Stop the Bleeding! An Update on the Prevention and

Vol. XV
Issue 2
Mar.Apr 2005
Stop the Bleeding! An Update on the Prevention and
Treatment of Intracerebral Hemorrhage
Intracerebral hemorrhage (ICH) is the most fatal
form of stroke. Mortality at 30 days can exceed 50%
while, among survivors, as few as 20% live
independently at 6 months (Figure 1).1, 2 ICH accounts for
10% to 15% of all strokes in the United States, affecting
approximately 65,000 people each year, with higher
figures in Asia where 20% to 40% of strokes may be due
to ICH.3 While effective strategies have been sorely
lacking for treating ICH when it occurs, as well as
preventing it in patients at risk, recent exciting
developments point the way to novel interventions that
may soon offer hope.
Epidemiologic studies suggest the majority of
primary ICH cases are the manifestation of two forms of
chronic small vessel disease, hypertensive vasculopathy
and cerebral amyloid angiopathy (CAA). Acute vascular
injuries, such as those associated with malignant
hypertension, account for a smaller proportion, while
secondary ICH can result from tumors, vascular
malformations, and the occasional ruptured aneurysm.
Hemorrhage location within the brain often provides
clues to the underlying cause, with longstanding
hypertension causing ICH in the basal ganglia, thalamus,
brain stem, and cerebellum, and CAA causing lobar and
rarely cerebellar ICH (Figure 2).4-8
S m a l l Ve s s e l D i s e a s e a n d I C H
Longstanding hypertension causes lipohyalinosis
of small, deep penetrating arteries, the rupture of which
results most commonly in deep hemispheric or brain
stem hemorrhage.4 Occasionally, lobar hemorrhages also
may occur in association with hypertension.
Figure 1. Outcome at 3 months for 435 patients with supratentorial ICH (333 unrelated to warfarin and 102 with warfarin-related
ICH) admitted to Massachusetts General Hospital. Mortality is reported as a percentage of the entire cohort. There were no survivors
in persistent vegetative state (Glasgow Outcome Scale (GOS) score. 2. Reprinted from Arch Intern Med 2004; 164;880-884.
STROKE Clinical Updates
© National Stroke Association
majority of anticoagulant-related ICH occurs when the
INR is 2.0 to 3.0,18 suggesting that factors other than
intensity of anticoagulation predispose to
hemorrhage. The current leading hypothesis is that, in
most cases, warfarin does not affect hemorrhage
occurrence, but rather hemorrhage severity. Thus, a
hemorrhage that might remain subclinical in the
absence of anticoagulation enlarges to become a
devastating ICH in an anticoagulated patient.16 The
identification of CAA as a risk factor for warfarinrelated hemorrhages in the lobar brain regions22
supports this hypothesis, as does the observation
that leukoaraiosis, a neuroimaging manifestation of
small vessel disease, is associated with a higher risk
of ICH in patients treated with warfarin.23, 24
Figure 2. Axial CT scans from 5 patients demonstrate ICH in the
pons (a), cerebellum (b), thalamus (c), basal ganglia (d), and the
corticosubcortical or lobar brain regions (e).
Epidemiologic studies support the association between
hypertension and nonlobar ICH, 8 and clinical trials
demonstrate a clear decrease in risk of ICH with
sustained blood pressure control.8-10
Cerebral amyloid angiopathy (CAA), defined as
amyloid deposition in cerebral vessel walls, affects
capillaries, arterioles, and small to medium-sized arteries
of the cerebral cortex, overlying leptomeninges, and
cerebellum.5, 11 12 In a process that begins with amyloid
deposition in the smooth muscle media of these vessels
and culminates in total obliteration of viable smooth
muscle cells, CAA causes ICH when severely affected
vessels rupture with extravasation of blood into the brain
parenchyma. The main constituent of vascular amyloid
in sporadic CAA is the b-amyloid peptide (Ab). The only
established risk factor for CAA, other than age, is
possession of the Apoliprotein E (APOE) e2 and e4
alleles.8, 13-15
Anticoagulation-related ICH
Anticoagulation with warfarin increases the risk
of ICH and worsens its severity, approximately doubling
its mortality (Figure 1).16-18 Of note, among the smaller
proportion of patients with warfarin-related ICH who
survive, functional outcome appears to be no different
from those surviving non warfarin-related ICH.18 The
annual risk of ICH in patients undergoing long-term
anticoagulation for atrial fibrillation is 0.2% to 0.6%, with
higher rates noted in clinical trials using target
international normalized ratio (INR) values > 4.0.19 The
excess mortality of ICH when it occurs is likely related to
prolonged bleeding after symptom onset, which is
commonly observed in patients with anticoagulationrelated ICH.20 This observation highlights the importance
of emergent reversal of anticoagulation for patients with
warfarin-related ICH.
While long-term anticoagulation clearly increases
the risk of developing ICH, the mechanisms by which it
leads to bleeding remain unclear. Risk of ICH rises with
increasing intensity of anticoagulation.21 Nonetheless, the
Acute ICH
Patients with acute ICH present like patients with
other types of stroke, with the sudden onset of focal
neurologic dysfunction, although seizure and reduction
in level consciousness tend to occur more commonly
with ICH. Decreased level of consciousness is prominent
with large hematomas as well as smaller lesions in the
thalamus and brainstem. Headache and vomiting due to
increased intracranial pressure are also common.
Approximately one-fourth of patients who are initially
alert experience deterioration in their levels of
consciousness within the first 24 hours.25, 26 Ongoing
bleeding, leading to larger accumulations of blood in the
brain, is the most important cause of this deterioration.27
Although hematoma formation sets off a series of
reactions in the involved tissue that contribute to
neurologic injury,28-31mass effect of the ICH itself appears
to be the primary mechanism of injury. The damage
caused by ICH is proportional to the volume of blood that
extravasates from the ruptured vessel or vessels.20, 32, 33
ICH was once thought to be a brief event lasting seconds
to minutes; however, several studies suggest that as
many as 30% to 40% of patients experience ongoing
bleeding while in the emergency room, particularly if
they are taking warfarin.20, 27, 34
Tr e a t m e n t o f A c u t e I C H
Although ICH patients frequently become
critically ill and require specialized care within the
intensive care unit, management interventions most
likely to affect outcome must be made within the first
few hours of ictus in the emergency department (ED).
Early intubation is essential for patients with impaired
arousal when they are at risk for aspiration, hypoxemia
and hypercarbia due to impairment of reflexes that
protect the airway. The CT scan must be evaluated for
evidence of herniation or hydrocephalus, findings that
should prompt emergent neurosurgical evaluation.
Osmotic agents are the treatment of choice for reducing
intracerebral pressure (ICP) and reversing mass effect in
patients with herniation. Because of the transient nature
of its effect on ICP and the high risk of rebound
elevations in ICP associated with prolonged exposure,
hyperventilation should be reserved for use in those
patients about to undergo emergent neurosurgical
intervention. Blood pressure elevation is common in
acute ICH, but whether it is a consequence of the
hemorrhage or a contributor to prolonged bleeding is
not understood. Current American Heart Association
Guidelines recommend maintaining the mean arterial
pressure <130 mm Hg, the systolic blood pressure <
180 mm Hg, and the cerebral perfusion pressure above
70 mm Hg.1, 2 Since roughly one-quarter of ICH patients
in the ICU may develop seizures within the first 72
hours,35 prophylactic antiepileptic therapy may be
reasonable in critically ill patients, but is unproven.
Prophylactic anticoagulation for prevention of deep
venous thrombosis may be started 24 to 48 hours after
ICH when there is no evidence of ongoing hematoma
expansion.36 Given the evidence linking hyperglycemia
to increased mortality in ICH, tight glucose control may
be an important supportive measure.37
Hemostatic Management
The volume of blood that extravasates from the
ruptured vessel is a potent determinant of outcome.
The documentation among ICH patients imaged within
3 hours of symptom onset, which showed 38% had
evidence of ongoing bleeding in the ED, suggests that
emergently arresting this bleeding will result in smaller
hematoma volumes and improvement in outcome.
Recombinant activated factor VII (rFVIIa) is approved as
a treatment for bleeding in patients with hemophilia
who have antibodies to factor VIII or IX. The results of
the recently published phase IIB, dose-ranging, proofof-concept study, the Recombinant Activated Factor VII
Intracerebral Hemorrhage Trial,38 raise the exciting
possibility that stopping the bleeding may well be the
first effective specific intervention for acute ICH.
To evaluate the effect of rFVIIa on hematoma
expansion, the investigators conducted a multicenter,
double-blind, placebo-controlled trial involving 399
patients with primary ICH without evidence of
coagulopathy. Patients were assigned to receive 1 of 3
doses of rFVIIa (40, 80, or 160 µg/kg of body weight) or
placebo. Serial CT scans were completed over the
course of each patient’s hospitalization, and the volume
of extravasated blood was measured on each scan to
determine whether the hematoma had expanded.
Primary outcome was mean percentage increase in
hematoma volume measured 24 hours after
administration of drug or placebo. The group receiving
the highest dose of rFVIIa had a significantly smaller
increase than the placebo group, but there was a trend
toward benefit with smaller doses as well (Figure 3).38
Strikingly, 3-month mortality in the combined rFVIIa
group was 18% compared to 29% in the placebo group,
without an increase in severe disability despite the fact
that severe arterial and venous thromboembolic
adverse events were more than 3 times as common in
the rFVIIa groups as in the placebo group (7% vs 2%).
These results, while promising, require confirmation in
the larger phase III trial already being planned. In
particular, it will be important to determine whether
lower doses of rFVIIa can achieve equally impressive
effects on hematoma expansion and clinical outcome
while minimizing thromboembolic complications.
Reversal of anticoagulation
The principles of hemostatic management
probably apply even more crucially to anticoagulantassociated ICH, where emergent reversal of
anticoagulant effect is likely to improve outcome.
Although the ideal agents and proper dosing strategies
remain to be determined, the present state of
knowledge suggests that immediate correction of the
coagulopathy is mandatory, along with frequent
monitoring of the coagulation status in the emergency
department to insure complete and sustained reversal
of coagulopathy
Ve n t r i c u l a r B l o o d a n d
The presence of blood within the ventricles is
common in patients with ICH, and associated with high
mortality.39 Although the deleterious effect of
intraventricular blood may be related to the
development of obstructive hydrocephalus, evidence
suggests blood within the ventricles can have direct
toxic effects independent of hydrocephalus. Ongoing
clinical trials are investigating whether the application
of thrombolytics through indwelling intraventricular
catheters is safe and improves outcome.40
Surgical Evacuation
Surgical evacuation of cerebellar hemorrhages
is life saving and deficit-sparing. While patients whose
hemorrhages are < 3 cm in diameter as measured on
CT scan may recover well without surgery, all patients
with cerebellar ICH should receive emergent
neurosurgical evaluation. The application of surgical
evacuation to hemorrhages elsewhere in the brain,
however, is less clear. Although evacuation offers the
theoretical benefits of reducing mass effect and
arresting the release of toxic byproducts of the
hematoma, its benefit has not been confirmed in
randomized trials.41 At present, many centers restrict
surgical intervention to patients with cerebellar ICH and
those with lobar ICH who develop neurologic
Primary Prevention of ICH
The most crucial intervention to prevent ICH is
adequate control of hypertension.10 Although no
existing medications have been proven to prevent
CAA-related hemorrhage, there are multiple potential
targets for therapies aimed at altering the metabolism
or bioactivity of Ab. One approach to reach early
clinical trials is the use of a low molecular weight
anionic molecule that interferes with the interaction of
ICH is the most lethal form of stroke.
Prompt evacuation of cerebellar
hemorrhages is both life-saving and deficitsparing. While the emergent institution of
supportive measures in the ED is crucial,
targeted hemostatic therapy with rFVIIa
provides the first promising specific
treatment for acute ICH. Primary and
secondary prevention of ICH at present
involve aggressive control of hypertension
and the judicious selection of patients for
long-term anticoagulation.
Figure 3. Estimated Mean Percent Change in ICH Volume 24 Hours after
administration of rFVlla or placebo for 399 patients enrolled in the
Recombinant Activated Factor VII Intracerebral Hemorrhage Trial. 38 RR
indicates relative reduction. Bars represent 98.3% confidence intervals.
Ab with sulfated glycosaminoglycans in the basement
membrane of vessel walls.42
Secondary prevention of ICH
Secondary prevention strategies differ
depending on whether the initial ICH was lobar or
nonlobar. The recurrence rate for lobar hemorrhage is
considerably higher than for nonlobar hemorrhage.43, 44
While careful control of hypertension reduces the risk
of recurrent nonlobar hemorrhage,10 it probably has
little effect on recurrent lobar hemorrhage.43 According
to a decision analysis model, the risk of recurrent
hemorrhage outweighs the benefit of anticoagulation in
patients with both nonvalvular atrial fibrillation and a
history of lobar hemorrhage, while patients with a
history of nonlobar hemorrhage may benefit from
anticoagulation if their ischemic stroke risk is high.45 The
risk of using aspirin in patients with atrial fibrillation
and previous lobar ICH may outweigh the benefits in
patients at low risk for ischemic stroke, but the
cardiovascular benefits of ASA must also be taken into
AmytisTowfighi, MD and Jonathan Rosand, MD, MSc
Vascular and Critical Care Neurology, Massachusetts
General Hospital/Harvard Medical School
Research Support
Research funding: American Academy of Neurology
Research and Education Foundation; National Stroke Association;
and the National Institute of Neurological Disorders and Stroke.
Dr. Rosand is a member of the Recombinant Activated Factor VII
Intracerebral Hemorrhage Trial Investigators Group and has
received research support and speaking fees from Novo Nordisk
Send correspondence to:
Sponsored by an
educational grant from
Novo Nordisk
Jonathan Rosand, MD, MSc
Neurology Clinical Trials Unit
15 Parkman Street, ACC 836
Boston, MA 02114 USA
Tel: (617)724-8773
Fax: (617)726-5346
Email: [email protected]
1.Lépine R. Note sur la paralysie glosso-labiée cérébrale à forme
pseudo-bulbaire. Revue Mensuelle de Médecine et de Chirurgie.
2.Davison C, Kelman H. Pathological laughing and crying. Arch Neurol
Psychiatry. 1939;1442:595-643.
3.Lawson JR, Macleod RDM. The use of imipramine ('tofranil') and
other psychotropic drugs in organic emotionalism. Br J Psychiatry.
4.Ross ED, Stewart RS. Pathological display of affect in patients with
depression and right frontal brain damage. J Nerv Ment Dis.
5.Hanger HC. Emotionalism after stroke (letter). Lancet. 1993 Nov
6.Wolf JK, Santana HB, Thorpy M. Treatment of 'emotional
incontinence' with levodopa. Neurology. 1979 Oct;29(10):1435-1436.
7.Wilson SAK. Some problems in neurology. Ii: Pathological laughing
and crying. J Neurol Psychopathol. 1923;4:299-333.
8.Langworth O, Hesser F. Syndrome of pseudobulbar palsy. Arch
Intern Med. 1940;65:106-121.
9.Poeck K. Pathological laughter and crying. In: Fredricks JAM, ed.
Handbook of clinical neurology. Amsterdam: Elsevier Science;
10.Robinson RG, Parikh RM, Lipsey JR, Starkstein SE, Price TR.
Pathological laughing and crying following stroke: Validation of
measurement scale and double-blind treatment study. Am J
Psychiatry. 1993 Feb;150(2):286-293.
11.Schiffer RB, Herndon RM, Rudick RA. Treatment of pathological
laughing and weeping with amitriptyline. N Engl J Med. 1985 Jun
12.Andersen G, Vestergaard K, Riis JO. Citalopram for post-stroke
pathological crying. Lancet. 1993; Oct 2;342(8875):837-839.
13.Burvill PW, Johnson GA, Jamrozik KD, Anderson CS, StewartWynne EG, Chakera TM. Anxiety disorders after stroke: Results from
the perth community stroke study. Br J Psychiatry. 1995
14.Piamarta F, Iurlaro S, Isella V, Atzeni L, Grimaldi M, Russo A,
Forapani E, Appollonio I. Unconventional affective symptoms and
executive functions after stroke in the elderly. Arch Gerontol Geriatr
Suppl. 2004;(9):315-323.
15.Morris PU, Robinson RG, Raphael B. Emotional lability following
stroke. Aust N Z J Psychiatry. 1993 Dec;27(4):601-605.
16.Kim JS, Choi-Kwon S. Poststroke depression and emotional
incontinence: Correlation with lesion location. Neurology. 2000 May
17.Tang WK, Chan SS, Chiu HF, Ungvari GS, Wong KS, Kwok TC.
Emotional incontinence in chinese stroke patients--diagnosis,
frequency, and clinical and radiological correlates. J Neurol. 2004
18.Calvert T, Knapp P, House A. Psychological associations with
emotionalism after stroke. J Neurol Neurosurg Psychiatry. 1998
19.MacHale SM, O'Rourke SJ, Wardlaw JM, Dennis MS. Depression
and its relation to lesion location after stroke. J Neurol Neurosurg
Psychiatry. 1998 Mar;64(3):371-374.
20.Brown KW, Sloan RL, Pentland B. Fluoxetine as a treatment for
post-stroke emotionalism. Acta Psychiatr Scand. 1998 Dec;98(6):455458.
21.Burns A, Russell E, Stratton-Powell H, Tyrell P, O'Neill P, Baldwin R.
Sertraline in stroke-associated lability of mood. Int J Geriatr
Psychiatry. 1999 Aug;14(8):681-685.
22.Andersen G. Treatment of uncontrolled crying after stroke. Drugs
and Aging. 1995 Feb;6(2):105-111.
23.Murai T, Barthel H, Berrouschot, J. Sorger, D., von Cramon DY,
Muller U. Neuroimaging of serotonin transporters in post-stroke
pathological crying. Psychiatry Res: Neuroimaging. 2003 Jul
24.Langhorne P, Stott DJ, Robertson L, MacDonald J, Jones L,
McAlpine C, Dick F, Taylor GS, Murray G. Medical complications after
stroke: A multicenter study. Stroke. 2000 Jun;31(6):1223-1229.
25.Allman P, Hope T, Fairburn CG. Crying following stroke. A report on
30 cases. Gen Hosp Psychiatry. 1992 Sep;14(5):315-321.
26.Kim JS. Post-stroke emotional incontinence after small
lenticulocapsular stroke: Correlation with lesion location. J Neurol.
2002 Jul;249(7):805-810.
27.Choi-Kwon S, Kim JS. Poststroke emotional incontinence and
decreased sexual activity. Cerebrovasc Dis. 2002;13(1):31-37.
28.House A, Dennis M, Molyneau A, Warlow C, Hawton K.
Emotionalism after stroke. Br Med J. 1989 Apr 15;2198(6679):991-994.
29.Robinson RG, Starr LB, Kubos KL, Price TR. A two year longitudinal
study of post-stroke mood disorders: Findings during the initial
evaluation. Stroke. 1983 Sep-Oct;14(5):736-7414.
30.Sloan RL, Brown KW, Pentland B. Fluoxetine as a treatment for
emotional lability after brain injury. Brain Inj. 1992 Jul-Aug;6(4):315319.
31.Ramasubbu R, Patten SB. Effect of depression on stroke morbidity
and mortality. Can J Psychiatry. 2003 May;48(4):250-257.
32.Derex L, Ostrowsky K, Nighoghossian N, Trouillas P. Severe
pathological crying after left anterior choroidal artery infarct.
Reversibility with paroxetine treatment. Stroke. 1997 Jul;28(7):14641466.
33.Mukand J, Kaplan M, Senno RG, Bishop DS. Pathological crying
and laughing: Treatment with sertraline. Arch Phys Med Rehabil. 1996
Wayne Clark, M.D.
Oregon Health Sciences University
Ashfaq Shuaib, M.D.
Director of Neurology
University of Alberta
Jeffrey Hecht, M.D.
Patricia Neal Rehabilitation Center
Don Smith, M.D.
Colorado Neurological Institute
William G. Barsan, M.D.
Emergency Medicine
University of Michigan
Robert W. Hobson II, M.D.
Vascular Surgeon
UMDNJ-NJ Medical School
Joseph Zambramski, M.D.
Barrow Neurological Institute
Jose Billér, M.D.
Indiana University
Marc Mayberg, M.D.
Executive Director
Seattle Neuroscience Institute
Editorial Board
Steven R. Levine, M.D.
Professor of Neurology
Stroke Program
Mt. Sinai School of Medicine