Cerebral HemorrhageGalen V. Henderson, M.D.

Brigham and Women’s HospitalDirector, Neuroscience ICU

Harvard Medical School

Disclosures• I have no industry relationships

Outline•Epidemiology•Imaging•Prognosis•Neurogenic stress cardiomyopathy•Subclinical seizures•Hypertonic saline•Protein complex concentrates•New treatments

Significance of cerebral hemorrhage• ICH represents 10 – 15% of all strokes

• Twice as common as subarachnoid hemorrhage and just as deadly

• Only 20% live independently at 6 months

• Worldwide incidence: 10–20 cases per 100,000 population

American Heart Association. Heart Disease and Stroke Statistics–2005 Update; Qureshi AI et al. N Engl J Med. 2001;344:1450-1460. Broderick JP et al. Stroke. 1999;30:905-915; Broderick JP et al. N Engl J Med. 1992;326:733-736.Broderick JP, et al. Stroke. 2007;38:1-23.

Significance of cerebral hemorrhage

• 30 day mortality rate 35-52%, half of deaths occur in the first 2 days

• Mortality rate unchanged over the last 20 years

• To date no therapies have shown benefit in randomized clinical trials– Surgical evacuation– Osmotic diuretics– Glucocorticoids

Intracerebral hemorrhage Subtypes

• Primary – Hematomas– Microbleeds

• Secondary– Tumors– Vascular

malformation– Aneurysms– Coagulopathy– Trauma– Ischemic stroke

with trans.– Drug use

• Subarachnoid– Aneurysmal– Non-aneurysmal

• Subdural hematoma

• Epidural hematoma

Qureshi AI et al. N Engl J Med. 2001;344:1450-1460.

Broderick JP, et al. Stroke. 2007;38:1-23.

Most Common Sites of ICH

Pons

Cerebral lobes

Basal ganglia

Thalamus

Cerebellum

50% deep35% lobar10% cerebellum6% brainstem

Early Hemorrhage Growth in Patients with ICH

2.0 hours after onset

6.5 hours after onset

2.0 hours after onset

6.5 hours after onset

NIHSS, National Institutes of Health Stroke Scale.Brott T et al. Stroke. 1997;28:1-5.Image courtesy T. Brott, MD.

Early Hemorrhage Growth in Patients with ICH

• 103 patients scanned < 3 hours of onset

• 38% experienced significant hematoma growth (> 33% increase in volume) – 26% within 1 hour of

baseline scan– 12% between 1- and 20-

hour scan• ICH growth was associated

with clinical deterioration on NIHSS

• In patients with putaminal ICH, hematoma growth (> 33%) occurs early (shown)

NIHSS, National Institutes of Health Stroke Scale.Brott T et al. Stroke. 1997;28:1-5.

ICH VolumePowerful Determinant of 30-day Outcome

Condition at 30 days (Oxford Handicap Scale)

Broderick JP et al. Stroke. 1993;24:987-993.

Good recovery with volume > 30 mL does not occur

28 mL

43 mL

Image courtesy T. Brott, MD.

Slide No. 12 • •

Goldstein, J. N. et al. Neurology 2007;68:889-894

Contrast within the hematoma

GRE Sequences and Cerebral Amyloid Angiopathy

Lobar Hemorrhag

e

Microbleeds

The ICH Score ComponentsGCS score

3–4 25–12 1

13–15 0ICH volume, cm3

>30 1<30 0IVHYes 1No 0

Infratentorial origin of ICH

Yes 1No 0

Age, y80 1

<80 0Total ICH Score 0–6

Hemphill, J. C. et al. Stroke 2001;32:891-897

The ICH Score and 30-day mortality

Rost, N. S. et al. Stroke 2008;39:2304-2309

FUNC score prediction tool

ICH: Blood Pressure Management

• BP Reduction: preferred IV agents–Labetolol or esmolol (beta blockers)–Nicardipine (CCBs)–Fenoldopam (dopamine agonist)

• Best to avoid–Nitroprusside

• Can simultaneously increase ICP lower MAP, and severely decrease CPP

Rose J and Mayer SA. Neurocritical Care 2004;1:287.

Neurogenic Stress Cardiomyopathy

• AKA “neurogenic stunned myocardium”• Develops within hours of SAH, etc.

– Sudden death in 12% of SAH– Post-menopausal females

• Spectrum of severity• Clinical features

– Substernal chest pain; dyspnea; cardiogenic shock– CXR with pulmonary edema– Elevated cardiac markers

• Troponin I peaks on day of rupture• BNP

Neurogenic Stress Cardiomyopathy

– EKG changes• 25-75% of patients with SAH• Sinus brady or tachy, ST abnormalities, T wave

inversions, QTc prolongation• Arrhythmias: A-fib, A-flutter, SVT, PVCs,

junctional rhythms, ventricular rhythms– Echo

• Regional wall motion abnormalities beyond single vascular territory

• Apical ballooning akinesis or dyskinesis • Reduced LVEF

– Normal coronary angiogram

Neurogenic Stress Cardiomyopathy

Normal Abnormal

Cardiac Echo

Normal Abnormal

Clinical Signs of Elevated ICPCombination of signs• Depressed level of consciousness• Reflex hypertension, with or without

bradycardia • Headache• Vomiting• Papilledema• Cranial nerve palsies

Cerebral Herniation Syndromes• Decreased cerebral

perfusion pressure causing ischemia

• Midline shift causing ventricular obstruction

• Types1. Uncal2. Central (and # 6)3. Cingulate

(subfalcine) 4. Transcalvarial5. Cerebellar

ICH: Cerebral Edema

• Dexamethasone– No benefit on outcome, but

complications (infections and hyperglycemia) are more common

Poungvarin N, et al, N Engl J Med 1987;316:1229Tellz H, et al, Stroke 1973;4(4):541-6.

STANDARD: No Steroids!

ICH: Cerebral Edema• Osmolar therapy

– Glycerol has no effect on outcome– High-dose mannitol (1.4 g/kg) results

in better ICP control and early clinical response than lower doses

Yu YL, et al, Stroke 1992; 23:967Cruz J, et al, Neurosurgery 2002; 51:628.

GUIDELINE: Mannitol 20% for patients with increased ICP or symptomatic mass effect

OPTION: 23.4% HTS (30 ml)

Intracranial HTN Teatment Modalities• Insert ICP monitor• General goals: Maintain ICP < 20 mm Hg and

CPP > 65 mm Hg• For ICP > 20-25 mm Hg for > 5 minutes

– Drain CSF via ventriculostomy– Elevate head of bed– Osmotherapy– Sedation, agitation and fever control– Hyperventilation– Pressor therapy to maintain MAP and ensure

CPP• For refractory intracranial HTN

– Phenobarbital/Hypothermia/Decompressive craniotomy

Osmolality of IV fluidsFluid Osmolality (mOsm/kg)

5% Dextrose 252Lactated ringers 250-260

Plasma 2855% Albumin 290

Normal Saline 0.9% 30825% Albumin 310

6% Hetastarch 3102% Normal Saline 6823% Normal Saline 1025

25% Mannitol 13757.5% Normal Saline23.4% Normal Saline

24008008

BWH NeuroICUProtocol for Mannitol

Na, BUN, Glu, Cr, Glu and osm1 hour prior to dosing mannitol

Check Na, BUN, Glu, OsmIs Osm > 310

Yes No

Calculate Osm Gap Administer mannitol

If gap < 10 & Na < 160Give mannitol

If gap > 10 or Na > 160Hold mannitol and notify HO

•Osm gap=measured osm-calculated osm•Calculated Osm 2(Na)+BUN/2.8+Glu/18

Early seizures after ICH• Clinically apparent seizures

– 4% in 1st 24 hours; 8% in 1st month– Predictors: lobar location, small ICH volume– No convincing effect on outcome

• Electrographic seizures– 28-31% by continuous EEG over ~ 72 hours– Predictors; hematoma enlargement on 24-hr

CT– Periodic discharges associated with poor

outcomePassero et al, Epilepsia, 2002Vespa et al, Neurology, 2003Classen et al, Neurology, 2007

Kilpatrick et, Arch Neurolgoy 1990Franke et al, JNNP, 1992

ICH: Seizure Prophylaxis

• Seizure after ICH – 10% have generalized tonic-clonic

seizures

Passero S, et al, Epilepsia 2002;43:1175.

• OPTION: Prophylactic anticonvulsants for 7 days for patients with large ICH at risk for increased ICP

ICH: Non-Convulsive Seizures

• Continuous EEG Monitoring–Stuporous or comatose patients with

nonconvulsive seizures or SE detected only with cEEG

–NCSE is associated with clinical worsening, increased midline shift, and hematoma expansion

Vespa P, et al, Neurology 2003;60:1441Claassen, J et al, Neurology 2007;69:1356

OPTION: Midazolam, Propofol, or Pentobarbital infusion for NCSE

– Increased rate of 33%-expansion (54% vs. 16%)

– Larger effect than admission SBP, DBP or pulse pressure

– Independent effect on mortality and functional outcome

Warfarin-related ICH most severe

Flibotte JJ. Neurology 2004;63:1059-1064.

Coumadin Reversal: FFP• Replaces all clotting factors• May need 6-8+ U FFP to fully reverse• May not reverse all patients• Takes time and resources• Takes volume ->CHF risk in elderly• Has been replaced EU with PCC to

reduce volume

Coumadin Reversal - PCCs• Contains varying amounts of Vitamin K dependent

factors (II, VII, IX, X) and particularly VII• Lot to lot variability in factor levels• Given over 10-15 minutes• May be superior to FFP as a source of factor

replacement• Recommended in critical/life threatening bleeding

associated with warfarin (Ansell, Chest 2004)• Difficult to use at most U.S. hospitals

– Unfamiliar to most ED personnel– May require hematology consultation

Treatment of Warfarin Associated ICH

Aguilar et al Mayo Clin Proc. 2007;82:82-92

Treatment of Warfarin Associated ICH

Aguilar et al Mayo Clin Proc. 2007;82:82-92

ICH: Coagulopathy• Emergency reversal of warfarin

–Prothrombin complex concentrate (PCC) corrects the INR faster than fresh frozen plasma (FFP)

–Worsening occurs more often when INR remains >1.4

Freeman WD, et al, Mayo Clin Proc 2004;79:1495Yasaka M, et al, Thromb Haemostasis 2003;89:278

GUIDELINE: Vitamin K 10 mg IV and FFP (15 ml/kg) or PCC (15-30 U/kg)

OPTION: Recombinant FVIIa

Reversal of Treatments• Warfarin– Vitamin K– Fresh frozen plasma– Protein complex concentrates

• Dabigatran – Direct Thrombin Inhibitor– No antidote– Hemodialysis

• Rivaroxaban/Apixiban – Direct Factor Xa Inhibitor– Hemostatics PCC, rFVIIa may be considered but not been evaluated– NOT dialyzable

Surgical Therapies for ICH• Surgical evacuation

– Large (>3 cm) cerebellar hemorrhages

– Large lobular hemorrhages

– Substantial mass effect

– Rapidly deteriorating condition.O’Connell KA, et al. JAMA. 2006;295:293-298.

STICH Trial: Surgery for ICH?

• 1033 enrolled• Eligible if clinical

equipoise• Enrollment within 72

hours of onset– Early surgery– No early surgery

• No effect on mortality• No effect of outcome

Early Surgery

No Early Surgery

Dead or Disabled 63% 64%Good Outcome 26% 24%

Mendelow DA, et al, Lancet 2005;365;387

42

365-Day MISTIE II MESSAGE• Greater benefit at 365 than 180 days

• 14% upward shift across mRS levels 5 to 0 at 365 days

• 13 -14% fewer MIS-treated subjects in LTC facilities

• Shorter hospital stay for MIS-treated subjects

• Estimated acute-care cost savings of $44,000

ICH: DVT Prophylaxis

• DVT prophylaxis –Heparin 5000 U SC q12H started on day 2 is safe and reduces DVT/PE

–STANDARD: Start low dose subcutaneous heparin on day 2

–OPTION: Enoxaparin 40 mg qdBoeer A, et al, J Neurology Neurosurg Psychiatry 1991;54:466

Neurocritical Care Units Can Improve ICH Outcome

Summary•Epidemiology•Imaging•Prognosis•Neurogenic stress cardiomyopathy•Seizures•Hypertonic saline•Protein complex concentrates•New research

Thank You

Galen V. Henderson, MDghenderson@partners.org