Cardiovascular

Emergency

Conference

Acute Management of

Stroke Patients

5th April 2014

Dr Siva Seeta Ramaiah

Consultant Neurologist

Hospital Kuala Lumpur

6 new stroke cases every hour

Burden of Stroke

• Globally:

• 3rd common cause of mortality

• Leading cause of disability

• 5.7 millions death from developing countries

• Decreasing trend in developed countries

• Better prevention treatment and aftercare

management

Murray CJL et al. 2012

Mathers CD et al. 2004

Hamidon BB et al. 2002

Burden of Stroke

• Malaysia

•top 5 leading causes of death

•Top 10 leading causes of

hospitalization

Loo KW et al. 2012

Burden of Stroke

Loo KW et al. 2012

Ischemic VS Hemorrhagic Stroke:

Incidence & Mortality

75%

25%

INCIDENCE

ISCHAEMIC STROKE

HEMORRHAGIC STROKE

0

10

20

30

40

MORTALITY

ISCHAEMIC STROKE

HAEMORRHAGIC STROKE

30

DA

Y M

OR

TA

LIT

Y (

%)

8%-12%

36%-37%

Hamidon BB et al. Neurology Asia 2003

American Heart Association Heart Disease and Stroke Statistics-2005 Update

Stroke & TIA definition

• Rapidly developing clinical neurological

signs of focal (or global) disturbance of

cerebral function, with symptoms lasting

24 hours or longer or leading to death,

with no apparent cause other than of

vascular origin

• TIA < 24 hrs

WHO 1998

TIA- tissue definition

• “transient ischemic attack (TIA): a brief

episode of neurological dysfunction caused

by focal brain or retinal ischemia, with

clinical symptoms typically lasting less

than one hour, and without evidence of

acute infarction

Assessed by imaging- absence of end organ injury

Oxfordshire Community Stroke Project

Classification (OCSP)

• Total Anterior Circulation Infarct

(TACI)

• Partial Anterior Circulation Infarct

(PACI)

• Posterior Circulation Infarct (POCI)

• Lacunar infarct (LACI)

50% 25%

20%

Differential diagnosis of stroke

• Metabolic/toxic encephalopathy (hypoglycaemia, HHS,Wernicke-Korsakoff syndrome, drug intoxication)

• Epileptic seizures (postictal Todd’s paresis)

• Hemiplegic migraine

• Structural intracranial lesions ( e.g. subdural haematoma, brain tumour, AVM)

• Encephalitis (e.g. HS virus), brain abscess, TB

• Head injury

• Hypertensive encephalopathy

• Relapsing MS

• Conversion disorders

• Hyperviscosity syndrome

• Peripheral nerve lesions (e.g. GBS)

Vascular risk factors

Time is brain

• Typical MCA infarct:

• 2 million nerve cells are lost each minute

• If reperfusion has not been achieved

Stroke Recognition

Aspirin ASAP

Risk Factor control

Thrombolysis

Neurosurgery

General Supportive Care and Treatment I

• Stroke is a primary failure of focal tissue

oxygenation and energy supply

• Systemic hypoxemia and hypotension

should be avoided and, if present,

corrected to limit further cellular damage

AHA/ASA GUIDELINES 2013

General Supportive Care and Treatment II

• Cardiac monitoring is recommended to screen for AF

and for at least the first 24 hours.

Class I, LOE B

• Patients who have high BP but eligible for IV rtPA

should have their BP carefully lowered so that their

SBP is <185 mm Hg and their DBP is <110 mm Hg

Class I, LOE B

• BP is stabilized at the lower level before treating with

IV rtPA and maintained <180/105 mm Hg for at least

the first 24 hrs after IV rtPA

Class I, LOE B

AHA/ASA GUIDELINES 2013

General Supportive Care and Treatment III

• Airway support and ventilatory assistance -

decreased consciousness or who have bulbar

dysfunction causing compromise of the airway.

Class I, LOE C

• Supplemental oxygen should be provided to

maintain oxygen saturation > 94%.

Class I, LOE C

• Sources of hyperthermia (T >38° C) should be

identified and treated with antipyretic

Class I, LOE C

AHA/ASA GUIDELINES 2013

General Supportive Care and Treatment Ⅳ

• If not thrombolysed- to lower BP by 15% during

the first 24 hrs

• Consensus exists that medications should be

withheld unless the SBP is >220 mm Hg or the

DBP is >120 mm Hg. Class I, LOE C

• Hypovolemia - corrected with IV normal saline

• Cardiac arrhythmias that might be reducing

cardiac output should be corrected. Class I, LOE C

• Hypoglycemia- should be treated to achieve

normoglycemia Class I, LOE C

AHA/ASA GUIDELINES 2013

General Supportive Care and Treatment of

Acute Complications

• Antihypertensive- within 24 hrs of stroke is relatively

safe.

• Restarting antihypertensive is reasonable after the first

24 hrs- pre-existing HPT and are neurologically stable.

Class IIa, LOE B

• Management of HPT in patients not undergoing

reperfusion strategies remains challenging as data

inconclusive or conflicting.

• Patients who have malignant hypertension or other

medical indications for aggressive treatment of BP

should be treated accordingly.

AHA/ASA GUIDELINES 2013

Recommendations for BP lowering in

patients with AIS

Ther Adv Chronic Dis. 2012 July; 3(4): 163–171.

REPERFUSION OF

ISCHAEMIC BRAIN

• Core of infarct tissue might not be salvageable, adjacent dysfunctional tissue (ischaemic penumbra) might be saved if the circulation is restored and metabolism is normalized

• IV Thrombolysis With rt-PA

• IV rt-PA (0.9mg/kg, max. 90mg) - 10% bolus followed by a 60-mins infusion, within 4.5 hrs of onset of ischaemic stroke.

(Level 1, Grade A)

Every 100 patients treated:

32 will have a better outcome

3 will have a worse final global disability outcome

rTPA

• 6 large RCTs

• NINDS (1 and 2)

• European Cooperative Acute Stroke Study (ECASS I and

II)

• ATLANTIS A and B

(ECASS 3) trial

• European Cooperative Acute Stroke Study

• A double-blind, placebo-controlled study of IVtPA, has

demonstrated that IVtPA given between 3-4.5 hours of

stroke onset was significantly associated with a good

clinical outcome (mRS score 0 to 1) compared with

placebo with an acceptably low rate of (sICH).

ECASS 3

International Stroke Trial [IST-3]

3035 patients were enrolled by 156 hospitals in 12 countries

(1515 in the rt-PA group vs 1520 in the control group)

1617 (53%) were older than 80 years of age.

For the types of patient recruited in IST-3, despite the early hazards,

thrombolysis within 6 h improved functional outcome.

Benefit did not seem to be diminished in elderly patients.

Lancet 2012

Time Dependency of Alteplase Effect

• Pooled analysis of individual patient data (n=2775) from 6 trials of i.v.

alteplase vs placebo showed that the effective treatment window may

extend to 4.5 hours

Time Interval from onset of symptoms to treatment initiation [min]

Ad

just

ed o

dd

s ra

tio

1.5h

OR

2.8

3h

OR

1.5

4.5h

OR

1.4

6h

OR

1.2

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

60 120 180 240 300 360

OR, odds ratio

Hacke et al. Lancet 2004; 363: 768–774.

Time is Brain

Excellent outcome (mRS0-1) n=3530

Lees et al Lancet 2010

NNT

4.5 9 14.1Treatment effect

p<0.001

Interaction with

time p=0.03

4.5

hours

Indications for rt-PA

IV tPA – contraindications?• Too mild, rapidly improving, too severe?

• Symptoms suggestive of SAH despite normal CT

• Seizure at onset

• BSL <2.7mmol/L

• BP >185/110

• Head trauma or prior stroke within 3 months

• Non-compressible arterial puncture within 7 days

• Any history of previous intra-cranial hemorrhage

• Evidence of active bleeding or acute trauma (fracture) on examination

• If on anticoagulation: warfarin+INR>1.7/heparin w/ abnormal APTT

• Platelets <100

• Myocardial infarction within 3 months

• Gastrointestinal or genitourinary hemorrhage within 21 days

• Major surgery within 14 days

• CT >1/3 MCA hypodensity

Europe add: Age>80

diabetes + prior stroke

use advanced imaging

RELATIVE Contra-indications

Weigh risk-benefit, d/w surgeon

Fix it then treat

beyond our help

IST-3

What about Asian patients?

Low dose vs standard dose tPA

• 0.6 mg/kg is the only approved dosage in Japan

since 2005

• Japan Alteplase Clinical Trial (J-ACT)

• J-ACT2 and

• Japan post-Marketing Alteplase Registration

Study (JMARS)

• SAMURAI register

• TTT- AIS (Taiwan)

Enhanced Control of Hypertension and

Thrombolysis in Stroke Disease

(ENCHANTED)

• Recently launched RCT study -to address 4 key

questions :

• Whether low-dose tPA (0.6 mg/kg) is truly equivalent

in efficacy, or even safer (low risk of SICH), to the

standard dose (0.9 mg/kg), not just in Asians but

around the world.

• Effect of intensive BP lowering on outcomes and the

risk of SICH.

Can we do better than IV tPA?

• Site of occlusion Recanalization after-tPA*

• ICA terminus 5%

• MCA M1 30%

• MCA M2 42%

• Basilar 11%

• Overall 30%

* Saqqur et al Stroke 2007 & Bhatia et al Stroke 2010

Intra-arterial thrombolysis (IAT)

Option for the treatment of selected patients who

have major stroke of <6 hours’ duration due to

occlusions of the MCA/ ICA and carotid terminus

who are not otherwise candidates for IV-rtPA.

Level II-2, Grade C

The Interventional Management

of Stroke (IMS III)

• phase 3, randomized, innovative design

• patients in whom IV t-PA administered within 3 hours

after stroke onset were randomly assigned to receive

IV t-PA alone (full dose) or IV t-PA (2/3 rd dose)

followed by endovascular treatment.

(IMS III)

• Outcome: mRS score < 3 at 90 days (40.8% with

endovascular therapy and 38.7% with IV t-PA; 95%

[CI], −6.1 to 9.1

• Mortality at 90 days: endovascular-therapy (19.1%)

and IV t-PA groups (21.6%) P = 0.52

(IMS III)- Conclusions

• The trial showed similar safety outcomes and no

significant difference in functional independence

with endovascular therapy after IVt-PA, as

compared with IV t-PA alone

362 patients with AIS within 4.5 hours

after onset, to endovascular therapy (IAT with [t-PA],

mechanical clot disruption or retrieval, or a

combination of these approaches) or IV t-PA.

Local versus Systemic Thrombolysis for Acute

Ischemic Stroke (SYNTHESIS Expansion)

trial

Outcome mRS score of 0 or 1 at 3 months;30.4% with

endovascular treatment 34.8% with (IV t-PA)

OR with endovascular treatment was 0.71 (95% CI, 0.44 to

1.14; P = 0.16)

(SYNTHESIS Expansion)

• The results of this trial in patients

with acute ischemic stroke indicate

that endovascular therapy is not

superior to standard treatment with

intravenous t-PA

• * the median time from stroke onset to the start of treatment

was 1 hour longer in the endovascular group than in the

medical-therapy group

MR RESCUE

Phase 2b, randomized, controlled,

open-label, multicenter trial (22 study sites) in North

America

MR RESCUE

• NIHSS score, 6–29; (ICA, M1, M2) assigned within

8 hrs to undergo either mechanical embolectomy

• or standard medical care (IV tPA)

• Pre-treatment CT/MR perfusion

• Randomization was stratified according to

whether the patient had a favorable penumbral

pattern (substantial salvageable tissue and small

infarct core) or a non-penumbral pattern (large

core or small or absent penumbra).

MR Rescue- methodology

MR RESCUE

mean mRS scores

did not differ

between

embolectomy and

standard medical

care (3.9 vs. 3.9, P

= 0.99)

MR Rescue-conclusions

• A favorable penumbral pattern on neuroimaging

did not identify patients who would differentially

benefit from endovascular therapy for AIS nor

was embolectomy shown to be superior to

standard care.

What next?

• Tenecteplase- a genetically engineered mutant t-PA,

was associated with significantly better reperfusion

and clinical outcomes at 24 hours than alteplase

• Desmoteplase- DIAS 3/4

• New endovascular devices- (stent retrievers) were

significantly more effective than 1st -generation

devices for improving reperfusion and outcome at 90

days

• EXTEND –IA

• ECASS-4

• MR WITNESS

HKL Experience

• Service started in June 2013

• Services offered from 8.00 am to 7.00pm daily

• Thrombolysis calls – 33 (likely underestimate)

• Thrombolysed cases – 12 patients

• Thrombectomy cases – 1 patient

Summary of thrombolysed cases-Premorbid status

CT

F

YZ

A

RM GS* ND

*

FM MF RS MA

J

KM M G

Age 63 61 70 55 37 49 43 58 44 57 58 70

Sex M F F M F F M M M M M M

HTN + + + + + + + + + + +

DM + +

Smoker +

IHD +

AF

Old stroke + +

Others Rena

l

Gout

BA

Mean age: 55.2 years

Main R/F – Hypertension (91.6%)

Summary of thrombolysed casesTime CT

F

YZ

A

RM

*

GS* ND

**

FM MF RS MA

J

KM M G

Time onset (H) 1430 0930 0700 0730 1100 0730 1330 0845

(W)

1045 1530 0730

(W)

1130

Time arrival to

ED (H)

1505 1030 0800 0915 1350 0900 1340 1015 1215 1815 1045 1320

Time CT done

(H)

1541 1110 0830 0930 1500 1014 1425 1110

(1300)

1320 1850 1130 1353

Door to CT

(min)

39 40 30 15 70 74 45 55 55 35 45 33

Time of

diagnosis (H)

1544 1120 0850 1000 1505 1130 1425 1300 1320 1900 1220 1353

Time tPA

started (H)

1615 1230 1000 1055 1520 1150 1510 1315 1415 1900 1230 1405

Door to needle

(min)

70 120 120 100 90 170 90 120 120 45 105 45

Onset to needle

(min)

105 180 180 205 260 260 100 270 210 210 300 155

mRS at 3

months/

*discharge

3 4 2 1 2 1 3 0 * 4 * 3 6 1

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

mRS 0 mRS 1 mRS 2 mRS 3 mRS 4 mRS 5 mRS 6

Outcome on discharge / 3months post stroke

Summary of thrombolysed cases

Best Worst Mean Median

Door to CT (min) 15 74 44.7 42.5

Door to Needle (min) 45 170 99.6 102.5

Onset to Needle 100 300 202.9 207.5

Summary of thrombolysed cases

“False Alarm”

Reasons Number of cases

Intracranial bleeding 10

NIHSS too good (<4) or too severe (>22) 4

Thrombolysis call after 7pm 2

Stroke mimics 3

Technical problem 1

Poor premorbid mRS/age 80 years 2

Case scenario 1

• 55/Punjabi/Man

• HPT- presented L sided weakness and slurred speech

at 7.30am

• Arrival A+E 9.15 am

• CT brain 9.30 am

• O/e; Visual neglect / Hand grip 2/5 hip/ shoulder and

elbow 4+ *(NIHSS 8)

• CT brain- NAD

• Thrombolysed 81.9 mg (alteplase) at 10.55 am

D2 post tPA D3 post tPA

Case scenario 1

• Post thrombolysis – NIHSS 2 (D2 stroke)

• D2 – CT – haemorrhagic transformation- aspirin withheld

• GCS dropped 13/15 –repeat CT worsening haemorrhagic transformation—referred neurosurgical – treated conservatively.

• 08/10/13- developed calf pain with swelling

• U/SS confirmed Left DVT

• Started clexane 0.6 ml bd and warfarin on D12

• Discharged D15

• NIHSS discharge 1

• mRS 1

Case scenario 2- Utility of CTP

• 58 years man Indian man, with no known medical

illness. Presented with sudden onset of inability to

talk upon waking up on the day of admission at

845 am associated with mild right sided body

weakness. Last seen well at 12 am the night

before. He presented to ED at around 1015 am.

• His NIHSS score was 8 on arrival, subsequently

deteriorated to 10. He had partial right gaze palsy,

marked expressive aphasia, right facial weakness,

right hemiparesis with power of 4+/5.

His initial CT brain noted left

MCA dense cord sign, with no

early ischemic changes

CTA were done at 1.00pm

(4hour 15 min after wake

up stroke)

CTP were done at 1.00pm (4 hours 15 mins after wake up

stroke) and noted perfusion mismatch

Case scenario 2- Progress

• He was in fast AF (HR ~170/min) with heart failure and

bibasal lungs crackles. After stabilization of his HR and

pulmonary oedema, decision made for tPA thrombolysis

at 2.30 pm (4 hour 30 min after wake up stroke) and

NIHSS score 11 before infusion.

• After thrombolysis, he was warded in CRW.

• Echo shows EF of 20%. Heart failure and rate controlled

were subsequently achieved.

• His NIHSS score has improved to 4 (day 2), 2(day 3) and

0 ( day 4)

• Dabigatran 150 mg bd started on D7

MRI DWI and ADC

showed diffusion

restriction in left parietal

regions on day 3

Repeated CT brain on day 6

showed only small infarct in left

corona radiata.

Case scenario 3– Intra-arterial therapy

• 62/M/Malay

• Underlying DM/HPT/CKD/Old PTB with bronchiectasis and Hx of CVA – 1st episode Jan 2013 and 2nd episode June 2013

• Onset 17/9/13 @ 11.00 am, R sided weakness and inability to talk. Arrival ED 1pm. Seen Neuro 1.10 pm-BP 160/95, NIHSS 23, GCS 10 (global aphasia), L gaze paresis, Visual field defect, Power R side 0/5 with normal Left UL and LL. CT done 1.25pm.

• Ct brain- loss of grey white matter differentiation L MCA.

• Not thrombolysed due to relative contraindications:

#recurrent stroke (last stroke in June 2013)

#NIHSS 23

#> 1/3 early loss of grey white matter differentiation in Left MCA

1st CT Brain – early loss of grey white matter differentiation in

Left MCA

Post retrieval DSA complete

recanalization.

DSA done –left M1/M2

junction occlusion

1 hour post clot retrieval 5 hours post clot retrieval

Case scenario 3 – IAT

Called Intervention team for possible IAT

Wife consented for clot retrieval

4pm- DSA done –left M1/M2 junction occlusion. R CFA Solitaire AB used to retrieve the occlusion. Post retrieval DSA complete recanalization.

Ct Brain repeat at 5pm shows reperfusion bleed at L MCA region with perilesional edema.

Admitted to HDU for close monitoring of BP and GCS ( NO ICU bed)

GCS dropped 8 pm – 5/15- intubated and ventilated in HDW, repeat CT Brain shows Left MCA territory bleed with extensive edema and mass effect.

Left decompressive craniectomy done 18/09/13@ 0155. – Brain very tense and noted brain herniating out through dural slit

Deteriorated next day

Thank You

Dr Siva Seeta Ramaiah

Neurologist

Department of Neurology

Hospital Kuala Lumpur

Acknowledgement

• Dato’ Dr Md. Hanip bin Rafia

• Neurology Department – HKL

• Casualty Department- HKL

• Radiology Department- HKL

• Neurosurgical Department- HKL

• Anesthesiology Department –HKL

• All HKL Staff