Intracerebral Hemorrhage

McGill Lecture SeriesMontreal, QC

September 19, 2012

J. Teitlelbaum, MD, FRCP(C)University of McGill

Case History G.S.Case History G.S.

68 year old R68 year old R HBP, DB2, CADHBP, DB2, CAD 5PM, sudden5PM, sudden

R paresisR paresis AphasiaAphasia Ø headache, N or VØ headache, N or V

G.S.G.S.

Exam on arrivalExam on arrival BP 190/100 P 75/minBP 190/100 P 75/min Alert, aware, mixed moderate aphasiaAlert, aware, mixed moderate aphasia CN: PERL, RHHA, R UMN VII, R ↓↓ CN: PERL, RHHA, R UMN VII, R ↓↓

sensationsensation 2/5 strength R UE & LE2/5 strength R UE & LE ↓↓ ↓↓ sensation R hemi-bodysensation R hemi-body

CT 5:30PMCT 5:30PM

G.S. Sudden G.S. Sudden DeteriororationDeteriororation

Exam at 7PMExam at 7PM GCS 10, very somnolent, not obeying GCS 10, very somnolent, not obeying

commands, groans & opens eyes to commands, groans & opens eyes to voice.voice.

Pupils 4mm L 3mm R reactivePupils 4mm L 3mm R reactive Poor airway protectionPoor airway protection Power 0/5 R UE & LEPower 0/5 R UE & LE

CT at 7:05 PMCT at 7:05 PM

G.S. Now what ??G.S. Now what ??

ICHICH Epidemiology & EtiologyEpidemiology & Etiology: :

primary vs secondaryprimary vs secondary Factors that affect Factors that affect prognosisprognosis ManagementManagement

Evidence-basedEvidence-based Eminence basedEminence based Experimental & anecdotalExperimental & 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

0

20,000

40,000

60,000

80,000

100,000

120,000

ICH

In

cid

ence

yea

r 20

03

USA Japan EU5

Intracerebral Intracerebral HemorrhageHemorrhage

15% of stroke in the West, 30% in 15% of stroke in the West, 30% in the Eastthe East

6 month prognosis dismal6 month prognosis dismal 40% dead (33% within 1 month)40% dead (33% within 1 month) 40% disabled and dependent40% disabled and dependent 20% independent20% independent

Classification of ICHClassification of ICH

PRIMARYPRIMARY (78- (78-88%)88%)

Hypertensive Hypertensive angiopathy angiopathy (fibrohyalinosis)(fibrohyalinosis)

Amyloid Amyloid angiopathyangiopathy

Anticoagulant Anticoagulant AssociatedAssociated

SECONDARYSECONDARY AVMAVM AneurysmAneurysm CavernomaCavernoma NeoplasmNeoplasm CoagulopathyCoagulopathy

Alcoholic liver Alcoholic liver diseasedisease

HemophiliaHemophilia Hemorrhagic infarctHemorrhagic infarct Toxic-cocaineToxic-cocaine

Dismal PrognosisDismal Prognosis

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

ICH Ischemic

Pro

po

rtio

n o

f p

ati

en

ts (

%)

Dead Dependent Independent

Factors Affecting Factors Affecting PrognosisPrognosis

GCS on presentationGCS on presentation AgeAge Hemorrhage locationHemorrhage location Intraventricular hemorrhageIntraventricular hemorrhage ? Blood pressure? Blood pressure Hemorrhage sizeHemorrhage size

Secondary DamageSecondary Damage

Hematoma expansion≥ 80 ml fatal

Cerebral edema

Secondary injury

ICH ScoreICH ScoreComponent ICH score pointsGCS

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 ScoreMortality and ICH Score

The relationship between The relationship between ICH volume and patient ICH volume and patient

outcomeoutcome

DEADFULL RECOVERY

Size is the most Size is the most important predictor for important predictor for

patient outcomepatient 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

Which are Modifiable ?Which are Modifiable ?

GCS on presentationGCS on presentation AgeAge Hemorrhage locationHemorrhage location Intraventricular hemorrhageIntraventricular hemorrhage ? Blood pressure? Blood pressure Hemorrhage volumeHemorrhage volume

Early growth occurs in all Early growth occurs in all locationslocations

Brott (1997)N=103

Kazui (1994)N=186

Fujii (1996)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 EvolutionHematoma Evolution3 h

6 h

3 h 2 h

24 h 24 h

Predicting ICH Predicting ICH expansionexpansion

Time since onsetTime since onset

Spot signSpot sign

Blood pressureBlood pressure

Shape of the hematomaShape of the hematoma

CTA Source Images: CTA Source Images: Additional DataAdditional Data

SpotSign

The Spot Sign: Growth Despite The Spot Sign: Growth Despite TreatmentTreatment

3 hours (CT Angiogram) 24 hours 2 hours

rFVIIa

Predictive Value of Spot Sign:Predictive Value of Spot Sign: Time Dependent? Time Dependent?

3 hours 4.5 hours 24 hours

Spot Sign

Early Growth: Conventional Early Growth: Conventional angiographyangiography

Prognosis and Acute Blood Prognosis and Acute Blood PressurePressure

1 m

onth

mor

talit

y (%

)

MAP (mm Hg)

Fogelhom et al, Stroke, 28: 1396-400, 1997 Okumura et al, J. Hypertension, 23: 1217-23, 2005

↑ Early Neurological Deterioration↓ Functional Outcome (90 days)

0

20

40

60

80

100

-117 118-132 133-144 145-

1 m

onth

mor

talit

y (%

)

Blood Pressure and Hematoma Blood Pressure and Hematoma EvolutionEvolution

Target Target max SBPmax SBP

No No EnlargemeEnlargeme

ntnt

Hematoma Hematoma EnlargemeEnlargeme

ntnt

140 mmHg140 mmHg 1616 22 9%9%

p=0.025p=0.025150 mmHg150 mmHg 1414 11

160 mmHg160 mmHg 2222 8830%30%

170 mmHg 170 mmHg 88 55

Ohwaki et al, Stroke, 35: 1353-1367, 2004

ICH ManagementICH Management

Treatment ModalitiesTreatment Modalities

General supportive careGeneral supportive care Treatment of ICHTTreatment of ICHT Hematoma resectionHematoma resection Management of intra-ventricular Management of intra-ventricular

hemorrhagehemorrhage Seizure prophylaxisSeizure prophylaxis Prevention of hematoma growthPrevention of hematoma growth BP managementBP management

Basic Basic AlgorithmAlgorithm

ABCABC’’ss Do no harmDo no harm Pain management & sedationPain management & sedation Hyperventilation pCO2 30-35 mm HgHyperventilation pCO2 30-35 mm Hg Osmotic therapyOsmotic therapy Ventricular drainageVentricular drainage

General Supportive CareGeneral Supportive Care

HOB 30°HOB 30° SO2 ≥ 95%SO2 ≥ 95% Glucose control ≤ 6.0 mmolGlucose control ≤ 6.0 mmol T° control ≤ 37.5° CT° control ≤ 37.5° C Pain control, sedationPain control, sedation

HyperventilationHyperventilation Regional blood flowRegional blood flow

Oxygen extractionOxygen extraction

But: CMROBut: CMRO22 stable ad pCO2 = 10 mm Hg stable ad pCO2 = 10 mm Hg

At the levels used in TBI, hyperV does At the levels used in TBI, hyperV does not result in ischemianot result in ischemia

Pressure autoregulation dysfunction is Pressure autoregulation dysfunction is improvedimproved

HyperventilationHyperventilation

Present recommendation:Present recommendation: Avoid during 1Avoid during 1stst 24H post TBI 24H post TBI pCO2 30 – 35 mm HgpCO2 30 – 35 mm Hg If no response: 25 – 30 mm HgIf no response: 25 – 30 mm Hg

HyperventilationHyperventilation

My recommendation:My recommendation: Use for acute ICHT, temporizing measureUse for acute ICHT, temporizing measure

pCO2 30 – 35 mm Hg 25 – 30 mm HgpCO2 30 – 35 mm Hg 25 – 30 mm Hg

Has no associated ischemia ad pCO2 10Has no associated ischemia ad pCO2 10

Beware of hypoperfused areas that are more fragileBeware of hypoperfused areas that are more fragile

Osmotic AgentsOsmotic AgentsMechanisms of ActionMechanisms of Action

MannitolMannitol BW in intact > affected brainBW in intact > affected brain volume vasoconsrictionvolume vasoconsriction viscosity CBF vasoconstrictionviscosity CBF vasoconstriction size of CVA, apoptosissize of CVA, apoptosis

HSHS BW in intact = affected brainBW in intact = affected brain Possible in size of CVAPossible in size of CVA

Osmotic AgentsOsmotic AgentsClinical UseClinical Use

Routinely recommended in edema of trauma Routinely recommended in edema of trauma and strokeand stroke

Lack of evidence of beneficial outcomeLack of evidence of beneficial outcome Little evidence of efficacy in strokeLittle evidence of efficacy in stroke or ICH or ICH

(especially Na)(especially Na)

Osmotic AgentsOsmotic AgentsClinical UseClinical Use

Intermittent boluses allowing clearing of Intermittent boluses allowing clearing of solute from blood.solute from blood.

Avoid continuous infusionsAvoid continuous infusions Smallest doses at the largest possible intervals, Smallest doses at the largest possible intervals,

with prn according to ICPwith prn according to ICP

Osmotic AgentsOsmotic AgentsClinical UseClinical Use

ICH with ICHTICH with ICHT:: MN firstMN first HS if refractory, Cr, OGHS if refractory, Cr, OG

Refractory to one agent: use the otherRefractory to one agent: use the other 250cc MN, then 100cc alternating MN250cc MN, then 100cc alternating MN/HS/HS

Treatment of ICHTTreatment of ICHT

IntubationIntubation HyperventilationHyperventilation SedationSedation Steroids: NO roleSteroids: NO role Osmotic agentsOsmotic agents

MannitolMannitol Hypertonic salineHypertonic saline

No Δ in outcomeNo Δ in outcome

Hematoma ResectionHematoma Resection

STICH trialSTICH trial ICH within a centimeter of the cortical ICH within a centimeter of the cortical

surface showed a benefit for early surface showed a benefit for early surgerysurgery

mortality, no other effect on mortality, no other effect on morbiditymorbidity

MISTIE: MISTIE: Intra-lesion rtpa with subsequent Intra-lesion rtpa with subsequent

aspirationaspiration

Intra-ventricular Intra-ventricular HemorrhageHemorrhage

EVDEVD Intra- ventricular rtpa (CLEAR)Intra- ventricular rtpa (CLEAR)

Intra-ventricular rTPAIntra-ventricular rTPA

Hanley DFHanley DF:: pilot, prospective, randomized, pilot, prospective, randomized, double-blind, controlled trialdouble-blind, controlled trial

SSpeedpeedss clearance of aneurysmal clearance of aneurysmal intraventricular hemorrhageintraventricular hemorrhage

NNormalizormalizeses intracranial pressure intracranial pressure ReducReduceses ventricular catheter obstruction ventricular catheter obstruction

2.0 hours after onset

6.5 hours after onset

Early Hematoma Growth

Prevent ICH GrowthPrevent ICH Growth

By By BP BP

By rFVIIaBy rFVIIa

Percent Change in ICH Volume by Treatment

fvii-1371/current - 20JUN2004 - fana_ct.sas/fana_ct.cgm

-20

-15

-10

-5

0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

Placebo 40 ug/kg rFVIIa 80 ug/kg rFVIIa 160 ug/kg rFVIIa-20

-15

-10

-5

0

5

10

15

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35

40

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65

70

Percent Change in ICH Volume at 24 Percent Change in ICH Volume at 24 HoursHours

Boxes depict 98.3%

confidence intervals

29%

11%14%

52% RR

16%

45% RR 62% RR

Modified Rankin Scale at Modified Rankin Scale at Day 90Day 90

0%20%40%60%80%100%

160 µg/kg

80 µg/kg

40 µg/kg

Placebo

mRS 6

mRS 4-5

mRS 2-3

mRS 0-1

Onset-CT Onset-CT interval interval (h(h))

ProspectivProspectivee

RetrospectiveRetrospective

BrottBrott FujiiFujii KazuiKazui TakizaTakizawawa

0-30-3 38%38% 18%18% 36%36% 17%17% 3-3-66 N/AN/A 8%8% 16%16% 6%6% 6-246-24 N/AN/A 2%2% 10%10% 0%0%

Hematoma Evolution and Hematoma Evolution and rFVIIarFVIIa

rFVIIa within 4 hours: • Dose dependent attenuation of hematoma expansion • no effect on mRS at 90 days

3.3ml 4.5ml5.8ml

Mayer et al. NEJM 2005; 352: 777-85

Spot Sign Negative

CTA Based rFVIIa Selection CTA Based rFVIIa Selection TrialsTrials

The SpoT sign fOr Predicting and treating ICH growTh study: STOP-IT SPOTRIAS/NINDSPI: M. Flaherty

‘SPOT sign’ seLection of Intracerebral hemorrhage to Guide Hemostatic Therapy: SPOTLIGHT CSN/ CIHRPI: D. Gladstone

CTA

Acute ICH < 6 hours

Spot Sign Positive

rFVIIa Placebo

NCCT at 24 hours

Seizure ProphylaxisSeizure Prophylaxis

Are seizures frequent post ICH ?Are seizures frequent post ICH ?

Do they change outcome ?Do they change outcome ?

Does prophylaxis Does prophylaxis frequency ? frequency ?

Does a Does a in Sz affect outcome ? in Sz affect outcome ?

Is therapy associated with Is therapy associated with adverse events ?adverse events ?

Are seizures frequent Are seizures frequent post ICH ?post ICH ?

↑early Sz and late epilepsy (2003-2004)

1/3 pts: 50% electrographic (Neurology 2007)

Do they change Do they change outcome ?outcome ?

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 Does prophylaxis Sz Sz frequency ?frequency ?

Redding et al 2011: No (DPH)

Taylor 2011 Neurocrit Care: Yes (Keppra) 21% vs 16%

Does a Does a in Sz Improve in Sz Improve Outcome 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 ManagementICH 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: ICH1

mo

nth

mo

rta

lity

(%)

n=425

MAP (mm Hg)

n=1097

Fogelhom et al, Stroke, 28: 1396-400, 1997 Okumura et al, J. Hypertension, 23: 1217-23, 2005

Acute BP Management: Acute BP Management: Competing RationalesCompeting Rationales

Impaired Autoregulation

IV therapy suggested only for Systolic BP ≥ 180 mmHg

(AHA Guidelines)

Guidelines for Acute BP Guidelines for Acute BP Management: Management: ICHICH

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 Acute ICH BP Treatment TrialsTrials

Trial Target Blood Pressure

Agent(s)

ATACH

n=60

170-200; 140-170; 110-140

systolic

Nicardipine

INTERACT

n=400

<140 mmHg systolic

Multiple

ICH ADAPT

n=164

<150 mmHg systolic

Labetalol±

Hydralazine

Blood Pressure and Hematoma Blood Pressure and Hematoma EvolutionEvolution

Target max SBP

No Enlargement

Hematoma Enlargement

140 mmHg 16 2 9%

p=0.025150 mmHg 14 1

160 mmHg 22 830%

170 mmHg 8 5

Ohwaki et al, Stroke, 35: 1353-1367, 2004

Temporal Profile of BP Temporal Profile of BP after ICHafter ICH

Blood Pressure over time in the three different target groups

120.00

140.00

160.00

180.00

200.00

220.00

Baselin

e

1 ho

ur

3 ho

urs

5 ho

urs

7 ho

urs

12 ho

urs

Time

Mea

n s

ysto

lic

blo

od

p

ress

ure

Systolic target<160mmHg

Systolic target 160-179mmHg

Systolic target>180mmHg

INTERACT: Efficacy of INTERACT: Efficacy of AntihypertensivesAntihypertensives

Target achieved: 42% (1h) 66% (6h)

Drugs Used: 1. Furosemide 2. Urapidil

INTERACT: Hematoma INTERACT: Hematoma ExpansionExpansion

Rationale for Rationale for NotNot Treating Treating Blood PressureBlood Pressure

Based on Dirangl and Pulsinelli, JCBFM, 1990 (SHR ICAO/MCAO)

Autoregulation in ICHAutoregulation in ICH

Sys

toli

c B

P (

mm

Hg)

Peri-hematoma Edema Peri-hematoma Edema and Injuryand Injury

Vasogenic?

PlasmaExtravasation

Ischemic?

Pc

Capillary

Astrocyte

Perihematoma Edema is Perihematoma Edema is NotNot Cytotoxic Cytotoxic

Butcher et al, Stroke 35:1879-1885, 2003

Peri-hematomal Oligemia: CT Peri-hematomal Oligemia: CT PerfusionPerfusion

** P=0.01

Peri-hematoma Peri-hematoma Oligemia: rCBFOligemia: rCBF

Penumbral Threshold

Extreme BP Reduction Extreme BP Reduction and CBFand CBF

TieBP

(m

mH

g)

Time (minutes)

Intracerebral Hemorrhage Acutely Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial Decreasing Arterial Pressure Trial

(ICH ADAPT) Protocol(ICH ADAPT) Protocol

Randomization (N=74)

Acute ICH - onset within 24 hours

SBP ≥ 150 mmHg

Primary Endpoint: rCBF measured with CT perfusion 2

hours after randomization

Target SBP <180 mmHg

Labetalol±Hydralazine

Target SBP <150 mmHg

Butcher et al, IJS, 2010

So…So…

in BP will prevent hematoma in BP will prevent hematoma growth if:growth if: Within 1 hourWithin 1 hour To ≤ 160 mm Hg systolicTo ≤ 160 mm Hg systolic Labetalol / HydralazineLabetalol / Hydralazine

BP does BP does CBF but no CBF but no in in ischemiaischemia

Ideal BP: 150 – 160 mm Hg systolicIdeal BP: 150 – 160 mm Hg systolic

ICH SummaryICH Summary

Poor prognosisPoor prognosis Hematoma expands early (≤4h)Hematoma expands early (≤4h) ICH Expansion can be predictedICH Expansion can be predicted HBP is a likely factor in prognosisHBP is a likely factor in prognosis

ExpansionExpansion Edema formationEdema formation otherother

ICH SummaryICH Summary

Treatment:Treatment: GeneralGeneral Prevention of ICH enlargement: Prevention of ICH enlargement:

BP within 1h to ≤ 160 mm Hg systBP within 1h to ≤ 160 mm Hg syst rFVIIarFVIIa

Seizure prophylaxis: likely useful Seizure prophylaxis: likely useful (Keppra IV)(Keppra IV)

ICHT therapy: no Δ in outcomeICHT therapy: no Δ in outcome Sx: little if any benefitSx: little if any benefit