18 feb 2011
TRANSCRIPT
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Advances in acute strokemanagement
Maj Arti Sawhney
Moderator: Wg Cdr Salil Gupta
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Introduction
Acute ischemic stroke is a medical
emergency Suspected stroke require urgent evaluation
to identify eligible patients for time sensitivetherapies
Safe and effective Rx requires establishingthe time of onset, focussed neurologicalexamination and rapid interpretation of ancillary tests
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Pathophysiology.
Most metabolically active organ.
Consumes 20% of CO and yet representsonly 2% of TBW.
120 ml/100gms/min
Minimal energy reserves
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Pathophysiology
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ISCHEMIC STROKE PATHOPHYSIOLOGY
The First Few Hours
³TIME IS BRAIN:
SAVE THE PENUMBRA´
Penumbra is zone of reversible ischemia around
core of irreversible infarction²salvageable in first
few hours after ischemic stroke onset
Penumbra damaged by:
Hypoperfusion
Hyperglycemia
Fever
Penumbra
Core
Clot inArtery
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ISCHEMIC PENUMBRA: PATHOPHYSIOLOGYOF THERAPEUTIC WINDOW
Penumbra
e
CEREBRAL
BLOOD
FLOW(ml/100g/min)
CBF< 8
CBF8-18
TIME (hours)
1 2 3
20
15
10
5
PENUMBRA
CORE
Neuronaldysfunction
Neuronaldeath
Normalfunction
Identification of penumbra through MRI perfusion-diffusion mismatch or perfusion CT may replace time as the major indication for emergency acute ischemic stroke therapies.
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Within that narrow window- What areour Goals of therapy
Time is brain, sooner you fix (reperfuse) the
better Optimising blood flow
> rapidly restore BF
> maximise collateral BF
Limiting the area of infarct
Salvaging the penumbra
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ORGANIZED CARE OF STROKE PATIENTS:
Acute stroke team
Stroke multidisciplinary team Stroke unit
Prewritten stroke orders
An organized approach enables
emergency treatment, a thorough evaluation,and improved patient outcome at decreased cost.
Stroke unit care results in decreased rate of aspiration pneumonia, stroke
progression or recurrence, and death.
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AIS ED STROKE CARE 24/7:1-H EVALUATION, 1-H INFUSION
I. Triage±10 min ± Review t-PA criteria
± inform acute stroke team
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
(CBC, BG, INR, ECG)
± Read CT
± Return pt to ED
IV. Treatment±60 min
± StartIV
rt-PA ± Monitor for ICH
HTN, headache
N/V, q neuro status
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Stroke emergency brain imaging
Non contrast CT scan
-modality of choice in acute stroke
-Combined with CT angio and CT perfusion to increase sensitivity andaccuracy
Diffusion weighted MRI
- detects ischemia earlier than CT
- posterior fossa and temporal lobes
- small infarcts on cortical surface
MRI perfusion studies with gadolinium contrast
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Diffusion perfusion mismatch in AIS
Diffusion perfusion mismatch in AIS. Perfusion abnormality is larger than
diffusion abnormality indicating penumbra which is at risk of infarction.
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Intravenous thrombolysis- first 03hours
NINDS recombinant tPA stroke study(1995)
- iv rtPA(0.9mg/kg to max 90mg,10% as bolus, remainder over
60 min)- Vs placebo within 03 hrs of onset
Results:
- ICH in 6.4% with rtPA and 0.6% with placebo
-12% increase in pts with minimal disability with rtPA- Iv rtPA improved clinical outcome within 03 hrs.
Only FDA approved treatment for acute ischemic stroke
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Indications of rtPA
Clinical diagnosis of ischemic stroke
Onset of symptoms to rtPA < 3hours CT scan showing no hemorrhage or edema of
>1/3rd of MCA territory
Age>18years
Consent by parents or surrogate
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Contraindications
Sustained BP>185/110mmhg despite Rx
platelets <1 lac, BG <50 or >400mg%
Use of heparin within 48hrs and prolonged aPTT/ elevated INR
Rapidly improving symptoms
Prior stroke/ head injury within 03 months
Prior ICH
Major surgery in preceding 14 days/ gi bleed in preceeding 21days
Recent MI
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Between 3- 4.5 hours
ECASS III
European study
NINDS like protocols with additional exclusions
- Age >80yrs old
- any anticoagulation
- NIHSS >25
- Prior stroke and DM
Absolute increase in favourable outcome in 7.2% of patients ascompared to placebo
Symptomatic ICH was more frequent in Rx group
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Endovascular options
Intra-arterial t-PAOnly preliminary evidence to date, not FDA approved
Theoretical window 6 hStudies ongoing, esp. combined w/ IV t-PAPROACT II trial
MELT Trial
MERCI or Penumbra device ± Mechanical embolectomy devices
± Theoretical window 8 h, available in limited centers
± Both FDA approved, but controlled trial results pending
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Antithrombotic treatment
Platelet inhibition
> Aspirin up to 325mg/day
- IST and CAST ± aspirin beneficial-After an acute persistent stroke, aspirin started within 48 hours of
onset improves long-term outcome. Treating 1000 patients for 2weeks prevents 13 being dead or dependent by 6 months
> GPIIb/IIIa receptor inhibitor, abciximab
- Recent clinical trial stopped because of excessive ICH
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Anticoagulation
Trials do not support use of sc/iv heparin
US trial of Organon in acute stroke treatment(TOAST)
-Failed to show any benefit of LMWH over aspirin.
-Excess risk of ICH and systemic hemorrhage with
acute anticoagulation.
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THE AIS-BP RELATIONSHIP
In AIS, high BP is a response,
not a cause²don¶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
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AIS IS NOT A HYPERTENSIVE
EMERGENCY!
ASA/AH A AIS Guidelines tables no longer include BP Rx in non t-PA
patients
Text of guidelines state ³Do 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
Avoid excessive lowering of BP just to give t-PA²
³Don¶t kill the penumbra to save the penumbra
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LOWERING BP IN T-PA PATIENTS
Nicardipine 5 mg/h IV infusion
± Increase 2.5 mg/h q5min to max 15 mg/h
± Easily titratable without an arterial line
Labetalol 10-20 mg IV
± May repeat q 10-15 min
± Pre-t-PA: only use a 2nd dose only if necessary
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Neuroprotection
Providing treatment prolonging the tolerance of brain cells to
ischemia
Ischemic cascade is so complex that targeting a single pathway
is ineffective
Search is still on for a safe agent that limits ischemic damage
Plethora of negative neuroprotective trials
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Neuroprotective agents
NMDA receptor antagonists
Dextrorphan
Salfotel
Magnesium
Free radical scavengers
Tirilazad
NYX09
Membrane stabilising agents
citicoline
Antiadhesion antibodies (block ICAM on endothelium)
Enlinomab
HU23F2G
Tetracycline antibodies
Hypothermia- minor reductions (1-3 degree C) in core temperature 10%increase in frequency of good outcomes
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Neuroprotective agents
NYX09
-iv within 6 hours x 72 hrs
SAINT I - better outcome at 90 daysSAINT II trial- negative result
Citicoline-
500-2000mg/day within 24hrs
Phase II trial- improved outcome
Phase III trial- no significant difference between placebo andciticoline after 06 months
Magnesium-
- iv within 12hrs
Phase III trial- did not show efficacy
FAST- M AG trial-ongoing
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Hypothermia
Reducing cerebral metabolism (approximately 6-8% per 1ºC)
Reducing excitatory amino acids (glutamate release) Membrane stabilization
Attenuation of oxygen free radical production and lipid peroxidation.
Inhibition of deleterious inflammatory products (ie, cytokines,interleukins, arachidonic acid cascade end products)
Minor degrees(1- 3) of reduction in core temperature protects braindamage due to ischemia.
Lancet Neurol. 2003 Jul;2(7):410-6
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Neurosurgical interventions
Early decompressive surgery
H AM
LET(H
emicraniectomy After M
iddle cerebral artery infarction with Life-threatening Edema Trial)
DECIM AL(Decompressive Craniectomy In malignant middle cerebral artery infarction)
DESTINY (Decompressive Surgery for the Treatment of malignant infarction of the middle cerebralartery)
Meta-analysis of the these three trial results suggest significant reduction in death rate butincreased rate of severe disability.
The Lancet Neurology, Volume 8, Issue 7, Pages 602 - 603, July 2009doi:10.1016/S1474-4422(09)70157-7
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Cerebral edema
Raised ICP
- damages cerebral cortex directly, pressure on
brainstem- Indirectly reduces cerebral perfusion pressure
Nurse with 30 deg head-up tilt, avoid flexion of head
Maintain good glycaemic control
Aim for core body temp b/n 36- 37deg
Avoid volume depletion or fluid overload
Mannitol
Decompressive craniectomy
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Management of acute stroke
Airway
Breathing Circulation
Hydration
Blood glucose Blood pressure
Incontinence
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SUPPORTIVE MEDICAL CARE:PREVENT COMPLICATIONS
Aspiration (NPO until swallowing evaluation)
Deep-vein thrombosis
± Maintain hydration ± Early mobilisation
± Compression stockings
± LMWH for high risk patients.
Urinary tract infection (avoid Foley catheters)
Pressure sores (move q2h, pressure relieving mattress)
Chest infection (avoid aspiration,nurse semi-erect,antibiotics) Fever (acetaminophen + antibiotics as indicated)
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AIS EMERGENCY THERAPY:IV TISSUE PLASMINOGEN ACTIVATOR (T-PA)
< 3.0 Hours
No upper age limit Can give if taking warfarin &
INR < 1.7
3.0-4.5 Hours
Do NOT give if: ± Pt > 80 yrs
± NIHSS > 25
± DM/ previous stroke
± Taking warfarin at all
Must give < 4.5 h²earlier 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 q 30% despite ~5% symptomatic ICH risk
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Conclusion
To date, intravenous recombinant tissue-typeplasminogen activator remains the only FDA-approvedtreatment for acute ischemic stroke within 4.5 hours of onset.
Benefits of reperfusion are clearly time dependent.
Although a longer time window has been tested, delaysshould be avoided as oppurtunity for improvement isgreater with earlier treatment.
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MCQs
ECASS III trial does not exclude patients with
a. Age>80yrs b. Diabetes mellitus
c. INE <1.7( on warfarin) d. NIHSS>15
Intraarterial thrombolysis is an option if patient with AIS comes after
a. 3 hours b. 4 hours
c. 5 hours d. 6 hours
Patient presenting after 6 hours of stroke, therapeutic approach will be
a. conservative b. mechanical thrombectomy
c. iv thrombolysis d. intraarterial thrombolysis
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References
Harrisons principles of internal medicine 17th edition
Davidsons principles and practice of medicine.21st edition
APICON 2011 American Stroke Association. Guidelines for the Early
Management of Adults With Ischemic Stroke. StrokeMay 2007.
NXY059 for AIS- NEJM Aug 9-2007;357-67
Lancet Feb7-2004;363;439-45
Lees KR, Zivin JA, Ashwood T, et al. NXY-059 for acuteischemic stroke. N Engl J Med . Feb 9 2006;354(6):588-600. [Medline]
Citicoline stroke study group. Neurology Sep 1997
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