18 Feb 2011

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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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