Intracerebral Hemorrhage
McGill Lecture Series
Montreal, QC
September 19, 2012
J. Teitlelbaum, MD, FRCP(C)
University of McGill
Case History G.S.



68 year old R
HBP, DB2, CAD
5PM, sudden
R paresis
 Aphasia
 Ø headache, N or V

G.S.

Exam on arrival
BP 190/100 P 75/min
 Alert, aware, mixed moderate aphasia
 CN: PERL, RHHA, R UMN VII, R ↓↓ sensation
 2/5 strength R UE & LE
 ↓↓ sensation R hemi-body

CT 5:30PM
G.S. Sudden Deteriororation

Exam at 7PM
GCS 10, very somnolent, not obeying commands,
groans & opens eyes to voice.
 Pupils 4mm L 3mm R reactive
 Poor airway protection
 Power 0/5 R UE & LE

CT at 7:05 PM
G.S. Now what ??

ICH

Epidemiology & Etiology:

primary vs secondary
Factors that affect prognosis
 Management

Evidence-based
 Eminence based
 Experimental & anecdotal

The Guidelines

Broderick J, Connolly S, Feldmann E, et al.
Guidelines for the management of spontaneous
intracerebral hemorrhage in adults:
Circulation. 2007;116:e391–413.
ICH Incidence in 2003
ICH Incidence year 2003
120,000
100,000
80,000
60,000
40,000
20,000
0
USA
Japan
EU5
Intracerebral Hemorrhage


15% of stroke in the West, 30% in the East
6 month prognosis dismal
40% dead (33% within 1 month)
 40% disabled and dependent
 20% independent

Classification of ICH
SECONDARY
PRIMARY (78-88%)



Hypertensive
angiopathy
(fibrohyalinosis)
Amyloid angiopathy
Anticoagulant
Associated







AVM
Aneurysm
Cavernoma
Neoplasm
Coagulopathy
 Alcoholic liver
disease
 Hemophilia
Hemorrhagic infarct
Toxic-cocaine
Dismal Prognosis
100%
90%
Proportion of patients (%)
80%
70%
60%
50%
40%
30%
20%
10%
0%
ICH
Dead
Dependent
Ischemic
Independent
Factors Affecting Prognosis






GCS on presentation
Age
Hemorrhage location
Intraventricular hemorrhage
? Blood pressure
Hemorrhage size
Secondary Damage
Hematoma expansion
≥ 80 ml fatal
Cerebral edema
Secondary injury
ICH Score
Component
ICH score points
GCS
3-4
2 (34/35 died)
5 - 12
1 (29/57 died)
13 - 15
0 (5/60 died)
ICH volume
≥ 30 ml
1
≤ 30 ml
0
IVH
yes
1
no
0
Infratentorial
1
Age > 80
1
Mortality and ICH Score
The relationship between ICH
volume and patient outcome
FULL
RECOVERY
DEAD
Size is the most important
predictor for patient outcome
38 ml
43 ml
A patient with a haemorrhage the
size of a ping pong ball is likely to
have a better outcome than a patient
with a haemorrhage the size of golf
ball:
–mortality on ’ping pong’ size:
app. 40%
–mortality on ’golf ball’ size:
app. 70%
Which are Modifiable ?






GCS on presentation
Age
Hemorrhage location
Intraventricular hemorrhage
? Blood pressure
Hemorrhage volume
Early growth occurs in all locations
Brott (1997) Kazui (1994) Fujii (1996)
N=103
N=186
N=359
Initial CT time
0-3 hrs
0-24 hrs
0-24 hrs
Putamen
34%
16%
19%
Thalamus
50%
21%
10%
Lobar
32%
29%
6%
Cerebellar
0%
25%
12%
Pons
40%
40%
28%
Other
43%
25%
13%
TOTAL
38%
22%
14%
Hematoma Evolution
3h
3h
2h
6h
24 h
24 h
Predicting ICH expansion

Time since onset

Spot sign

Blood pressure

Shape of the hematoma
CTA Source Images: Additional
Data
Spot
Sign
The Spot Sign: Growth Despite
Treatment
2 hours
3 hours (CT Angiogram)
rFVIIa
24 hours
Predictive Value of Spot Sign:
Time Dependent?
3 hours
4.5 hours
24 hours
Spot
Sign
Early Growth: Conventional angiography
Prognosis and Acute Blood Pressure
↑ Early Neurological Deterioration
↓ Functional Outcome (90 days)
1 month mortality (%)
1 month mortality (%)
100
80
60
40
20
0
-117
118-132
133-144
MAP (mm Hg)
145-
Fogelhom et al, Stroke, 28: 1396-400, 1997
Okumura et al, J. Hypertension, 23: 1217-23, 2005
Blood Pressure and Hematoma Evolution
Target max
SBP
No
Enlargement
Hematoma
Enlargement
140 mmHg
16
2
150 mmHg
14
1
160 mmHg
22
8
9%
p=0.025
30%
170 mmHg
8
5
Ohwaki et al, Stroke, 35: 1353-1367, 2004
ICH Management
Treatment Modalities
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General supportive care
Treatment of ICHT
Hematoma resection
Management of intra-ventricular hemorrhage
Seizure prophylaxis
Prevention of hematoma growth
BP management
Basic Algorithm

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



ABC’s
Do no harm
Pain management & sedation
Hyperventilation pCO2 30-35 mm Hg
Osmotic therapy
Ventricular drainage
General Supportive Care

HOB 30°

SO2 ≥ 95%

Glucose control ≤ 6.0 mmol

T° control ≤ 37.5° C

Pain control, sedation
Hyperventilation

Regional blood flow

Oxygen extraction

But: CMRO2 stable ad pCO2 = 10 mm Hg

At the levels used in TBI, hyperV does not
result in ischemia

Pressure autoregulation dysfunction is
improved
Hyperventilation

Present recommendation:
Avoid during 1st 24H post TBI
 pCO2 30 – 35 mm Hg
 If no response: 25 – 30 mm Hg

Hyperventilation

My recommendation:

Use for acute ICHT, temporizing measure

pCO2 30 – 35 mm Hg

Has no associated ischemia ad pCO2 10

Beware of hypoperfused areas that are more fragile
25 – 30 mm Hg
Osmotic Agents
Mechanisms of Action

Mannitol





BW in intact > affected brain
volume
vasoconsriction
viscosity
CBF
vasoconstriction
size of CVA, apoptosis
HS
BW in intact = affected brain
 Possible in size of CVA

Osmotic Agents
Clinical Use



Routinely recommended in edema of trauma
and stroke
Lack of evidence of beneficial outcome
Little evidence of efficacy in stroke or ICH
(especially Na)
Osmotic Agents
Clinical Use



Intermittent boluses allowing clearing of solute
from blood.
Avoid continuous infusions
Smallest doses at the largest possible intervals,
with prn according to ICP
Osmotic Agents
Clinical Use

ICH with ICHT:
MN first
 HS if refractory, Cr, OG



Refractory to one agent: use the other
250cc MN, then 100cc alternating MN/HS
Treatment of ICHT
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
Intubation
Hyperventilation
Sedation
Steroids: NO role
Osmotic agents
Mannitol
 Hypertonic saline

 No Δ in outcome
Hematoma Resection

STICH trial
ICH within a centimeter of the cortical surface
showed a benefit for early surgery
  mortality, no other effect on morbidity


MISTIE:

Intra-lesion rtpa with subsequent aspiration
Intra-ventricular Hemorrhage

EVD

Intra- ventricular rtpa (CLEAR)
Intra-ventricular rTPA
Hanley DF: pilot, prospective, randomized,
double-blind, controlled trial
 Speeds clearance of aneurysmal
intraventricular hemorrhage
 Normalizes intracranial pressure
 Reduces ventricular catheter obstruction
Early Hematoma Growth
2.0 hours after onset
6.5 hours after onset
Prevent ICH Growth

By  BP

By rFVIIa
Percent Change in ICH Volume at 24
Hours
Percent Change in ICH Volume by Treatment
70
70
65
65
Boxes depict 98.3%
60
60
confidence intervals
55
55
50
50
45
45
40
40
35
35
30
30
29%
25
25
20
20
16%
15
10
14%
15
11%
10
5
5
0
0
-5
-5
-10
-10
-15
-15
-20
-20
P lacebo
40 ug/kg rFV IIa
45% RR
80 ug/kg rFV IIa
52% RR
160 ug/kg rFV IIa
62% RR
f vii- 1371/ cur r ent
- 20JUN2004 - f ana_ct . sas/ f ana_ct . cgm
Modified Rankin Scale at
Day 90
160 µg/kg
80 µg/kg
mRS 0-1
mRS 2-3
mRS 4-5
mRS 6
40 µg/kg
Placebo
100%
80%
60%
40%
20%
0%
Hematoma Evolution and rFVIIa
Prospective
Onset-CT
interval (h)
Brott
Retrospective
Fujii
Kazui
3.3ml
Takizawa
4.5ml
0-3
38%
18%
36%
17%5.8ml
3-6
N/A
8%
16%
6%
6-24
N/A
rFVIIa within 4 hours:
• Dose dependent attenuation of hematoma
2%
10%
0%
expansion
• no effect on mRS at 90 days
Mayer et al. NEJM 2005; 352: 777-85
CTA Based rFVIIa Selection Trials
The SpoT sign fOr Predicting and
treating ICH growTh study: STOP-IT
SPOTRIAS/NINDS
PI: M. Flaherty
‘SPOT sign’ seLection of Intracerebral
hemorrhage to Guide Hemostatic
Therapy: SPOTLIGHT CSN/ CIHR
PI: D. Gladstone
Acute ICH < 6 hours
CTA
Spot Sign Positive
rFVIIa
Placebo
NCCT at 24 hours
Spot Sign Negative
Seizure Prophylaxis

Are seizures frequent post ICH ?

Do they change outcome ?

Does prophylaxis  frequency ?

Does a  in Sz affect outcome ?

Is therapy associated with adverse events ?
Are seizures frequent post ICH ?

↑early Sz and late epilepsy (2003-2004)

1/3 pts: 50% electrographic (Neurology
2007)
Do they change outcome ?
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
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Associated with expanding hemorrhages
 ICU stay
Greater treatment cost
 edema, midline shift, re-bleeding, decreased
functional recovery
 likelihood of poor long-term outcomes
Does prophylaxis  Sz frequency ?

Redding et al 2011: No (DPH)

Taylor 2011 Neurocrit Care: Yes (Keppra)

21% vs 16%
Does a  in Sz Improve Outcome

Taylor 2011 Neurocrit Care: Yes (Keppra)
Improved cognitive outcome vs DPH
 No untreated group


CHANT study 2009: No (DPH mainly)
So…

There is an ↑in Sz post ICH (lobar)

There is a likely effect on outcome

Rx do ↓ Sz incidence

This MAY improve outcome (Keppra IV)
ICH BP Management
Does BP affect outcome ?
 Does BP affect the penumbra?
 Does BP influence ICH growth?
 Does treatment alter any of these??

Prognosis and Acute Blood Pressure: ICH
n=1097
1 month mortality (%)
n=425
MAP (mm Hg)
Fogelhom et al, Stroke, 28: 1396-400, 1997
Okumura et al, J. Hypertension, 23: 1217-23, 2005
Acute BP Management:
Competing Rationales
Impaired Autoregulation
IV therapy suggested only for
Systolic BP ≥ 180 mmHg
(AHA Guidelines)
Guidelines for Acute BP Management:
ICH
Stroke Council, American Heart Association
IV therapy suggested only for Systolic BP ≥ 180
mmHg
(or MAP > 130 mmHg)
2007: Consider target of 160 mmHg systolic,
IF ↑ ICP not suspected
Acute ICH BP Treatment Trials
Trial
Target Blood
Pressure
Agent(s)
ATACH
n=60
Nicardipine
INTERACT
n=400
170-200;
140-170; 110-140
systolic
<140 mmHg
systolic
ICH ADAPT
n=164
<150 mmHg
systolic
Labetalol±
Hydralazine
Multiple
Blood Pressure and Hematoma Evolution
Target max
SBP
No
Enlargement
Hematoma
Enlargement
140 mmHg
16
2
150 mmHg
14
1
160 mmHg
22
8
9%
p=0.025
30%
170 mmHg
8
5
Ohwaki et al, Stroke, 35: 1353-1367, 2004
Temporal Profile of BP after ICH
220.00
200.00
180.00
Systolic target
<160mmHg
160.00
140.00
Systolic target 160179mmHg
Time
ho
ur
s
12
ho
ur
s
7
ho
ur
s
5
ho
ur
s
3
ho
ur
1
in
e
120.00
Ba
se
l
Mean systolic blood
pressure
Blood Pressure over time in the three different target
groups
Systolic target
>180mmHg
INTERACT: Efficacy of
Antihypertensives
Target achieved: 42% (1h)
66% (6h)
Drugs Used: 1. Furosemide 2. Urapidil
INTERACT: Hematoma Expansion
Rationale for Not Treating Blood
Pressure
Based on Dirangl and Pulsinelli, JCBFM, 1990 (SHR ICAO/MCAO)
Systolic BP (mmHg)
Autoregulation in ICH
160
150
140
130
120
First
CTP
30
60
90
minutes minutes
minutes
Second
CTP
Peri-hematoma Edema and
Injury
Ischemic?
Vasogenic?
Astrocyte
Pc
Plasma
Extravasation
Capillary
Perihematoma Edema is Not
Cytotoxic
Butcher et al, Stroke 35:1879-1885, 2003
Peri-hematomal Oligemia: CT Perfusion
Peri-hematoma Oligemia: rCBF
* P=0.01
*
Penumbral Threshold
BP (mmHg)
Extreme BP Reduction and CBF
Tie
Time (minutes)
Intracerebral Hemorrhage Acutely Decreasing
Arterial Pressure Trial (ICH ADAPT) Protocol
Acute ICH - onset
within 24 hours
SBP ≥ 150 mmHg
Randomization (N=74)
Target SBP <150 mmHg
Target SBP <180 mmHg
Labetalol
±Hydralazine
Primary Endpoint: rCBF
measured with CT perfusion 2
hours after randomization
Butcher et al, IJS, 2010
So…

 in BP will prevent hematoma growth if:
Within 1 hour
 To ≤ 160 mm Hg systolic
 Labetalol / Hydralazine


 BP does  CBF but no  in ischemia

Ideal BP: 150 – 160 mm Hg systolic
ICH Summary




Poor prognosis
Hematoma expands early (≤4h)
ICH Expansion can be predicted
HBP is a likely factor in prognosis
Expansion
 Edema formation
 other

ICH Summary

Treatment:
General
 Prevention of ICH enlargement:

 BP within 1h to ≤ 160 mm Hg syst
 rFVIIa

Seizure prophylaxis: likely useful (Keppra IV)
 ICHT therapy: no Δ in outcome
 Sx: little if any benefit
