Current Management of Intracerebral Hemorrhage

Edward C. Jauch, MD MS1

Current Management of Current Management of Intracerebral HemorrhageIntracerebral Hemorrhage


Edward C. Jauch, MD, MSAssistant ProfessorDirector of Research

Department of Emergency MedicineUniversity of Cincinnati College of Medicine

Faculty, Greater Cincinnati / Northern Kentucky Stroke Team


DisclosureDisclosure• Novo Nordisk

– Consultant & Site investigator phase III trial• American Heart Association

– ASA and ACLS Stroke Guidelines Committee– Various AHA Committee

• National Institutes of Health– Ventricular and hematoma aspiration trials

(Genentech providing drug)


Global ObjectivesGlobal Objectives• Review epidemiology of ICH

• Discuss current treatment recommendations

• Review recent developments in ICH treatment

• Discuss lessons from acute ischemic stroke


A Clinical CaseA Clinical Case


Patient Initial Clinical HistoryPatient Initial Clinical History• 57 yo male develops sudden onset

headache and left sided weakness• Family calls 911 (112, 115, etc)• EMS transport to hospital• Symptoms progress to full hemiplegia• Initial VS: 210 / 120 mmHg, HR 110, R 24


Patient ED PresentationPatient ED Presentation• PMHX: Hypertension for 10 years,

hyperlipidemia• SHX: Smoking 30 years• Meds: ACE inhibitor, ASA• ROS: No recent illness or injuries

No new medications


Patient ED PresentationPatient ED Presentation• Physical examination:

• VS - 220 / 140 mmHg, HR 110, RR 22, T 98.6oF• Neuro (NIHSS = 12)

• LOC mildly depressed (GCS 13)• Left facial droop & partial gaze palsy• Dense left hemiplegia• Mild left sensory loss• Speech slurred

• Laboratory and ECG normal• Neuroimaging shows


Key QuestionsKey Questions• What is your differential diagnosis?• What medical management should be

initiated in this patient?• What additional imaging is required?• What laboratory tests should be

completed?• What are treatment options and issues?


Stroke SubtypesStroke Subtypes

(Foulkes, NINCDS Stroke Data Bank Stroke, 1988)

ICH13%

SAH13%

Lacunar19% Thromboembolic

6%Cardioembolic

14%

Other 3%Unknown

32%

Ischemic71%

Hemorrhagic 26%

Up to 65,000 ICH per yearUp to 65,000 ICH per year


ICH ClassificationsICH Classifications• Primary (80%)

– Hypertensive arteriolopathies– Cerebral amyloid angiopathies

• Secondary (20%)– Vascular abnormalities– Neoplasms– Coagulation disorders– Anticoagulants or thrombolytic agents– Drugs (cocaine, ephedra, etc)– Trauma


LocationLocation• Lobar

– Associated with amyloid angiopathy • Nonlobar

– Due to hypertension• Cerebellar• Brain stem

Pons

Cortex

Basal ganglia

Thalamus

Cerebellum


Clinical PresentationClinical Presentation• Symptoms and signs

– 82% change in mental status– >75% hemiparesis/plegia– 63% headache– 22% vomiting– Symptoms

• 2/3 with progression of symptoms • 1/3 maximal at onset

(Brott, Stroke 1997;28:1-5)


Clinical Presentation by LocationClinical Presentation by Location• Lobar

– Headache (headache location related to ICH site)– Motor, sensory deficit, or VF deficits (not all)

• Deep– Unilateral motor, sensory, VF loss– Aphasia (D) or neglect (ND)

• Cerebellum– Nausea, vomiting, ataxia, coma

• Pontine– Coma, quadriplegia, pinpoint pupils


Primary Risk FactorsPrimary Risk Factors• Age• Hypertension• Alcohol intake• Gender (M > F)• Race• Smoking• Diabetes

• Vascular malformations– Moyamoya / aneurysms

• Infections– Vasculitis– Mycotic aneurysms

• Cerebral venous thrombosis

• Genetic– Apolipoprotein E ε4


PathophysiologyPathophysiology• Initial hemorrhage into tissues causes:

– Cytotoxic and vasogenic edema formation– Mediators: MMP-9, inflammatory response, blood

degradation products

• Elevated intracranial pressure due to:– Hematoma mass effect – Perihematomal edema – Intraventricular extension and hydrocephalus

• Decreased regional perfusion and herniation


ICH ProgressionICH Progression• Symptoms often progress,

associated with ICH growth• Within 3 hours from onset:

– 26% with 33% or greater growth in next 1 hour

– 12% with 33% or greater growth 1-20 hours

(Brott, Stroke 1997;28:1-5)

2.0 hours after onset





PrognosisPrognosis• Worse

– Volume > 60 cm3 and GCS < 9• 91% dead at 30 days

– Patients with > 30 cm3

• 1 / 71 independent at 30 days– Other: age, seizures, intraventricular extension

• Better– Volume < 30 cm3 and GCS 9 or higher

• 19% dead at 30 days

(Broderick, Stroke 1993;24:987- 93)

28 mL

43 mL

(Image courtesy T. Brott, MD)


Hematoma VolumeHematoma Volume• Formula for volume of an ellipsoid

– 4/3π (A/2)(B/2)(C/2)– Simplified A*B*C / 2

(Kothari, Stroke 1996;27:1304-5)

A

B

C


Mortality and MorbidityMortality and Morbidity• Outcome:

– 35-52% dead at 1 month– 50% of deaths within 48o

– 10% independent at 30 days– 20% independent at 6

months

• Lifetime ICH cost $125K

0

20

40

60

80

100

0 1 2 3 4 5 Dead

Modified Oxford Handicap Scale

(Broderick, Stroke 1993;24:987- 93)

# patients

Current Recommendations for Current Recommendations for Management of Intracerebral HemorrhageManagement of Intracerebral Hemorrhage

(Broderick, Stroke 1999;30(4):905-15)

New guidelines due 2005New guidelines due 2005Edward C. Jauch, MD MS FACEP


Emergent EvaluationEmergent Evaluation• Baseline labs

– CBC, coagulation parameters, electrolytes• Neuroimaging

– CT remains gold standard• Identify ICH and complications (hydrocephalus, herniation)

– MRI / MRA • For structural abnormalities (AVM, aneurysms)

– Angiography• Rarely emergently indicated, identifies vascular issues


ICH ManagementICH Management• Immediate stabilization (ABC’s)• Supportive medical care

– Frequent comorbidities• Neurologic specific care• Hemorrhage specific interventions


Medical ManagementMedical Management• ABC’s

– Maintain oxygen saturation ≥92%– Rapid sequence intubation

• Medical management– Prevention of hyperthermia (<37.5oC)– Glycemic control (<10 nmol/L)– Coagulopathy correction (FFP, vitamin K)– No glycerol, corticosteroids, hemodilution– Secondary complication prevention

(EUSI, Cerebrovasc Dis 2003;16:311-318)


Blood Pressure ManagementBlood Pressure Management• Hypertension very common

– MAP > 140 in 34%, > 120 in 78%– Many ‘normalize’ over first 24 hours

• General goals– Maintain MAP < 130 mmHg with history of hypertension– Prevent hypotension (SBP < 90 mmHg)– Maintain:

• Cerebral perfusion pressure (CPP=MAP-ICP) CPP > 70 mmHg• Central venous pressure from 5-12 mmHg

• Optimal blood pressure still to be determined


Blood Pressure ManagementBlood Pressure Management

(Broderick, Stroke 1999;30(4):905-15)(Ohwaki, Stroke 2004;35:1364-1367)

For now -Common agents

•Labetalol•Nicardipine•Nitroprusside (theoretical risk of increasing ICP)

New data suggest SBP < 150 mm Hg


Management of ICP Management of ICP • Definition

– ICP > 20 mm Hg for > 5 minutes• Treatment goal

– ICP < 20 mm Hg and CPP > 70 mm Hg• Recommendations

– ICP monitoring with GCS < 9• Management

– Patient positioning– Osmotherapy– Hyperventilation– Ventricular drainage


Management of ICPManagement of ICP

(Broderick, Stroke 1999;30(4):905-15)

• Osmotherapy– Mannitol 0.25-0.5 g/kg every 6 hours up to 5 days– Target mOsm < 310 mmol/L

• Hyperventilation– Tidal volume of 12-15 ml/kg– Target pCO2 30-35 mm Hg

• Neuromuscular paralysis– Nondepolarizing agents


SeizuresSeizures• More common in ICH than you think

– Over 25% will seizure (vs 6% for ischemic stroke)– Much more common if lobar– Focal with secondary generalization– Most in first 72 hours

• Treatment– Phenytoin (minimizes sedation)– Does not convey life long epilepsy

(Vespa, Neurology 2003;60:1441-6)


What can be Fixed?What can be Fixed?• Stop the bleeding

– Until now no option• Remove the blood

– Multiple trials without clear impact• Reduce the edema

– No treatment yet


Surgical TreatmentSurgical Treatment• Direct evacuation, endoscopic, stereotactic

Surgical Treatment RecommendationsSurgical Treatment Recommendations

•7000 procedures a year in U.S. despite lack of data•STICH: Largest surgical trial without general benefit

(Mendelow, 2005;365:387-97)(Broderick, 1999;30(4):905-15)


Hemostatic TherapyHemostatic Therapy

(Mayer, Stroke 2005;36:74-79)(Mayer, NEJM 2005;352:777-785)

• Few late studies (mostly in SAH*)– Aminocaproic acid– Tranexamic acid*

• Ultra-early studies– rFVIIa

• Pilot (n=48)• F7ICH-1371 (n=399)• Phase III (n=675) ongoing


Study DesignStudy Design

Patients presenting with stroke-like symptoms

2° Efficacy• Mortality• mRS• Barthel Index • E-GOS • NIHSS • GCS• Euro-QOL

24-72 hours 90 days< 3 hours

CTBaseline

Safety• Adverse events

until discharge• Serious adverse

events until day 90

• Exacerbation of edema

CT24 h

Placebo N = 100

rFVIIa 40 µg/kgN = 100



≤ 60 mins

CT72 h

20 Countries73 Trial Sites

1° EfficacyPercent change in ICH volume at 24 hours

Baseline CT scan

(Mayer, NEJM 2005;352:777-785)


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

%

29%

11%14%16%

*Combined treatment groups vs placebo: P = 0.0112.

Estimated Mean Percent Change Estimated Mean Percent Change in ICH Volume at 24 Hoursin ICH Volume at 24 Hours

Percent Change in ICH Volume by Treatment

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

Placebo 40 µg/kg 80 µg/kg 160 µg/kgTreatment Groups

52% RR45% RR 62% RR

14%

CombinedTreatment

Groups

%

*

(Mayer, NEJM 2005;352:777-785)


0–1no significant disability

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

160 µg/kg

80 µg/kg

40 µg/kg

Placebo

2–3slight to moderate disability

4–5moderately severe to severe disability

6 dead*

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

(Mayer, NEJM 2005;352:777-785)

*29% vs 18% rFVIIa vs placebo, RRR 38%, Chi-square test; P = 0.02


Thromboembolic SAEsThromboembolic SAEs

Placebo 40 µg/kg 80 µg/kg 160 µg/kg P Value*

2% 6% 4% 10% 0.12

Frequency of Thromboembolic SAEs

• Arterial thromboembolic SAEs (myocardial ischemia 7 and cerebral infarction 9) with rFVIIa treatment (5%) vs placebo (0%), P = 0.01

• Fatal or disabling thromboembolic SAEs in 2% of rFVIIa-treated patients compared with 2% in the placebo group

• Nonsignificant dose trend in events (P = 0.12)

(Mayer, NEJM 2005;352:777-785)


Potential Future ToolsPotential Future Tools• Medical therapies

– Optimizing blood pressure (ATACH)– Tight glycemic control (THIS)– Neuroprotectives (CHANT, Fast-MAG, hypothermia)– Ultra-early hemostatic therapy (rFVIIa)

• Surgery– Surgical patient selection and new approaches

• Stereotactic evacuation with tPA• Intraventricular evacuation with fibrinolysis (ITT, DITCH)

What Can We Learn From What Can We Learn From Acute Ischemic Stroke?Acute Ischemic Stroke?


Time Will Always Mean Brain!Time Will Always Mean Brain!• ICH continue to expand• Early medical

management essential • Early coagulation

correction critical (drip and ship)

• Hemostatic therapy may work best early

(Lancet (Lancet 2004; 363: 768–74)2004; 363: 768–74)

• Development: Protocol and pathway development• Detection: Early recognition• Dispatch: Early EMS activation• Delivery: Transport & management• Door: ED triage• Data: ED evaluation & management• Decision: Neurologic input, therapy selection• Drug: Thrombolytic (hemostatic) agents• Disposition: Admission or transfer

Same Chain: No Weak LinksSame Chain: No Weak Links


NINDS RecommendationsNINDS RecommendationsSame for ICH?Same for ICH?

• Door-to-MD: 10 minutes

• Door-to-”Expert”? 15 minutes

• Door-to-CT scan: 25 minutes

• Door-to-Drug: 60 minutes

• Door-to-Admission 3 hours

(NINDS Stroke Symposium 2003)(NINDS Stroke Symposium 2003)


There May Be Major BarriersThere May Be Major Barriers• Education • Timely radiology involvement• Access to neurologic

expertise • Post treatment management

– Availability of ICU beds– Complications occur early

• Resources and cost


ED Treatment & Patient OutcomeED Treatment & Patient Outcome• Patient’s GCS declined to 11 over 48o

• Mild edema & shift seen on 48o CT• Blood pressure managed with

labetalol• Patient required inpatient rehab• Moderately disabled at 3 months but

at home


Key Learning PointsKey Learning Points• ICH is a dynamic process• Critical management frequently required

and required early• General management impacts outcome• Targeted therapies time dependent• Hemostatic therapies may play a role if

administered early• Surgery for selected cases


Key Role of Emergency MedicineKey Role of Emergency Medicine


Questions??Questions??www.ferne.org

[email protected]

Edward C. Jauch, MD, [email protected]

ferne_2005_aaem_france_jauch_ich_fshow.ppt 8/29/2005 1:45 AM

http://www.ferne.org/


Ethnicity of ICH RiskEthnicity of ICH Risk• Age and sex adjusted rate

– U.S. 15 per 100,000– World wide 10-20 per 100,000

• Rates: 13.5 per 100,000 Caucasian38 per 100,000 African

Americans 55 per 100,000 Japanese


ICH Rate by AgeICH Rate by Age

25 30 35 40 45 50 55 60 65 70 75 80 85 9025 30 35 40 45 50 55 60 65 70 75 80 85 900

50

100

150

200

250

0

50

100

150

200

250Cincinnati - 1988Oxfordshire – 1981-86Rochester – 1975-84Dijon – 1985-89Finland – 1985-89

Age (years)

Inci

denc

e ra

te /

100,

000

per y

ear


Systolic Blood Pressure & IncidenceSystolic Blood Pressure & Incidence

0

50

100

150

200

250

<110 110-139 140-179 180+

Inci

denc

e ra

te /

100,

000

per y

ear

Systolic Blood Pressure (mmHg)


Prognostic InformationPrognostic Information• Hemorrhage volume• Clinical presentation / Initial GCS• Age• Intraventricular extension• Use of anticoagulants• Associated seizures


Intracranial Hemorrhage

IschemicStroke

Trauma

Subarachnoid Hemorrhage

Similar PathophysiologySimilar Pathophysiology

Documents

Current Management of Intracerebral Hemorrhage