edward c. jauch, md ms 1 current management of intracerebral hemorrhage
TRANSCRIPT
Edward C. Jauch, MD MS1
Current Management of Current Management of Intracerebral HemorrhageIntracerebral Hemorrhage
Edward C. Jauch, MD MS2
Edward C. Jauch, MD, MS
Assistant ProfessorDirector of Research
Department of Emergency MedicineUniversity of Cincinnati College of Medicine
Faculty, Greater Cincinnati / Northern Kentucky Stroke Team
Edward C. Jauch, MD MS3
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)
Edward C. Jauch, MD MS4
Global ObjectivesGlobal Objectives
• Review epidemiology of ICH
• Discuss current treatment recommendations
• Review recent developments in ICH treatment
• Discuss lessons from acute ischemic stroke
Edward C. Jauch, MD MS6
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
Edward C. Jauch, MD MS7
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
Edward C. Jauch, MD MS8
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
Edward C. Jauch, MD MS9
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?
Edward C. Jauch, MD MS10
Stroke SubtypesStroke Subtypes
(Foulkes, NINCDS Stroke Data Bank Stroke, 1988)
ICH13%
SAH13%
Lacunar19% Thromboembolic
6%
Cardioembolic14%
Other 3%
Unknown32%
Ischemic
71%
Hemorrhagic 26%
Up to 65,000 ICH per yearUp to 65,000 ICH per year
Edward C. Jauch, MD MS11
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
Edward C. Jauch, MD MS12
LocationLocation• Lobar
– Associated with amyloid angiopathy
• Nonlobar– Due to hypertension
• Cerebellar• Brain stem
Pons
Cortex
Basal ganglia
Thalamus
Cerebellum
Edward C. Jauch, MD MS13
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)
Edward C. Jauch, MD MS14
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
Edward C. Jauch, MD MS15
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
Edward C. Jauch, MD MS16
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
Edward C. Jauch, MD MS17
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
6.5 hours after onset
2.0 hours after onset
6.5 hours after onset
Edward C. Jauch, MD MS18
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)
Edward C. Jauch, MD MS20
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
Edward C. Jauch, MD MS21
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 2005
Edward C. Jauch, MD MS FACEP
Edward C. Jauch, MD MS23
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
Edward C. Jauch, MD MS24
ICH ManagementICH Management
• Immediate stabilization (ABC’s)
• Supportive medical care– Frequent comorbidities
• Neurologic specific care
• Hemorrhage specific interventions
Edward C. Jauch, MD MS25
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)
Edward C. Jauch, MD MS26
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
Edward C. Jauch, MD MS27
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
Edward C. Jauch, MD MS28
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
Edward C. Jauch, MD MS29
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
Edward C. Jauch, MD MS30
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)
Edward C. Jauch, MD MS31
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
Edward C. Jauch, MD MS32
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)
Edward C. Jauch, MD MS34
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
Edward C. Jauch, MD MS35
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
rFVIIa 80 µg/kgN = 100
rFVIIa 160 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)
Edward C. Jauch, MD MS36
-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)
Edward C. Jauch, MD MS37
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
Edward C. Jauch, MD MS38
Thromboembolic SAEsThromboembolic SAEs
Placebo 40 µg/kg 80 µg/kg160
µg/kgP 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)
Edward C. Jauch, MD MS39
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)
Edward C. Jauch, MD MS41
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
Edward C. Jauch, MD MS43
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)
Edward C. Jauch, MD MS44
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
Edward C. Jauch, MD MS45
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
Edward C. Jauch, MD MS46
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
Edward C. Jauch, MD MS48
Questions??Questions??www.ferne.org
Edward C. Jauch, MD, [email protected]
ferne_2005_aaem_france_jauch_ich_fshow.ppt 8/29/2005 1:45 AM
Edward C. Jauch, MD MS49
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
Edward C. Jauch, MD MS50
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 - 1988
Oxfordshire – 1981-86
Rochester – 1975-84
Dijon – 1985-89
Finland – 1985-89
Age (years)
Inci
den
ce
rat
e /
100
,000
pe
r y
ear
Edward C. Jauch, MD MS51
Systolic Blood Pressure & IncidenceSystolic Blood Pressure & Incidence
0
50
100
150
200
250
<110 110-139 140-179 180+
Inci
den
ce
rat
e /
100
,000
pe
r y
ear
Systolic Blood Pressure (mmHg)
Edward C. Jauch, MD MS52
Prognostic InformationPrognostic Information
• Hemorrhage volume
• Clinical presentation / Initial GCS
• Age
• Intraventricular extension
• Use of anticoagulants
• Associated seizures