Acute Stroke and Transient Ischemic Attack

Guidelines for Treatment of
Acute Stroke
and Transient Ischemic Attack
Stroke Society of the Philippines

Rm. 1403 14/F North Tower, Cathedral Heights Bldg. Complex
St. Luke’s Medical Center, E. Rodriguez Sr. Ave., Quezon City
Telephone No.: (632) 723-0101 Loc 5143
Telefax No.: (632) 722-5877
E-mail: ssp_secretariat@yahoo.com
Website: www.strokesocietyphil.org
Acute Stroke and Transient Ischemic Attack
Stroke Society of the Philippines
Rm. 1403 14/F North Tower, Cathedral Heights Bldg. Complex
St. Luke’s Medical Center, E. Rodriguez Sr. Ave., Quezon City
Telephone No.: (632) 723-0101 Loc 5143
Telefax No.: (632) 722-5877
E-mail: ssp_secretariat@yahoo.com
Website: www.strokesocietyphil.org
Board of Trustees 2015-2016
President Maria Cristina Z. San Jose, MD

1st Vice-President Alejandro C. Baroque II, MD
2nd Vice-President Ma. Epifania V. Collantes, MD
Secretary Romulo U. Esagunde, MD
Treasurer Johnny K. Lokin, MD
Public Relation Officer Raquel M. Alvarez, MD
Immediate Past President Artemio A. Roxas, Jr., MD
Members Pedro Danilo J. Lagamayo, MD

Betty D. Mancao, MD
Manuel M. Mariano, MD
Orlino A. Pacioles, MD
Peter P. Rivera, MD
Ma. Socorro F. Sarfati, MD
Jose Alvin P. Mojica, MD
Jose Leonard R. Pascual V, MD
Maria Christina M. Valdez, MD
Pedro Danilo J. Lagamayo, MD
Orlino A. Pacioles, MD
Stroke: Think Globally, Act Locally

Principles:
1. Stroke is a “brain attack”

...needing emergency management, including specific treatments and secondary and
tertiary prevention.
2. Stroke is an emergency
...where virtually no allowances for worsening are tolerated.
3. Stroke is treatable
...optimally, through proven, affordable, culturally-acceptable and ethical means.
4. Stroke is preventable
...in implementable ways across all levels of society.
The recommendations contained in this document are intended to merely guide practitioners in the prevention, treatment and rehabilitation of patients
with stroke. In no way should these recommendations be regarded as absolute rules, since nuances and peculiarities in individual patients, situations or
communities may entail differences in specific approaches. The recommendations should supplement, not replace, sound clinical judgments on a case-
to-case basis.
www.TheFilipinoDoctor.com l Sign up and open your clinic to the world. 155

Clinical Pathway for Malignant MCA Infarcts
(UPCM Department of Neurosciences Protocol for Malignant MCA Infarction)*
Patients with suspected large MCA infarct
• Age 18-65
• GCS 5-8 or NIHSS >15 (non-dominant) or NIHSS >20 (dominant)
• Pre-morbid MRS <3
• Hemiplegia, forced eye deviation, aphasia, contralateral neglect
• Consult within first 48 hours of symptom onset
• No comorbidities OR controlled comorbidities
• Family understands expectations and consents to surgical evaluation
Immediate
neurosurgical Y Infarct volume 50% of N
referral for urgent Medical
MCA territory on cranial
decompressive management
CT 6 hours from onset
hemicraniectomy
(OR in 4-6 hours)
Clinical
deteriorationa
Exclusion criteria:
A. Pre-stroke MRS ≥2
B. GCS 3 or 4
C. Contralateral ischemia or other brain lesion that could
affect outcome
D. Space-occupying hemorrhagic transformation
(≥ PH2b) Y
E. Life expectancy <3 years
F. Other serious illness that could affect outcome
G. Known coagulopathy or synthetic bleeding Repeat cranial CT scan
H. Contraindication for anesthesia
I. Pregnancy
a
Deterioration defined as decline in GCS score by 2 points
b
Dense hematoma >30% of the infarcted area with substantial space-occupying effect or any hemorrhagic lesion outside the infarcted area
*Adapted from the STATE Criteria of the Massachusetts General Hospital Stroke Service
156
Guidelines for Treatment of Acute Table 2. Recommended Place of Treatment Accord-
ing to Stroke Severity
Stroke and Transient Ischemic Attack
Transient a. Outpatient if TIA occured
I. SSP CLASSIFICATION OF ACUTE STROKE Ischemic attack >2 weeks prior (work-up should
BASED ON CLINICAL SEVERITY be done within 24-48 h)
b. Hospital (acute stroke unit
Background and Rationale for the Simplified Initial [ASU]) if:
Classification • TIA within 48 hours
��
• Crescendo TIAs (multiple &��
The use of standardized stroke classification schemes increasing symptoms)
such as those based on stroke type, localization or brain/ • TIA with known high-risk
vascular territory involvement, pathologic mechanism, cardiac source of embolism
and time course may be difficult and time-consuming • known hypercoagulable state
especially for non-neuroscience specialists in acute or symptomatic ICA stenosis
care setting. The working committee of the first edition of • ABCD2 score >3
SSP Stroke Guidelines (1999) has developed a practical
and locally relevant initial classification scheme (Table Mild Stroke Hospital (ASU/regular room)
1), which is based simply on the observed severity of Moderate Stroke Hospital (ASU/intensive care unit
patient's neurologic deficits including level of sensorium [ICU])
and response to pain. The present working committee Severe Stroke Hospital (ICU)
still finds this format useful particularly in emergency
situations, and advocates its continuous use of help both
medical and paramedical professionals regarding deci- II. GUIDELINES FOR MANAGEMENT OF
sions and cruicial actions at the emergency room. TRANSIENT ISCHEMIC ATTACK
After stabilization and initial management of the patient,
MANAGEMENT PRIORITIES
additional diagnostic work-ups are recommended for
determining and further classifying stroke based on • Ascertain clinical diagnosis of TIA (history, P.E. and
underlying pathologic mechanism, which is neces- neurologic exam are very important).
sary for selection of appropriate secondary prevention • Exclude common TIA mimics (see Chapter 1).
strategies. • Identify comorbidities (e.g., cardiac disease, DM, liver
disease, gastric ulcer).
Table 1. SSP Definition of Stroke Severity • Provide basic emergent supportive care (ABCs of
resuscitation).
MILD MODERATE SEVERE • Monitor neuro-vital signs (NVS) including pupil size,
Stroke Stroke Stroke
blood pressure (BP), mean arterial pressure (MAP),
Alert patients Awake patient w/ Deep stupor or respiratory rate (RR), temperature, O2 saturation.
with any (or significant motor comatose • Perform stroke scales (i.e., NIHSS, GCS; see Appen-
combination) of and/or sensory patient with non-
the following: and/or language purposeful res-
dix B) and risk stratification using ABCD2 scale (see
1. Mild pure motor and/or visual ponse, decorti- Chapter 1)
weakness of deficit. cate, or dece- • Treat BP if MAP >130. Precaution: Avoid precipitous
one side of the rebrate postu- drop (not >15% of baseline MAP) within 24 hours.
body, defined or ring to painful Do not use rapid-acting sublingual (SL) agents; when
as: can can stimuli. needed, use easily titratable intravenous (IV) or short-
raise arm above Disoriented, acting oral antihypertensive medication.
shoulder has drowsy or light or • Ensure appropriate hydration. Recommended IVF (if
clumsy hand, stupor with pur-
needed): 0.9% NaCl.
or can ambuate poseful response Comatose
without assist- painful stimuli. patient with no
ance. response to EMERGENT DIAGNOSTICS
2. Pure sensory painful stimuli.
deficit • Complete blood count (CBC)
3. Slurred but intel- • Blood glucose (CBG or RBS)
ligible speech • Coagulation studies: Prothrombin time (PT), activated
4. Vertigo with partial thromboplastin time (aPTT)
incoordination • Electrocardiogram (ECG)
(e.g., gait dis- • Cranial MRI-diffusion weighted imaging (DWI) is pre-
turbance, un- ferred; may do non-contrast Cranial CT (NCCT) scan
steadiness, or
if MRI is not available/possible.
clumsy hand)
5. Visual field
defects alone EARLY SPECIFIC TREATMENT
or or or
NIHSS score: NIHSS score: NIHSS score: CARDIOEMBOLISM CARDIOEMBOLISM
0 - 5 6 - 21 >22 NOT SUSPECTED SUSPECTED
See Guidelines See Guidelines See Guidelines • Start Aspirin (ASA) 160- • Consider careful anti-
for Mild for Moderate for Severe 325 mg/day as early as coagulation with intra-
Stroke Stroke Stroke possible and continue for venous (IV) heparin or
NIHSS: National Institutes of health Stroke Scale (see Appendix B)
14 days. The combination subcutaneous (SQ) low-

of ASA 80 mg + clopido- molecular-weight heparin III. GUIDELINES FOR MANAGEMENT OF MILD
grel 75 mg may be con- (LMWH) for individuals STROKE (NIHSS score: 0-5)
sidered for short-term at high risk of early
treatment. recurrence (e.g., AF with MANAGEMENT PRIORITIES
• Ensure neuroprotection* thrombus, valvular heart • Ascertain clinical diagnosis of stroke (history, P.E. and
disease, or myocardial neurologic exam are very important).
infarction) or ASA 160- • Exclude common stroke mimics (see Chapter 1).
325 mg/day (if anti- • Identify comorbidities (e.g., cardiac disease, DM, liver
coagulation is not pos- disease, gastric ulcer).
sible or is contraindi- • Provide basic emergent supportive care (ABCs of
cated). resuscitation).
• Ensure neuroprotection* • Monitor neuro-vital signs (NVS) including pupil size,
• If infective endocarditis blood pressure (BP), mean arterial pressure (MAP),
(IE) is suspected, give respiratory rate (RR), temperature, O2 saturation
antibiotics and DO NOT (SaO2).
anticoagulate. • Perform and monitor stroke scales (i.e., NIHSS, GCS;
see Appendix B)
DELAYED MANAGEMENT AND SECONDARY • Provide O2 support to maintain SaO2 >94%.
PREVENTION • Treat BP if MAP >130. Precaution: Avoid precipitous
CARDIOEMBOLISM CARDIOEMBOLISM drop (not >15% of baseline MAP) within 24 hours.
NOT SUSPECTED SUSPECTED Do not use rapid-acting sublingual (SL) agents; when
needed, use easily titratable intravenous (IV) or short-
• Give antiplatelets (e.g., • Request echocardio- acting oral antihypertensive medication.
ASA, clopidogrel, cilos- graphy and/or refer to • Ensure appropriate hydration. Recommended IVF (if
tazol, trifusal, dipyrida- cardiologist. needed): 0.9% NaCl.
mole, extended-release • Novel oral anticoagu-
dipyridamole + ASA lants (NOACs) are pre- EMERGENT DIAGNOSTICS
combination) (see ferred over dose-adjust-
Chapter 4) ed warfarin (see • Complete blood count (CBC)
• Control/treat risk factors Chapter 5) • Blood glucose (CBG or RBS)
• Recommend carotid • If anticoagulation is • Coagulation studies: PT, aPTT
ultrasound (UTZ) to contraindicated, give • Electrocardiogram (ECG)
document extracranial ASA 160-325 mg/day. • Cranial NCCT scan or MRI-DWI as soon as possible.
stenosis; if UTZ reveals The addition of clopido- If intracranial hemorrhage (ICH) is evident, compute
>70% stenosis, refer to grel to ASA therapy is for the hematoma volume (see Chapter 7).
a neurologist/neuro-sur- reasonable.
geon/vascular surgeon EARLY SPECIFIC TREATMENT
for decision-making (treatment requires neuroimaging confirmation)
regarding carotid endar-
terectomy (CEA) or ISCHEMIC
stenting.
CARDIO-
• Recommend transcranial
EMBOLISM NOT CARDIO- HEMO-
Doppler (TCD) studies
SUSPECTED EMBOLISM RRHAGIC
or CT or MR angio-
(Thrombotic, SUSPECTED
graphy (CTA/MRA) to
Lacunar)
document intracranial
stenosis. • Start Aspirin • Consider care- • Early neuro-
(ASA) 160-325 ful anticoagula- logy and/or
Others: mg/day as early tion with intra- neurosurgery
• Specialized tests: screening for hypercoagulable states as possible and venous (IV) he- consult for all
(e.g., protein C, protein S, antithrombin III, fibrinogen, continue for 14 parin or sub- ICH cases.
homocysteine) and drug/toxicology tests (e.g., met- days. The com- cutaneous (SQ) • Monitor and
amphetamine, cocaine) may be considered for young bination of ASA low-molecular- maintain
patients with TIA/stroke especially when no vascular 80 mg + clopi- weight heparin target SBP
risk factors exist and no underlying cause is identified dogrel 75 mg (LMWH) for ≈140 mmHg
(see Chapter 9). may be consi- individuals at during the first
• If vasculitis is suspected, may do erythrocyte sedi- dered for short- high risk of early week.
mentation rate (ESR), antinuclear antibody (ANA), and term treatment. recurrence (e.g., • Ensure neuro-
lupus anticoagulant tests. • Ensure neuro- AF with throm- protection*
• Trans-esophageal echocardiography (TEE) to rule out protection* bus, valvular • Early rehabi-
PFO in cryptogenic stroke. heart disease, litation once
*See section on Neuroprotection or, myocardial stable within
infarction) or 72 hours.
ASA 160-325 • Give anti-
mg/day (if anti- epileptic drugs
coagulation is (AEDs) for
not possible or clinical
158
is contra- seizures and transcranial
indicated) proven sub- Doppler (TCD)
• Ensure neuro- clinical or studies or CT or
protection* electrographic MR angiography
• If infective endo- seizures. (CTA/MRA) to
carditis (IE) is • Prophylactic document intra-
suspected, give AEDs and cranial stenosis.
antibiotics and steroids are
DO NOT anti- generally not IV. GUIDELINES FOR MANAGEMENT OF
coagulate. recommended. MODERATE STROKE (NIHSS score: 6-21)
• Monitor/correct
for metabolic MANAGEMENT PRIORITIES
parameters
and coagula- • Ascertain clinical diagnosis of stroke (history, P.E. and
tion/bleeding neurologic exam are very important).
abnormalities. • Exclude common stroke mimics (see Chapter 1).
• Follow recom- • Identify comorbidities (e.g., cardiac disease, DM, liver
mendations for disease, gastric ulcer).
neurosurgical • Provide basic emergent supportive care (ABCs of
intervention. resuscitation).
• For specific • Monitor neuro-vital signs (NVS) including pupil size,
details on ICH blood pressure (BP), mean arterial pressure (MAP),
and treatment respiratory rate (RR), temperature, O 2 saturation
of aneurysmal (SaO2).
SAH, see • Perform and monitor stroke scales (i.e., NIHSS, GCS;
Chapter 6. see Appendix B)
• Provide O2 support to maintain SaO2 >94%.
*See section on Neuroprotection • Treat BP if MAP >130. Precaution: Avoid precipitous
drop (not >15% of baseline MAP) within 24 hours.
DELAYED MANAGEMENT AND SECONDARY Do not use rapid-acting sublingual (SL) agents; when
PREVENTION needed, use easily titratable intravenous (IV) or short-
acting oral antihypertensive medication.
ISCHEMIC
• Recognize and treat for early signs and symptoms of
CARDIO- increased ICP (see Management of Increased ICP).
EMBOLISM NOT CARDIO- HEMO- • Ensure appropriate hydration. Recommended IVF (if
SUSPECTED EMBOLISM RRHAGIC needed): 0.9% NaCl.
Lacunar) EMERGENT DIAGNOSTICS
• Give antiplate- • Request echo- • Long-term strict • Complete blood count (CBC)
lets (e.g., ASA, cardiography BP control • Blood glucose (CBG or RBS)
clopidogrel, and/or refer to and monitoring • Coagulation studies: PT, aPTT
cilostazol, triflu- cardiologist • Consider • Serum Na+ and K+
sal, dipyrida- • Novel oral anti- contrast CT • Electrocardiogram (ECG)
mole, extended- coagulants scan, 4-vessel • Cranial NCCT scan or MRI-DWI as soon as possible.
release dipyri- (NOACs) are cerebral angio- If ICH is evident, compute for the hematoma volume
damole + ASA preferred over gram, MRA or (see Chapter 7).
combination) dose-adjusted CTA if the patient
(see Chapter 4) warfarin. is: EARLY SPECIFIC TREATMENT
• Control/treat • If anticoagu- a. <45 years old (treatment requires neuroimaging confirmation)
risk factors lation is contra- b. normotensive
• Recommend indicated, give c. has lobar ICH SCHEMIC
carotid ultra- ASA 160-325 d. has uncertain
sound (UTZ) to mg. The addi- cause of ICH CARDIO-
document extra- tion of clopi- e. suspected to EMBOLISM NOT CARDIO- HEMO-
cranial stenosis; dogrel to ASA have aneu- SUSPECTED EMBOLISM RRHAGIC
if UTZ reveals therapy is rysm, AVM, (Thrombotic, SUSPECTED
>70% stenosis, reasonable or vasculitis Lacunar)
refer to a neuro-
logist/neuro- • Refer to neuro- • Refer to a neu- • Early neuro-
surgeon/vascu- logist for eva- rologist for eva- logy and/or
lar surgeon for luation and luation and neurosurgery
decision-making decision. decision. consult for all
regarding caro- • If the patient • If the patient ICH cases.
tid endarterecto- presents within presents within • Monitor and
my (CEA) or 3 hours of 3 hours of maintain
stenting. stroke onset, stroke onset, target SBP:
• Recommend consider IV consider IV = 140 mmHg

thrombolysis thrombolysis during the first identified risk tion is contra- c. has lobar ICH
with recombi- with rt-PA. week. factors. indicated, give d. has uncer-
nant tissue • Selected • Ensure neuro- • If carotid UTZ ASA 160-325 tain cause of
plasminogen patients within protection* reveals >70% mg. The addi- ICH
activator (rt-PA). 3 to 4.5 hour- • Early rehabili- stenosis, refer tion of clopido- e. suspected to
• Selected time window tation once to a neurolo- grel to ASA have aneu-
patients within may benefit stable within gist/neurosur- therapy is rysm, AVM,
3 to 4.5 hour- with IV rt-PA. 72 hours. geon/vascular reasonable. or vasculitis
time window • If the stroke • Give AEDs surgeon for
may benefit onset is within 6 for clinical decision-making
with IV rt-PA. hours, consider seizures and regarding caro-
• If the stroke IA thrombolysis proven sub- tid endarterec-
onset is within (only in special- clinical or tomy (CEA) or
6 hours, consi- ized centers). electrographic stenting.
der intra-arterial • If the patient is seizures.
(IA) thrombo- ineligible for • Prophylactic V. GUIDELINES FOR MANAGEMENT OF SEVERE
lysis (only in thrombolytic AEDs and STROKE (NIHSS score: >22)
specialized therapy, or 24 steroids are
centers). hours post-rt- generally not MANAGEMENT PRIORITIES
• Start ASA PA treatment, recommended.
• Ascertain clinical diagnosis of stroke (history, P.E. and
160-325 mg/day consider careful • Monitor/correct
neurologic exam are very important).
24 hours after anticoagulation for metabolic
• Exclude common stroke mimics (see Chapter 1).
IV rt-PA treat- with IV heparin parameters and
• Identify comorbidities (e.g., cardiac disease, DM, liver
ment and conti- or SQ LMWH coagulation/
disease, gastric ulcer).
nue for 14 days. for individuals bleeding abnor-
• Provide basic emergent supportive care (ABCs of
• Ensure neuro- at high risk of malities.
resuscitation).
protection* early recur- • Follow recom-
• Monitor neuro-vital signs (NVS) including pupil size,
• Early rehabilita- rence; or ASA mendations for
blood pressure (BP), mean arterial pressure (MAP),
tion once stable 160-325 mg/ neurosurgical
respiratory rate (RR), temperature, O 2 saturation
within 72 hours day if anticoa- intervention.
(SaO2).
gulation is not • For specific
• Perform and monitor stroke scales (i.e., NIHSS, GCS;
possible or is details on ICH
see Appendix B).
contraindicated. and treatment
• Provide O2 support to maintain SaO2 >94%.
• Ensure neuro- of aneurysmal
• Treat BP if MAP >130. Precaution: Avoid precipitous
protection* SAH, see
drop (not >15% of baseline MAP) within 24 hours.
• If infective endo- Chapter 6.
Do not use rapid-acting sublingual (SL) agents; when
carditis (IE) is
needed, use easily titratable intravenous (IV) or short-
suspected, give
acting oral antihypertensive medication.
antibiotics and
• Recognize and treat for early signs and symptoms of
DO NOT anti-
increased ICP (see Management of Increased ICP).
coagulate.
• Ensure appropriate hydration. Recommended IVF (if
• Early rehabili-
needed): 0.9% NaCl.
tation once
stable within EMERGENT DIAGNOSTICS
72 hours.
• Complete blood count (CBC)
DELAYED MANAGEMENT AND SECONDARY • Blood glucose (CBG or RBS)
PREVENTION • Coagulation studies: PT, aPTT
• Serum Na+ and K+
SCHEMIC • Electrocardiogram (ECG)
CARDIO- • Cranial NCCT scan or MRI-DWI as soon as possible.
EMBOLISM NOT CARDIO- HEMO- If ICH is evident, compute for the hematoma volume
SUSPECTED EMBOLISM RRHAGIC (see Chapter 7).
Lacunar) EARLY SPECIFIC TREATMENT
(treatment requires neuroimaging confirmation)
• Give antiplate- • Request echo- • Long-term
lets (e.g., ASA, cardiography strict BP control ISCHEMIC
clopidogrel, and/or refer to and monitoring CARDIO- CARDIO-
cilostazol, tri- cardiologist • Consider con- EMBOLISM NOT EMBOLISM HEMO-
flusal, dipyrida- • Novel oral anti- trast CT scan, SUSPECTED SUSPECTED RRHAGIC
mole, extended- coagulants 4-vessel cere-
release dipyri- (NOACs) are bral angiogram, • May give ASA • May give ASA • Supportive
damole) preferred over MRA or CTA if 160-325 mg/ 160-325 mg/ treatment: Man-
(see Chapter 4). dose-adjusted the patient is: day. day. nitol 20% 0.5-1
warfarin. a. <45 years old • Ensure neuro- • Ensure neuro- g/kg BW every
• Control/treat • If anticoagula- b. normotensive protection* protection* 4-6 hours for
160
• Refer to a neu- • Refer to a 3-7 days. identified risk tion is contra- c. has lobar ICH
rologist for neurologist for • Ensure neuro- factors. indicated, give d. has uncertain
cases of post- cases of post- protection* ASA 160-325 cause of ICH
erior circula- erior circulation • Give antiepilep- mg. The add- e. suspected to
tion strokes strokes (see tic drugs ition of clopido- have aneu-
within 12 hours Chapter 1) (AEDs) for grel to ASA rysm, AVM,
of onset for within 12 hours clinical seizures therapy is or vasculitis
evaluation and of onset for and proven reasonable.
decision regard- evaluation and subclinical or
ing thrombolytic decision re- electrograph- VI. EARLY SPECIFIC TREATMENT FOR ISCHEMIC
therapy. garding throm- ic seizures. STROKE
• For cases of bolytic therapy. Prophylactic
cerebellar • For cases of AEDs are gene- A. Antithrombotic Therapy In Acute Stroke
infarct, refer to cerebellar rally not recom-
a neurosurgeon infarct, refer to mended. DRUG TRIAL STUDY DESIGN RESULT
as soon as a neurosur- • Neurosurgical
possible. geon as soon consult if: Aspirin IST: Inter- 19,435 patients ASA-treated
• Early supportive as possible. - the patient is (ASA) national with acute ische- patients had
rehabilitation. • Early support- not herniated Stroke mic stroke within slightly fewer
ive rehabilita- - the location Trial 48 hours were deaths at 14
tion. of bleed is randomized to days, significant-
lobar, puta- (Lancet either ASA 300 ly fewer recurrent
men, palli- 1997; mg/day, sub- ischemic strokes
dum, or cere- 349: cutaneous hepa- at 14 days, and
bellum 1569- rin 5000 units no excess of
- the patient's 1581) BID or 12,500 hemorrhagic
family is will- units BID, ASA strokes.
ing to accept plus heparin or
consequen- neither. In heparin-treat-
ces of irrever- ed patients, there
sible coma or were fewer deaths
persistent or recurrent
vegetative strokes; how-
state ever, there were
- ICP monitor- more hemorrha-
ing is contem- gic strokes &
plated and serious extracra-
salvage sur- nial hemorrhage,
gery is consi- mostly in the
dered higher-dose
• Early supportive heparin group,
rehabilitation resulting in no
• Goal is reduct- net benefit.
ion of mortality
ASA CAST: 21,106 patients Aspirin signifi-
Discuss the prognosis of the patient with family/relatives in the Chinese with acute cantly reduced
most compassionate manner
*see section on Neuroprotection Acute ischemic stroke the risk of recur-
Stroke within 48 hours rent stroke or
DELAYED MANAGEMENT AND SECONDARY Trial were rando- vascular death.
PREVENTION mized to ASA
(Lancet 160 mg OD or
ISCHEMIC 1997; placebo for up
449: 1641- to 4 weeks.
CARDIO- CARDIO- 1649)
EMBOLISM NOT EMBOLISM HEMO-
SUSPECTED SUSPECTED RRHAGIC [Clopi- FASTER: 392 patients This trial was
dogrel Fast with TIA or prematurely
• Give antiplate- • Request echo- • Long-term + ASA] Assess- minor stroke terminated be-
lets (e.g., ASA, cardiography strict BP control versus ment of within 24 hours cause of failure
clopidogrel, and/or refer to and monitoring ASA Stroke and were rando- to recruit patients
cilostazol, tri- cardiologist • Consider con- alone Transient mized to Clopi- at the pre-speci-
fusal, dipyrida- • Novel oral anti- trast CT scan, Ischemic dogrel (300 mg fied recruitment
mole, extended- coagulants 4-vessel cere- Attack to loading dose rate due to in-
release dipyri- (NOACs) are bral angiogram, Prevent then 75 mg/day creased use of
damole + ASA preferred over MRA or CTA if Early plus ASA 81 mg statins.
combination) dose-adjusted the patient is: Recur- or ASA 75 mg
(see Chapter 4). warfarin. a. <45 years old rence alone, with or Recurrent stroke
• Control/treat • If anticoagula- b. normotensive without Simvas- at 90 days were

(Lancet tatin (in factorial as follows: Clopi- B. Neuroprotection
Neurol design) and dogrel- ASA
2007; 6: followed up for (7.1%), ASA The Five "H" Principle:
961-969) 90 days. alone (10.1%); AVOID hypotension, hypoxemia, hyperglycemia,
absolute risk re- hypoglycemia, and hyperthermia during acute stroke
duction of 3.8% in an effort to "salvage" the ischemic penumbra.
(p=0.19).
1. Neuroprotective Interventions:
Hemorrhagic a) Avoid hypotension and allow permissive hy-
events were pertension during the first seven (7) days
higher with the Aggressive BP lowering is detrimental in acute
combination stroke. Manage hypertension as per recom-
treatment. mendation (see Management of BP in Acute
Stroke).
Clopi- CHANCE: 5170 patients The rate of recur-
dogrel Clopidogrel within 24 hours rent stroke at b) Avoid hypoxemia
ASA in High-risk of minor ische- 90 days were: • Routine oxygen supplementation is not war-
versus Patients mic stroke or Clopidogrel- ranted for all stroke patients. Only give supple-
ASA with Acute high-risk TIA ASA (8.2%), mentation O2 if with evidence of hypoxemia or
alone Non-Dis- were random- ASA alone desaturation.
abling ized either to (11.7%), hazard • Monitor oxygenation via pulse oximetry and/or
Cerebro- Clopidogrel ratio=0.68 determine arterial blood gases (ABG).
vascular 300 mg loading (p<0.001). • Maintain adequate tissue oxygenation (target
Event dose than 75 mg There was no SAO2 >94%).
OD for 21 days, increase in rate • Provide ventilatory support if the upper airway
(N Eng J followed by of moderate- is threatened, sensorium is impaired, or ICP is
Med 2013; Clopidogrel severe bleeding increased.
369: 11-19) vs. ASA alone and hemorrhagic
75 mg OD or stroke with the c) Avoid hyperglycemia or hypoglycemia
90 days. combination • Hyperglycemia can increase the severity of
treatment. ischemic injury (i.e., causes lactic acidosis,
increases free radical production, worsens
Cilos- CAIST: 458 patients The primary end- cerebral edema, and weakens blood vessels),
tazol Cilostazol with acute point of modified whereas hypoglycemia can mimic a stroke.
versus in Acute ischemic stroke Rankin Score • Prompt determination of blood should be done
ASA Ischemic with NIHSS (mRS) 0-2 was in all stroke patients.
Stroke score <15 with- achieved in 76% • In a meta-analysis of 11 trials involving 1,583
Treatment in 48 hours of patients subjects, keeping the blood glucose level within
were randomly randomized to a tight range (4-7.5 mmol/L) immediately after a
(Cerebro- assigned to Aspirin, sup- stroke did not improve the outcomes of neuro-
vasc Des Cilostazol 200 porting the logical deficit and dependency, and significantly
2011; 32: mg/day or ASA pre-specified increased the risk of hypoglycemia, which can
65-71) 300 mg/day for non-inferiority be harmful and may cause further brain dam-
90 days. outcome. age and death. Thus, there is no benefit with
intensive glycemic control after stroke.
LMWH Meta-ana- Ten trials invol- The use of LMWH/ • Treat acute ischemic stroke patients according
lysis of ran- ving 2,885 heparinoids was to the American Diabetes Association (ADA)
domized patients with associated with inpatient glycemic control guidelines. Initiate
controlled acute ischemic significant reduc- therapy achieve glucose targets of 140 to 180
trials on stroke given tion in venous mg/dL if the fasting glucose is greater than 140
low mole- LMWH or hepa- thromboembo- mg/dL or random glucose is consistently higher
cular rinoids within 7 lism (i.e., DVT than 180 mg/dL.
weight days of stroke. and PE). How- • Use an established and standardized IV insulin
heparins ever, it did not protocol for patients who present with extreme or
and hepa- have significant persistent hyperglycemia, are critically ill, or who
rins in effect on redu- have received thrombolytic therapy for at least
acute cing death and the first 24 to 48 hours of hospitalization. Patients
ischemic disability at 6 should then be transitioned to a subcutaneous
stroke. months. insulin regimen which includes a basal long-act-
ing insulin, preferably a rapid-acting insulin which
(Stroke can be administered immediately before or after
2000; 31: a meal.
31: 1770- • Avoid glucose-containing (D5) IV fluids. Use
1778) isotonic saline (0.9% NaCl).
• Closely monitor and address hypoglycemia
especially in patients with type 1 DM, hepatic
or renal impairment, or with complicated feeding
regimens.
162
d) Avoid hyperthermia Trial on Acute Stroke (ICTUS) was designed to confirm
Fever in acute stroke is associated with poor outcome the encouraging results of the data pooling analyses
possibly related to increased metabolic demand, and replicate trends. Global recovery at 90 days was
increased free radical production, and enhanced similar in patients who received citicoline and in those
neurotransmitter release. Hyperthermia increases who received placebo. Some important characteristics
the relative risk (RR) of 1-year mortality by 3.4 times. in the ICTUS trial which may have influenced the
For every 1°C increase in the body temperature, the neutral results include randomization of more severe
RR of death or disability increases by 2. On the other stroke and substantial number of patients receiving
hand, hypothermia can reduce the infarct size by 44% thrombolytic therapy (47%), which may have resulted
in animal studies. in ceiling effect from maximum improvement due to
• Maintain normothermia for all stroke patients. rt-PA effect.
• Treat fever with antipyretics and cooling blankets.
Investigate for the source of fever (e.g., infection). In addition to neuroprotective properties, citicoline also
possesses neuroregenerative properties which may
2. Neuroprotective and Neurorestorative Drugs explain the long-term beneficial effects in post-stroke
patients. In an open-label randomized trial among 347
Drugs with neurovascular protective properties: patients with first-ever ischemic stroke, the citicoline-
• Protect against excitotoxins and help prolong neuro treated group (at 1 g/day for 12 months) had better
nal survival. outcome in attention-executive functions and temporal
• Block the release of glutamine and inflammatory orientation at 6 and 12 months.
cytokines and inhibit free radical formation and
apoptosis. The two other pharmacologic agents with putative
neuroprotective and neurorestorative properties which
Drugs with neurotrophic/neurorestorative proper- have recently completed phase III clinical trials are
Cerebrolysin® and NeuroAiD™.
ties:
• Stimulate endogenous repair mechanisms such as Cerebrolysin® is composed of low-molecular-weight
angiogenesis, neurogenesis, and synaptic plasticity. peptides and free amino acids, which mimics the
• Help in the production of new sprouts and dendritic effects of naturally-occuring neurotrophic factors that
spines in surviving neurons, as well as formation of help improve and accelerate recovery of neurologic
new synapses. function. Cerebrolysin also exerts pleitropic and
multimodal effects and blocks the pathological cascade
Over fifty (50) neuroprotective agents including glu- of events involved in dementia, traumatic brain injury,
tamate, NMDA/AMPA antagonists, calcium channel and ischemic stroke at various levels. Clinical trials
blockers, and free radical scavengers have undergone involving more than 1,500 patients since 1994, has
Phase III clinical trials, but all failed to show statistically shown favorable results on motor function, activities of
significant benefit. Several reasons have been raised daily living, cognitive performance, and faster recovery
to explain this apparent failure: animal models were with use of Cerebrolysin®. The Cerebrolysin in Patients
wrong, and that human trials were not done optimally with Acute Ischemic Stroke in Asia (CASTA) trial has
(e.g., time-window determination, patient heterogene- shown no overall difference in outcomes between
ity, "targeted" neuroprotection which addresses single those who received Cerebrolysin and those in the
mechanism of neuronal injury at a time, exclusion of placebo group at 90 days. Outcome may have been
concomitant treatment with thrombolytics agents). affected by large number of mild strokes included in the
trial. A favorable trend towards benefit was seen in the
Cytidine 5'-diphosphate (CDP)-choline (citicoline) more severely affected patients in post hoc analysis.
is one of the most well-studied neuroprotective
agent. It has multimodal effects on the ischemic and NeuroAiD™, a product that combines extracts of nine
reperfusion cascade. It helps increase synthesis of herbal and five animal components in capsule form,
phosphatidylcholine for membrane stabilization and has been shown to restore neurological and cellular
repair. It inhibits the activation of phospholipase A2 function in non-clinical models of ischemic stroke. A
and reduces oxygen free radicals and inflammatory systematic review of earlier clinical trials in non-acute
cytokines within the injured brain during ischemia. stroke showed that NeuroAiD™ significantly enhances
Citicoline has been shown to reduce caspase activa- recovery of functional outcome and neurological dis-
tion products inhibiting apoptosis. Citicoline favors ability. The Chinese Medicine NeuroAiD™ Efficacy
on Stroke recovery (CHIMES) trial in acute stroke
synthesis of nucleic acids, proteins, acetylcholine,
patients showed a trend in favor of NeuroAiD™,
and other neurotransmitters.
although this did not achieve statistical significance.
Post-hoc analysis revealed a significant reduction in
Experimental studies have shown consistent improved risk of recurrent fatal or non-fatal vascular event during
functional outcome and reduced infarct size in animal three months of treatment.
models of stroke. Several trials in ischemic and hemor-
rhagic strokes conducted worldwide have documented Pre-planned subgroup analysis of Filipino patients
its excellent safety profile. In individuals patient data included in the CHIMES study showed a statistically
pooling analysis (4 trials, 1652 patients), oral citicoline significant effect of NeuroAiD™ on functional and
given within the first 24 hours of moderate to severe neurological outcomes. A prognosis-based responder
ischemic stroke significantly increased the probabi analysis of the CHIMES data revealed statistically
lity of global recovery by 30% at 3 months. A similar significant treatment effect of NeuroAiD™ particu-
positive result in reduction of death and disability from larly among patients with poorer prognosis for full
acute stroke was obtained in a meta-analysis in 2010 functional recovery (modified Rankin Scale [mRS]
(10 trials, 2279 patients). The International Citicoline score of 0-1).

Table 3. Neuroprotective and Neurorestorative Drugs "The use of drugs with neurorestorative and neuropro-
tective properties in acute stroke remains as a matter
of preference of the attending physician."
DRUG TRIAL STUDY RESULT
DESIGN Bibliography
Cerebro- CASTA: 1,070 patients There was no 1. Alvarez-Sabin J, Ortega G, Jacas C, et al. Long-term treatment with
citicoline may improve poststroke vascular cognitive impairment.
lysin® Cerebrolysin® with acute significant dif- Cerebrovasc Dis. 2013;35(2):146-54.

in Patients ischemic ference in 2. Bellolio MF, Gilmore RM, Ganti L. Insulin for glycaemic control in
with Acute stroke within functional out- acute ischaemic stroke. Cochrane Database Syst Rev. 2014 Jan 23;1:
Ischemic 12 hours come between CD005346.
3. Capes S, Hunt D, Malmberg K, et al. Stress hyperglycemia and
Stroke in were rando- treatment prognosis of stroke in nondiabetic and diabetic patients: A Systemic
Asia mized to IV groups at 90 Overview. Stroke. 2001;32: 2426-2432.
Cerebrolysin® days. 4. Chankrachang S, Navarro JC, De Silva DA, et al. Towanabut S, Chua
CL, Lee CF, Bousser MG, Chen C; CHIMES Study Investigators.
(Stroke 2012 30 mL daily Prognostic Factors for Functional Outcome and Treatment Effect in the
Mar; 43(3): or placebo Post hoc CHIMES Study. Presented during the 23rd European Stroke Congress
630-6) for 10 days. analysis shows (ESC), Nice, France, 6-9 May 2014.
favorable 5. Chen LCH, Young SHY, Gan HH, et al. Chinese Medicine NeuroAiD
Efficacy on Stroke recovery (CHIMES): A double-blind, placebo-
trend towards controlled, randomized study. Stroke. 2013;44:2093-2100.
the more 6. Chen CLH, Venketasubramanian N, Lee CF, et al. CHIMES Study
severely affect- Investigators. Effects of MLC601 on early vascular events in patients
after stroke - The CHIMES Study. Stroke. 2013;44:3580-3583.
ed patients 7. Clark WM, Warachi SJ, Pettigrew LC, et al.; for the Citicoline Stroke
(NIHSS >12). Study Group. A randomized dose response trial of citicoline in acute
ischemic stroke patients. Neurology. 1997;29:671-678.
Citicoline ICTUS: Inter- 2,298 patients Global recovery 8. Davalos A, Castillo J, Alvarez-Sabin J, et al. Oral citicoline in acute
ischemic stroke: an individual patient data pooling analysis of clinical
national Citi- with moderate at 90 days was trials. Stroke. 2002; 33:2850-2857.
coline Trial in to severe similar to both 9. Davalos A, Castillo J, Alvarez-Sabin J, et al. Citicoline in the treatment of
Acute Stroke acute ische- groups acute ischemic stroke: an international randomized multicenter placebo
mic stroke (OR=1.03). controlled study (ICTUS). Lancet. 2012 Jul 28;380(9839):349-57.
10. Hajat C, Hajat S, Sharma P. Effects of postroke pyrexia on stroke
(Lancet 2012 within 24 outcome: a meta-analysis of studies in patients. Stroke. 2000;
Jul 28; 380 hours were Citicoline 31(2):410-414.
(9839): randomized appears more 11. Heiss WD, Brainin M, Bornstein N, et al.; for the CASTA Investigators.
Cerebrolysis in patients with acute ischemic stroke in patients
��
with acute
349-57) to citicoline beneficial in ischemic stroke in Asia: results of a double blind placebo controlled
1000 mg patients aged randomized trial. Stroke. 2012;43:630-636.
every 12 hrs. >70 years 12. Heurteaux C, Gandin C, Borsotto M, et al. Neuroprotective and
or placebo (p=0.001), neuroproliferative activities of NeuroAiD (MLC601, MLC901), a Chinese
medicine, in vitro and in vivo. Neuropharmacology. 2010;58:987-1001.
for 6 weeks. patients with 13. Hong Z, Bornstein N, Brainin M, Heizz WD. A double blind placebo
moderate controlled randomized trial to evaluate the safety efficacy of
strokes NIHSS Cerebrolysin in patients with acute ischemic stroke (CASTA). Int J
stroke. 2009;4:406-412.
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and in patients choline improves functional recovery and increases neuronal plasticity
not treated after experimental stroke. Neurobiol Dis. 2007;26:105-111.
with rt-PA 15. Kreisel S, Alonso A, Szabo K, et al. Sugar and nice-aggressive
hyperglycemic control in ischemic stroke and what can we learn from
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Cerebrovasc Dis. 2010; 29:518-522.
Neuro- CHIMES: 1,100 patients There was no 16. Lizasaoin I, Cardenas A, Hurtado O, et al. targets of cytoprotection in
AiD™ Chinese with acute difference in acute ischemic stroke: present and future. Cerebrovasc Dis. 2006;21
(suppl 2)1-8.
Medicine ischemic primary efficacy 17. Lyden P, Wahlgren N. Mechanism of action of neuroprotectants in
��
NeuroAiD™ ��
stroke of inter- outcome of stroke. J Stroke Cerebrovasc Dis. 2000; 9(6):9-14.
Efficacy in ��
mediate ��
seve- ordinal analysis 18. Moha Ou Maati H, Borsotto M, Chatelain F, et al. Activation of ATP-
sensitive potassium channels as an element of the neuroprotective
Stroke rity within 72 in mRS scores effects of the Traditional Chinese Medicine MLC901 against oxygen
Recovery hours were at 90 days glucose deprivation. Neuropharmacology. 2012;63:692-700.
��
randomized (OR=1.09, 95% 19. Navarro JC, Gan HH, Lao Ay, et al.; CHIMES Study Investigators.
(Stroke 2013 ��
to NeuroAiD™ Cl, 0.86-1.32) Baseline Characteristics and Treatment Responses of Patients including
from the Philippines in the CHIMES Study. Int J Stroke (published online
��
Aug; 44(8): 4 caps TID or Trend of benefit 7 Jul 2014).
2093-100) placebo for was observed 20. Quinn TJ, Lees KR. Hyperglycemia in acute stroke - to treat or not to
90 days. for subgroup of treat. Cerebrovasc Dis. 2009;27 suppl 1:148-155.
21. Quintard H, Borsotto M, Veyssiere J, et al. MLC901, a traditional
�� patients recei- Chinese medicine protects the brain against global ischemia.
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after 48 hours. 22. Sabin J, Roman G. The role of Citicoline in neuroprotection and
neurorepair in stroke. Brain Sci. 2013,3,1395-1414.
NeuroAiD™ 23. Secades J, Lorenzo J. Citicoline: Pharmacological and clinical review
2006 update: Methods Find Exp Clin Pharmacol. 2006:26 (suppl B):
treatment was 1-56.
associated with 24. Siddiqui FJ, Venketasubramanian N, Chan ES, Chen C. Efficacy
significant and safety of MLC601 (NeuroAiD), a traditional Chinese medicine,
in postroke recovery: a systematic review. Cerebrovasc Dis. 2013;35
reduction in the (Suppl 1):8-17.
risk of recurrent 25. ��
Venketasubramanian N, Chen CL, Gan RN, et al.; on behalf of the
vascular CHIMES Investigators, A double-blind, placebo-controlled, randomized,
events. multicenter study to investigate Chinese Medicine NeuroAiD efficacy
on Stroke recovery (CHIMES Study). Int J Stroke. 2009;4:54-60.
164
C. Anticoagulation In Acute Cardioembolic Stroke 2. Procedure:
a. Start intravenous infusion at 600 - 800 units
a. Sources of Cardioembolic Stroke heparin per hour, ideally via infusion pump.
IV heparin bolus is not recommended.
Low or b. Perform aPTT as often as necessary, every
Uncertain Risk High Risk 4-6 hours after dose adjustments, to keep
aPTT levels at 1.5-2.5 times the control. The
Mitral valve prolapse AF (valvular or non-valvular) risk of major hemorrhage, including intracra-
Mitral annular Rheumatic mitral stenosis nial bleed, progressively increase as aPTT
calcification Prosthetic heart valves exceeds 80 seconds.
Patent foramen Recent myrocardial c. Infusion may be discontinued once oral
ovale (PFO) infarction (MI) anticoagulation with warfarin has reached
Atrial septal aneurysm LV/LA thrombus therapeutic levels or once antiplatelet medi-
Calcific aortic stenosis Atrial myxoma cation is initiated for secondary prevention.
Mitral valve strands Infective endocarditis
Dilated cardiomyopathy To date, there has been no trial which directly com-
Marantic endocarditis pared the efficacy of UFH vs LMWH in patients with
acute cardioembolic stroke. However, LMWH has the
b. Features Suggestive of Cardioembolic Stroke advantage of easier administration and does not require
• Sudden onset of maximal deficit (<5 minutes) aPTT monitoring.
• Decreased level of consciousness
• Rapid regression of initially massive symptoms Bibliography
("spectacular shrinking deficit") 1. Adams H. Emergent use of anticoagulation for treatment of patients with
• Wernicke's aphasia or global aphasia without ischemic stroke. Stroke. 2002;33:856-861.
hemiparesis 2. Hart R, Palacio S, Pearce L. Atrial fibrillation, stroke and acute
• Visual field abnormalities antithrombotic therapy. Stroke. 2002;33:2722-2727.
• Onset of symptoms after a Valsalva-provoking 3. Guedes L, Ferro J. A systemic review of immediate anticoagulation for
ischemic stroke of presumed cardioembolic mechanism.Stroke. 2008;39:
activity (e.g., coughing, bending) e81-82.
• Infratentorial ischemic stroke (cerebellar, PCA, 4. Guyatt G, Akl E, Crowther M, et al. Antithrombotic therapy and prevention
and multi-level infarcts, top-of-the basilar syn- of thrombosis, 9th ed. American College of Chest Physicians Evidence-
drome) based Clinical Practice Guidelines. Chest. 2012;141(2)(Suppl):7S-
47S.
• Hemorrhagic transformation and early recanaliza- 5. Jauch E, Saver J, Adams H, et al. Guidelines for the early management of
tion of occluded intracranial vessel patients with ischemic stroke: guideline for healthcare professional from
• Neuroimaging finding of acute infarcts involving the American Heart Association/American Stroke Association. Stroke.
multiple vascular territories in the brain (predomi- 2013;44:870-947.
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nantly carotid and MCA territories), or multiple acute ischemic stroke and an indication for anticoagulation. Eur J Neuro.
levels of the posterior circulation 2013;20(6):962-967.
7. Moonis M, Fisher M. Considering the role of heparin and low-molecular
c. Indications and Contraindications for Anti- weight heparin in acute ischemic stroke. Stroke. 2002;33:1927-1933.
coagulation in Patients with Cardioembolic 8. Paciaroni M, Agnelli G, Micheli S, et al. Efficacy and safety of
anticoagulant treatment in acute cardioembolic stroke: A meta-analysis
Stroke of randomized controlled trials. Stroke. 2007;38:423-430.
Probably indicated Contraindicated

D. ADMINISTRATION OF rt-PA IN ACUTE ISCHEMIC
Intracardiac thrombus Bleeding diathesis STROKE
Mechanical prosthetic Non-petechial intra-
valve cranial hemorrhage 1. Eligibility for IV thrombolysis with rt-PA
Recent MI Recent major surgery • Age 18 years or older
Congestive heart or trauma • Clinical diagnosis of ischemic stroke which
failure (CHF) Infective endocarditis causes a measurable neurologic deficit.
Bridging measure for • Time of symptom onset is well-established to
long-term coagulation be less than 180 minutes before the initiation of
treatment.
d. When considering anticoagulation in acute cardio-
embolic stroke within 14 days, the benefits of re- 2. Patient Selection
ducing early stroke recurrence should be weighed
against the risk of hemorrhagic transformation. A. Contraindications and Warnings
The latter is higher in patients with large infarc- • Evidence of intracranial hemorrhage on pretreat-
tion, severe strokes or neurological deficits, and ment CT or MRI
uncontrolled hypertension. • Evidence of multi-lobar infarction (>1/3 cerebral
hemisphere) on neuroimaging
e. How to Anticoagulate • Only minor or rapidly improving stroke symp-
1. Requirements for intravenous anticoagulation of toms
patients with cardiogenic source of embolism: • Clinical presentation suggestive of subarachnoid
a. Heparin sodium in D5W hemorrhage (SAH), even with normal CT
b. Infusion pump, if available • Significant head trauma or prior stroke within 3
c. Activated partial thromboplastin time (aPTT) months
or clotting time • History of previous intracranial hemorrhage

(ICH) 4. Sequence of events

• Known arteriovenous malformation or aneu- • Draw blood for tests while preparing for neuro-
rysm imaging.
• Arterial puncture at a non-compressible site • Monitor blood pressure every 15 minutes
within 7 days and manage accordingly (see Pretreatment
• Recent intracranial or spinal surgery BP).
• Active internal bleeding • Perform neurologic examination.
• Known bleeding diathesis, including but not • Perform neuroimaging using non-contrast CT or
limited to: MRI scan. Search for any evidence of hemor-
- Platelet count <100,000/mm3 rhage.

- Patient has received heparin within 48 hours • If the patient has severe head or neck pain,
and has an elevated aPTT (greater than upper or is somnolent or stuporous, confirm/rule out
limit of normal for laboratory) subarachnoid hemorrhage.
- Current or recent use of oral anticoagulants • If there is a significant abnormal lucency on
(e.g., warfarin sodium) with an elevated pro- imaging suggestive of infarction, reconsider
thrombin time >15 seconds or INR >1.7 the patient's history, since the stroke may have
• The use of rt-PA in patients receiving NOACs occured earlier.
(e.g., direct thrombin inhibitions, direct factors • Review required test results - hematocrit, platelet
X inhibitors) maybe harmful and is not recom- count, blood glucose, PT or aPTT (in patients
mended unless PT-INR, aPTT, and platelet with recent use of oral anticoagulants or hepa-
counts are normal, or if the patient has not rin).
received any dose of these agents >2 days (if • Infuse intravenous rt-PA: 0.9 mg/kg (initially 10%
with normal renal function) of total dose as bolus over 1 minute).
• Abnormal blood glucose (i.e., <50 mg/dL or >400 • Do not use cardiac dose.
mg/dL) • Do not exceed the 90 mg maximun dose.
• On repeated measurements, the systolic • Monitor the patient closely and carefully, espe-
blood (SBP) is greater than 185 mmHg or cially the BP and neurologic status. Manage BP
diastolic blood pressure (DBP) is greater than accordingly.
110 mmHg at the time of initiation of therapy, • No adjunctive treatment (e.g., heparin, warfarin,
and the patient requires aggressive treatment aspirin) should be given during the first 24 hours
for reducing blood pressures to within these after symptom onset and 24 hours post-rt-PA
limits. treatment. If heparin or other anticoagulant is
indicated after 24 hours, consider performing
B. Relative contraindications a follow-up non-contrast CT scan or MRI at 24
Under certain circumstances patients may receive hours after IV rt-PA prior to initiating antiplatelet
thrombolytic therapy despite the pressure of 1 or anticoagulant agents to rule out any intracra-
or more relative contraindication. Consider risk- nial hemorrhage.
benefit of IV rt-PA treatment carefully if any of the • Delay placement of nasogastric tubes, indwell-
following is present: ing bladder catheters, or intra-arterial pressure
• Patient has had major surgery or serious trauma catheters if the patient can be safely managed
(excluding head trauma) within previous 14 without them.
days
• History of gastrointestinal or urinary tract hemor- 5. Blood Pressure control during thrombolytic
rhage within previous 21 days therapy
• Only minor or rapidly improving stroke symptoms Pretreatment BP should be <185/110 mmHg.
(clearing spontaneously) Above this level, patient may be treated with
• Myocardial infarction within the past 3 months nitroglycerin paste and/or:
• Patient was observed to have seizures at the • Labetalol 10-20 mg IV over 1-2 minutes, may
time of onset of stroke symptoms with post-ictal repeat one time; or
neurological impairment • Nicardipine 5 mg/hour, titrate up by 2.5 mg/hour
• Pregnancy every 5-15 minutes (maximum: 15 mg/hour)
3. Intravenous Administration of rt-PA Once the desired BP is achieved, adjust to main-

• 0.9 mg/kg (maximum of 90 mg) infused over 60 tain proper BP limits. If after these measures the
minutes, with 10% of the total dose administered BP does not decreased and maintain <185/110
as an initial intravenous bolus over 1 minute. mmHg, the patient should not be treated with rt-
• The use of low-dose 0.6 mg/kg IV rt-PA is an PA.
option because of reduced cost, however a
recent review article involving small case series During and After rt-PA treatment:
of Asian patients showed a trend towards less • BP monitoring should be as follows: every
favorable clinical outcome compared with the 15 minutes for 2 hours from the start of rt-PA
standard dose. infusion, then every 30 minutes for 6 hours,
• Whether low-dose rt-PA is truly as efficacious and then hourly thereafter for 16 hours. During
or even safer will be addressed in the ongo- antihypertensive therapy, monitor BP every 15
ing Enchanted Control of Hypertension and minutes. Watch out for hypotension.
Thrombolysis in Stro ke D i s e a s e ( EN- • If systolic BP >230 mmHg and/or diastolic BP is
CHANTED) trial (ClinicalTrials.gov identifier 121-140 mmHg, give labetalol 20 mg IV over 1
NCT01422616). to 2 minutes. The dose may be repeated and/or
166
doubled every 10 minutes, up to 15 mg. Alterna- The search for a thrombolytic agent which can be
tively, an IV infusion of labetalol 2 to 8 mg/min used beyond the 3 hours of acute ischemic stroke
may be initiated after the first bolus of labetalol, is being investigated in the ongoing Desmoteplase
or a nicardipine infusion at 5 mg/hour titrated up To Treat Acute Stroke (DIAS-3) study to which the
by 2.5 mg/hour every 5 to 15 minutes interval Philippines is participatory. This double-blind RCT will
until the desired BP is achieved. For persistently determine whether desmoteplase is safe and effec-
elevated BP, IV sodium nitroprusside may be tive in the treatment of patients with acute ischemic
used. stroke when given within 3-9 hours from the onset
• If systolic BP is 180 to 230 mmHg and/or dia- of stroke symptoms. Patients should have an NIHSS
stolic BP is 105-120 mmHg on two readings score of 4-24 and a documented vessel occlusion
(taken 5 to 10 minutes apart), give labetalol 10 or high-grade stenosis on MRI or CTA in proximal
mg IV over 1 to 2 minutes. The dose may be cerebral arteries. This trial has completed its target
repeated and/or doubled every 10 to 20 minutes, enrollment of 480 patients in December 2013, with
up to 15 mg. Alternatively, following the first the last few randomized patients still undergoing
bolus of labetalol, an IV infusion of labetalol 2 follow-up evaluation.
to 8 mg/min may be initiated and continued until
the desired BP is reached.
• If upon the clinical judgement of the treating Table 4. Randomized Controlled Trials (RCT) of
physician, an intracranial hemorrhage is sus- Intravenous rt-PA in Acute Ischemic Stroke
pected, the administration of rt-PA should be
discontinued and an emergency CT scan or TRIAL DESIGN RESULT
other diagnostic neuroimaging sensitive to the
presence of intracranial hemorrhage should be NINDS t-PA trial: 291 patients No difference in
obtained. National Institute with acute ische- neurologic im-
of Neurological mic stroke <3 provement at 24
6. Management of ICH following thrombolytic Disorders and hours were hours, but patients
therapy Stroke t-PA trial randomized to given IV t-PA
In the event that a hemorrhage is suspected (e.g., IVt-PA (0.9 mg/ were 30% more
acute neurological deterioration, new headache, (N Eng J Med kg) or placebo likely than controls
acute hypertension, nausea, vomiting) during rt-PA 1995; 3 33: and assessed to have minimal or
therapy, do the following: 1581 - 1587) for 4-point no disability at 3
• Discontinue rt-PA infusion (unless other causes improvement in months, despite
of neurological deterioration are apparent). NIHSS or reso- more symptomatic
• Perform immediate CT scan or other diagnos- lution of neuro- ICH (6.4% vs 0.6).
tic imaging sensitive to presence of hemo- logical deficit Overall, there was
rrhage. within 24 hours; no difference in
• Draw blood for STAT prothrombotin time, aPTT, 333 patients mortality at at 3
platelet count, fibrinogen, blood type and cross- received IV t-PA months.
matching. within 3 hours of
• Prepare for administration of 6 to 8 units of symptom onset
cryoprecipitate containing factor VIII. and were
• Prepare for administration of 6 to 8 units of assessed for
platelets. functional and
clinical outcome
If intracranial hemorrhage is present: at 3 months.
• Obtain fibrinogen results.
• Consider administering cryoprecipitate or plate- ECASS: 620 patients No difference in
lets if indicated. European with acute ische- disability using
• Consider referring to a hematologist and/or Australasian mic stroke <6 Intention-to-treat
neurosurgeon. Cooperative hours were ran- analysis. However,
• Consider decision regarding further medical Acute Stroke domized to t-PA there were 109
and/or surgical therapy. Study 1.1 mg.kg or major protocol vio-
• Consider second CT to assess progression of placebo. lations. Post hoc
ICH. (JAMA 1995; analysis exclu-
• Emergent neurosurgical consultation is highly 274:1017-1025) ding these patients
recommended. indicated better
recovery for t-PA
7. Expansion of IV rt-PA treatment time window group at 90 days.
up to 4.5 hours ECASS II: 800 patients No significant dif-
The eligibility for thrombolysis follows the same Second with acute ische- ference was seen
criteria as treatment within the first 3 hours, with the European mic stroke <6 in the rate of favor-
following additional relative exclusion criteria: Australasian hours were ran- able outcome at 3
• Patients older than 80 years old. Cooperative domized to rt-PA months between
• Patients on oral anticoagulants, regardless of Acute Stroke 0.9 mg/kg or rt-PA- and place-
the INR. Study placebo. bo-treated group.
• Patients with NIHSS score >25.
• Patients with history of both ischemic stroke and (Lancet 1998;
diabetes. 352:1245-1251)

ATLANTIS A: 142 patients No significant rt-PA group (11%
Alteplase Throm- with acute ische- difference was seen vs 7%, OR=1.60,
bolysis for Acute mic stroke <6 on any of the 95% Cl,1.22-2.08,
Non-interven- hours were planned efficacy p=0.001). At 6
tional Therapy in randomized endpoints at 30 months, 27% of
Ischemic Stroke to rt-PA 0.9 mg/ and 90 days patients have died
kg or placebo. between groups. in both groups.
(Stroke 2000; The risk of symp-
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PA treatment part- Stroke Council. Expansion of the Time Window for Treatment of Acute
icularly in patients Ischemic Stroke with Tissue Plasminogen Activitor, a science advisory
treated between from the American Heart Association/American Stroke Association.
Stroke. 2009; 40:2945-2948.
5 to 6 hours. 2. Jauch E, Saver J, Adams H, et al. Guidelines for the early management
of patients with ischemic stroke guidelines for healthcare professionals
ATLANTIS B: 613 patients No significant dif- from the American Heart Association/American Stroke Association.
Alteplase Throm- with acute ische- ference in functional Stroke. 2013;44:870-947.
3. Ramaiah S, Yan B. Low-Dose Tissue Plasiminogen Activitor and
bolysis for Acute mic stroke with- recovery at 90 days Standard-Dose Tissue Plasminogen Activitor in Acute Ischemic Stroke
Non-interven- in 3-5 hours were between groups. in Asian Populations: A Review. Cerebrovasc Dis. 2013;36:161-166.
tional Therapy in randomized to Risk of symptoma-
Ischemic Stroke t-PA or placebo. tic intracerebral
hemorrhage was E. BLOOD PRESSURE MANAGEMENT IN ACUTE
(JAMA 1999; increased in t-PA. STROKE
282:2019-2026)
A. BP Management in Acute Ischemic Stroke
J-ACT: Japanese 103 patients 36.9% achieved
Alteplase within 3 hours an mRS of 0-1 at (1) Definition/Formulae:
Clinical Trial of ischemic 3 months; symp-
Mean Arterial = 2 (Diastolic BP) + Systolic BP
(Stroke 2006; stroke were tomatic ICH
Pressure (MAP) 3
37:1810-1815) given 0.6 mg/kg occured in 5.8%
IV rt-PA as Data is compa-
Cerebral Perfusion Pressure (CPP) = MAP - ICP
single arm, rable with pub-
open-label lished data using Normal values: ICP: 5-10 mmHg; CPP: 70-100 mmHg
study. IV rt-PA.
(2) Check if patient has any condition that may
ECASS III: 821 patients Significantly more increase BP (e.g., pain, stress, bladder disten-
European with acute ische- patients in rt- PA- tion, constipation) and address accordingly.
Australasian mic stroke within treated group had (3) Allow for "permissive hypertension" during
Cooperative 3 to 4.5 hours favorable outcome the first week to ensure adequate CPP, but
Acute Stroke were rando- at 3 months (52.4% ascertain cardiac and renal protection. Treat
Study mized to rt-PA vs 45.2%, p=0.04). if SBP >220 mmHg or DBP >120 mmHg, or
0.9 mg/kg or The incidence of MAP >130
(N Eng J Med placebo. intracranial hemo- • Defer emergency BP therapy if MAP is within
2008; 359: rrhage was higher 110-130, or SBP = 185-220 mmHg or DBP =
1317-1329) with rt-PA, but 105-120 mmHg, unless the patient is a can-
mortality did not didate for thrombolytic therapy, and/or in the
significantly differ presence of acute MI, CHF, aortic dissection,
between the 2 acute pulmonary edema, acute renal failure,
groups. and hypertensive encephalopathy.
IST III: Third 3,035 patients The proportion of Rationale for Permissive Hypertension:
International with acute ische- patients alive & in- • In acute ischemic stroke, autoregulation is
Stroke Trial mic stroke within dependent at 6 paralyzed in the affected tissues with cerebral
6 hours were months (OHS 0-2) blood flow (CBF) passively following MAP.
(Lancet 2012 randomized to was 37% in the Rapid BP lowering can lead to a further de-
Jun 23; 379 rt-PA 0.9 mg/kg rt-PA group versus crease in perfusion at the penumbra.
(9834):2352-63 or placebo. 35% in the placebo • Hypertension is typically present in acute
group (OR=1.13, stroke, with spontaneous decline in the first 5-7
Open label study; 95% Cl 0.95-1.35, days with attainment of neurological stability.
no upper limit for p=0.181). Ordinal SBP dropped by ≈28% during the first day
age and broader analysis showed whether or not medications were given.
BP eligibility. significant shift in • Increased ICP during the acute phase of large
Oxford Handicap infarcts reduces the net CPP.
Score (OHS). • There is lack of convincing evidence of benefit

More deaths oc- of treating arterial hypertension. Several re-
cured during the ports documented neurological deterioration
first 7 days in the and poor outcome from rapid and steep BP
reductions.
168
Table 5. Intravenous Antihypertensives Agents for Control of BP in Acute Stroke
Onset Duration Availability/ Adverse Mechanism of

Drug Dose of of Dilution Stability reaction Action
action action
Nicardipine 1-15 mg/hour 5-10 1-4 hours (10 mg/10 mL 1-4 hours Tachycardia, Inhibits calcium ion
minutes amp); 10 ��
mg��
headache, from entering slow
in 90 mL flushing, channel, producing
�� NSS/��
D5W dizziness, coronary, vascular,
somnolence, smooth muscle
nausea relaxation &
vasodilatation
Hydralazine IV push 10-20 10-20 3-8 hours 25 mg/mL 4 days Tachycardia, Direct vasodilatation
mg/dose q4-6 minutes amp; 25 flushing, of arterioles &
hours as mg/tab headache, decreased systemic
needed, may vomiting, resistance
increase to 40 increased
mg/dose angina
Labetalol 5 mg IV push 2-5 2-4 hours 5 mg/mL in 40 72 hours Orthostatic Alpha- & beta-
over 2 minutes, minutes mL vial; 250 hypotension, blocker. Beta-
repeat with mg in 250 mL drowsiness, adrenergic blocking
incremental NSS/D5W dizziness, activity is 7x > than
dose of 10, 20, light-headed- alpha-adrenergic
40, 80 mg until ness, dyspnea, blockers.
desired BP is wheezing,
achieved or a and broncho- Produces dose-
total dose of spasm dependent ↑ in BP
300 mg has without significant ↑ in
been admi- HR or cardiac output
nistered
Esmolol 0.25-0.5 mg/kg 2-10 10-30 100 mg/10 48 hours Hypotension, Short-acting beta-
IV push 1-2 minutes minutes mL vial; 2,500 bradycardia, adrenergic blocking
mins followed mg in 250 mL AV block, agent. At low doses,
by infusion of D5W/NSS agitation, it has little effect on
0.05 mg/kg/min confusion, beta 2 receptors of
wheezing/ bronchial & vascular
If there is no broncho- smooth muscle
response, constriction,
repeat 0.5 mg/ phlebitis
kg bolus dose
& infusion to
0.10 mg/kg/min
maximum infu-
sion rate = 0.30
mg/kg/min
• SBP and DBP drops of >20 mmHg were as- (4) The use of intravenous nicardipine is reason-
sociated with early neurological worsening, able. It is readily available, easy to administer
high rates of poor outcome or death, and larger and titrated, has short duration of action,
volumes of infarctions. and does not significantly affect intracranial
• There was no indication that BP-lowering pressure. Other locally available intravenous
treatment with an angiotensin receptor blocker antihypertensives for acute stroke are listed in
is beneficial in patients with acute stroke and Table 5.
raised BP. If anything, the evidence suggested (5) Treat patients who are potential candidates for
a harmful effect. rt-PA therapy who have persistent elevations
• The latest Efficacy of Nitric Oxide in Stroke in SBP >185 mmHg or DBP >110 mmHg with
(ENOS) trial, presented during the 2014 small doses of IV antihypertensives agents.
European Stroke Congress, showed no benefit Maintain BP just below these limits.
in functional outcome in continuing prestroke (6) Arterial Hypotension in Acute Ischemic Stroke:
BP-lowering therapy during the acute phase • Although rare in acute ischemic stroke, a
of stroke. Much of the harm in continuing baseline SBP <100 mmHg, or DBP <70 mmHg
BP medication was attributed to pneumonia is associated with higher rates of neurological
among patients with dysphagia. worsening, poor neurological outcomes, or
death.
• The cause of arterial hypotension in acute ATACH II: Anti- 1,280 patients ongoing
stroke should be determined and addressed: hypertensive with acute ICH (Clinicaltrials.gov
e.g., aortic dissection, volume depletion, blood Treatment on randomized to identifier
loss, and decreased cardiac outcome second- Acute Cerebral receive intensive NCT01176565)
ary to MI or cardiac arrhythmias. Hemorrhage-2 treatment to
• Correct hypovolemia with plain NSS, and treat lower SBP to
arrhythmias to optimize cardiac output. (Neurocritical <140 mmHg
• Available vasopressors agents include dopa- Care 2011; (3): versus guideline-
mine, dobutamine, and phenylephrine. 559-576) based manage-
ment to SBP
B. BP Management in Acute Hypertensive Intra <180 mmHg
cerebral Hemorrhage within 24 hours
of randomization
• BP is often markedly elevated in acute ICH, with
using IV Nicar-
elevations greater than that seen in ischemic stroke.
dipine.
• Mechanism:
• Stress activation of neuroendocrine system
° Unlike SAH, isolated ICH does not have the
(sympathetic NS, renin-angiotensin axis,
same propensity to cause cerebral vaso-
glucocortocoid system) partly in response to
spasm, thus BP lowering can be somewhat
increased ICP.
more aggressive.
��
• The absence of ischemic penumbra allows for
more aggresive BP management.
Recommendations:
• Hypertension could theorically contribute to
• Treat if SBP >180 mmHg.
hydrostatic expansion of the hematoma, peri-
• Acute lowering of SBP to ≈140 mmHg within 7
hematoma edema, and rebleeding.
days is safe and improves outcome in patients
• Hypothension may result in cerebral hypoperfu-
with small-moderate size ICH not requiring
sion especially in the setting of increased ICP.
surgical intervention (Class I, level B).
• if ICP monitor is available, keep CPP >70
Clinical Evidence
mmHg.
• Phase II clinical trials on BP lowering (INTER-
ACT and ATACH) have shown that intensive
(See Chapter 6 for further details on Hypertensive ICH)
BP lowering to SBP ≈140 mmHg in acute ICH
is feasible and probably safe.
C. BP management in Acute Subarachnoid
° Intensive Blood Pressure Reduction in Hemorrhage
Acute Cerebral Hemorrhage Trial (INTER-
ACT): trend to less hematoma volume growth • Treat hypertension with modest reductions in BP
in 24 hours with intensive BP lowering to goal to minimize vasospasm and delayed cerebral
of SBP 140 mmHg (versus 180 mmHg); with ischemia (see Chapter 6 for further details on
no excess in neurologic deterioration SAH).
° Antihypertensive Treatment in Acute Cere- • Preoperatively, for unsecured aneurysms, the
bral Hemorrhage (ATACH) trial: early, rapid use of IV Nicardipine to a target SBP <150
BP lowering in ICH (with IV Nicardipine) is mmHg is reasonable.
clinically feasible and probably safe.
Bibliography
Table 6. Phase II Clinical Trial on BP lowering in Acute ICH 1. Anderson C, Huang Y, Wang J, et al. for the INTERACT Investigators.
Intensive blood pressure reduction in acute cerebral haemorrhage trial
TRIAL DESIGN RESULT (INTERACT): a randomised pilot trial. Lancet Neurol. 2008; 7:391-99.
2. Castillo J, Leira R, Garcia MM, et al. Blood pressure decrease during
INTERACT II: 2,388 patients There was no the acute phase of ischemic stroke is associated with brain injury and
poor stroke outcome. Stroke. 2004; 35:520-526.
Intensive Blood with sponta- difference in the 3. Connolly E Jr, Rabinstein A, Carhuapoma J, et al. Guidelines for the
Pressure neous ICH with- rate of primary Management of Aneurysmal Subarachnoid Hemorrhage: A Guideline
Reduction in in 6 hours and outcome of death for Healthcare Professionals from the American Heart Association/
American Stroke Association. Stroke. 2012; 43:1711-1737.
Acute Cerebral SBP >150 - 220 and disability 4. Hubert GJ, Müller-Barna P, Haberl RL. Unsolved Issues in the
Hemorrhage mmHg rando- between 2 treat- Management of High Blood Pressure in Acute Ischemic Stroke. Int J
Trial-2 mized to ment groups at Hypertens. 2013;2013:349782.
received inten- 90 days. 5. Jauch E, Saver J, Adams H, et al. Guidelines for the early management
of patients with ischemic stroke guidelines for healthcare professionals
(N Eng J of MED sive treatment to from the American Heart Association/American Stroke Association.
2013; 368: lower SBP to Pre-specified Stroke. 2013;44:870-947.
2355-2365) <140 mmHg vs. ordinal analysis 6. Morgenstern L, Hemphil JC III, Anderson C, et al. Guidelines for
the Management of Spontaneous ICH: A Guideline for Healthcare
guideline based showed signifi- Professionals form the American Heart Association/American Stroke
to SBP <180 mm cantly lower mRS Association. Stroke. 2010 Sep;41(9):2108-29.
Hg using drugs scores with inten- 7. Oliveira-Fiho J, Silva SC, Trabuco CC, et al. Detrimental effect of blood
of physician's sive treatment pressure reduction in the first 24 hours of acute stroke onset. Neurology.
2003;61:1047-1051.
choice for 1 (OR for greater 8. Patarroyo S and Anderson C. Blood pressure lowering in acute phase
week. disability=0.87, of stroke: latest evidence and clinical evidence. Ther Adv Chronic Dis.
95% Cl, 0.77- 2012;3(4):163-171.
9. Qureshi AI, Tariq N, Divani AA, et al.; ATACH Investigators.
1.00, p=0.04). Antihypertensive treatment of acute cerebral hemorrhage. Crit Care
Med. 2010 Feb;38(2):637-48.
170
10. Sandset EC, Bath PM, Boysen G, et al. The angiotensin-receptor then maintained at 3-5 mg/kg; or Levetiracetam
blocker candesartan for treatment of acute stroke (SCAST): a
randomised, placebo-controlled, double-blind trial. Lancet. 2011 Feb
500 mg IV q12. Status epilepticus should be
26;377(9767):741-50. treated accordingly.
4. Strict blood glucose control between 140-180
VII. MANAGEMENT OF INCREASED INTRACRANIAL mg/dL.
PRESSURE (ICP) 5. Maintain normal fluid and electrolyte balance.
a. Avoid excessive free water or any hypotonic
A. Signs and Symptoms of Increased ICP fluids such as D5W. Potential sources of
1. Deteriorating level of sensorium free water including hypotonic tube feed-
2. Cushing's triad: hypertension, bradycardia, ings, medications mixed in in D5W, and
irregular respiration nasogastric tube flushes with water, should
3. Anisocoria be minimized.
b. Maintain normal volume status (i.e., 3.0-3.5
B. Management Options of Increased ICP liters per day in a 60 kg patient).
General: c. Encourage hyperosmolar state with hyper-
1. Control agitation and pain with short-acting tonic saline and/or induce free water clear-
medications, such as NSAIDs and opioids ance with mannitol or diuretics.
(Table 7). 6. Use stool softeners to prevent staining.
2. Treat fever aggressively. Avoid hyperthermia.
3. Control seizures if present. May treat with phe- Specific:
nytoin at a loading dose of 18-20 mg/kg slow IV, 1. Elevate the head at 30 at 45 degrees to assist
Table 7. Locally Available Sedatives and Narcotics
Onset of Duration of Availability/

Drug Usual Dose Comments
Action Effect Dilution
Midazolam 0.025-0.035 mg/kg 1-5 min 2 hours Unpredictable sedation 15 mg/3 mL amp
5 mg/ 5 mL amp
50 mg in 100 mL
NSS/D5W
Diazepam 0.1-0.2 mg/kg Immediate 20-30 minutes Sedation can be reversed 10 mg/2 mL amp;
with flumazenil (0.2-1 mg 50 mg in 250 mL
at 0.2 mg/min at 20 min NSS/D5W
intervals, max dose of 3
mg in 1 hr)
Propofol 5-50 µg/kg/min <40 sec 10-15 minutes Expensive (10 mg/mL) 100 mL
vial (premixed)
Ketorolac 50-100 mg IV 1 hour 6-8 hours NSAID 30 mg/mL amp
Tramadol 50-100 mg IV 1 hour 9 hours Centrally acting synthetic 50 mg/2 mL amp;

analgesic compound not 100 mg/2 mL amp
chemically related to
opiates but thought to
bind to opioid receptors
and inhibit reuptake of
NE and serotonin
Fentanyl 50-100 µg/hour 1-2 min >60 minutes Can be easily reversed 100 µg/2 mL; 2500
with naloxone (0.4-2 mg µg in 250 mL amp
IVP; repeat at 2-3 min
intervals, max dose 10 g)
*110x more potent than
morphine
Morphine 2-5 mg/hour 5 min >60 minutes Opioid 10 mg/mL gr 1/6

16 mg/mL gr 1/4
Dexmede- 1 µg/kg/hour LD 30-60 sec 3-5 minutes 200 µg/2 mL vial

tomidine for 10 min then
(Precedex®) maintenance
dosing at 0.4
µg/kg/hour (dose
range: 0.2-0.7
µg/hour)

venous drainage. Because of the limitations of current medical therapies
2. Do CSF drainage in the setting of hydrocepha- in preventing brain herniation and improving patient
lus. outcome, varying surgical decompression techniques
3. Administer osmotic therapy: have been proposed and used to achieve the following
• Give Mannitol 20% IV infusion. Typical doses objectives: decrease mass effect or intracranial pressure
range from 0.5-1.5 g/kg every 3-6 hours Doses from malignant brain edema, prevent brain herniation,
up to 1.5 g/kg are appropriate when treating a reduce or avert secondary injury to the brain, and reduce
deteriorating patient bacause of mass effect. or avert further conversion of areas of ischemic penumbra
• Hypertonic saline is an option. It has the advan- to infarct. This would ultimately translate to reduction in
tage of maintaining an effective serum gradient overall mortality rates and improvement in long-term
or rise in osmolarity for sustained periods with functional outcomes.
lower incidence of intracranial hypertension.
• Always maintain serum osmolarity at 300-320 Criteria for Patient Selection
mosmol/kg. [Formula for Serum Osmolarity = 1. Patients who present clinically with a severe
2 (Na) + glucose/18 + BUN/2.8] hemispheric stroke syndrome: hemiplegia, forced
4. Hyperventilate only in impending herniation by eye deviation and head deviation to the side of
adjusting tidal volume to achieve target pCO2 the infarct, aphasia, contralateral neglect, and
levels of 30-35 mmHg. Hyperventilation is progressive decline in the level of consciousness
recommended only for a short term as its ef- usually within the first 48 hours.
fect on CBF and ICP is short lived (≅ 6 hours). 2. Imaging findings showing an infarct volume involv-
Prophylactic hyperventilation without regard to ing >50% MCA territory.
patient's ICP level and clinical state should not 3. Age: 60 years and below. Mortality rate was 20.8%
be done. and 51.3% in patients aged <60 years and >60
5. Careful intubate patients with respiratory years respectively. Poor outcome was seen in
failure (defined as SaO2 of less than 90% by 33.1% of patients <60 years vs. 81.8% in patients
pulse oximetry and PaO2 <60mmHg, and/or >60 years.11 However, some authors suggested
PaCO2 >55 mm Hg by arterial blood gas [ABG] that other factors might be more important than
analysis). age, which include functional and cognitive status
6. Consider surgical evacuation or decompressive at admission, social situation, extent of family
hemicraniectomy if indicated. support, and psychosocial and financial burden
7. ICP catheter insertion is useful for the diag- of care.
nosis, monitoring and therapeutic lowering of 4. Dominance of hemisphere involved: Though some
increased ICP. It is recommended in patients have expressed concern that doing decompres-
with GCS ≤8, those with significant IVH, and sive hemicraniectomy for malignant MCA infarcts
hydrocephalus. CPP should be maintained at involving the dominant hemisphere will lead to
60-70 mmHg. a worse functional outcome, this has not been
seen in several studies, due to recovery of varying
VIII. HEMICRANIECTOMY FOR MALIGNANT MIDDLE extents of communication skills or to the equally
CEREBRAL ARTERY (MCA) INFARCTION negative impact of hemiplegia.12

5. Exclusions: terminal illness, significant co-morbid
Ten to fifteen percent of supratentorial infarcts will conditions like significant cardiac disease and
involve the entire MCA.1 Cerebral ischemic infarcts are bleeding disorders.
associated with cytotoxic, interstitial, and vasogenic 6. The Massachusetts General Hospital (MGH) has
brain edema of varying extents. Depending on the proposed the STATE Criteria (Table 8) to deter-
severity and extent of edema formation, as well as the mine eligibility for hemicraniectomy and a treatment
patient's compensatory mechanisms, ischemic brain algorithm (see Clinical Pathway) on this criteria.
edema in large MCA infarcts may lead to transtentional
or transforaminal herniation, usually within 2-5 days from Pre-surgical and surgical management13
ictus.2-3 Herniation accounts for 78% of deaths during the 1. If hemicraniectomy is offered, withhold anticoa
first week.4 This subgroup of catastrophic infarcts was gulation and antiplatelets until deemed safe post-
first labeled as malignant MCA infarcts by Hacke et al. in procedure with input from neurosurgery.
1996.3 2. For adequate external decompression, the size
of the bone flap removed should ideally be 12 cm
The prognosis of patients with malignant edema for- (anterior-posterior) by 9 cm (superior-inferior),
mation after MCA infarcts is poor despite maximum combined with duraplasty.
conservative treatment, and in randomized or larger 3. Temporal lobectomy may be considered during
prospective observation studies, mortality averages the procedure, at the neurosurgeon's discretion.
50-80%. 5-10 If performed, tissue should be submitted for neuro
pathological examination.
4. The bone flap should be placed in a subcutaneous
abdominal pouch or stored in the bone bank.
Post-surgical management13
1. Admit the patient to an intensive care unit, prefer-
ably the Neuro ICU. The Neurocritical Care attend-
ing will be the attending of record.
2. Once appropriate,a protective helmet should be
FIGURE 1: Natural Course of Malignant MCA Infaction worn until the bone flap is replaced.
172
Table 8. State Criteria for Immediate Neurosurgical B. Hyperventilation: a temporary measure to reduce
Consultation for Hemicraniectomy for Malignant ICP if signs of brain herniation develop. This
MCA Infarction13 should be avoided unless other measures have
been exhausted and there is a plan to proceed
Factor Criteria immediately to surgery.
C. Osmotic therapy
Score*,** NIHSS item 1a >1 or GCS <8, and D. Invasive ICP monitoring (subarachnoid screw or
NIHSS >15 (non-dominant) or >20 bolt) is not required to determine suitability for
(dominant) decompressive surgery. An external ventricular
drain should be considered if neuroimaging
Time <48 hours since last seen without shows evidence of acute hydrocephalus. It may
neurological deficits be useful to monitor the ICP post-operatively if
there is a concern that the decompression was
Age <60 years insufficient.
Territory Infarcts lesion volume >150 cm3 (use Key Points in the Surgical Management of Malig-
ABC/2 formula for estimating lesion nant MCA Infarction
volume), or >50% MCA territory 1. Anticoagulation and antiplatelet therapy should be
infarction withheld until deemed safe post-procedure.
2. Optimal medical therapy including osmotic therapy
Expectations Life expectancy 'reasonable' in the should be instituted while preparing the patient
opinion of the Neurology Attending for hemicraniectomy and then postoperatively as
or Neuro-ICU Fellow. In addition, the indicated.
health care proxy or family members 3. Timing of surgery: Better outcomes have been
understand that while the procedure shown if surgery is performed early, within 24-48
is proven to reduce disability and hours from ictus14-17 and before the clinical signs
mortality, the patient may still sur- of herniation (e.g., pupillary dilatation, posturing).15
vive with severe disability. Surgical procedure consists of decompressive
hemicraniectomy with duraplasty. Removal of
If all the above "STATE" criteria are met, proceed to bone flap decreases ICP by 15% while opening the
hemicraniectomy urgently (to OR within 4-6 hours). dura reduces ICP by 70%.16-17 Dimensions of the
*for intubated/sedated patients, monitoring of the level of bone flap removed should be generous, by which
alertness can be challenging and the clinical judgement some institutions recommend a size of 12 cm by 9
of the Neurology Attending is important in determining cm. Removal of a bone flap with a diameter of <10
whether a patient meets this criterion.
cm has been associated with increased incidence
**for patients who meets all STATE criteria except the
of shearing injury due to herniating brain abutting
level of drowsiness, patients should be triaged to the
Neuro ICU for close neuromonitoring. against the edge of the craniectomy defect.17
4. Strokectomy (removal of infarcted tissue) should
Indications for EMERGENT HEMICRANIECTOMY: not be routinely done because it is usually difficult
STATE criteria met above, AND: to delineate between an infarcted versus ischemic
tissue, and outcomes have not been shown to be
Early Signs of Asymmetry in pupil size significantly better.
Herniation 5. The removed bone flap may be stored in a sub-
cutaneous abdominal pocket or at a bone bank (if
Midline Shift >10 mm at spectum pellicidum, such is available).
or >5 mm at pineal gland 6. Bone flap is replaced as soon as functional reco
very has stabilized and the patient has no systemic
contraindications.
3. The bone flap should be replaced as soon as the
patients can tolerate the surgery preferably within Outcomes:
12 weeks, unless the patient develops intercur- Results of different studies have shown that de-
rent infections or other complications requiring compressive hemicraniectomy with duraplasty has
delay. improved survival rates to 67-84% versus 20-30%
for patients managed conservatively. Although the
Adjunctive therapy13 significant reduction in mortality from surgery is ir-
Although not proven efficacious, medical strategies refutable, its impact on functional outcome is still the
may reduce the risk of developing fulminant brain subject of some debate. Different prospective studies
edema. These strategies should be used in all patients and RCTs have shown that decompressive hemicra-
with large MCA stroke as an adjunct to hemicraniec- niectomy has increased the number of survivors with
tomy (if the patient is deemed eligible). They should moderate or moderately severe disability. Whether or
not be used to defer or delay hemicraniectomy if not this translates to a poorer quality of life is relative,
STATE criteria are met. because such as outcome is acceptable if patients
and/or families value prolongation of life more than the
A. General management patients with raised intra- risk of almost certain death with medical management
cranial pressure require special attention to pain alone.18
relief, avoidance of noxious stimuli, proper head
positioning, adequate oxygenation, maintenance More recent trials have shown that decompressive
of normothermia, and prevention of DVT. Avoid surgery can improve long-term functional outcome,
oral or gastric feedings if the patient is likely to go number needed to treat (NNT) of 2 to achieve a
to surgery imminently. mRS score of ≤4, and NNT of 4 to achieve an mRS

Table 9. Benefit of Hemicraniectomy
Time Primary
Study Year # Inclusion to Tx Outcome Mortality (%) Good Outcome
Name
Pts Criteria (hrs) Measure
Surg Med Surg Med
DESTINY 2007 32 Age:18-60 36 Death at 30 days, 17.6 53 47 27
mRS <4 at 6 mos.
DECIMAL 2007 38 NIHSS: 24 mRS <4 at 6 mos. 25 77.8 50 22.2
>18-20
HAMLET 2009 64 Age:18-55 96 mRS <4 at 12 mos. 22 59 25 25
HeADD NA 26 Age: 18-60 96 Death
FIRST19 functional
outcome, quality
of life, pt. Results pending
perceptions,
acute health care
use at 21, 90, 100
days
HeMMI20 2012 29 Acute 72 Good status: n=5 n=6 n=3 n=4
unilateral mRS 0-3; Death (38.5%)+ (54.5%)* (23.1%)* (36.4%)*
MCA
ischemia
DESTINY II 2011 112 Age:18-65 48 Primary Outcome: mRS 5-6 mRS 5-6 mRS 0-4 mRS 0-4
GCS:10-14 mRS at 6 mos. Tx Control Tx Control
(right) or (mRS 0-4 vs. mRS 59.2% 84.1% 40.8% 15.9%
5-9 (left) 5-6)
Zhao et al. 2012 47 CT: 48 mRS at 6 mos Mortality mRS >4 (%)
ischemia Secondary
>50% Outcome: mRS at 6 mos 6 mos 6 mos 6 mos
MCA 1 year; ��
12.5 60.91 33.3 82.6��
mortality
at 6 and 12 ��
12 mos 12mos 12 mos 12 mos
mos. ��
16.7 69.6 25 87
For every 10 hemicraniectomies performed for MCA infarction, 5 patients will escape death; at one year, 1 of these
patients will have mild disability, 1 will have moderate disability, and 3 will have severe disability.21 Among patients
younger and older than 60 years old, decompressive surgery for malignant MCA infarction significantly increases
the probability of survival.
score of ≤3 at one year. The decision as to whether a multicentre, open, randomised trial. Lancet Neurol. 2009;8:326-33.
11. Arac A, Blanchard V, Lee M, Steinburg GK. Assessment of outcome
decompressive surgery be offered to a patient following decompressive craniectomy for malignant middle cerebral
presenting with malignant MCA infarction must be artery infarction in patients older than 60 years of age. Neurosurg
individualized.13 Focus. 2009 Jun;26(6):E3.
12. Lanzino D, Lanzino G. Decompressive craniectomy for space-occupying
Bibliography supratentorial infarction: Rationale, indications, and outcome. Neurosur
Focus. 2000;8:1-7.
1. Berrouschot J, Sterker M, Bettin S, et al. Mortality of space-occupying 13. Marquevich V, Kimberly WT, Ogilvy CS, et al. Hemicraniectomy
(malignant) middle cerebral artery infarction under conservative for Large MCA infarction. Massachusetts General Hospital Stroke
intensive care. Intensive Care Med. 1998;24:620-623. Service Website. http://www2.massgeneral.org/stopstroke/
2. Ropper AH, Shafran B. Brain edema after stroke. Clinical syndrome protocolHemicraniectomyGuidelines.aspx. Updated January 13,
and intracranial pressure. Arch Neurol. 1984;41:26-9. 2011. Accessed April 15, 2014.
3. Hacke W, Schwab S, Horn M, et al. "Malignant" middle cerebral 14. Schwab S, Steiner T, Aschoff A, et al. Early hemicraniectomy in patients with
artery infarction. Clinical course and prognostic signs. Arch Neurol. complete middle cerebral artery infarction. Stroke. 1998;29:1888-1893.
1996;53:309-15. 15. Schwab S, Hacke W. Surgical decompression of patients with large
4. Heinsius T, Bogousslavsky J, Van Melle G. Large infarcts in the middle middle cerebral artery infarcts is effective. Stroke. 2003;34:2304-2305.
cerebral artery territory. Etiology and outcome patterns. Neurology. 16. Smith ER, Carter BS, Ogilvy CS. Proposed use of prophylactic
1998;59:341-50. decompressive craniectomy in poor-grade aneurismal subarachnoid
5. Kasner SE, Demchuk AM, Berrouschot J, et al. Predictors of fatal brain hemorrhage patients presenting with associated large sylvian
edema in massive hemispheric ischemic stroke. Stroke. 2001;32:2117-23. hematomas. Neurosurgery. 2002;51(1):117-124.
6. Berrouschot J, Sterker M, Bettin S, et al. Mortality of space-occupying 17. Tazbir J, Marthaler M, Moredich C, Keresztes P. Decompressive
(malignant) cerebral artery infarction under conservative intensive care. hemicraniectomy with duraplasty: a treatment for large-volume
Intensive Care Med. 1998;24:620-3. ischemic stroke. J Neurosci Nurs. 2005 Aug;37(4):194-9.
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randomised controlled trials. Lancet Neurol. 2007;6:215-22. 24;75(8):682-7.
8. Vahedi K, Vicaut E, Mateo J, et al. Sequential-design, multicenter, 19. Frank JI, Schumm LP, Wroblewski K, et al.; HeADDFIRST Trialists.
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malignant middle cerebral artery infarction (DECIMAL Trial). Stroke. related swelling trial (HeADDFIRST). Stroke. 2014;45:781-787.
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174
Index of Drugs Related to the Guideline
This index lists the products of interest and/or their therapeutic classifications related to the guideline. This index
is not part of the guideline. For the doctor's convenience, brands available in the PPD references are listed under
each of the classes. For drug information, refer to the PPD references (PPD, PPD Pocket Version, PPD Tabs, and
www.TheFilipinoDoctor.com).
Anticoagulants Inotropic agents Opiates & Antagonists

Fentanyl
Heparin Dobutamine Durogesic D Trans
Bruhep 5000/ Cardease Fendermal
Bruhep 25000 Dobuject Morphine
Heparin Leo Dobulex MST Continus
Warfarin Doburan Tramadol
Coumadin Hospira Dobutamine in MNS Solution for Inj
5% Dextrose inj (IM/IV/SC)
Antiplatelets Hospira Dobutamine Inj Radol
Tramal
Aspirin Dopamine Tramadol + Paracetamol
Aspen Hospira Dopamine Algesia
Aspilets/Aspilets-EC (Premixed) Dolcet
Bayer Aspirin 100 mg Dolcet Mini
CNS Stimulants, Nodolor P
Bayer Aspirin 300 mg
Neurotonics, & Nutram
Bayprin EC Neurotrophics P-Dol
Cor-30 (Neuroprotective & Paratram
Cortal 500 Neurorestorative Drugs) Pradonal
Tromcor Vistramol
Aspirin + Clopidogrel Cerebrolysin
CoPlavix Cerebrolysin
Norplat-S
Cilostazol Citicoline
Ciletin Cholinerv
Clazol Citilin
Pencil Cyline
Platecil Zyndes
Pletaal
Trombocil Nueropsychiatric drugs,
Other (Herbal & Other
Vaxol
Natural Products)
Clopidogrel
NeuroAid
Actaclo
Aforex Nitrates/Nitrites, Organic
Avancur
Cardogrel Nitroglycerin
Clopikline Deponit NT 5
Clopimet Transderm-Nitro
Cloplat
Clotigen Hypnotic/Sedative
Clotiz
Dinclop 75 mg Diazepam
Film-Coated Tab Valium
Hemaflow Midazolam
Norplat Dormicum
Pharex Clopidogrel Midazolex
Sedacum
Plavix
Dexmedetomidine
Plogrel
Precedex
Proflow
RiteMED Clopidogrel Anesthetics, Parenteral
Syclopid
Thromvix Propofol
Winthrop Clopidogrel Fresofol MCT/LCT 1%
Dipyridamole Lexofol
Persantin Lipuro
Triflusal
Grendis Non-Steroidal Anti-inflam-
matory Drugs (NSAIDs)
Calcium Antagonist Ketorolac
Acular
Nicardipine Ketomed
Remopain
Cardepine
Toradol

Acute Stroke and Transient Ischemic Attack

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Acute Stroke and Transient Ischemic Attack

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Guidelines for Treatment of

Stroke Society of the Philippines

Board of Trustees 2015-2016

President Maria Cristina Z. San Jose, MD

Members Pedro Danilo J. Lagamayo, MD

Stroke: Think Globally, Act Locally

1. Stroke is a “brain attack”

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Patients with suspected large MCA infarct

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Probably indicated Contraindicated

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3. Intravenous Administration of rt-PA Once the desired BP is achieved, adjust to main-

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Onset Duration Availability/ Adverse Mechanism of

Table 7. Locally Available Sedatives and Narcotics

Onset of Duration of Availability/

Ketorolac 50-100 mg IV 1 hour 6-8 hours NSAID 30 mg/mL amp

Tramadol 50-100 mg IV 1 hour 9 hours Centrally acting synthetic 50 mg/2 mL amp;

Morphine 2-5 mg/hour 5 min >60 minutes Opioid 10 mg/mL gr 1/6

Dexmede- 1 µg/kg/hour LD 30-60 sec 3-5 minutes 200 µg/2 mL vial

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Anticoagulants Inotropic agents Opiates & Antagonists

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