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