
on need for intubation, blood pressure control, and determining risk/benefit for
thrombolytic intervention.

Airway and breathing

Patients presenting with Glasgow Coma Scale scores less than or equal to 8,
rapidly decreasing Glasgow Coma Scale scores, or inadequate airway protection
or ventilation require emergent airway control via rapid sequence intubation.

When increased intracranial pressure is suspected, rapid sequence induction

should be directed at minimizing the potentially adverse effects of intubation.

In unusual cases of potential imminent brain herniation where the goal of

mechanical ventilation is hyperventilation to decrease intracranial pressure by
decreasing cerebral blood flow, the recommended endpoint is an arterial pCO2 of
32-36 mm Hg. Intravenous mannitol can be considered as well.

Supplemental oxygen use should be guided by pulse oximetry. Patients should

receive supplemental oxygen if their pulse oximetry reading or arterial blood gas
measurement reveals that they are hypoxic. The most common cause of hypoxia
in the patient with acute stroke is partial airway obstruction, hypoventilation,
atelectasis, or aspiration of stomach or oropharyngeal contents.21,22

Circulation

Patients with acute stroke require intravenous access and cardiac monitoring in
the ED. Patients with acute stroke are at risk for cardiac arrhythmias and elevated
cardiac biomarkers. In addition, atrial fibrillation may be associated with acute
stroke as either the cause (embolic disease) or as a complication.23,24

Stroke 12
Blood glucose control

Recent data suggest that severe hyperglycemia is independently associated with

poor outcome and reduced reperfusion in thrombolysis as well as extension of the
infarcted territory.[45, 46, 47] Additionally, normoglycemic patients should not
be given excessive glucose-containing intravenous fluids, as this may lead to
hyperglycemia and may exacerbate ischemic cerebral injury. Blood sugar control
should be tightly maintained with insulin therapy with the goal of establishing
normoglycemia (90-140 mg/dL). Additionally, close monitoring of blood sugar
level should continue throughout hospitalization to avoid hypoglycemia.9

Head positioning

Studies have shown that cerebral perfusion pressure is maximized when patients
are maintained in a supine position. However, lying flat may serve to increase
intracranial pressure and thus is not recommended in cases of subarachnoid or
other intracranial hemorrhage. Because prolonged immobilization may lead to its
own complications, including deep venous thrombosis, pressure ulcer aspiration,
and pneumonia, patients should not be kept flat for longer than 24 hours.25

Blood pressure control

In poor flow states as occurs with thrombotic and embolic ischemic stroke as well
as in increased intracranial pressure due to cerebral edema, the cerebral
vasculature is without vasoregulatory capability and thus relies directly on mean
arterial pressure (MAP) and cardiac output for maintenance of cerebral blood
flow. Therefore, aggressive efforts to lower blood pressure may decrease
perfusion pressure and may prolong or worsen ischemia. Both elevated and low
blood pressure are associated with poor outcomes in patients with acute stroke.26,27

Recent studies have demonstrated that blood pressure typically drops in the first
24 hours after acute stroke whether or not antihypertensives are administered.
Further, studies reveal poorer outcomes in patients with lower pressures, and these
poorer outcomes correlated with the degree of pressure decline. 26 However, other
data suggest that blood pressure control, particularly when systolic or diastolic
pressures are extreme and when thrombolytics are planned, can be an important
treatment intervention. As a result, the control of hypertension in the setting of
acute stroke is controversial.12 Because a systolic blood pressure greater than 185
mm Hg or a diastolic pressure of greater than 110 mm Hg is a contraindication to
thrombolytics, emergency blood pressure control is indicated in order to allow for
thrombolytic administration.

Outside of the consideration of thrombolytic administration, in the absence of

hypertension-related complications or organ dysfunction, no data support the
administration of emergency antihypertensives in acute stroke.

Stroke 13
The consensus recommendation is to lower blood pressure only if systolic
pressure is in excess of 220 mm Hg or if diastolic pressure is greater than 120 mm
Hg.12 However, rapid reduction of blood pressure, no matter the degree of
hypertension may in fact be harmful.

The management of blood pressure in patients with acute ischemic stroke is

divided into those who are candidates for thrombolytics and those who are not.

Non–t-PA candidates

For patients who are not rt-PA candidates and whose systolic blood pressure is
less than 220 mm Hg and whose diastolic blood pressure is less than 120 mm Hg
in the absence of evidence of end-organ involvement (ie, pulmonary edema, aortic
dissection, hypertensive encephalopathy), blood pressure should be monitored
(without acute intervention) and stroke symptoms and complications should be
treated (increased ICP, seizures).

For patients with elevated systolic blood pressures above 220 mm Hg or diastolic
blood pressures between 120 and 140 mm Hg, labetalol (10-20 mg IV for 1-2
min) should be the initial drug of choice, unless a contraindication to its use
exists. Dosing may be repeated or doubled every 10 minutes to a maximum dose
of 300 mg. Alternatively, nicardipine (5 mg/h IV initial infusion) titrated to effect
via increasing 2.5 mg/h every 5 minutes to a maximum dose of 15 mg/h may be
used for blood pressure control. Lastly, nitroprusside at 0.5 mcg/kg/min IV
infusion may be used in the setting of continuous blood pressure monitoring. The
goal of intervention is a reduction of 10-15% of blood pressure.

For patients who will be receiving rt-PA, systolic blood pressure greater than 185
mm Hg and diastolic blood pressure greater than 110 mm Hg require intervention.
Monitoring and control of blood pressure during and after thrombolytic
administration are vital as uncontrolled hypertension is associated with
hemorrhagic complication.[20] The initial drug of choice is labetalol (10-20 mg
IV for 1-2 min), and one dose may be repeated. One to two inches of transdermal
nitropaste may also be used. As an alternative to these choices nicardipine
infusion at 5 mg/h titrated up to a maximum dose of 15 mg/h can be used.

Monitoring of blood pressure is crucial, and, for the first 2 hours, blood pressure
should be checked every 15 minutes, then every 30 minutes for 6 hours, and
finally every hour for 16 hours. The goal of therapy should be to reduce blood
pressure by 15-25% within the first day, with continued blood pressure control
during hospitalization. In order to assure adequate blood pressure control during
hospitalization, the following agents and doses may be considered:

Stroke 14
Systolic blood pressure (SBP): 180-230 mm Hg or diastolic blood pressure (DBP)
105-120 mm Hg: Labetalol 10 mg IV over 1-2 minutes may repeat every 10-20
minutes up to 300 mg total or an infusion of labetalol up to 2-8 mg/min.

For SBP >230 mm Hg or DBP 121-140 mm Hg labetalol at the above doses can
be considered or nicardipine infusion at 5 mg/h to a maximum of 15 mg/h. For
difficult to control blood pressure, sodium nitroprusside can be considered.

Use of sublingual nifedipine to lower blood pressure in the ED is discouraged

since extreme hypotension may result. Trials of nimodipine, initially thought to be
beneficial given its vasodilatory effect as a calcium channel blocker, have failed
to demonstrate any beneficial outcome in comparison to placebo.

Consensus agreement is that these blood pressure guidelines should be maintained

in the face of other interventions to restore perfusion such as intra-arterial
thrombolysis.9

Given the need to maintain adequate cerebral blood flow, severe hypotension
should be managed in standard fashion with aggressive fluid resuscitation a search
for the etiology of hypotension and, if necessary, vasopressor support. Evidence
suggests that baseline SBP < 100 mg Hg and DBP < 70 mm Hg correlate with
worse outcome.26

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 I clinical trials.28,29

High body temperature in the first 12-24 hours after stroke onset has been
associated with poor functional outcome. The Paracetamol (Acetaminophen) In
Stroke (PAIS) trial assessed whether early treatment with paracetamol improves
functional outcome in patients with acute stroke by reducing body temperature
and preventing fever. Patients (n=1400) were randomly assigned to receive
acetaminophen (6 g daily) or placebo within 12 hours of symptom onset. After 3
months, improvement on the modified Rankin scale was not beyond what was
expected. These results do not support routine use of high-dose acetaminophen in
patients with acute stroke.30

Cerebral edema control

Stroke 15
Cerebral edema occurs in up to 15% of patients with ischemic stroke, reaching
maximum severity 72-96 hours after the onset of stroke. Hyperventilation and
mannitol are used routinely to decrease intracranial pressure quickly and
temporarily. No evidence exists supporting the use of corticosteroids to decrease
cerebral edema in acute ischemic stroke. Prompt neurosurgical assistance should
be sought when indicated.

Seizure control

Seizures occur in 2-23% of patients within the first days after stroke. Although
seizure prophylaxis is not indicated, prevention of subsequent seizures with
standard antiepileptic therapy is recommended.9

Acute decompensation or escalation

In the case of the rapidly decompensating patient or the patient with deteriorating
neurologic status, reassessment of 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. Some advocate resetting the time window to zero in this
circumstance and encourage consideration of reperfusion strategies.

2.10 Medication

Medications for the management of ischemic stroke can be distributed into the
following categories: (1) anticoagulation, (2) reperfusion, (3) antiplatelet, and (4)
neuroprotective.

Anticoagulation

Although heparin prevents recurrent cardioembolic stroke and may help inhibit
ongoing cerebrovascular thrombosis, current guidelines do not recommend
anticoagulation for any subset of patients with stroke because of insufficient data.
Both randomized prospective trials evaluating t-PA for acute ischemic stroke
(ECASS and NINDS) excluded patients who were receiving anticoagulants.
Heparin is known to prolong the lytic state caused by t-PA. Immobilized stroke
patients who are not receiving anticoagulants, such as IV heparin or an oral
anticoagulant, may benefit from low-dose subcutaneous unfractionated or low
molecular weight heparin, which reduces the risk of deep vein thrombosis.

Stroke 16
The use of low molecular weight heparin as treatment of acute ischemic stroke
has not yet been studied adequately. However, multiple past studies have failed to
show any beneficial effect of anticoagulation in acute ischemic stroke. Although
trials of anticoagulants in the treatment of acute ischemic stroke are ongoing, no
current data exist to support their use in acute ischemic stroke.9

Reperfusion agents (thrombolytics)

Patients who are eligible for treatment with rt-PA within 3 hours of onset of stroke
should be treated as recommended in the 2007 guidelines.[12] Although a longer
time window for treatment with rt-PA has been tested formally, delays in
evaluation and initiation of therapy should be avoided because the opportunity for
improvement is greater with earlier treatment. rt-PA should be administered to
eligible patients who can be treated in the time period of 3 to 4.5 hours after
stroke (Class I recommendation, level of Evidence B). Eligibility criteria for
treatment in the 3 to 4.5 hours after acute stroke are similar to those for treatment
at earlier time periods, with any one of the following additional exclusion criteria:

(1)Patients older than 80 years (2) All patients taking oral anticoagulants are
excluded regardless of the international normalized ratio (INR) (3) Patients with
baseline NIH Stroke Scale >25 (4) Patients with a history of stroke and diabetes

Risks of thrombolytics

Meta-analysis of studies published thus far revealed an overall rate of

symptomatic hemorrhage to be 5.2%.59

Current American Heart Association (AHA)/American Stroke Association (ASA)

inclusion guidelines for the administration of rt-PA are as follows:

1. Diagnosis of ischemic stroke causing measurable neurologic deficit

2. Neurologic signs should not be clearing spontaneously
3. Neurologic signs should not be minor and isolated
4. Caution should be exercised in treating patients with major deficits
5. Symptoms should not be suggestive of subarachnoid hemorrhage
6. Onset of symptoms < 3 hours before beginning treatment
7. No head trauma or prior stroke in past 3 months
8. No MI in prior 3 months
9. No GI/GU hemorrhage in previous 21 days
10. No arterial puncture in noncompressible site during prior 7 days
11. No major surgery in prior 14 days
12. No history of prior intracranial bleed
13. SBP < 185 mm Hg, DBP < 110 mm Hg
14. No evidence of acute trauma or bleeding
15. Not taking an oral anticoagulant, or if so INR < 1.7

Stroke 17
 16. If taking heparin within 48 hours must have a normal activated
prothrombin time (aPT)
17. Platelet count >100,000 μL
18. Blood glucose level greater than 50 mg/dL (2.7 mmol)
19. No seizure with residual postictal impairments
20. CT scan does not show evidence of multilobar infarction (hypodensity
>1/3 hemisphere)
21. The patient and family understand the potential risks and benefits of
therapy

Intra-arterial thrombolysis

No human trials comparing the intravenous versus intra-arterial administration of

thrombolytics exist. However, several authors have posited potential benefits from
the intra-arterial approach. These advantages include the higher local
concentrations of thrombolytic possibly allowing lower total doses (and
theoretically less risk of systemic bleed) and a suggested longer therapeutic
window, potentially out to 6 hours. However, the longer time to administration via
the intra-arterial approach versus the intravenous approach may mitigate some of
this advantage.

One agent in particular, prourokinase, administered intra-arterially was found to

have benefit when administered in less than 6 hours' duration since the
development of symptoms in patients with MCA strokes. This agent is not
currently available for use in the United States, and further studies regarding its
effectiveness intra-arterially are warranted. The time window for intra-arterial
thrombolysis is 6 hours, but it may be extended up to 12 hours in unique
circumstances. As such, the administration of intra-arterial thrombolytics has been
most common in situations when intravenous thrombolysis is expected to be
limited, as in major vascular occlusions, presentation between 3-6 hours since
symptom onset and severe neurologic deficit.9

In addition, there appears to be some benefit of intra-arterial administration of

thrombolytics (urokinase) in patients with vertebral or basilar artery occlusion
treated within 24 hours of symptom onset.31,32,33Furthermore, intra-arterial
thrombolysis may be indicated in patients with contraindications to intravenous
thrombolytic administration such as recent surgery.9,31,32,33

Ultrasonographic-assisted thrombolysis

Stroke 18
A meta-analysis of studies of ultrasound-enhanced thrombolysis in ischemic
stroke found that the likelihood of complete recanalization was higher in patients
receiving the combination t-PA with transcranial Doppler or transcranial color-
coded duplex versus intravenous t-PA alone (pooled odds ratio, 2.99; 95%
confidence index, 1.70-5.25; P=0.0001).67 The use of high-frequency ultrasound
did not increase the risk of symptomatic intracerebral hemorrhage. The endpoints
reported in the review did not include clinical improvement. This is a promising
technology for further study.

Anticoagulants

Patients with embolic stroke who have another indication for anticoagulation (eg,
atrial fibrillation) may be placed on anticoagulation therapy with the goal of
preventing further embolic disease.9

Induced hypothermia

Hypothermia is fast becoming standard of care for the ongoing treatment of

patients surviving cardiac arrest due to ventricular tachycardia or ventricular
fibrillation. No major clinical study has demonstrated a role for hypothermia in
the early treatment of ischemic stroke. It isadvisable to prevent hyperthermia for
the first several days after acute ischemic stroke because fever has been
independently associated with poor outcome and failure of thrombolysis. 9

Neuroprotective agents

Calcium channel blockers (eg, nimodipine) should have the narrowest window of
therapeutic opportunity, since calcium influx is one of the earliest events in the
ischemic cascade. A recent study suggests that lubeluzole (an inhibitor of
glutamate release) may benefit patients with acute ischemic stroke if given within
6 hours. Aptiganel (noncompetitive inhibitor of the NMDA receptor) also appears
promising when given early in the course of ischemia.

Neuroprotectants affecting later events in the ischemic cascade include free-

radical scavengers (tirilazad, citicoline, cerovive) and neuronal membrane
stabilizers [citicoline]). Cerovive is currently being evaluated in a large placebo-
controlled randomized study. Monoclonal antibodies against leukocyte adhesion
molecules also are being evaluated as late neuroprotectants (enlimomab). No set
classification system yet exists for the many neuroprotectants being investigated,
since many agents appear to have more than one mechanism of action. 34

Stroke 19
Surgical and endovascular interventions

Many surgical and endovascular techniques have been studied in the treatment of
acute ischemic stroke. Carotid endarterectomy has been used in the acute
management of internal carotid artery occlusions with some success (Gay, Huber,
guidelines). Other interventions have included laser, intra-arterial suction, snares,
angioplasty, as well as clot retrieval devices.

Medication Classification

Fibrinolytic agents

Alteplase (Activase)

Tissue plasminogen activator (t-PA) used in management of acute MI, acute

ischemic stroke, and pulmonary embolism. Safety and efficacy with concomitant
administration of heparin or aspirin during first 24 h after symptom onset have not
been investigated.

Anti-Platelet Agents

These agents convert entrapped plasminogen to plasmin and initiate local

fibrinolysis by binding to fibrin in a clot.

Aspirin (Bayer Aspirin, Anacin, Bufferin)

Blocks prostaglandin synthetase action, which, in turn, inhibits prostaglandin

synthesis and prevents formation of platelet-aggregating thromboxane A2. Also
acts on hypothalamic heat-regulating center to reduce fever.

Ticlopidine (Ticlid)

Second-line antiplatelet therapy for patients who cannot tolerate aspirin or in

whom aspirin not effective.

Stroke 20
2.11 Further Inpatient Care

Comorbid medical problems need to be addressed. Assessments of swallow

function, prior to the reinstitution of oral feeding is recommended. 12 Patients
should receive deep venous thrombosis prophylaxis, although the timing of
institution of this therapy is unknown. Serial monitoring and interventions when
necessary early in the clinical course and eventual stroke rehabilitation and
physical and occupational therapy are the ideals.

2.12 Complications

The most common and important complications of ischemic stroke include

cerebral edema, hemorrhagic transformation, and seizures. Significant cerebral
edema after ischemic stroke is thought to be somewhat rare (10-20%).

Early indicators of ischemia on presentation and on noncontrast CT scan are

independent indicators of potential swelling and deterioration. Mannitol and other
therapies to reduce intracranial pressure may be utilized in emergency situations,
although their usefulness in swelling secondary to ischemic stroke are unknown.
Some patients furthermore experience hemorrhagic transformation of their infarct.
This is estimated to occur in 5% of uncomplicated ischemic strokes, in the
absence of thrombolytics. Hemorrhagic transformation is not always associated
with neurologic decline and ranges from small petechial hemorrhages to
hematomas requiring evacuation.

The incidence of seizures ranges from 2-23% in the immediate post-stroke

recovery period. Post-ischemia strokes are usually focal but may be generalized.
A fraction of patients who have experienced stroke develop chronic seizure
disorders. Seizures secondary to ischemic stroke should be managed in the same
manner as other seizure disorders that arise as a result of neurologic injury. 9

Stroke 21
 CHAPTER III

HEMORRHAGE STROKE

3.1 Epidemiology

Frequency

United States

Intracerebral hemorrhage accounts for 10-15% of all strokes.35 Recent reports

indicate an incidence exceeding 500,000 new strokes of all types per year.

Mortality/Morbidity

Stroke is a leading killer and disabler. Combining all types of stroke, it is the third
leading cause of death and the first leading cause of disability. Morbidity is more
severe and mortality rates are higher for hemorrhagic stroke than for ischemic
stroke. Only 20% of patients regain functional independence. The 30-day
mortality rate for hemorrhagic stroke is 40-80%. Approximately 50% of all deaths
occur within the first 48 hours. 35

A recent study of 474 ICH patients found that for those younger than 75 years of
age, male sex predicted a poor outcome. Within 28 days, 20% of women and 23%
of men died (P=0.38); in those 75 years or older, the corresponding figures were
26% and 41%, respectively (P=0.02). Other independent predictors of death were
high age, central and brainstem hemorrhage location, intraventricular hemorrhage,
increased volume, and decreased level of consciousness. 36

Race

African Americans have a higher incidence of hemorrhagic and ischemic strokes

than other races in the United States. The incidence of hemorrhagic stroke in the
Japanese population is increased.

Age

The risk of stroke increases with age.

Stroke 22
3.2 Physical

(1)intracerebral hemorrhage (ich) may be clinically indistinguishable from

ischemic stroke. (2) hypertension is commonly a prominent finding. (3) an altered
level of consciousness or coma is more common with hemorrhagic stroke than
with ischemic stroke. often, this is due to an increase in intracranial pressure. (4)
meningismus may result from blood in the ventricles. (5) focal neurologic deficits
(6) the type of deficit depends upon the area of brain involved. (7) if the dominant
hemisphere (usually left) is involved, a syndrome consisting of right hemiparesis,
right hemisensory loss, left gaze preference, right visual field cut, and aphasia
may result. (8) if the nondominant (usually right) hemisphere is involved, a
syndrome of left hemiparesis, left hemisensory loss, right gaze preference, and left
visual field cut may result. nondominant hemisphere syndrome may also result in
neglect when the patient has a left-sided hemi-inattention and ignores the left side.
(9) if the cerebellum is involved, the patient is at high risk of herniation and
brainstem compression. herniation may cause a rapid decrease in the level of
consciousness, apnea, and death.

Other signs of cerebellar or brainstem involvement include the following:

(1)gait or limb ataxia (2) vertigo or tinnitus (3) nausea and vomiting (4)
hemiparesis or quadriparesis (5) hemisensory loss or sensory loss of all 4 limbs
(6) eye movement abnormalities resulting in diplopia or nystagmus (7)
oropharyngeal weakness or dysphagia (8) crossed signs (ipsilateral face and
contralateral body)

Many other stroke syndromes are associated with intracerebral hemorrhage (ICH),
ranging from mild headache to neurologic devastation. At times, a cerebral
hemorrhage may present as a new-onset seizure.

3.3 Causes

(1)Hypertension (up to 60% of cases) (2) Advanced age (risk factor) (3) Cerebral
amyloidosis (affects people who are elderly and may cause up to 10% of
intracerebral hemorrhages [ICHs]) (4) Coagulopathies (eg, due to underlying
systemic disorders such as bleeding diathesis or liver disease) (5) Anticoagulant
therapy (6) Thrombolytic therapy for acute myocardial infarction (MI) and acute
ischemic stroke (can cause iatrogenic hemorrhagic stroke) (7) Abuse of cocaine
and other sympathomimetic drugs (8) Arteriovenous malformation (9) Intracranial

Stroke 23
aneurysm (10) Vasculitis (11) Intracranial neoplasm (12) History of prior stroke
(risk factor)

3.4 Pathophysiology

In intracerebral hemorrhage (ICH), bleeding occurs directly into the brain

parenchyma. The usual mechanism is thought to be leakage from small
intracerebral arteries damaged by chronic hypertension. Other mechanisms
include bleeding diatheses, iatrogenic anticoagulation, cerebral amyloidosis, and
cocaine abuse. Intracerebral hemorrhage has a predilection for certain sites in the
brain, including the thalamus, putamen, cerebellum, and brainstem. In addition to
the area of the brain injured by the hemorrhage, the surrounding brain can be
damaged by pressure produced by the mass effect of the hematoma. A general
increase in intracranial pressure may occur.

3.5 Differential Diagnoses

(1) Encephalitis (2) Headache, Migraine (3) Hypernatremia (4) Hyperosmolar

Hyperglycemic Nonketotic Coma (5) Hypertensive Emergencies (6)
Hypoglycemia (7) Hyponatremia (8 )Labyrinthitis (9) Meningitis (10) Neoplasms,
Brain (11) Stroke, Ischemic (12) Subarachnoid Hemorrhage (13) Subdural
Hematoma (14) Transient Ischemic Attack

3.7 Laboratory Studies

(1) Complete blood count (2) Coagulation profile (3) Electrolyte level (4) Serum
glucose level (5) Blood type and screen

3.8 Imaging Studies

Brain may identify complications including intraventricular hemorrhage, brain

edema, or hydrocephalus. Either noncontrast CT or MRI of the brain is the
modality of choice.

Stroke 24
Noncontrast CT of the brain

Noncontrast CT differentiates hemorrhagic stroke from ischemic stroke. It is

useful in distinguishing stroke from other intracranial pathology. Noncontrast CT
can identify virtually all intracerebral hematomas greater than 1 cm in diameter.

MRI

In the past, noncontrast CT was the criterion standard for diagnosing hemorrhagic
stroke. Recent progress has demonstrated that current MRI techniques are capable
of accurately diagnosing hemorrhagic stroke.

MRI, especially newer techniques such as diffusion-weighted imaging, has been

shown to identify ischemic stroke earlier and more reliably than CT scanning.
MRI is being used with increasing frequency in the evaluation of ischemic stroke.

MRI may identify an underlying vascular malformation or lesion that caused the
bleeding.

Intracerebral hemorrhage associated with a right frontal arteriovenous

malformation is shown below.

Head CT should be obtained in patients with contraindications to MRI.

Chest radiography

Chest radiography should be obtained to screen for comorbid conditions.

Electrocardiogram (ECG) and begin cardiac monitoring.

Cardiac dysrhythmias and myocardial ischemia have a significant coincidence

with stroke.

3.9 Emergency Department Care

Assess the ABCs. Address any compromise in the patient's status as clinically
indicated.

Establish intravenous (IV) access.

Obtain bedside glucose determination.

Stroke 25
Hypoglycemia may mimic stroke.

Hyperglycemia has been associated with poorer outcomes in patients experiencing

stroke. (Also see Metabolic Disease & Stroke: Hyperglycemia/Hypoglycemia.)

Institute cardiac monitoring and obtain an ECG.

Intubation should be performed for patients who demonstrate potential loss of

airway protective mechanisms or signs of brainstem dysfunction. If intubation is
needed, rapid sequence intubation should be performed with technique and
medications aimed at limiting any increase in intracranial pressure.

Seizures:

Early seizure activity occurs in 4-28% of patients with intracerebral hemorrhage,

and these seizures are often nonconvulsive seizures. 37,38

Seizure activity should be rapidly controlled with a benzodiazepine, such as

lorazepam or diazepam, accompanied by either phenytoin or fosphenytoin
loading.

Prophylactic anticonvulsant therapy is recommended in patients with lobar

hemorrhages to reduce the risk of early seizures.35,37 However, the use of
prophylactic anticonvulsant therapy in all cases of intracerebral hemorrhage is
controversial, as no prospective controlled trials have demonstrated a clear
benefit.

Careful blood pressure (BP) monitoring is important.

No controlled studies define optimum BP levels.

Greatly elevated BP is thought to lead to rebleeding and hematoma expansion.

Patients who have had a stroke may lose their cerebral autoregulation of cerebral
perfusion pressure.

Rapid or aggressive BP lowering may compromise cerebral perfusion.

Nicardipine, labetalol, esmolol, and hydralazine are agents that may be used when
necessary for BP control. Avoid nitroprusside because it may raise intracranial
pressure.

The American Heart Association guidelines for treating elevated BP are as

follows: 35

If systolic BP is >200 mm Hg or mean arterial pressure (MAP) is >150 mm Hg,

then consider aggressive reduction of BP with continuous intravenous infusion
with frequent BP (every 5 min) checks.

Stroke 26
If systolic BP is >180 mm Hg or MAP is >130 mm Hg and there is evidence or
suspicion of elevated intracranial pressure (ICP), then consider monitoring of ICP
and reducing BP using intermittent or continuous intravenous medications to
maintain cerebral perfusion pressure >60-80 mm Hg.

If systolic BP is >180 or MAP is >130 mm Hg and there is NOT evidence or

suspicion of elevated ICP, then consider modest reduction of BP (target MAP of
110 mm Hg or target BP of 160/90 mm Hg) with BP checks every 15 minutes.

Intracranial pressure control:

Elevated intracranial pressure (ICP) may result from the hematoma itself,
surrounding edema, or both. The frequency of increased ICP in patients with
intracerebral hemorrhage (ICH) is not known.

Elevate the head of the bed to 30 degrees. This improves jugular venous outflow
and lowers ICP. The head should be midline and not turned to the side.

Provide analgesia and sedation as needed.

More aggressive therapies such as osmotic therapy (mannitol, hypertonic saline),

barbiturate anesthesia, and neuromuscular blockage generally require concomitant
monitoring of ICP and BP with an ICP monitor to maintain adequate cerebral
perfusion pressure (CPP) of above 70 mmHg. A randomized controlled study of
mannitol in ICH failed to demonstrate any difference in disability or death at 3
months. 39

Hyperventilation (paCO2 of 25-30-35 mm Hg) is not recommended. Its effect is

transient, it decreases cerebral blood flow, and it may result in rebound elevated
intracranial pressure. 35

Glucocorticoids are not effective and result in higher rates of complications with
poorer outcomes.

Ventriculostomy (cerebrospinal fluid drainage by intraventricular catheter

drainage) is often used in the setting of obstructive hydrocephalus. Obstructive
hydrocephalus is a common complication of thalamic hemorrhage with third
ventricle compression and of cerebellar hemorrhage with fourth ventricle
compression. Ventriculostomies are associated with high rates of complications
including bacterial meningitis.

Hemostatic therapy:

Much interest has been generated to determine if treatment with hemostatic

therapy to stop ongoing hemorrhage or prevent hematoma expansion may be
effective.

Stroke 27
Recombinant factor VIIa

A preliminary study of treatment with recombinant factor VIIa demonstrated

reduced mortality and improved functional outcomes. However, unfortunately, the
results of the larger randomized trial revealed no overall benefit of treatment.
Hemostatic therapy with rFVIIa reduced growth of the hematoma but did not
improve survival or functional outcome. 40

Diringer et al conducted a study using recombinant activated factor VIIa (rFVIIa)

in patients (n=841) presenting less than 3 hours after spontaneous intracerebral
hemorrhage.[9] Patients considered at higher risk for thromboembolic events (eg,
Glasgow Coma Scale score < 5, planned early surgery, coagulopathy, recent
thromboembolic event) were excluded. Participants were randomized to receive
20 or 80 mcg/kg of rFVIIa, or placebo. Venous events were similar between
groups. Arterial events were associated with receiving 80 mcg/kg dose of rFVIIa
(P=0.031), cardiac or cerebral ischemia at presentation (P=0.01), advanced age
(P=0.0123), or antiplatelet use (P=0.035). Additional research is needed to
measure the benefit of hemorrhage control in patients with cerebral hemorrhage
with the risk for arterial thromboembolic events.

Currently, no effective targeted therapy for hemorrhagic stroke exists. Further

studies are necessary to develop other potential treatment options.

Anticoagulation-associated ICH:

Warfarin

Patients on warfarin have an increased incidence of hemorrhagic stroke.

Morbidity and mortality for warfarin associated bleeding is high, over half of
patients die within 30 days. Most episodes occur with a therapeutic INR but
overanticoagulation is further associated with an increased risk of bleeding.

Reversal of warfarin anticoagulation is a true medical emergency and must be

accomplished as quickly as possible to prevent further hematoma expansion.

Warfarin reversal options include IV vitamin K, fresh frozen plasma (FFP),

prothrombin complex concentrates (PCC), and recombinant factor VIIa.

Because vitamin K requires more than 6 hours to normalize the INR, it should be
administered with either FFP or PCC.

FFP needs to be given 15-20 mL/kg and therefore requires a large volume
infusion. Prothrombin complex concentrate contains high levels of vitamin K-
dependent cofactors with a smaller volume of infusion than FFP, resulting in more
rapid administration. If available, PCC is preferable over FFP as a reversal agent.
41,42

Stroke 28
Based upon the available medial evidence, the use of factor VIIa is currently not
recommended over other agents.

Heparin

Patients on heparin (either unfractionated or low molecular weight heparin) who

develop a hemorrhagic stroke should immediately have anticoagulation reversed
with protamine. 35

The dose of protamine is dependent upon the dose of heparin that was given and
the time elapsed since that dose.

Reversal of antiplatelet therapy and platelet dysfunction:

Patients on antiplatelet medications including aspirin, aspirin/dipyridamole

(Aggrenox), and clopidogrel should be given desmopressin (DDAVP) and platelet
transfusion.

Patients with renal failure and platelet dysfunction may also benefit from the
administration of desmopressin (DDAVP).

3.10 Consultations

Emergent neurosurgical or neurological consultation often is indicated; local

referral patterns may vary.

A potential treatment of hemorrhagic stroke is surgical evacuation of the

hematoma. The role of surgical treatment for supratentorial intracranial
hemorrhage remains controversial. Outcomes in published studies are conflicting.
A published meta-analysis of studies suggested some promise for early surgical
intervention. However, one study comparing early surgery versus initial
conservative treatment failed to demonstrate a benefit with surgery. 43

Surgical intervention for cerebellar hematoma has been shown to improve

outcome. It can be lifesaving in the prevention of brainstem compression.

Need for invasive intracranial pressure monitoring should be assessed by the

neurosurgeon.

Need for emergent cerebral angiography should be assessed by the neurosurgeon.

Patients with no clear cause of the hemorrhage and who would otherwise be
candidates for surgery should be considered for angiographic evaluation.

Stroke 29
3.13 Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent

complications.

Anticonvulsant

Anticonvulsants prevent seizure recurrence and terminate clinical and electrical

seizure activity.

1. Fosphenytoin (Cerebyx)

Diphosphate ester salt of phenytoin that acts as water-soluble prodrug of

phenytoin. Following administration, plasma esterases convert fosphenytoin to
phosphate, formaldehyde and phenytoin. Phenytoin, in turn, stabilizes neuronal
membranes and decreases seizure activity.

To avoid need to perform molecular weight-based adjustments when converting

between fosphenytoin and phenytoin sodium doses, express dose as phenytoin
sodium equivalents (PE). Although can be administered IV and IM, IV route is
route of choice and should be used in emergency situations.

Concomitant administration of an IV benzodiazepine will usually be necessary to

control status epilepticus. The antiepileptic effect of phenytoin, whether given as
fosphenytoin or parenteral phenytoin, is not immediate.

2. Phenytoin (Dilantin)

May act in motor cortex where may inhibit spread of seizure activity. Activity of
brainstem centers responsible for tonic phase of grand mal seizures may also be
inhibited.

Dose to be administered should be individualized. Administer larger dose before

retiring if dose cannot be divided equally.

3. Diazepam (Diastat, Diazemuls, Valium)

Useful in controlling active seizures and should be augmented by longer-acting

anticonvulsants, such as phenytoin or phenobarbital.

Stroke 30
Modulates postsynaptic effects of GABA-A transmission, resulting in an increase
in presynaptic inhibition. Appears to act on part of the limbic system, the
thalamus, and hypothalamus, to induce a calming effect. Also has been found to
be an effective adjunct for the relief of skeletal muscle spasm caused by upper
motor neuron disorders.

Rapidly distributes to other body fat stores. Twenty minutes after initial IV
infusion, serum concentration drops to 20% of Cmax.

Individualize dosage and increase cautiously to avoid adverse effects.

4. Lorazepam (Ativan)

Short-acting benzodiazepine with moderately long half-life. Has become drug of

choice in many centers for treating active seizures.

Antihypertensive Agent

The treatment of hypertension should be designed to reduce the blood pressure

and other risk factors of heart disease. Pharmacologic therapy should be
individualized based on a patient's age.

1. Labetalol (Trandate)

Blocks beta1-, alpha-, and beta2-adrenergic receptor sites decreasing blood

pressure.

2. Esmolol (Brevibloc)

Ultra–short-acting agent that selectively blocks beta1-receptors with little or no

effect on beta2-receptor types. Particularly useful in patients with elevated arterial
pressure, especially if surgery is planned. Shown to reduce episodes of chest pain
and clinical cardiac events compared to placebo. Can be discontinued abruptly if
necessary. Useful in patients at risk for experiencing complications from beta-
blockade; particularly those with reactive airway disease, mild-moderate LV
dysfunction, and/or peripheral vascular disease. Short half-life of 8 min allows for
titration to desired effect and quick discontinuation if needed.

Stroke 31
3. Hydralazine (Apresoline)

Decreases systemic resistance through direct vasodilation of arterioles. Used to

treat hypertensive emergencies. The use of a vasodilator will reduce SVR, which,
in turn, may allow forward flow, improving cardiac output.

4. Nicardipine (Cardene, Cardene IV, Cardene SR)

Relaxes coronary smooth muscle and produces coronary vasodilation, which, in

turn, improves myocardial oxygen delivery and reduces myocardial oxygen
consumption.

Diuretic Osmotic

These agents are used in an attempt to lower pressure in the subarachnoid space.
As water diffuses from the subarachnoid space into the intravascular
compartment, pressure in the subarachnoid compartment may decrease.

Mannitol (Osmitrol)

Clinical Context: Reduces cerebral edema with help of osmotic forces and
decreases blood viscosity, resulting in reflex vasoconstriction and lowering of
ICP.

Vitamin

Vitamin K is used to promote the formation of clotting factors.

Phytonadione (Mephyton)

Can overcome competitive block produced by warfarin and other related

anticoagulants. Vitamin K-3 (menadione) is not effective for this purpose. Clinical
effect is delayed several hours while liver synthesis of clotting factors is initiated
and plasma levels of clotting factors II, VII, IX, and X are gradually restored.

Not to be administered prophylactically. Use only if evidence of anticoagulation

exists. Required dose varies with clinical situation, including amount of

Stroke 32
anticoagulant ingested and whether it is a short-acting or long-acting
anticoagulant.

Blood products

These agents are indicated for the correction of abnormal hemostatic parameters.

1. Fresh Frozen Plasma

Plasma is the fluid compartment of blood containing the soluble clotting factors.
For use in patients with blood product deficiencies.

2. Platelets

Platelet activity may be abnormal.

3. Prothrombin complex concentrate (Bebulin VH, Profilnine SD)

A mixture of vitamin K–dependent clotting factors found in normal plasma.

Replaces deficient clotting factors. Provides increase in plasma levels of factor IX
and can temporarily correct coagulation defect of patients with factor IX
deficiency.

Heparine Antidote

This agent is used to neutralize the effects of anticoagulants.

Protamine sulfate

Clinical Context: Forms a salt with heparin and neutralizes its effects.

Antihemophilic agents

Desmopressin acetate (DDAVP, Stimate)

These agents improve bleeding time and hemostasis.

Stroke 33
Releases von Willebrand protein from endothelial cells. Improves bleeding time
and hemostasis in patients with some vWf (mild and moderate von Willebrand
disease without abnormal molecular forms of von Willebrand protein). Effective
in uremic bleeding. Tachyphylaxis usually develops after 48 h, but the drug can
be effective again after several days.

3.14 Further Inpatient Care

ICU admission is mandatory for patients experiencing hemorrhagic stroke.

Monitor the patient for airway compromise.

Monitor and carefully address the patient's BP.

Reassess the patient’s neurologic status frequently.

Monitor cardiovascular status continuously.

Select patients may require intracranial pressure monitoring.

Select patients may require intraventricular catheterization for hydrocephalus.

3.15 Transfer

Patients with intracerebral hemorrhage (ICH) should be considered for transfer to

a facility with neurosurgical capabilities.

3.16 Complications

Increased intracranial pressure and herniation are the dreaded complications of

intracerebral hemorrhage. Worsening cerebral edema is often implicated in
neurologic deterioration in the first 24-48 hours.

Early hemorrhage growth is associated with neurologic deterioration. Expansion

of the hematoma is the most common cause of neurologic deterioration in the first
3 hours.

In patients who are initially alert, 25% will have a decrease in consciousness
within the first 24 hours.

Stroke 34
Poststroke seizures may develop.

Stroke is the leading cause of permanent disability.

3.17 Prognosis

The prognosis varies depending on the severity of stroke and the location and the
size of the hemorrhage.

Lower Glasgow Coma Scores are associated with poorer prognosis and higher
mortality rate.

A larger volume of blood at presentation is associated with a poorer prognosis.

Growth of the hematoma volume is associated with a poorer functional outcome

and increased mortality rate.

The presence of blood in the ventricles is associated with a higher mortality rate.
In one study, the presence of intraventricular blood at presentation was associated
with more than a 2-fold increase in death.

Patients with oral anticoagulation–associated intracerebral hemorrhage have

higher mortality rates and poorer functional outcomes.

Other complicating medical comorbidities also affect the prognosis.

Stroke 35