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 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

 

PRIMARY (78-88%) Hypertensive angiopathy (fibrohyalinosis) Amyloid angiopathy



Anticoagulant Associated

      

SECONDARY AVM Aneurysm Cavernoma Neoplasm Coagulopathy



Alcoholic liver disease



Hemophilia Hemorrhagic infarct Toxic-cocaine

Dismal Prognosis

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Dead ICH 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

Component

GCS 3 - 4 5 - 12 13 - 15 ICH volume ≥ 30 ml ≤ 30 ml IVH yes no Infratentorial Age > 80

ICH Score

ICH score points

1 0 2 (34/35 died) 1 (29/57 died) 0 (5/60 died) 1 0 1 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 Initial CT time Putamen Thalamus Lobar Cerebellar Pons Other Brott (1997) N=103 0-3 hrs 34% 50% 32% 0% 40% 43% TOTAL 38% Kazui (1994) N=186 0-24 hrs 16% 21% 29% 25% 40% 25% 22% Fujii (1996) N=359 0-24 hrs 19% 10% 6% 12% 28% 13% 14%

3 h

Hematoma Evolution

3 h 2 h 6 h 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) 24 hours

rFVIIa

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

100

↑ Early Neurological Deterioration ↓ Functional Outcome (90 days)

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 140 mmHg No Enlargement 16 150 mmHg 160 mmHg 170 mmHg 14 22 8 Hematoma Enlargement 2 1 8 5 9% p=0.025

30%

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

ICH Management

Treatment Modalities

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

Basic Algorithm

 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: CMRO 2 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 1 st 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 25 – 30 mm Hg  Has no associated ischemia ad pCO2 10  Beware of hypoperfused areas that are more fragile

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

 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

10 5 0 - 5 - 10 - 15 - 20 70 65 60 55 50 45 40 35 30 25 20 15

Percent Change in ICH Volume at 24 Hours

Percent Change in ICH Volume by T reatment Boxes depict 98.3% confidence intervals

29% 16% 14% 11%

10 5 0 - 5 - 10 - 15 - 20 70 65 60 55 50 45 40 35 30 25 20 15 Placebo 40 ug/kg rFVIIa 80 ug/kg rFVIIa 160 ug/kg rFVIIa

160 µg/kg

Modified Rankin Scale at Day 90

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

Onset-CT interval (h )

0-3 3-6 6-24

Prospective

Brott 38% N/A N/A

Retrospective

Fujii 18% Kazui



3.3ml

36% Takizawa



4.5ml

17%



5.8ml

8% 16% 6% rFVIIa within 4 hours:

• • Dose dependent attenuation of hematoma

2% 10% 0%

no effect on mRS at 90 days Mayer et al. NEJM 2005; 352: 777-85

CTA Based rFVIIa Selection Trials

The S po T sign f O r P redicting and treating I CH grow T h study: STOP-IT SPOTRIAS/NINDS PI: M. Flaherty ‘ SPOT sign ’ se L ection of I ntracerebral hemorrhage to G uide H emostatic T herapy: 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 ?

     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=425 n=1097 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 ATACH n=60 INTERACT n=400 ICH ADAPT n=164 Target Blood Pressure 170-200; 140-170; 110-140 systolic <140 mmHg systolic <150 mmHg systolic Agent(s) Nicardipine Multiple Labetalol ± Hydralazine

Blood Pressure and Hematoma Evolution

Target max SBP 140 mmHg No Enlargement 16 Hematoma Enlargement 2 150 mmHg 160 mmHg 170 mmHg 14 22 8 1 9% p=0.025

8 30% 5 Ohwaki et al, Stroke, 35: 1353-1367, 2004

Temporal Profile of BP after ICH

Blood Pressure over time in the three different target groups

220.00

200.00

180.00

160.00

140.00

120.00

B as el in e 1 ho ur 3 ho ur s 5 ho ur s 7 ho ur s 12 h ou rs

Time

Systolic target <160mmHg Systolic target 160 179mmHg 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)

Autoregulation in ICH

160 150 140 130 120 First CTP 30 minutes 60 minutes 90 minutes Second CTP

Peri-hematoma Edema and Injury

Ischemic?

Vasogenic?

Pc Astrocyte 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

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