1. Intracerebral Hemorrhage
McGill Lecture Series
Montreal, QC
September 19, 2012
J. Teitlelbaum, MD, FRCP(C)
University of McGill

2. Case History G.S. 68 year old R HBP, DB2, CAD 5PM, sudden R paresis
Aphasia
Ø headache, N or V

3. 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

4. CT 5:30PM

5. 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

6. CT at 7:05 PM

7. G.S. Now what ?? ICH Epidemiology & Etiology:
primary vs secondary
Factors that affect prognosis
Management
Evidence-based
Eminence based
Experimental & anecdotal

8. 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.

9. ICH Incidence in 2003

10. 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

11. Classification of ICH PRIMARY (78-88%) SECONDARY
Hypertensive angiopathy (fibrohyalinosis)
Amyloid angiopathy
Anticoagulant Associated
SECONDARY
AVM
Aneurysm
Cavernoma
Neoplasm
Coagulopathy
Alcoholic liver disease
Hemophilia
Hemorrhagic infarct
Toxic-cocaine

12. Dismal Prognosis

13. Factors Affecting Prognosis
GCS on presentation
Age
Hemorrhage location
Intraventricular hemorrhage
? Blood pressure
Hemorrhage size

14. Secondary Damage Hematoma expansion ≥ 80 ml fatal Cerebral edema
Secondary injury

15. ICH Score Component ICH score points GCS 3 - 4 2 (34/35 died) 5 - 12
0 (5/60 died)
ICH volume
≥ 30 ml 1
≤ 30 ml
IVH
yes no
Infratentorial
Age > 80

16. Mortality and ICH Score

17. The relationship between ICH volume and patient outcome
DEAD
FULL RECOVERY

18. Size is the most important predictor for patient outcome
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%
38 ml
43 ml

19. Which are Modifiable ? GCS on presentation Age Hemorrhage location
Intraventricular hemorrhage
? Blood pressure
Hemorrhage volume

20. Early growth occurs in all locations
Brott (1997)
N=103
Kazui (1994)
N=186
Fujii (1996)
N=359
Initial CT time
0-3 hrs
0-24 hrs
Putamen
34%
16%
19%
Thalamus
50%
21%
10%
Lobar
32%
29% 6%
Cerebellar 0%
25%
12%
Pons
40%
28%
Other
43%
13%
TOTAL
38%
22%
14%

21. Hematoma Evolution
3 h
3 h
2 h
6 h
24 h
24 h

22. Predicting ICH expansion
Time since onset
Spot sign
Blood pressure
Shape of the hematoma

23. CTA Source Images: Additional Data
Spot
Sign
shape: spot-like, serpiginous, or linear
location: within the margin of a parenchymal hematoma without connection to an outside vessel
size: >1.5 mm diameter in at least one dimension
density: at least double the density (HU) of the hematoma
number: single or multiple
not caused by hyperdensity in same location on NCCT

24. The Spot Sign: Growth Despite Treatment
2 hours
3 hours (CT Angiogram)
24 hours
rFVIIa

25. Predictive Value of Spot Sign: Time Dependent?
3 hours hours hours
Spot Sign

26. Early Growth: Conventional angiography

27. Prognosis and Acute Blood Pressure
↑ Early Neurological Deterioration
↓ Functional Outcome (90 days)
1 month mortality (%)
1 month mortality (%)
MAP (mm Hg)
Fogelhom et al, Stroke, 28: , 1997
Okumura et al, J. Hypertension, 23: , 2005

28. Blood Pressure and Hematoma Evolution
Target max SBP
No Enlargement
Hematoma Enlargement
140 mmHg 16 2 9%
p=0.025
150 mmHg 14 1
160 mmHg 22 8
30%
170 mmHg 5
Ohwaki et al, Stroke, 35: , 2004 28

29. ICH Management

30. Treatment Modalities General supportive care Treatment of ICHT
Hematoma resection
Management of intra-ventricular hemorrhage
Seizure prophylaxis
Prevention of hematoma growth
BP management

31. Basic Algorithm ABC’s Do no harm Pain management & sedation
Hyperventilation pCO mm Hg
Osmotic therapy
Ventricular drainage

32. General Supportive Care
HOB 30°
SO2 ≥ 95%
Glucose control ≤ 6.0 mmol
T° control ≤ 37.5° C
Pain control, sedation

33. 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

34. Hyperventilation Present recommendation: Avoid during 1st 24H post TBI
pCO2 30 – 35 mm Hg
If no response: 25 – 30 mm Hg

35. Hyperventilation My recommendation:
Use for acute ICHT, temporizing measure
pCO2 30 – 35 mm Hg – 30 mm Hg
Has no associated ischemia ad pCO2 10
Beware of hypoperfused areas that are more fragile

36. 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

37. 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)

38. 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

39. 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

40. Treatment of ICHT  No Δ in outcome Intubation Hyperventilation
Sedation
Steroids: NO role
Osmotic agents
Mannitol
Hypertonic saline
 No Δ in outcome

41. Hematoma Resection STICH trial MISTIE:
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

42. Intra-ventricular Hemorrhage
EVD
Intra- ventricular rtpa (CLEAR)

43. 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

44. Early Hematoma Growth
2.0 hours after onset
6.5 hours after onset

45. Prevent ICH Growth
By  BP
By rFVIIa

46. Percent Change in ICH Volume at 24 Hours
Boxes depict 98.3%
confidence intervals
29%
16%
14%
11%
45% RR
52% RR
62% RR

47. Modified Rankin Scale at Day 90
160 µg/kg
80 µg/kg
mRS 0-1
mRS 2-3
mRS 4-5
40 µg/kg
mRS 6
Placebo
100%
80%
60%
40%
20% 0%

48. Hematoma Evolution and rFVIIa
Onset-CT interval (h)
Prospective
Retrospective
Brott
Fujii
Kazui
Takizawa
0-3
38%
18%
36%
17%
3-6
N/A 8%
16% 6%
6-24 2%
10% 0%
3.3ml
4.5ml
5.8ml
rFVIIa within 4 hours:
Dose dependent attenuation of hematoma expansion
no effect on mRS at 90 days
Mayer et al. NEJM 2005; 352:

49. 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
Spot Sign Negative
rFVIIa
Placebo
NCCT at 24 hours

50. 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 ?

51. Are seizures frequent post ICH ?
↑early Sz and late epilepsy ( )
1/3 pts: 50% electrographic (Neurology 2007)

52. Do they change outcome ? Associated with expanding hemorrhages
 ICU stay
Greater treatment cost
 edema, midline shift, re-bleeding, decreased functional recovery
 likelihood of poor long-term outcomes

53. Does prophylaxis  Sz frequency ?
Redding et al 2011: No (DPH)
Taylor 2011 Neurocrit Care: Yes (Keppra)
21% vs 16%

54. 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)

55. 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)

56. ICH BP Management Does BP affect outcome ?
Does BP affect the penumbra?
Does BP influence ICH growth?
Does treatment alter any of these??

57. Prognosis and Acute Blood Pressure: ICH
1 month mortality (%)
A number of observational studies have examined the association of presentation BP levels with clinical outcomes. Left figure shows survival curves of acute ICH according to BP quartiles. The risks of early death were greater among higher BP groups. Likewise, most studies have shown that higher BP levels are associated with worse outcomes. In contrast, some studies have also identified J-shaped associations (right fig). What is clear is that if there is any adverse effect of low BP it is not apparent until SBP levels reach 140 or less.
MAP (mm Hg)
Fogelhom et al, Stroke, 28: , 1997
Okumura et al, J. Hypertension, 23: , 2005

58. Acute BP Management: Competing Rationales
Impaired Autoregulation
IV therapy suggested only for Systolic BP ≥ 180 mmHg
(AHA Guidelines)

59. 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
Very high BP levels in acute ICH are generally considered to require treatment, but there is a wide range of recommendations for BP management available from national and international guidelines. This marked variation serves to highlight the persisting clinical uncertainty. 59

60. Acute ICH BP Treatment Trials
Target Blood Pressure
Agent(s)
ATACH
n=60
; ; systolic
Nicardipine
INTERACT
n=400
<140 mmHg systolic
Multiple
ICH ADAPT
n=164
<150 mmHg systolic
Labetalol±
Hydralazine 60

61. Blood Pressure and Hematoma Evolution
Target max SBP
No Enlargement
Hematoma Enlargement
140 mmHg 16 2 9%
p=0.025
150 mmHg 14 1
160 mmHg 22 8
30%
170 mmHg 5
Ohwaki et al, Stroke, 35: , 2004 61

62. Temporal Profile of BP after ICH

63. INTERACT: Efficacy of Antihypertensives
Target achieved: 42% (1h) 66% (6h)
Drugs Used: 1. Furosemide 2. Urapidil 63

64. INTERACT: Hematoma Expansion64

65. Rationale for Not Treating Blood Pressure
One fear is that normal cerebral autoregulation of CBF is impaired in patients with acute ICH. Thus, any decrease in BP may result in a concomitant fall in CBF.
The autoregulatory curve described above is an oversimplified MODEL, based on animal data primarily and the McHenry study of low bp in medical students (1961); work of Derdeyn and Powers + others show that rCBF decreases and OEF increases approx 18% IN the autoregulatory range as CPP falls; the relationship also differs between individuals.
Based on Dirangl and Pulsinelli, JCBFM, 1990 (SHR ICAO/MCAO)

66. Autoregulation in ICH
Systolic BP (mmHg)

67. Peri-hematoma Edema and Injury
Ischemic?
Vasogenic?
Astrocyte
Plasma
Extravasation Pc
Capillary 67

68. Perihematoma Edema is Not Cytotoxic
Butcher et al, Stroke 35: , 2003

69. Peri-hematomal Oligemia: CT Perfusion
Maps of CBF (flow) and CBV (volume) generated with CTP in an acute ICH patient. Once again, we see oligemia, but not ischemia.

70. Peri-hematoma Oligemia: rCBF*
Penumbral Threshold
Perihematoma CBF (32.585.64 ml/100g/min) was significantly lower than contralateral homologous regions (35.195.60 ml/100g/min; p=0.001). This corresponded to a reduction in perihematoma CBV (2.910.58 vs 3.130.55 ml/100g; p=0.006).

71. Extreme BP Reduction and CBF
Tie
BP (mmHg)
Time (minutes)

72. Acute ICH - onset within 24 hours
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
Outline of ICH ADAPT trial, which utilizes a physiological endpoint (CBF) to assess the effects of two different BP targets.
Primary Endpoint: rCBF measured with CT perfusion 2 hours after randomization
Butcher et al, IJS, 2010 72

73. 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

74. ICH Summary Poor prognosis Hematoma expands early (≤4h)
ICH Expansion can be predicted
HBP is a likely factor in prognosis
Expansion
Edema formation
other

75. 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