UPDATE IN ACUTE ISCHEMIC STROKE MANAGEMENT

OU NeurologyOU Neurology

UPDATE IN ACUTE ISCHEMIC STROKE

MANAGEMENT


DLG DISCLOSURES

FINANCIAL DISCLOSUREI have no financial relationships or affiliations

to disclose.

UNLABELED/UNAPPROVED USES DISCLOSUREI will reference the following off-label or

investigational use of drugs or products: intra-arterial t-PA in stroke patients


STROKE IN THE UNITED STATES

Affects > 780,000 persons per year Major cause of death (#3) & long-term disability Oklahoma has 6th-highest stroke death rate Estimated U.S. cost for 2008 = $65.5 billion

Mostly hospital (esp. LOS) & poststroke costsAppropriate use of IV t-PA s long-term costDRG 559 for AIS w/ thrombolysis ( hospital

reimbursement from $5k to $11.5k)


THREE STROKE TYPES

IschemicStroke

Clot occludingartery

Intracerebral Hemorrhage

Bleedinginto brain

Subarachnoid Hemorrhage

Bleeding around brain

Focal Brain Dysfunction

Diffuse Brain Dysfunction

85% 10% 5%


ACUTE ISCHEMIC STROKE (AIS) & TIALOW BLOOD FLOW TO FOCAL AREA OF BRAIN

Pathophysiology: Usually thromboembolism

(blood clot forms in vascular system, travels downstream, plugs cerebral artery)

Acute therapy: Thrombolysis (or thrombectomy) Do NOT lower BP Avoid aspiration / IV glucose

2 prevention: Antithrombotic therapy Vascular risk factor therapy Possible carotid endarterectomy

(CEA) or angioplasty (CAS)

CLOTCLOT

INFARCTINFARCT

Ischemic stroke = Infarction with sequelae

Transient ischemic attack = No infarction and no sequelae


TRANSIENT ISCHEMIC ATTACK (TIA) AND “ACUTE NEUROVASCULAR SYNDROME”

Transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischemia, without infarction

Typically < 1 h, but time limit is no longer part of definition

Risk of stroke = 5% w/in 2 d, 10% w/in 3 m Appropriate antithrombotic therapy based on cause Urgently evaluate for cause

MRI w/ DWI, intracranial MRA, carotid duplex, echo Can admit to “observation status”

Discover cause, determine therapy, decrease risk!


ISCHEMIC STROKE PATHOPHYSIOLOGYThe First Few Hours

Penumbra

Core

Clot in Artery

“TIME IS BRAIN:SAVE THE PENUMBRA”

Penumbra is zone of reversible ischemia around core of irreversible infarction—salvageable in first few hours afterischemic stroke onset

Penumbra damaged by:• Hypoperfusion• Hyperglycemia• Fever• Seizure


ISCHEMIC PENUMBRA: PATHOPHYSIOLOGYOF THERAPEUTIC WINDOW

Penumbra

Core

CEREBRALBLOODFLOW(ml/100g/min)

CBF< 8

CBF8-18

TIME (hours)

1 2 3

20

15

10

5

PENUMBRA

CORE

Neuronal dysfunctio

n

Neuronal death

Normal function

Identification of penumbra through MRI perfusion-diffusion mismatch or perfusion CT may replace time as the major indication for emergency acute ischemic stroke therapies.


ORGANIZED CARE OF STROKE PATIENTS:PERFORMANCE IMPROVEMENT / UTILIZATION REVIEW

Acute stroke team

Stroke multidisciplinary team

Stroke unit

Prewritten stroke orders

Address each aspect of care each day

An organized approach enablesemergency treatment, a thorough evaluation,

and improved patient outcome at decreased cost.

Stroke unit care results in decreased rate of aspiration pneumonia, decubiti, stroke progression or recurrence, and death.

Supportive medical careTreatment of acute strokeRehabilitationOutpatient planningKeep away future strokesEtiologic evaluation


STROKE EMERGENCY BRAIN IMAGING:NONCONTRAST CT SCAN

Acute (4 hours)Infarction

Subtle blurring of gray-white junction & sulcal

effacement

Subacute (4 days) Infarction

Obvious dark changes & “mass effect” (e.g.,

ventricle compression)

RR L L


STROKE EMERGENCY BRAIN IMAGING:NONCONTRAST CT SCAN

CT detects all ICHs immediately

CT detects 90% of SAHs;if SAH suspected &

CT negative, must LP

Intracerebral Hemorrhage Subarachnoid Hemorrhage


AIS EMERGENCY THERAPY: IV TISSUE PLASMINOGEN ACTIVATOR (T-PA)

< 3.0 Hours No upper age limit No limit on stroke size Can give if taking warfarin &

INR < 1.7

3.0-4.5 Hours Do NOT give if:

Pt > 80 yo NIHSS > 25 DM w/ previous stroke Taking warfarin at all

Must give < 4.5 h—earlier you give it, better the outcome Stroke onset = last time known to be normal Do NOT give if glucose < 50 Do NOT give if BP > 185/110 Disability risk 30% despite ~5% symptomatic ICH risk Lawsuits for not giving >>> lawsuits for giving


FAST TestUse the FAST test for recognizing and responding to stroke

symptoms.

Facial Droop:

Ask the person to smile. Does one side of the face droop?

Arm Drift:

Ask the person to raise both arms. Does one arm drift downward?

Slurred Speech:

Ask the person to repeat a simple sentence. Does the speech sound slurred or strange?

Time:

If you observe any of these signs, it’s time to call a senior doctor.


The goal

the acute management of patients with stroke is to stabilize the patient and

to complete initial evaluation and assessment, including imaging and laboratory studies, within 60 minutes of patient arrival


Time Target

Door to doctor 10 minAccess to neurologic expertise 15 minDoor to CT scan completion 25 minDoor to CT scan interpretation 45 minDoor to treatment 60 min


AIS ED STROKE CARE 24/7:1-H EVALUATION, 1-H INFUSION

I. Triage–10 min Review t-PA criteria Page acute stroke team Draw pre t-PA labs*

II. Medical Care–25 min Place O2 , 2 NS IVs Obtain BP, weight, NIHSS Obtain 12-lead ECG Send patient to CT

III. CT & Labs–45 min Obtain lab results Read CT Return pt to ED

IV. Treatment–60 min Start IV t-PA Monitor for ICH sxs

HTN, headache N/V, neuro status

*CBC, platelets, PT/INR, PTT, chem 7, cardiac panel


Inclusion Criteria

Diagnosis of ischemic stroke causing measurable neurologic deficit

Onset of symptoms 3hours before beginning of treatment.

The patient and family understand the potential risks and benefits of therapy

Recent AHA/ASA guidelines recommend extension of IV rtPA treatment window up to 4.5hours based on ECASS(III) trial


Obslute contindications

ICH (whenever the previous history) Acute MI Pericaditis Endocarditis Bleeding tendency


Exclusion Criteria

Neurologic signs are clearing spontaneously Neurologic signs are minor and isolated Systolic blood pressure >185 mm Hg, diastolic blood

pressure >110 mm Hg Head trauma or prior stroke in the past 3 months MI in the last 3 months GI/GU hemorrhage in previous 21 days Arterial puncture at a non-compressible site during prior

7 days Major surgery within the last 14 days


Taking any anticoagulant or if on anticoagulant INR >1.7 Patient received heparin in the last 48 hours with

elevated partial thromboplastine time (aPTT) Platelet count of <100,000/μl Blood glucose less than 50 mg/dl or greater than 400mg Seizure with residual postictal focal impairments CT scan shows evidence of multi-lobar infarction (hypo-

density greater than one third of MCA territory)


Recent evidences suggest to expand the window time for the administration of rtPA from 3 hrs to 4.5 hrs to the above eligible patients excluding any one of the following:

*Patients older than 80 years* All patients taking oral anticoagulants are excluded regardless of the (INR)*Patients with baseline NIHSS greater than 25* Patients with a history of stroke and diabetes


No antiplatelet or anticoagulant therapy should be administered for 24 hours following tPA.

Obtain a repeat head CT scan or MRI 24 hours after tPA to rule out asymptomatic

hemorrhagic transformation prior to initiating antithrombotic therapy.


OTHER AIS THERAPIES:MAYBE IA, YES ASA, NO HIGH-DOSE HEPARIN

Intra-arterial t-PA Only preliminary evidence to date, not FDA approved Theoretical window 6 h—but do NOT preclude IV t-PA w/in 4.5 h Studies ongoing, esp. combined w/ IV t-PA

MERCI or Penumbra device Mechanical embolectomy devices Theoretical window 8 h Both FDA approved, but controlled trial results pending

Aspirin Aspirin 325 mg per day begun within 48 h of stroke onset

decreases morbidity & mortality (may begin 24 h after t-PA) Heparin(s)

Insufficient evidence to recommend routine use of high-dose IV heparin, LMW heparin, or heparinoid as Rx for AIS per se


THE AIS-BP RELATIONSHIP

In AIS, high BP is a response,not a cause—don’t lower it!

BP increase is due to arterial occlusion (i.e., an effort to perfuse penumbra)

Failure to recanalize (w/ or w/o thrombolytic therapy) results in high BP and poor neuro outcomes

Lowering BP starves penumbra, worsens outcomes

Penumbra

Core

Clot in Artery


AIS IS NOT A HYPERTENSIVE EMERGENCY!

ASA/AHA AIS Guidelines tables no longer include recs for BP Rx in non t-PA patients

Text of guidelines state “Do not Rx unless BP > 220/120,” but also state: No data to suggest 220/120 is dangerous & requires Rx

Evidence that BP lowering worsens outcomes is concerning

Goal is to avoid overtreating pts until definitive data available

Only definite indications to BP emergently in AIS: AMI, CHF, Ao dissection, ARF, or HTN encephalopathy

Candidate for thrombolysis and BP > 185/110


MAY LOWER BP SLIGHTLY PRE T-PAMUST PICK AN UPPER LIMIT TO TREAT—220/120 IS ONE OPTION

If all t-PA criteria met except sustained BP > 185/110:

Ensure 2 IVs (NS @ 75 cc/h, saline lock) Calm patient, empty bladder Recheck BP, lower slightly if necessary

SBP > 220 orDBP > 120

SBP > 185 and < 220 orDBP > 110 and < 120

Avoid excessive lowering of BP just to give t-PA—“Don’t kill the penumbra to save the penumbra”

Lower BPpre-t-PA

No BP med,No t-PA


The aim is to maintain MAP = 70 - 130 mm Hg MAP = DP + 1/3 (SP-DP) OR {(2xDP) + SP}/3 Labetalol Initial: 20 mg IV over 2 min, then 40-80 mg IV q10min to no more

than 300 mg, OR 1-2 mg/min continuous IV infusion Nicardipine I V: Initial 5 mg/hr slowly, may increase q15min by 2.5 mg/hr;

maximum 15 mg/h; when desired blood pressure reached, lower to 3 mg/h Enalapril 1.25 - 5 mg IVP every 6 h Esmolol 250 μg/kg IVP loading dose, then 25 - 300μ/kg/ min Hydralazine 5 - 20 mg IVP every 30 min OR 1.5 to 5 μg /kg/ min Nitroglycerin 20 - 400 μg/min Sodium nitroprusside (0.5 mcg/kg/min)


LOWERING BP IN T-PA PATIENTS

Nicardipine 5 mg/h IV infusion Increase 2.5 mg/h q5min to max 15 mg/hEasily titratable without an arterial line

Labetalol 10-20 mg IVMay repeat q 10-15 minPre-t-PA: only use a 2nd dose only if necessary

Note Different Target BPs Pre & Post T-PAPre t-PA: < 185/110Post t-PA: < 180/105


WORRYING ABOUT THE LUNGS:ASPIRATION, DYSPHAGIA, & OXYGEN

Weak oropharyngeal muscles common Neurogenic dysphagia: liquids worse than solids (purees best) Stroke pts on ventilator: 2/3 mortality, most survivors disabled

Recommendations (science): Keep pt 100% NPO until evaluation Use NG feeding tube if necessary (& IV NS 75-125 cc/h) Evaluate with video fluoroscopy whenever possible Use continuous feed only if Dobhoff tip distal to pylorus

Recommendations (art): Maintain HOB > 30° Maintain O2 sat > 92 or 95% w/ 2-4L O2


HYPERGLYCEMIA & ACUTE STROKE /DIABETES & 2 STROKE PREVENTION

Acutely, peri-stroke hyperglycemia associated with worse clinical outcomes

Inpatient goal BG < 150 Chronically, each 1% in Hgb A1C results in

significant in risk of death, MI, vascular complications, including 12% in stroke risk

Outpatient goal Hgb A1C < 7.0


SECONDARY STROKE PREVENTION:RISK-FACTOR MODIFICATION

HypertensionDay 1 poststroke, start low-dose ACE-I or ARBSlowly (days to weeks) dose, add diuretic, watch K+Anti-HTN meds benefit those w/ and w/o HTN historyEvaluate for sleep apnea and treat w/ CPAPOutpatient goal < 120/80—over weeks to months

*In stroke pts, ACE-Is & ARBs appear to decrease risk of stroke, MI, & vascular death beyond effect on BP alone. Based on theory and animal models, ARBs may be more effective than ACE-Is.


SECONDARY STROKE PREVENTION:MECHANISMS OF ACE-I/ARB BENEFITS

ANGIOTENSIN I ANGIOTENSIN II

ANGIOTENSINCONVERTING

ENZYMEAT 1TheBad

AT 2The

Good

VasoconstrictionNa retention Vascular proliferation Endothelial functionInflammation LDL transport

VasodilatationNatriuresis Vascular proliferation Endothelial functionApoptosisNo cholesterol effect

ARBACE-I

Based on animal studies and pathophysiologic considerations, ARBs may be superior to ACE-Is for stroke prevention, but ONTARGET found no difference between telmisartan & ramipril in reducing vascular risk.



HypercholesterolemiaDo not discontinue statins on admissionObtain LDL w/in 48 of stroke onset If LDL > 100, use hi-dose statin shown to

stroke/MI/death risk atorvastatin 20-80 mg/d pravastatin 40-80 mg/d simvastatin 40-80 mg/d rosuvastatin 10-40 mg/d

If LDL < 100, use lower statin doseOutpatient goal LDL < 70 (but give statin to all pts)


SUPPORTIVE MEDICAL CARE:PREVENT COMPLICATIONS

Aspiration (NPO until swallowing evaluation) Deep-vein thrombosis

Sequential compression devices (if stroke < 48 h)Heparin 5000 q8h or enoxaparin 40 mg/d

Urinary tract infection (avoid Foley catheters) Constipation (docusate sodium for all) Decubitus ulcers (move q2h, out of bed TID by day 2) UGI bleed (H2B, but not cimetidine) Fever (acetaminophen + antibiotics as indicated)


REHAB & OUTPATIENT PLANNING:BEGIN ON ADMISSION, DECREASE LENGTH OF STAY

SP—swallowing evaluation before oral feedings PT, OT—bedside first, out of bed ASAP Social worker—plan based on level of care, pay

source, caregiver support Communicate with primary-care clinician Educate pt, caregiver daily (not just on discharge)

Call 911Follow-up after dischargeMedicationsRisk FactorsStroke Symptoms


POSTSTROKE DEPRESSION

Suspect if sxs persist 1-2 wks after stroke Is an “organic,” not “reactive” depression Occurs in ~ 50% of stroke pts May affect rehab and recovery Often resolves w/in one year SSRIs equally effective, but if pt takes warfarin:

Escitalopram (Lexapro) 5-10 mg qAMCitalopram (Celexa) 10-20 mg qAMSertraline (Zoloft) 25-50 mg qAM


CAUSES (ETIOLOGIES) OF ISCHEMIC STROKE:SIX MAIN CATEGORIES

Hypercoagulablestates

Nonatheroscleroticvasculopathies

YOUNGER PATIENTS(< 55)

Correct therapy depends on cause of stroke!“Cause” & “risk factor” are not synonymous—must Rx both!

Large-arteryatherosclerosis

Small-arterydisease

OLDER PATIENTS(> 55)

Cardioembolism

Hypotension


ETIOLOGIC EVALUATION:IDENTIFY STROKE, FIND SOURCE OF CLOT

INVASIVEDay 2

*Catheterangiogram

*TEE

NONINVASIVEDay 1

ARTERIES

HEART

BLOOD

ECG & monitorCardiac biomarkers

Transthoracic echo (TTE)

MRI & intracranial MRACarotid duplex (CD)

*Hypercoagulable profile *in selectpatients


MRI BRAIN IN HYPERACUTE ISCHEMIC STROKE

DWI & ADC: Early infarction visible FLAIR: No signal changes; possible sulcal

effacement in area of infarction

DWI ADC FLAIR

R RRL LL


INTRACRANIAL MRA:AP VIEWS OF ANTERIOR CIRCULATION

Normal Paucity of R MCA Branchesc/w Embolic Occlusions

RICA RICALICA LICA

RMCA LMCA

RACA LACA


CAROTID DUPLEX

Evaluates carotid arteries in neck (operable area) Excellent screen in the right hands May not differentiate 99 vs. 100% stenosis Need contrast angiography for clinically relevant stenosis

measurement

Carotid duplex =Doppler (velocities) +B-mode ultrasound(echo picture)

Plaque

CCA

ICA

ECA


ECHOCARDIOGRAPHY:TTE VS. TEE

Left Ventricle Thrombus Dilatation SEC/smoke Dyskinesis Aneurysm

Identifiessource in

37.2% of pts in

NSR

SEC/EF 20%

LV

TRANSTHORACIC ECHO

Identifiessource in

30-40% of pts with

unknown cause

LA

PFO

Left Atrium Thrombus Dilatation SEC/smoke Tumor

PFO/IASA > 5 mm

Endocarditis

Aortic Arch Athero > 4 mm Thrombus Tumor

TRANSESOPHAGEAL ECHO


HYPERCOAGULABLE PROFILEPATIENTS < 55 YEARS OLD

CBC w/ diff & platelets PT/aPTT Fibrinogen Factor VIII Factor VII C-reactive protein Antithrombin III Protein C Protein S (total & free) Lipoprotein (a)

Activated protein C resistance (APCR) (& Leiden factor V mutation if APCR -)

Prothrombin G20210A mutation Antiphospholipid antibodies

Lupus anticoagulant Anticardiolipin abs Anti-β-2-glycoprotein I abs Antiphosphatidylserine abs

Methyltetrahydrofolatereductase (MTHFR) C677T & A1298C mutations

Sickle cell screen


CT / MRI APPEARANCE CANNOT DETERMINE ETIOLOGY OF SMALL CEREBRAL INFARCTS

small-art. “occlusion” = small-art. “disease”

Dx of small-artery “disease” requires: Lacunar syndrome

e.g., pure motor, pure sensory,

pure sensorimotor

Medial, small (< 1.5 cm) infarct on CT or MRI History of longstanding HTN or DM Otherwise normal etiologic evaluation

Small L subcorticalinfarction in 40 yo

woman w/ DM—dueto embolus fromaortic papilloma

Small-artery “disease” is a diagnosis of exclusion


SECONDARY STROKE PREVENTION:ANTITHROMBOTIC RX BASED ON CAUSE

High-flow states:platelets cause clots

Platelets are like Velcrosticking to bumpy walls

Low-flow & hypercoagulable states:clotting factors cause clots

Clotting factors are like dissolved powdered gelatinthat forms clumps of Jello when liquid is static

large-arteryatherosclerosis

small-arterydisease

cardioembolismhypercoagulable

state

ANTIPLATELET AGENTaspirin 81-325/dclopidogrel 75/d

aspirin + dipyridamole XR 25/200 twice/d

ANTICOAGULANTwarfarin

INR 2.0-3.0or

INR 2.5-3.5


SECONDARY STROKE PREVENTION:ANTIPLATELET AGENTS FOR ARTERIAL DISEASE Aspirin

Prevents MI & stroke Stroke rec 50-365 mg/d, but MI rec 75-162 mg/d Low dose with less side effects, > 1200 mg/d ineffective Enteric coating, NSAIDs may lessen efficacy

Clopidogrel 75 mg per day Prevents MI and stroke Routine combination with aspirin not indicated in stroke pts,

though not resolved for subset of pts with large-artery athero PPIs lessen efficacy

Aspirin / dipyridamole XR 25/200 twice daily Data regarding MI prophylaxis lacking Headache common side effect of dipyridamole Not superior to clopidogrel…with more bleeding side effects


SECONDARY STROKE PREVENTION:WARFARIN FOR CARDIOEMBOLISM

Underused for a. fib./flutter, esp. blacks, Hispanics, elderly Starting dose 5 mg qPM INR monitoring

Target 2.5, range 2.0-3.0 (mechanical HVR 2.5-3.5) Reflects dose 2-3 days ago, stabilizes in 10-14 days Vitamin K (greens, NG feedings, Ensure, Slimfast, MVI) Other meds, EtOH, cranberry juice Dose and formulation changes

Limit holding for procedures (e.g., dental, GI, surgery)


SECONDARY STROKE PREVENTION:CAROTID STENOSIS PROCEDURES

Carotid Endarterectomy (CEA) Clear benefit if 70-99% stenosis Some benefit if 50-69% stenosis Accept complication rate < 6%

Carotid Angioplasty/Stenting (CAS) Now, option only in high-risk pts

Restenosis after CEA Radiation-induced stenosis Increased medical risk for CEA Contralateral carotid occlusion

Cerebral protection devices improving, trials continue

D

N

stenosisin ICA bulb

ExternalCarotidArtery

InternalCarotidArtery

CommonCarotid

Artery

% stenosis = (D-N)/D

by contrastangiography



Cigarette smoking cessationBupropion (Wellbutrin SR or XL, Zyban)

Start 150 mg daily x 3 days Then 150 mg BID x 3 months

Nortriptyline (Pamelor) Start 10-25 mg each night gradually to 75 mg each night

Nicotine patch/gum/inhaler Concurrent with bupropion or nortriptyline

Varenicline (Chantix) Start 0.5 mg daily x 3 days gradually to 1 mg BID x 11 wk



Lifestyle Alcohol: men < 2 oz / d, women < 1 oz / d Diet: Low saturated fat, low Na+, high K+,

fruits > vegetables, Mediterranean diet Exercise: > 20 min aerobic exercise, > 3 x / wk Weight: maintain BMI 18.5-24.9 kg/m2

Drugs to Avoid Estrogen (oral contraceptives, HRT) Sympathomimetic agents (incl. decongestants, diet pills) NSAIDs (if taking aspirin) PPIs (if taking Plavix)


ISCHEMIC STROKE / TIA2 PREVENTION SUMMARY 1 OF 2 Prescribe:

Antithrombotic agent based on causeARB or ACE-I regardless of BPStatin regardless of cholesterol

Maintain:Hgb A1C < 7.0BP < 120/80, including ARB or ACE-ILDL < 70, including statinNutrition w/ fruits, Mediterranean dietAlcohol intake < 2 oz/d (men) or < 1 oz/d (women)BMI 18.5-24.9 kg/m2

Aerobic exercise > 20 min/d, > 3 d/wk


ISCHEMIC STROKE / TIA2 PREVENTION SUMMARY 2 OF 2

Discontinue:Cigarette smokingSympathomimetic agents (incl. decongestants)Estrogens

Treat:Carotid stenosis 50/70-99% (CEA or CAS)Sleep apnea (CPAP)Sickle cell disease (monitor TCD, Hgb S < 30%)

THE END


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UPDATE IN ACUTE ISCHEMIC STROKE MANAGEMENT