Intracerebral Hemorrhage - 2021

REVIEW ARTICLE
Intracerebral
Hemorrhage

C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E
ONLINE
By Christa O’Hana S. Nobleza, MD, MSCI
ABSTRACT
PURPOSE OF REVIEW: Nontraumatic intracerebral hemorrhage (ICH) is the
second most common type of stroke. This article summarizes the basic
pathophysiology, classification, and management of ICH and discusses the
available evidence on therapy for hematoma, hematoma expansion, and
perihematomal edema.
RECENT FINDINGS: Current available data on potential therapeutic options for

ICH are promising, although none of the trials have shown improvement in
mortality rate. The literature available on reversal of anticoagulation and
antiplatelet agents after an ICH and resumption of these medications is
also increasing.
SUMMARY: ICH continues to have high morbidity and mortality. Advances in

therapeutic options to target secondary brain injury from the hematoma,
hematoma expansion, and perihematomal edema are increasing. Data on
reversal therapy for anticoagulant-associated or antiplatelet-associated
ICH and resumption of these medications are evolving.
INTRODUCTION
N
ontraumatic intracerebral hemorrhage (ICH) is the second most
CITE AS: prevalent type of stroke in the world, with a prevalence of
CONTINUUM (MINNEAP MINN) 17.9 million globally,1 and it accounts for up to 20% of all strokes.2
2021;27(5, NEUROCRITICAL CARE):
1246–1277. Primary ICH, usually due to cerebral small vessel damage,
comprised 26.2% of the 11,931,000 global incident strokes in 2017.3
Address correspondence to The American Heart Association’s 2020 stroke statistics show that a persistent
Dr Christa O’Hana S. Nobleza,
2500 N State St, Jackson,
racial disparity of ICH exists, with higher age-adjusted incidence of first-ever
MS 39216, christaohana14md@ ICH in Blacks than in Whites.1 In women, late menopause, gestational
yahoo.com. hypertension, pregnancy-associated hypertensive disorders, preterm delivery,
RELATIONSHIP DISCLOSURE:
and stillbirth increase risk for ICH.4
Dr Nobleza reports no In the United States, the mortality rate for ICH declined from 31.6% for the
disclosure. years 2005-2009 to 24% in 2012-2015.5 The overall burden of ICH on patients,
UNLABELED USE OF caregivers, and society encompasses not only the financial burden of health care
PRODUCTS/INVESTIGATIONAL but also impaired patient and caregiver quality of life, severe disability, caregiver
USE DISCLOSURE:
burnout, and post–intensive care syndrome.6,7
Dr Nobleza reports no
disclosure.
INTRACEREBRAL HEMORRHAGE CLASSIFICATION
© 2021 American Academy
ICH can be classified according to etiology, risk factors, or anatomic location. A
of Neurology. general classification subdivides ICH into primary (or spontaneous) and
1246 OCTOBER 2021
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

secondary (or nonspontaneous) ICH. Primary ICH comprises ICH due to KEY POINTS
cerebral small vessel damage, most commonly associated with hypertension or
● The American Heart
cerebral amyloid angiopathy (CAA), whereas secondary ICHs are those with Association’s 2020 stroke
associated known etiologies. The classification schemes may have implications statistics show that a
for both clinical management and patient outcomes; however, this has not been persistent racial disparity of
well established, and their application should still be individualized. intracerebral hemorrhage
(ICH) exists, with higher
Primary intraventricular hemorrhage (IVH) is a type of nontraumatic ICH
age-adjusted incidence of
that occurs mainly in the ventricles and adjacent ependyma without associated first-ever ICH in Blacks than
parenchymal ICH. It is much less common than other types of nontraumatic in Whites. In women, late
ICH, accounting for only 3.1% of all nontraumatic ICH.8 Primary IVH is usually menopause, gestational
hypertension, pregnancy-
idiopathic; however, 11.4% of patients with IVH have associated etiologies,
associated hypertensive
including hypertension, arteriovenous malformation (AVM), moyamoya disorders, preterm delivery,
disease, coagulopathy, and arteriovenous fistula. IVH in association with ICH has and stillbirth increase risk
a prevalence of 40%.9 The presence of IVH dictates the potential need for for ICH.
external ventricular drain and intraventricular thrombolysis.10 The 2017 CLEAR
● Classification schemes
III (Clot Lysis: Evaluating Accelerated Resolution of Intraventricular for ICH may have
Hemorrhage Phase III) trial10 and three meta-analyses on intraventricular implications for both clinical
fibrinolysis clinical trials11 showed that intraventricular fibrinolysis had a trend of management and patient
improved mortality with no significant increase in complication rates, but no outcomes; however, this has
not been well established,
difference was seen in the primary outcome measure (good functional outcome) and their application should
and more patients in the thrombolysis group survived in a severely dependent still be individualized.
state (modified Rankin Scale [mRS] score of 5). Potential complications analyzed
in IVH and intraventricular fibrinolysis studies include symptomatic rebleeding ● Hypertension can be
present in patients with
and ventriculitis. Hydrocephalus may also develop in association with IVH.
either lobar or nonlobar ICH,
Assessing for acute hydrocephalus on noncontrast head CT is important because although it is more
of its association with poor outcome in patients with ICH.12 Acute hydrocephalus prominent in those with
can be seen as dilatation of a part or all of the ventricles, whereas subtle signs nonlobar ICH.
such as rounding of frontal horn, sulcal effacement, and increase in temporal
horn width can be seen as well.13,14 Some common manifestations include
headaches, nausea, vomiting, double vision, blurred vision, gait difficulty,
upgaze impairment, personality changes, and seizures.
COMMON ETIOLOGIES OF INTRACEREBRAL HEMORRHAGE

This section discusses common etiologies of nontraumatic ICH that can be
encountered by neurologists.
Hypertensive Angiopathy
Hypertension is the most common cause of ICH, affecting up to 35 per 100,000
people per year (CASE 3-1).15 Hypertensive ICH is associated with chronic
changes in small cerebral vasculature resulting in arteriosclerotic changes that,
under pressure, lose the autoregulatory mechanism and become prone to
rupture.16 Proinflammatory cytokines such as interleukin (IL), tumor necrosis
factor-a, and vascular endothelial growth factor (VEGF) have been found to play
an important role in the cascade of secondary injury in ICH due to
hypertension.17 The most common locations associated with hypertensive ICH
include the basal ganglia, pons, cerebellum, and thalamus, although it may
involve the lobar areas as well. Usage of the term hypertensive ICH to refer only to
nonlobar ICH has recently been put into question as data are showing that
hypertension can be present in patients with either lobar or nonlobar ICH,
although it is more prominent in those with nonlobar ICH.18 Use of illicit or
CONTINUUMJOURNAL.COM 1247

INTRACEREBRAL HEMORRHAGE
CASE 3-1 A 49-year-old man with a history of hypertension presented to the

emergency department with a chief complaint of sudden severe
headache and acute-onset left-sided weakness.
His Glasgow Coma Scale (GCS) score was 14. Emergent head CT
revealed a 22-mL right frontal hemorrhage (FIGURE 3-1). His systolic blood
pressure was found to be 220 mm Hg. Hydralazine 10 mg IV was
administered. An hour later, while in the emergency department, the
patient deteriorated to a GCS score of 5 and was subsequently intubated.
A repeat CT head was obtained (FIGURE 3-2).
His systolic blood pressure remained around 200 mm Hg. Nicardipine
infusion was started with a target systolic blood pressure goal of less than
140 mm Hg. Neurosurgery was called to assess him for candidacy for
external ventricular drain placement. Mannitol 1 g/kg was administered
while awaiting central vascular access.
An external ventricular drain was placed in the emergency department
while waiting transfer to the neurocritical care unit. His examination was
unchanged after external ventricular drain placement. His systolic blood
pressure was better controlled after titration of the nicardipine infusion
to 10 mg/h. The patient was then admitted to the neurocritical care
service for close neurologic monitoring and further supportive care.
His course was further complicated by ventilator-associated
pneumonia and requirement of tracheostomy and gastrostomy tube
placement because of his persistent comatose state. Other workup
during the hospitalization included a CT angiogram, MRI with and without
contrast, and digital subtraction angiography; however, no tumor or
vascular malformation was found. The workup for his intracerebral
hemorrhage suggested that the likely etiology for the spontaneous lobar
ICH was hypertension.
Palliative care was consulted to discuss goals of care with the family.
The family wanted to give the patient a time-limited trial before further
considering transitioning goals of care to a palliative level of care. He was
eventually transferred to a long-term acute care facility. At the 90-day
visit, the patient was off the ventilator; however, he continued to be in a
vegetative state that required maintenance of tracheostomy and
gastrostomy tube.
1248 OCTOBER 2021

FIGURE 3-1
Imaging of the patient in CASE 3-1. Axial noncontrast CT head shows a right frontal lobar
hemorrhage (A) with associated intraventricular extension without evidence of
hydrocephalus (B, C).
FIGURE 3-2
Repeat imaging of the patient in CASE 3-1. Repeat axial noncontrast CT head shows
increased size of lateral (A, B), third (C), and fourth (D) ventricular hemorrhage with
hydrocephalus.
This case of hypertensive hemorrhage demonstrates hematoma expansion COMMENT

and worsening hydrocephalus because of the hematoma more extensively
involving the ventricular system. Underlying this gross worsening in imaging
is secondary brain injury occurring because of the inflammatory cascade
activated both focally and globally by the hematoma expansion. This
patient could have been a candidate for intraventricular thrombolysis after
the hematoma was found to be stable. For blood pressure control, IV
nicardipine was used. When the patient worsened, it was reasonable, as
seen in this case, to administer mannitol to manage increased intracranial
hypertension. Hypertonic saline is also an option, depending on
institutional policies in its administration (eg, central venous access
requirement). The patient was admitted to the neurocritical care unit for
close monitoring, but despite all the aggressive measures for this patient,
his functional status did not improve significantly.

recreational substances, such as cocaine, amphetamines, alcohol, or tobacco, and

diet (high saturated fat, high sodium, and high calorie) are common factors
associated with hypertension.1 Other unique contributors to hypertension
include climate, autumn season (specifically increased air pressure and higher
temperature on the day of the ictus),19 and licorice root, because of its active
component, glycyrrhizin.20 Hypertension as the etiology, elevated systolic blood
pressure on admission, and lower calcium levels all are associated with worse
outcome in ICH. It is recommended that blood pressure should be controlled
immediately after an ICH; however, how much or how quickly the blood
pressure should be lowered is still being debated.21 A long-term systolic blood
pressure goal of less than 130 mm Hg and diastolic blood pressure goal of less than
80 mm Hg may be ideal.15
Anticoagulant- and Antiplatelet-associated Intracerebral Hemorrhage

About one-third of patients presenting with ICH are taking anticoagulant or
antiplatelet medications, or both. The underlying theory for anticoagulant-
associated ICH is that it prolongs the hematoma formation but is not the direct
cause of it.22 The annual ICH rate increases from 0.3% to 0.6% in patients taking
anticoagulants, the majority of which are nontraumatic ICH with an associated
mortality rate of 40% to 65%.22 Although antiplatelet-associated ICH was not
found to have worse outcomes compared to the general ICH population, use of
combined antiplatelet and anticoagulant medications was associated with larger
ICH volume and worse functional outcome (mRS score of 4 to 6). Interestingly,
animal and human studies on warfarin-associated ICH revealed worse functional
outcomes as well as higher hematoma volumes compared to direct oral
anticoagulant–associated ICHs.23 Worth mentioning here is ICH associated with
the administration of IV recombinant tissue plasminogen activator (rtPA), which
is administered to up to 5.2% of patients with acute ischemic stroke.24 A more
in-depth discussion on ICH after IV rtPA is beyond the scope of this article;
however, it should be noted that symptomatic ICH, which is generally defined as
a neurologic deterioration (≥4 points on the National Institutes of Health Stroke
Scale score) that is attributed to the ICH, can occur in up to 11.3% of patients,25
depending on the timing of imaging, definition followed, imaging
characteristics, and whether mechanical reperfusion is considered. Because of
this, clinicians who make decisions regarding IV rtPA administration should be
aware of how to reverse IV rtPA as well.
The suspicion of potential medication-associated ICH should raise the level of
urgency in the management of patients with ICH because some patients may be
candidates for surgery if they receive timely reversal therapy; at times, reversal
therapy may be the only treatment that can be administered in addition to
supportive therapy. Important aspects in history taking for patients on
anticoagulant or antiplatelet medications include the dose, administration, and
last time the medication was taken. For patients who received IV rtPA, a high
index of suspicion is helpful if a patient deteriorates. Principles of airway,
breathing, and circulation assessment should be immediately applied followed by
an emergent CT head while preparing for possible reversal.
Cerebral Amyloid Angiopathy

Accumulation of amyloid β (Aβ) proteins along the cortical and leptomeningeal
vessel wall leading to degeneration is the common pathology involved in
1250 OCTOBER 2021

CAA-associated ICH, resulting in cerebral microbleeds and cortical superficial KEY POINTS
siderosis.26 The prevalence of CAA has been reported to be 5% of the population
● Hypertension as the
older than 65 years of age,27 with 14.7% of all spontaneous ICH likely associated etiology, elevated systolic
with CAA.28 Patients with CAA may be asymptomatic or may have a range of blood pressure on
symptoms, including having recurrent neurologic deficits in association with the admission, and lower
location of the ICH or catastrophic hemispheric hemorrhages. CAA-associated calcium levels all are
associated with worse
ICH can also present as progressive cognitive dysfunction followed by a sudden
outcome in ICH.
focal neurologic deficit, focal seizures, or transient ischemic attack–type events
(amyloid spells).13 MRI sequences such as gradient recalled echo (GRE), ● Important aspects in
susceptibility-weighted imaging (SWI), or T2* sequences are sensitive to history taking for patients on
susceptibility artifacts produced by hemosiderin manifesting as cerebral anticoagulant or antiplatelet
medications include the
microbleeds and macrobleeds. In the modified Boston criteria, the presence of dose, administration, and
ICH, cerebral microbleeds, or cortical superficial siderosis in lobar and cerebellar last time the medication was
areas in patients older than 55 years of age with no other etiology for ICH are taken.
commonly attributed to possible or probable CAA with a high sensitivity.14
● Differentiation of
However, in the setting of an older adult patient with concomitant hypertension, cerebral amyloid angiopathy
the presence of cerebral microbleeds on MRI may not fully distinguish a from hypertensive ICH has
hypertensive hemorrhage from CAA, especially if the ICH is located in deeper clinical implications that
structures. Differentiation of CAA from hypertensive ICH has clinical may affect future
antiplatelet and
implications that may affect future antiplatelet and anticoagulant medication risk
anticoagulant medication
assessments for these patients who are also at high risk for cardiovascular disease, risk assessments for these
since CAA carries a higher ICH recurrence risk29 (especially with the use of patients who are also at high
anticoagulants30) compared to hypertensive ICH, which has a low recurrence risk for cardiovascular
disease, since cerebral
risk of approximately 2% per year and does not carry an absolute
amyloid angiopathy carries a
contraindication for anticoagulants.31 Avoidance of long-term anticoagulants has higher ICH recurrence risk.
traditionally been suggested for patients with CAA15,31; however, more recent
data on resumption of anticoagulants in patients with lobar ICH indicate benefit ● Prior or known cerebral
for mortality, functional outcome, and stroke incidence.32 Antiplatelet agents are microbleeds are not
established to be a
generally not considered contraindicated in the setting of CAA,15 although an contraindication to the use
increased risk of recurrent ICH after lobar ICH has been reported in the general of IV recombinant tissue
population treated with antiplatelet therapy in a study of survivors of lobar plasminogen activator for
ICH.33 Prior or known cerebral microbleeds are not established as a acute ischemic stroke, and
MRI before thrombolysis
contraindication to the use of IV rtPA for acute ischemic stroke, and MRI before administration is not
thrombolysis administration is not recommended.34 recommended.
Vascular Malformation ● The most common clinical

presentation of
The most common vascular malformations that may cause ICH include AVMs
arteriovenous malformation
with or without associated arteriovenous fistula and cavernous malformations. is ICH followed by seizures.
Recognizing and diagnosing these as the etiology for ICH is important for
management. Increased suspicion of the presence of these vascular anomalies is
also important to guide diagnostic testing in ICH. The gold standard for the
diagnosis of AVMs and arteriovenous fistulas is digital subtraction angiography
(DSA). Cavernous malformations are usually diagnosed via MRI by their unique
popcornlike appearance on a T2-weighted sequence. Brain AVMs are tangled
dysplastic cerebral arteries and veins that meet at a vascular center without
intervening normal brain parenchyma. The overall incidence of AVMs ranges
from 1.10 per 100,000 to 1.42 cases per 100,000 patients.35 The most common
clinical presentation of AVM is ICH followed by seizures.36 Treatment options
for AVMs include microsurgical resection, embolization via endovascular
therapy, and stereotactic radiosurgery.35 Cavernous malformations account for

13% of cerebral vascular malformations37 and commonly present with seizures or

headaches in addition to ICH. Treatment may involve surgical treatment for
patients with symptomatic cavernous malformations38 and supportive care.
Other Etiologies of Intracerebral Hemorrhage

ICH can be found in up to 30% to 40% of patients with cerebral venous sinus
thrombosis (CVST) and should be ruled out, especially if the ICH distribution on
imaging is lobar or associated with an infarction that does not follow a typical
arterial distribution.39 The mechanism underlying the development of ICH in
CVST is primarily associated with the cerebral vein’s thrombosis causing venous
infarction and petechial hemorrhages, which then progresses to a parenchymal
hematoma.40 The incidence of CVST has increased from 0.2 to 0.5 per 100,000
person-years to 1.32 to 1.57 per 100,000 person-years, likely because of the use of
advanced imaging.41 The most common venous sinuses affected are the superior
sagittal sinus, lateral sinus, and sigmoid sinus,41 and the most common
presentation is throbbing, bandlike, burning, pounding, or thunderclap
headaches with acute to subacute and rarely chronic intermittent onset and
progression. It has been reported that ICH in the setting of CVST is considered a
risk factor for early seizures and death.41 Treatment remains anticoagulation
with unfractionated heparin or low-molecular-weight heparin, although the use
of non–vitamin K antagonist oral anticoagulants42 has also been recently
reported. For severe CVST unresponsive to anticoagulation, endovascular
therapy may be an option41; however, this is still not always available. The overall
prognosis of CVST is good with improved diagnosis and early treatment;
however, patients can still develop severe disability and death, especially in
severe cases.
Moyamoya disease is a chronic, progressive, spontaneous cerebrovascular
occlusive disease characterized by stenosis at the terminal portion of the internal
carotid artery and an associated vasculature that is usually described as netlike at
TABLE 3-1 Common Genetic Loci and Association With Spontaneous Intracerebral
Hemorrhagea
Association with spontaneous intracerebral

Genetic loci hemorrhage
APOE, COL4A1, COL4A2, CD36, TIMP1, TIMP2, MMP2, MMP9, Increased susceptibility to spontaneous intracerebral
KCNK17, CR1, STYK1, ACE, 1q22, CETP hemorrhage
FGA Thr312Ala, LIMK1, KCNK17 Protective against spontaneous intracerebral

hemorrhage
APOE ε2, ε4, ε2/ε3, GPX1 Lobar spontaneous intracerebral hemorrhage
APOE ε4, 1q22, COL4A2, TIMP1, TIMP2, MMP2, MMP9, ACE Deep spontaneous intracerebral hemorrhage
COL4A1, TIMP1, TIMP2, ACE Vascular integrity
Loci 17p12, gp130 (G/A), von Willebrand factor (rs216321), LIMK1, Hematoma expansion, admission level of consciousness,
APOE ε2, CFH Y402H, KCNK17 and functional outcomes
a
Data from Wahab KW, et al, J Neurol Sci.51
1252 OCTOBER 2021

the base of the brain or stenosed internal carotid arteries, which can be either KEY POINTS
unilateral or bilateral.43 Its diagnosis requires CT angiography (CTA), DSA, or
● Approximately 30% of
MRI/magnetic resonance angiography (MRA). Moyamoya disease is more patients with moyamoya
common in East Asia; in the United States, the reported incidence is 0.086 per disease can present with an
100,000,44 with a pattern of bimodal age distribution peaks in the first and ICH because of friable
fourth decades. Although moyamoya disease commonly presents with an collateral vessels that may
have formed micro and/or
ischemic event, approximately 30% of patients with moyamoya disease can
false aneurysms. Herpes
present with an ICH because of friable collateral vessels that may have formed simplex virus, varicella-
micro and/or false aneurysms.45 zoster virus, syphilis, and
Herpes simplex virus, varicella-zoster virus, syphilis, and severe acute severe acute respiratory
syndrome coronavirus 2
respiratory syndrome coronavirus 2 (SARS-CoV-2)46 infections have been
(SARS-CoV-2) infections
implicated as causes of ICH, with the primary pathology of vasculitic infiltration have been implicated as
of the blood vessels. Vascular irregularity is a common characteristic in imaging causes of ICH, with the
studies.47 More recently, endotheliopathy in SARS-CoV-2 infection was primary pathology of
proposed as a cause of ICH in patients affected, with prevalence reported to be vasculitic infiltration of the
blood vessels.
21.7% of all cases of cerebrovascular disease with COVID-19 (n = 23) in a cohort
of 1683 patients with COVID-19.46 ● Solid or hematologic
Vasculitis of the central nervous system (CNS), another potential etiology of malignancy can cause ICH
ICH, remains a diagnostic challenge because of its protean manifestations. because of vasculature
involvement, primary brain
Primary angiitis of the CNS is unique in that the patient only has vasculitis in the tumor, or metastatic
brain; a brain biopsy is usually required for definitive diagnosis.48 The use of disease.
black blood MRI sequences is increasing, especially in vasculitis, revealing vessel
wall contrast enhancement in 85% of patients with suspected vasculitis.48 ICH
was considered a “minor” neuroradiologic feature of vasculitis in a narrative
review that analyzed publications from 2002 to 2019, although it was seen in
20.5% of all patients included in the study48 and can be recurrent. Of note,
systemic vasculitis may also present with ICH49; this is usually differentiated
from primary angiitis of the CNS by its association with other constitutional
symptoms and serum markers, such as elevated erythrocyte sedimentation rate,
C-reactive protein, and antinuclear antibodies.
Solid or hematologic malignancy can cause ICH due to vasculature
involvement, primary brain tumor, or metastatic disease. Note that patients with
malignancies are hypercoagulable and are sometimes taking anticoagulant or
antiplatelet therapies as an outpatient. ICH can also be the initial presentation of
solid brain tumors50 or hematologic malignancies.
ROLE OF GENETICS
Genomic studies have evolved in the past decade, and their role in unraveling
pathomechanisms and therapy for ICH is increasing.51 TABLE 3-1 presents the
various genetic variants associated with nontraumatic ICH identified in a
systematic review.51 Their application in the clinical setting is limited to research
and providing guidance on the underlying pathophysiology and etiology of ICH.43
PATHOPHYSIOLOGY OF PERIHEMATOMAL EDEMA AND

INFLAMMATORY CASCADE
Thirty percent of patients with ICH may have hematoma expansion within the
first 6 hours of ICH occurrence,52 whereas up to 12% may have hematoma
expansion between 1-hour and 20-hour noncontrast head CTs.53 The insult from
the intracerebral hematoma after the onset of ICH may result in secondary brain
injury from the mass effect of the hematoma, hematoma expansion, or the

inflammatory cascade that ensues as reflected by perihematomal edema and

perihematomal expansion rate.54
An inflammatory reaction after ICH has implicated release of inflammatory
cytokines and chemokines after the focal brain injury in ICH.55 Immediately after
the hemorrhage, damage to neuronal cells and the release of damage-associated
molecular patterns (DAMPs) start a cascade of proinflammatory changes that
have been shown to last between 7 and 25 days in hemorrhagic stroke.56
Proinflammatory changes may persist beyond weeks and may be associated with
cognitive dysfunction after ICH.55 The focal mechanism of inflammation
involves DAMPs and subsequent increase in excitotoxicity, oxidative stress,
mitochondrial disturbances, thrombin activation, and hemoglobin and iron
release in the area of the hematoma. DAMPs induce adenosine, heat shock
protein, high mobility group box 1, and IL-33,57 and, together with
thromboinflammatory changes,58 cause immune cell recognition that activates
intracellular signaling pathways that subsequently activates microglia.59
Microglia activation releases cytokines and chemokines that also communicate
with astrocytes to recruit immune cells from the periphery.60 These peripheral
immune cells increase cytokines and produce reactive oxygen species and matrix
metalloproteinases in addition to their direct effect on the breakdown of the
blood-brain barrier.61 As the peripheral immune cells cross the blood-brain
barrier, platelet dysregulation and endothelial cell activation ensue, which cause
damage to the blood vessels and brain parenchyma and inflammation. All of
these changes are thought to contribute to edema expansion, which has been
shown to be associated with worse clinical outcomes.55
The global inflammatory cascade is thought to be activated via a similar
pathway through DAMPs. It is likely initiated by the hematoma mass effect that
may cause some mechanical injury to the contralateral hemisphere, which is seen
as intracranial injury that starts activation of DAMPs.55 Studies have shown
microglia activation in remote areas of the brain after an ICH.62 Evidence of
increased mRNA levels for IL-1β, IL-6, transforming growth factor β, tumor
necrosis factor-α, and IL-27 has been found in the contralateral hemisphere up to
7 days postictus.63
TABLE 3-2 History Data Important for Patients With Intracerebral Hemorrhage
◆ Age
◆ Current medications with timing of last intake, if possible: anticoagulants, antiplatelet
medications, antihypertensive medications, stimulants, weight-loss drugs
◆ Past medical history: recent trauma or operations, known comorbidities, past intracerebral
hemorrhage, liver or renal disease, hematologic or solid tumor malignancies
◆ Alcohol and illicit substance use
◆ Last known well, symptom onset and progression
◆ Family history of intracerebral hemorrhage
◆ Functional baseline
◆ Review of systems: blurring of vision, chest pain, headache, nausea, vomiting, dizziness,
fever, loss of appetite
1254 OCTOBER 2021

HISTORY AND PHYSICAL EXAMINATION KEY POINTS
Acute ischemic stroke, seizures, and ICH can present similarly, with an acute
● The insult from the
focal deficit or alteration in mental status often the main symptom. Because of intracerebral hematoma
this, prehospital system protocols have been established that emphasize elements after the onset of ICH may
of history and physical examination that should be obtained by emergency result in secondary brain
medical services to guide receiving clinicians on the potential diagnosis of the injury from the mass effect
of the hematoma,
patient being transported to the emergency department. Patients with acute
hematoma expansion, or the
neurologic change should be called into the emergency systems as stroke alerts. inflammatory cascade that
Several unique points in the history are important specifically for patients with ensues as reflected by
ICH to guide receiving clinicians on what they should prepare in advance in the perihematomal edema and
perihematomal expansion
emergency department for the arriving patients (TABLE 3-2). Unique features
rate. An inflammatory
that make it likely to be ICH rather than an ischemic stroke include symptoms reaction after ICH has
progressing after onset, associated headache, dysarthria, systolic blood pressure implicated release of
of 165 mm Hg or greater, diastolic blood pressure of 95 mm Hg or greater, inflammatory cytokines and
disturbance of consciousness, conjugate eye deviation, dysarthria, and upper chemokines after the focal
brain injury in ICH.
limb paralysis, with the last two features having the highest point value in the
Japan Urgent Stroke Triage (JUST) score.64 Improvement of symptoms after ● Patients with acute
onset, history of a cerebral infarction, and arrhythmia make it less likely to be neurologic change should be
ICH.64 This is demonstrated in CASE 3-1 with a patient who was hypertensive and called into the emergency
systems as stroke alerts.
had a focal neurologic deficit and an acute decline in consciousness with
associated headache. ● A nationwide US sample
Included in history taking is inquiry into the comorbid conditions of the showed mortality was higher
patient, such as hypertension, diabetes, renal failure, chronic obstructive in patients with ICH with
coagulopathy, liver disease,
pulmonary disease, congestive heart failure, obesity, and coagulopathy. A
acquired immunodeficiency
nationwide US sample showed mortality was higher in patients with syndrome, and congestive
coagulopathy, liver disease, acquired immunodeficiency syndrome (AIDS), and heart failure and,
congestive heart failure and paradoxically significant lower in those with paradoxically, significantly
hypertension, obesity, and hypothyroidism.5 Chronic alcohol use is associated lower in those with
hypertension, obesity, and
with hypertensive ICH, whereas the association of binge alcoholic consumption hypothyroidism.
with ICH is still unclear.65
● Immediate diagnosis of
DIAGNOSTIC CONSIDERATIONS ICH is important to be able
to institute measures to
Immediate diagnosis of ICH is important to be able to institute measures to stabilize the patient and, it is
stabilize the patient and, it is hoped, prevent hematoma expansion. Immediately hoped, prevent hematoma
after medical stabilization, neuroimaging should be done. The initial diagnostic expansion.
modality of choice is a noncontrast head CT. If the facility is capable, CTA should
● The initial diagnostic
be considered in some patients to exclude obvious vascular etiologies of ICH,
modality of choice for ICH is
especially for patients with associated risk factors for vascular lesions as an a noncontrast head CT.
etiology of the ICH, such as female sex, age younger than 65 years old,
nonsmoker, lobar ICH, IVH, and absence of hypertension or coagulopathy.15 The
sensitivity and specificity of CTA is high for vascular abnormalities with the
advantage of being noninvasive.66 DSA can still be considered if high clinical
suspicion remains or the noninvasive studies suggest a vascular lesion,15 for
example, in a young adult who is not hypertensive and presents with a cortical or
lobar hemorrhage with an unrevealing CTA. As part of the workup for etiologies
in the nonemergent setting, MRI with and without contrast and MRA can be
considered. Imaging features that are important to review specifically for ICH
include hematoma volume, presence of perihematomal edema, midline shift,
presence of IVH, location of the hemorrhage (infratentorial or supratentorial,
cortical versus subcortical), presence of signs of hydrocephalus, and evidence of

FIGURE 3-3
ABC/2 measurement and ICH Score calculation.
GCS = Glasgow Coma Scale; ICH = intracerebral hemorrhage; IVH = intraventricular hemorrhage.
TABLE 3-3 Six-point Approach to Radiologic Herniation Syndromea
Clinical information
◆ Directs image reviewer to potential area of interest and affected regions
◆ Includes history and physical examination
Anatomic landmarks
◆ Distinct known structures that are common reference points for measurements,
comparison, and locating other structures
Direction of mass effect
◆ In association with where the primary lesion is, the direction of force of the mass effect
assists in identifying directly and indirectly affected structures
Displayed structure
◆ Used to classify herniation type or syndrome
Indirect signs
◆ Analyzes other structures that may be affected by the herniated structure
Herniation-related complications
◆ Complications from herniation may be from compression of other structures, such as
adjacent brain parenchyma, tracts, blood vessels, or ventricles, which may result in
additional clinical deficit, areas of infarctions, or hydrocephalus
a
Modified with permission from Riveros Gilardi B, et al, Radiographics.73 © 2019 Radiological Society of
North America.
1256 OCTOBER 2021

herniation. Several radiologic signs, such as the black hole sign, swirl sign, or KEY POINTS
blend sign, and other findings can be associated with poor outcome.67 Hematoma
● The presence of
volume on noncontrast head CT is calculated by the ABC/2 method, where A is herniation is an important
the largest hematoma diameter, B is the diameter perpendicular to A, and C is the radiologic feature that
approximate number of CT slices with hemorrhage multiplied by the slice should be recognized and
thickness, which can vary from 3 mm to 10 mm68 with π estimated as 3 correlated with the clinical
examination of the patient.
representing an ellipsoid model.69 The ICH volume has been shown to predict
mortality in ICH.70 FIGURE 3-3 demonstrates an example of the application of ● Noncontrast head CT
ICH Score with ICH volume calculation. indicators of herniation
Perihematomal edema is another radiographic marker that has been a include midline shift,
therapeutic target of several trials; however, no trials have shown improvement hydrocephalus, or new
areas of infarction adjacent
in functional outcome.71 Imaging features such as hematoma volume, to displaced structures.
intraventricular hemorrhage, and perihematomal edema have been shown to be
associated with patient outcome.72
The location of the hemorrhage will also guide diagnostic and therapeutic
options for patients with ICH. For example, in an older adult with a
supratentorial cortical ICH, MRI may be helpful to determine the extent and
distribution of cerebral microbleeds, whereas CTA may be needed in a younger
patient with a subcortical supratentorial ICH who has a drug screen positive for
cocaine to rule out cocaine-induced vascular changes and determine the need for
aggressive management of blood pressure. A supratentorial cortical hemorrhage
in a young patient who is not hypertensive and has no other indications of
vasculopathy should lead the clinician to proceed with a DSA and/or MRI with
and without contrast for further workup of the ICH.
The presence of herniation is an important radiologic feature that should be
recognized and correlated with the clinical examination of the patient. Common
locations of herniation include subfalcine, uncal, descending or ascending
transtentorial, and tonsillar.73 A six-point approach has been suggested for the
radiologic assessment of herniation (TABLE 3-3).73 Consequences of herniation as
discovered by noncontrast head CT include midline shift, hydrocephalus, or new
areas of infarctions adjacent to displaced structures.
MANAGEMENT CONSIDERATIONS
The management of ICH is complex and involves coordination of care along the
health care continuum as well as integration of the management of the acute
brain injury and other organ system issues. TABLE 3-4 lists the diagnostic tests to
be considered in the management of ICH and their relevance.
Intracerebral Hemorrhage Systems of Care

Coordination of care for patients with ICH is important to ensure the proper
standards along the continuum and transition of care for these patients. Patients
presenting from the community with a suspected stroke should be brought to a
hospital with the capability of emergent brain imaging. TABLE 3-5 lists important
aspects of ICH systems of care, and FIGURE 3-4 depicts an algorithm for decision
making in ICH. Increasing data suggest that step-down units or intermediate care
units can be safe alternatives for patients with ICH.74 Deterioration (early
<24 hours and late 1 to 7 days) not resulting from hematoma expansion and
associated poorer outcome occur in as many as 17.3% of patients.75 Comorbidities
are highly prevalent, may manifest in the acute period of ICH, and will require
close primary care and potentially subspecialty follow-up, such as from

TABLE 3-4 Diagnostic Tests to Be Considered in the Management of Intracerebral

Hemorrhage
Tests Rationale Comments
Neuroimaging Exclude ischemic stroke Location of ICH may guide

further neuroimaging beyond
Assess intracerebral hemorrhage (ICH)
emergent noncontrast head CT
characteristics
and CT angiography
Evaluate for signs of high intracranial pressure or
herniation
Evaluate for potential for hematoma expansion
Evaluate need for external ventricular drain
Blood tests
Complete blood cell count White blood cell count demonstrates evidence of Elevated white blood cell count
underlying infection has been shown to be
associated with worse outcome
Red blood cell count demonstrates concurrent
systemic bleeding
Platelet count guides need for transfusion
Electrolytes Guide replacement of electrolytes as part of Patients may come in with

supportive care concomitant indicators of
hypovolemia
Guide hyperosmolar therapy
Renal function (blood urea nitrogen Guide risk assessment for ICH Patients with a history of
[BUN]/creatinine) chronic kidney disease are
Guide supportive care
prone to ICH; kidney disease
has also been associated with
poor outcome in ICH
Glucose Guide supportive care and need for feeding Elevated glucose has been
shown to be associated with
worse outcome
Coagulation studies (prothrombin Guide reversal and factor replacement Vitamin K antagonist–
time, international normalized ratio associated hemorrhages have
[INR] and activated partial been found to be associated
thromboplastin time) with worse outcomes
Cardiac-specific troponin May detect concomitant active cardiac ischemia Elevated troponin levels are
associated with worse outcomes
Alcohol level Risk assess complications from alcohol abuse that Is a risk factor for ICH
may affect management, such as liver cirrhosis,
platelet dysfunction, and alcohol withdrawal
Urinalysis and urine drug screen Guide differential diagnosis of etiology for
intracerebral hemorrhage
Exclude pregnancy
Exclude proteinuria associated with pregnancy
Other
ECG Demonstrate concurrent cardiac strain or ischemia
CT = computed tomography; ECG = electrocardiogram.
1258 OCTOBER 2021

hypertension specialists, cardiologists, nephrologists, and endocrinologists.
Nonetheless, not every patient with ICH requires intensive care unit (ICU) level
of care. Admitting patients to a step-down unit rather than the ICU had reported
advantages of decreasing ICU and hospital length of stay significantly.74 The
most important factors to consider in patient selection for step-down unit
admission are lack of infratentorial involvement and lack of IVH at least in the
third or fourth ventricles.
Emergent/Intensive Care Management Considerations

This section discusses the immediate management considerations for patients
presenting with an ICH.
MEDICAL STABILIZATION. Mechanical ventilation is required in up to 30% of

patients with ICH.76 Postintubation interventions initiated in the emergency
department, including appropriate tidal volume, proper endotracheal tube
position confirmed by chest radiography, assessing arterial blood gas values,
orogastric or nasogastric tube insertion for decompression, urethral catheter
insertion, utilization of quantitative capnography, and early sedative
administration, have been found to improve outcomes of in-hospital mortality
and likelihood of home discharge77 and should be considered by the consulting
neurologist. Initial blood tests for the workup of a patient with an acute
neurologic deficit should proceed (TABLE 3-4).
BLOOD PRESSURE MANAGEMENT. Blood pressure control is recommended upon

confirmation of the diagnosis of ICH, although the timing and target blood
pressure remain controversial.15,21 TABLE 3-678-80 summarizes several trials on
blood pressure management that have recently been published. Systolic blood
pressure has been found to be associated with hematoma volume.81 Hematoma
expansion occurs in up to 38% of patients with ICH82 and represents a
therapeutic target and an outcome measure.21 However, although it seems
implicit that lowering blood pressure might reduce hematoma expansion, the
relationship between the degree of lowered blood pressure and hematoma
expansion is still not fully elucidated, nor has a clear effect of blood
pressure–lowering strategies to mitigate hematoma expansion been shown. The
Important Points to Consider in Intracerebral Hemorrhage Systems of Care TABLE 3-5
◆ Emergent alert systems for stroke apply for intracerebral hemorrhage (ICH)
◆ Patients with a suspected stroke/ICH should be brought to the nearest hospital with
emergent brain imaging capabilities
◆ Simultaneous assessment and stabilization should be done immediately upon arrival
◆ Emergent brain imaging should follow
◆ Neurosurgical consultation should be done when ICH is confirmed
◆ Admission team is hospital dependent (eg, neurology, neurosurgery, neurocritical care teams
as primary team)
◆ Admission should be in a hospital area capable of frequent neurologic checks (eg,
neurocritical care unit, general intensive care unit, stroke unit)

2015 American Heart Association (AHA)/American Stroke Association (ASA)

recommendation is to reach a systolic blood pressure goal of less than 140 mm Hg.15
INTERACT2 (The Second Intensive Blood Pressure Reduction in Acute Cerebral
Haemorrhage Trial) showed a benefit from intensive treatment of blood pressure
in terms of improved functional outcome and health-related quality of life,
although a difference in death or severe disability was not detected.78 The
ATACH-II (Antihypertensive Treatment of Acute Cerebral Hemorrhage-II)
trial comparing lowering of systolic blood pressure within 4.5 hours to either
110 mm Hg to 139 mm Hg (treatment) or 140 mm Hg to 179 mm Hg (standard)21
did not find a significant difference for death or disability between the groups
but found that 7-day renal adverse events were higher in the treatment group
compared to the standard group (9.0% compared to 4.0%, P=.002). The trial was
stopped at 1000 participants because of futility. Critical assessment of the results
from INTERACT2 and ATACH-II raises the question of whether selection (eg,
large versus smaller ICH and deep versus lobar) might shed light not only on
the mechanism by which blood pressure lowering might exert its effect but also
the individual patients for whom it might work best. The SAMURAI (Stroke
Acute Management With Urgent Risk-factor Assessment and Improvement)
ICH study showed that reaching the target systolic blood pressure of less than
160 mm Hg within 38 minutes from ictus decreased the odds of hematoma
expansion.83 A study analyzing the effect of the hospital’s change in blood
FIGURE 3-4
Approach to the management of intracerebral hemorrhage from prehospital to the
neurocritical care unit.
ABC = airway, breathing, circulation; CT = computed tomography; CTA = computed tomography
angiography; ICH = intracerebral hemorrhage; NSTEMI = non–ST segment myocardial infarction;
SIADH = syndrome of inappropriate secretion of antidiuretic hormone; STEMI = ST segment elevation
myocardial infarction.
1260 OCTOBER 2021

pressure control protocol based on INTERACT1 and INTERACT2 found a KEY POINTS
significant difference in the proportion of patients with hematoma expansion
● Blood pressure control is
(defined as increase in lesion size no less than 10% or presence of more recommended upon
hemorrhagic lesions) in the aggressive blood pressure reduction group compared confirmation of the
to control (13.9% compared to 21.1%, P=.018), without a significant increase in diagnosis of ICH, although
kidney dysfunction.84 In their multivariate logistic regression analysis, the study the timing and target blood
pressure remain
authors determined that intensive blood pressure control was inversely
controversial.
associated with hematoma expansion after controlling for age, sex, baseline
National Institutes of Health Stroke Scale score and Glasgow Coma Scale score.84 ● Increased blood pressure
Another post hoc analysis to determine whether ultra-early intensive blood variability, defined as the
pressure lowering less than 2 hours from symptom onset would improve mean of the absolute
differences between two
outcomes showed that the intensive treatment group had less hematoma consecutive blood pressure
expansion and improved functional outcome at 90-day follow-up.85 In addition variations, variation of blood
to early blood pressure control, the role of blood pressure variability and the pressure during a period of
influence on patient outcomes after ICH is currently being studied. Increased time, or coefficient of
variation, in patients with
blood pressure variability, defined as the mean of the absolute differences between ICH has been found to be
two consecutive blood pressure variations, variation of blood pressure during a associated with worsening
period of time, or coefficient of variation,86 in patients with ICH has been found to neurologic status and poor
be associated with worsening neurologic status and poor outcome.87 Care should outcome.
be taken to prevent blood pressure variability as much as possible.
The current recommendation for systolic blood pressure goal in ICH is less than
140 mm Hg for patients presenting with systolic blood pressure between 150 mm Hg
and 220 mm Hg who have no other contraindication to intensive blood pressure
control.15 Note that no recommendation has been made on the specific medication
to be used to control blood pressure.15 Considerations in selection of medication
are usually dependent on potential side effects, patient comorbidity, allergy
history, refractoriness of the blood pressure, and availability of the medication.
REVERSAL OF COAGULOPATHY. Reversal of antiplatelet or anticoagulant

medications for patients with ICH is emergent. Common anticoagulants and
reversal agents are presented in TABLE 3-7. All patients with ICH associated with
antiplatelet or anticoagulation should be monitored in an ICU (FIGURE 3-4).
AHA/ASA guidelines recommend demonstration of ICH stability before
restarting antiplatelet medications when necessary to restart.15 Routine platelet
transfusions for patients who were on antiplatelet medication before ictus are not
recommended because of higher death and dependence at 90 days88 but can be
considered (as can desmopressin) for patients who will undergo neurosurgical
intervention or those demonstrating ongoing bleeding in the setting of potential
neurosurgical intervention.
Activated partial thromboplastin time, international normalized ratio (INR), and
prothrombin time should be monitored frequently to make certain the coagulopathy
is controlled. Thromboelastometry, a cheap, readily available, and easy-to-use test of
coagulation function, assesses hemostatic components such as platelets, fibrinogen,
coagulation factors, and erythrocytes by analyzing the interaction of the components,
coagulation times, clot strength, and lysis. The 2015 AHA/ASA guidelines for ICH
recommend specific reversal agents only for warfarin and heparin.15 The antiplatelet
medications most commonly used include aspirin, clopidogrel, dipyridamole, and
cilostazol. Glycoprotein IIb/IIIa antagonists are another group of medications that
carry risk of ICH. For antiplatelets, desmopressin 0.4 mcg/kg IV is recommended by
guidelines; however, the level of evidence is low.89

TABLE 3-6 Landmark Clinical Trials on Blood Pressure Management in Intracerebral

Hemorrhage
Research question Primary

Trial answered Comparison groups outcome Result Remarks
ATACH-II Is intensive blood Intensive blood 90-day No difference in Higher rate of

(Antihypertensive pressure control pressure lowering mortality or outcome of renal adverse
Treatment of (systolic blood pressure (systolic blood severe death or events in
Acute Cerebral 110-139 mm Hg) superior pressure goal disability disability in patients under
Hemorrhage-II)21 to standard treatment 110-139 mm Hg) (modified intensive group intensive
(systolic blood pressure compared to Rankin Scale compared to treatment
140-179 mm Hg) while standard treatment [mRS] score standard within 7 days
using nicardipine in (systolic blood 4-6) treatment
Subgroup
patients with pressure
Intensive analysis on
intracerebral 140-179 mm Hg)
treatment was patients with
hemorrhage (ICH) in within 4.5 hours
NOT superior in spot sign or
terms of death or after symptom
terms of other imaging
disability? onset using IV
decreasing markers of
nicardipine, blood
death and hematoma
pressure target
disability expansion did
maintained for
not show
24 hours
benefit
Stopped for
futility
No difference in
ordinal
distribution of
mRS score
Decreased
perihematomal
edema
expansion rate
in intensive
group with
deep ICH
CONTINUED ON PAGE 1263
1262 OCTOBER 2021

CONTINUED FROM PAGE 1262
Research question Primary

Trial answered Comparison groups outcome Result Remarks
INTERACT2 (The What is the effect of Target systolic 90-day death No difference In a
Second Intensive early intensive blood blood pressure and moderate between the prespecified
Blood Pressure pressure lowering <140 mm Hg or severe two groups in ordinal shift
Reduction in (systolic blood compared to disability (mRS terms of main analysis of the
Acute Cerebral pressure <140 mm Hg) systolic blood score of 3-6) outcome mRS score,
Haemorrhage versus conservative pressure functional
Trial)78 guideline-based blood <180 mm Hg; outcomes were
pressure lowering antihypertensive better in the
(systolic blood pressure not specified; intensive group
of <180 mm Hg) on death patients are to compared to
and dependency at remain below the the
90 days among patients blood pressure nonintensive
with ICH? target for 7 days group
Serious adverse
events were
similar between
the two groups
ICH ADAPT Is cerebral blood flow in 39 patients Perihematomal Intensive group Within 2 hours,
(Intracerebral acute ICH unaffected by assigned to systolic relative did not the <150 mm Hg
Hemorrhage blood pressure blood pressure cerebral blood significantly target group
Acutely reduction? target of <150 mm flow lower had a
Decreasing Hg compared to 36 perihematomal significantly
Arterial Pressure patients assigned cerebral blood lower mean
Trial)79 to systolic blood flow compared systolic blood
pressure target of to the <180 mm pressure
<180 mm Hg Hg target group
Rapid blood Is lowering the blood 21 patients each Clinical decline No significant Secondary
pressure pressure to mean arterial assigned to a (National difference in outcomes
reduction in acute pressure <110 mm Hg standard target Institutes of early neurologic included mRS
intracerebral within 8 hours of ICH blood pressure Health Stroke deterioration score at 90 days
hemorrhage: safe and feasible? with mean arterial Scale [NIHSS] and 24-hour
feasibility and pressure score decrease hematoma
safety80 110-130 mm Hg ≥2 points within enlargement;
compared to 48 hours) no significant
aggressive blood difference was
pressure goal of found between
mean arterial the two groups
pressure <110 mm
Hg, with mean
arterial pressure
control sustained
for 24 hours
IV = intravenous.

Other Pharmacologic Therapeutic Considerations

The multicenter TICH-2 (Tranexamic Acid for Hyperacute Primary
IntraCerebral Haemorrhage-2) trial showed that tranexamic acid use within
8 hours of ICH occurrence did not result in improved functional outcome,
although the tranexamic acid cohort had a lower proportion of patients with
hematoma expansion at day 2 compared to placebo.90 Thromboembolic events
and arterial occlusion were not significantly higher in the tranexamic acid group.
STOP-AUST (The Spot Sign and Tranexamic Acid On Preventing ICH
Growth–AUStralasia Trial), a prospective double-blind randomized
placebo-controlled phase 2 trial of adult patients with ICH less than 70 mL with
positive spot sign, also did not show a significant difference in terms of
hematoma expansion between the intervention and control groups.91
Deferoxamine emerged as a potential target for ICH therapy because of its
potential for neuroprotection as an iron chelator.92 A prospective multicenter
double-blind randomized placebo-controlled phase 2 clinical trial randomly
assigning participants to deferoxamine or placebo showed that deferoxamine
was safe, but it did not increase the chance of a good functional outcome at
90 days.93
Intracranial Pressure Management

Intracranial hypertension, defined as intracranial pressure greater than 20 mm
Hg, has a prevalence of up to 67% in patients with ICH,94 with lower admission
Glasgow Coma Scale score, presence of a greater than 6 mm midline shift, age,
hematoma volume, and presence of hydrocephalus correlated with intracranial
hypertension. For more information, refer to the article “Management of
Cerebral Edema, Brain Compression, and Intracranial Pressure” by Eric M.
Liotta, MD, MS,95 in this issue of Continuum. Prophylactic hyperosmolar therapy
is not recommended as it does not improve outcomes.96 The agents most
commonly used are hypertonic saline and mannitol, with the common goal to
TABLE 3-7 Common Anticoagulants and the Corresponding Reversal Agents
Anticoagulant/antiplatelet/antifibrinolytic Reversal agent options
Vitamin K antagonists warfarin, acenocoumarol, phenprocoumon, Three-factor or four-factor prothrombin complex

dicoumarol, tecarfarin, and fluindione concentrate, vitamin K
Dabigatran, argatroban, bivalirudin Idarucizumab
Rivaroxaban Andexanet alfa, prothrombin complex concentrate
Apixaban Andexanet alfa, prothrombin complex concentrate
Heparin Protamine, andexanet alfa
Fondaparinux Andexanet alfa, prothrombin complex concentrate
Enoxaparin Andexanet alfa, protamine
Antiplatelet agents Desmopressin acetate
IV recombinant tissue plasminogen activator (rtPA) Cryoprecipitate, fresh frozen plasma, platelets,
tranexamic acid, aminocaproic acid
1264 OCTOBER 2021

increase the osmotic gradient across the blood-brain barrier and to shift water KEY POINTS
into the intravascular space. For use in ICH, 2020 cerebral edema
● Prophylactic
recommendations from the Neurocritical Care Society suggest hypertonic saline hyperosmolar therapy is not
as the hyperosmolar agent preferred over mannitol, with the caveat that the recommended in patients
quality of evidence for this is very low.96 Clinicians should consider the available with ICH as it does not
IV access for administration of hyperosmolar therapy as well as the potential improve outcomes.
adverse effects of the hyperosmolar agents.
● American Heart
Association/American
Seizure Prophylaxis Stroke Association
The role of seizure prophylaxis for ICH is controversial, and current AHA/ASA guidelines do not
guidelines do not recommend it.15 Although one study reported lower risk of recommend seizure
prophylaxis in ICH.
seizures for patients with ICH placed on seizure prophylaxis with newer
antiseizure medications, more studies are needed to prospectively evaluate their ● The target temperature
benefit.97 A meta-analysis on seizure prophylaxis and short- and long-term for patients with ICH in
outcomes of patients with ICH found no association between seizure prophylaxis consensus guidelines is
36.5 °C to 37.5 °C (97.7 °F
and improved functional outcome and mortality; however, most studies to 99.5 °F).
analyzed were retrospective studies.98 Early seizures in patients with ICH have
an incidence rate of 4.3%, whereas late seizures have an incidence rate of 2.3%,
with an overall incidence of post-ICH seizures of 6.6% in a cohort of 1920
patients with ICH.99 Patients who have had a seizure should be treated
accordingly.15 The threshold for ordering EEG or continuous EEG for patients
with ICH in a comatose state should be low because up to 8.8% of patients with
ICH may have nonconvulsive status epilepticus.100 Lobar involvement and
craniotomy increase the risk of nonconvulsive status epilepticus.100 Risk factors
for acute seizure development in patients with ICH include younger age,
nonhypertensive ICH, cortical involvement, and a high National Institutes of
Health Stroke Scale score.99 Post-ICH–associated epilepsy was found to develop
in 15.7% of patients with ICH with initial post-ICH seizures, with the ICH volume
being an independent predictor associated with recurrent seizures.99 Very scant
data are available on whether patients with acute symptomatic seizures require
lifelong antiseizure medications or whether and when they can safely be weaned
off antiseizure medications.
Other Supportive Measures

Hyperthermia worsens outcomes101 and increases perihematomal edema.
Decreasing temperature to lower than 37.5 °C (99.5 °F) and responsiveness to
antihyperthermic treatment may have benefit in decreasing perihematomal
edema.102 The target temperature in consensus guidelines is 36.5 °C to 37.5 °C
(97.7 °F to 99.5 °F) for patients with ICH.103
The effect of glucose level on outcomes in patients with ICH continues to be
controversial. A subanalysis of the INTERACT2 trial found that 51% of the
patients had hyperglycemia at baseline, and these patients also had significantly
more occurrence of early neurologic deterioration, death, and nonfatal adverse
events.104 Based on older studies associating hyperglycemia with poor outcomes,
the AHA/ASA guidelines for ICH recommend avoidance of both hyperglycemia
and hypoglycemia.15
Up to 50% of patients with stroke have concomitant dysphagia,105 which
increases the risk of malnutrition, dehydration, and aspiration. The AHA/ASA
guidelines recommend dysphagia screening for any patient with ICH before oral
intake.15 Nutritional considerations in patients with ICH include early initiation

CASE 3-2 A 53-year-old man with a history of hypertension was found unconscious
by his wife in the bathroom 1 hour after eating dinner. When emergency
medical services arrived, he was found to have sonorous breathing, fixed
and dilated pupils, and extensor posturing. He had a Glasgow Coma Scale
score of 4 (eyes, 1; voice, 1; motor, 2). He was intubated immediately for
airway protection and transferred to the nearest Level 1 trauma center.
Upon arrival in the emergency department, his blood pressure was
found to be 180/100 mm Hg. IV nicardipine was immediately started, and
a neurosurgery consult was called. Mannitol was also administered, and
noncontrast head CT obtained (FIGURE 3-5). The patient was immediately
taken for Level 1 surgery for posterior decompression and hematoma
evacuation.
After surgery, the patient was admitted to the neurocritical care unit.
After 2 weeks of hospitalization, he did not have meaningful functional
change. His Glasgow Coma Scale score remained at 4. After multiple
family meetings with the primary team and the palliative care team in the
2 weeks following admission, the family decided to transition to a
palliative level of care and not proceed with tracheostomy and
gastrostomy tube placement since they felt the patient would not want
to continue in his current state.
FIGURE 3-5
Imaging of the patient in CASE 3-2. Axial noncontrast head CT shows bilateral cerebellar
hemorrhage (A, B) and obstructive hydrocephalus (C, D).
COMMENT The poor clinical examination and severity of the cerebellar intracerebral
hemorrhage in this patient did not preclude his candidacy for
decompressive craniectomy after stabilization. This case highlights that
continued engagement with the family is important after the acute period
as decision making on tracheostomy, gastrostomy, and transitions of care
are needed. Although no score can accurately determine the future
functional outcome of the patient, the lack of improvement and a higher
likelihood of prolonged recovery helped the family decide on what the
patient would probably have wanted using the principle of substituted
judgment.
1266 OCTOBER 2021

of feeding via oral intake or enteral feeding as soon as possible. If prolonged
dysphagia is likely, enteral feeding via a temporary gastrostomy may be
warranted.105
Neurosurgical Management Considerations

Neurosurgical management of ICH usually includes external ventricular drain
placement for CSF diversion, intracranial pressure monitoring, and hematoma
evacuation. The most readily available neurosurgical treatment is external
ventricular drain placement with or without thrombolysis administration. In
association with the CLEAR III trial, a subsequent study analyzed the efficacy
and safety of intraventricular fibrinolysis with lumbar drain placement to
prevent shunt dependency for patients with ICH and IVH, and results showed
0% of the patients in the treatment group needed a permanent shunt compared
to 43.8% in the control group needing a permanent shunt.106
The AHA/ASA ICH guidelines recommend carefully selecting patients for
neurosurgical intervention; however, the level of evidence is not high.15
Hematoma volume reduction as a surgical target may decrease midline shift and
intracranial pressure and potentially decrease the neurotoxic and
proinflammatory effects of the hematoma, which may subsequently decrease the
likelihood of secondary brain injury.107 Neither of the main trials on
supratentorial ICH evacuation, STICH (Surgical Trial in Intracerebral
Haemorrhage) and STICH II, showed improvement in outcome, but the trials
provided insight on subgroup selections that may benefit from early surgery.
Considerations in Restarting Antiplatelet or Anticoagulation After an TABLE 3-8

Intracerebral Hemorrhage
◆ For patients with a spontaneous lobar intracerebral hemorrhage (ICH) or those with multiple
cerebral microbleeds without strong indications for anticoagulants (eg, mechanical heart
valves or cardiac thrombus), especially warfarin, waiting 4-8 weeks is recommended15,31
◆ In patients with nonlobar ICH with strong indications for anticoagulation, anticoagulants may
be considered15
◆ For patients with indications for antithrombotics after an anticoagulant-associated ICH,
aspirin monotherapy may be safe within days of the ICH15
◆ Factors that should be considered before restarting oral anticoagulants include, but are not
limited to, the severity of ICH, presence of cerebral microbleeds, lobar ICH, no reversible
cause of bleeding, older age, bleeding with adequately or underdosed direct oral
anticoagulant, difficult to control hypertension, chronic alcohol abuse, need for dual
antiplatelet therapy28,31
◆ Scoring systems that weigh bleeding risk versus thrombotic risk are available and should be
used with caution
◆ Because the studies on direct oral anticoagulants showed lower risk of ICH compared to
vitamin K antagonists, it has been recommended to consider switching to a direct oral
anticoagulant after an ICH if anticoagulation is needed114
◆ Ongoing clinical trials to increase information on anticoagulant or antiplatelet use after ICH
include A3ICH (Avoiding Anticoagulation After IntraCerebral Haemorrhage),115 ASPIRE
(Anticoagulation in ICH Survivors for Stroke Prevention and Recovery),116 and APACHE-AF
(Apixaban After Anticoagulation-associated Intracerebral Haemorrhage in Patients With
Atrial Fibrillation),117 among others

TABLE 3-9 Intracerebral Hemorrhage Prognostic Scores Comparison
FUNC (Functional Outcome in

Intracerebral Modified Patients with Primary
Intracerebral Hemorrhage Grading Intracerebral Intracerebral Hemorrhage)
Hemorrhage Score122 Scale123 Hemorrhage Score124 Score125
Original Patients who Primary ICH confirmed Nontraumatic ICH; 142 ICH with functional status data
population presented with by CT head; 378 patients included at 90 days; final cohort was a
tested intracerebral patients included total of 629 patients
hemorrhage (ICH)
(ICD-9 code 431) who
primarily presented in
the study institutions;
152 patients included
Excluded Transfers from outside Traumatic ICH Traumatic ICH Secondary ICH from vascular
patients clinic or hospital abnormality, tumor, trauma or
ischemic stroke, vasculitis,
anticoagulation, or
coagulopathy
Primary In-hospital and 30-day In-hospital and 30-day In-hospital and 30-day 90-day functional outcome
outcome mortality mortality mortality
measured
Secondary None Good functional Functional outcome None

outcome outcome (Glasgow measured by modified
measured Outcome Scale score Rankin Scale score at
4 and 5) at 30 days 30 days after ICH with
good outcome being
modified Rankin Scale
score ≤2
Score Glasgow Coma Scale Glasgow Coma Scale National Institutes of Glasgow Coma Scale score
components score score Health Stroke Scale
<9 = 0
score
3-4 = 2 3-8 = 3
≥9 = 2
21-40 = 2
5-12 = 1 9-12 = 2
11-20 = 1
13-15 = 0 13-15 = 1
0-10 = 0
Hematoma volume Hematoma volume Hematoma volume Hematoma volume

≥30 mL = 1 Infratentorial ≥30 mL = 1 >60 mL = 0
<30 mL = 0 >20 mL = 3 <30 mL = 0 30-60 mL = 2
10-20 mL = 2 <30 mL = 4
<10 mL = 1
Supratentorial
>70 mL = 3
40-70 mL = 2
<40 mL = 1
1268 OCTOBER 2021


Hematoma location Hematoma location Hematoma location Hematoma location
Infratentorial = 1 Infratentorial = 2 Infratentorial = 1 Infratentorial = 0
Supratentorial = 0 Supratentorial = 1 Supratentorial = 0 Deep =1
Lobar = 2
Age Age Age Age

≥80 years = 1 ≥65 = 3 ≥80 = 1 ≥80 = 0
<80 years = 0 45-64 = 2 <80 = 0 70-79 = 1
<45 = 1 <70 = 2
Intraventricular Intraventricular Intraventricular Cognitive impairment

hemorrhage hemorrhage hemorrhage
Yes = 0
Yes = 1 Yes = 2 Yes = 1
No = 1
No = 0 No = 1 No = 0
Total score 0-6 5-13 0-6 0-11
Score Each increase in point Score of 5 had the Each point increase is Score of 11 indicates high
interpretation is associated with an lowest probability of associated with an likelihood of functional
increase in 30-day dying; scores ≥10 increase in 30-day independence (0-4 = 0%;
mortality (0, 13%, 26%, showed 87% mortality 5-7 = 1-20%; 8 = 21-60%;
72%, 97%, and 100% for in-hospital and 30-day 9-10 = 61-80%; and 11 = 81-100%)
those with ICH Score mortality and higher,
of 0 to 5, respectively) and 0% to 4% had good
functional outcome
Strengths Most validated; can be Higher sensitivity than Better than the ICH Collected pre-ICH cognitive
easily applied; ICH Score in predicting Score for predicting impairment by proxy interview
applicable to both in-hospital (78.2% good outcome and Informant Questionnaire on
supratentorial and compared to 63.8%, Cognitive Decline in the Elderly
infratentorial ICH P<.05) and 30-day
Can be done at bedside
mortality (78.5%
compared to 64.4%, Needs information from the
P<.05) initial patient evaluation and CT
scan only
Analysis done to control for ICH
survivors to control for the
effect of withdrawal of care on
functional outcome


Limitations Did not account for Did not account for Did not account for Requires assessment of pre-ICH
withdrawal of care; withdrawal of care withdrawal of care; cognitive impairment
only analyzed 30-day less accurate than the
mortality; no ICH Score in
functional outcome predicting mortality;
several patients with
missing data points;
not widely validated
Remarks Use data at the time of Use data at the time of Study to determine if Functional independence =
presentation; hospital arrival; ICH the ICH Score can Glasgow Outcome Scale
hematoma volume volume measured by predict morbidity and score ≥4
measured by ABC/2 ABC/2 method mortality at 30 days
Useful for goals-of-care
method; their cohort and if modification can
discussion regarding likelihood
did not have a patient improve the
of survival with recovery of
with ICH Score of 6 prediction; National
function, not just survival or
Institutes of Health
mortality
Stroke Scale score
found to be predictive
of both 30-day
mortality and good
outcome, not Glasgow
Coma Scale score
CT = computed tomography; ICD-9 = International Classification of Diseases, Ninth Revision.
However, further clinical trials are needed to firmly establish the role of early
surgery for supratentorial ICH.108 Minimally invasive neurosurgical approaches
include making a small cranial opening with a smaller intraparenchymal incision
with the goal of reducing parenchymal manipulation and decreasing procedure
time and anesthesia exposure with the concomitant advantage of faster hematoma
evacuation compared to external ventricular drain alone.109 Several minimally
invasive neurosurgical devices and approaches are currently available to achieve
the goal of hematoma evacuation. Trials are ongoing to determine whether the
specific minimally invasive neurosurgical device is a factor that contributes to
patient outcomes.109 The MISTIE III (Minimally Invasive Surgery Plus Rt-PA for
ICH Evacuation Phase III) trial involved using minimally invasive neurosurgery
combined with image-guided rigid catheter insertion targeted toward the middle
two-thirds of the hematoma, with the intervention group receiving 1 mg rtPA
every 8 hours for up to nine doses.71 Although the study did not show
improvement in the proportion of patients with good functional outcome (mRS
score of 0 to 3) at 365 days, it showed a lower rate of mortality in the treatment
group compared to the standard treatment cohort.110 Other minimally invasive
neurosurgery trials are currently ongoing using end-port–mediated evacuation
and stereotactic aspiration, both of which require a small craniotomy with the
main difference of the advantage of visualization in the latter approach.109
1270 OCTOBER 2021

Cerebellar hemorrhage (CASE 3-2), which accounts for up to 10% of all ICH, KEY POINTS
has a 30-day mortality of up to 38%.111 In patients with cerebellar ICH, low Glasgow
● Neurosurgical
Coma Scale score (<8), obstructed quadrigeminal cistern, and hydrocephalus were management of ICH may
independent predictors of in-patient mortality and poor functional outcome at include external ventricular
discharge.112 Expert consensus incorporated in the AHA/ASA guideline drain placement for CSF
recommends consideration for hematoma evacuation for ICH greater than 3 cm or if diversion, intracranial
pressure monitoring, and
signs of herniation with or without hydrocephalus are seen.15 However, in analyzing
hematoma evacuation.
the effect of surgical hematoma evacuation in these patients and the association with
outcomes, a 2019 meta-analysis including 578 patients revealed that hematoma ● In patients with
evacuation did not result in improved functional outcome but was associated with cerebellar ICH, low Glasgow
improved survival at 3 and 12 months.113 It is generally difficult to conduct a Coma Scale score (<8),
obstructed quadrigeminal
trial on surgical evacuation in cerebellar ICH because of the lack of clinical cistern, and hydrocephalus
equipoise, which makes forgoing intervention ethically challenging. were independent
predictors of in-patient
Resumption of Antithrombotic or Anticoagulant Medications After an mortality and poor
functional outcome at
Intracerebral Hemorrhage discharge.
Recommendations for restarting anticoagulation involve meticulous analysis of
the benefits of anticoagulation and the risk of ICH recurrence. TABLE 3-8 lists ● Recommendations for
considerations in the shared decision making for restarting anticoagulants restarting anticoagulation
after ICH involve meticulous
or antiplatelets.114-117
analysis of the benefits of
anticoagulation and the risk
Palliative Care Considerations in Intracerebral Hemorrhage of ICH recurrence.
Palliative care measures are instituted in 6.2% to 16.2% of patients with ICH in
the United States.118,119 The length of stay for patients with ICH who received ● Prognostic scoring
systems for ICH should only
palliative care were significantly shorter compared to those who did not,118,119 be used to provide guidance
and hospital costs averaged $4753 less for those who received palliative care in evaluating the risk of ICH
compared to those who did not.119 The AHA recommendations on palliative care intervention and in research
for stroke states that all patients and families affected by this disease with but not to precisely predict
outcome. It is recommended
subsequent effect in their daily function and quality of life should be provided to delay any change in goals
with (at least) primary palliative care services120 (ie, a non–palliative care of care for patients with ICH
specialist administering palliative care services that include support for the who did not have
patient and family and symptom management). Involvement and use of treatment-limiting orders on
admission, because early
palliative care were found to have increased from 4.3 % in 2007 to 16.2% in 2011 treatment limitations in ICH
in patients with ICH in a study analyzing the Nationwide Inpatient Sample.119 are associated with
increased mortality in some
OUTCOMES AND PROGNOSTICATION patients who could have
survived with good
High mortality and severe disability continue to be associated with ICH; thus,
functional outcome.
futility and prognostication are commonly discussed when caring for ICH. Up to
37 clinical prognostic scales for ICH are available, but some do not account for the
effect of withdrawal of care or surgical intervention.121 TABLE 3-9 shows a
comparison of the most validated prognostic scoring systems for ICH, including
their limitations.122-125 These scores should only be used to provide guidance in
evaluating the risk of ICH intervention and in research but not to precisely
predict outcome. It is recommended to delay any change in goals of care for
patients with ICH who did not have treatment-limiting orders on admission,15
because early treatment limitations in ICH are associated with increased
mortality in some patients who could have survived with good functional
outcome.126 An individualized approach is recommended for treating patients
with ICH, and self-fulfilling prophecies should be avoided when it comes to
prognostication during goals-of-care discussion.

CONCLUSION
This article summarizes the important basic foundations of acute ICH and the
considerations for its assessment and management along the patient care
continuum. Emergent stabilization, blood pressure control, reversal of
anticoagulation, neurosurgical consultation, and medical stabilization remain the
mainstays of ICH therapy.
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Intracerebral Hemorrhage - 2021

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Intracerebral Hemorrhage - 2021

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REVIEW ARTICLE

RECENT FINDINGS: Current available data on potential therapeutic options for

SUMMARY: ICH continues to have high morbidity and mortality. Advances in

1246 OCTOBER 2021

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COMMON ETIOLOGIES OF INTRACEREBRAL HEMORRHAGE

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CASE 3-1 A 49-year-old man with a history of hypertension presented to the

1248 OCTOBER 2021

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This case of hypertensive hemorrhage demonstrates hematoma expansion COMMENT

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recreational substances, such as cocaine, amphetamines, alcohol, or tobacco, and

Anticoagulant- and Antiplatelet-associated Intracerebral Hemorrhage

Cerebral Amyloid Angiopathy

1250 OCTOBER 2021

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Vascular Malformation ● The most common clinical

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13% of cerebral vascular malformations37 and commonly present with seizures or

Other Etiologies of Intracerebral Hemorrhage

Association with spontaneous intracerebral

FGA Thr312Ala, LIMK1, KCNK17 Protective against spontaneous intracerebral

APOE ε2, ε4, ε2/ε3, GPX1 Lobar spontaneous intracerebral hemorrhage

COL4A1, TIMP1, TIMP2, ACE Vascular integrity

1252 OCTOBER 2021

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PATHOPHYSIOLOGY OF PERIHEMATOMAL EDEMA AND

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inflammatory cascade that ensues as reflected by perihematomal edema and

1254 OCTOBER 2021

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TABLE 3-3 Six-point Approach to Radiologic Herniation Syndromea

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Intracerebral Hemorrhage Systems of Care

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TABLE 3-4 Diagnostic Tests to Be Considered in the Management of Intracerebral

Tests Rationale Comments

Neuroimaging Exclude ischemic stroke Location of ICH may guide

Electrolytes Guide replacement of electrolytes as part of Patients may come in with

ECG Demonstrate concurrent cardiac strain or ischemia

CT = computed tomography; ECG = electrocardiogram.

1258 OCTOBER 2021

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Emergent/Intensive Care Management Considerations

MEDICAL STABILIZATION. Mechanical ventilation is required in up to 30% of

BLOOD PRESSURE MANAGEMENT. Blood pressure control is recommended upon

Important Points to Consider in Intracerebral Hemorrhage Systems of Care TABLE 3-5

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2015 American Heart Association (AHA)/American Stroke Association (ASA)

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REVERSAL OF COAGULOPATHY. Reversal of antiplatelet or anticoagulant

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TABLE 3-6 Landmark Clinical Trials on Blood Pressure Management in Intracerebral

Research question Primary

ATACH-II Is intensive blood Intensive blood 90-day No difference in Higher rate of

CONTINUED ON PAGE 1263

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Research question Primary

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