2018 Book IntracerebralHemorrhageTherape PDF

Intracerebral
Hemorrhage
Therapeutics
Concepts and Customs

Bruce Ovbiagele
Adnan I. Qureshi
Editors
123
Intracerebral Hemorrhage Therapeutics
Bruce Ovbiagele • Adnan I. Qureshi
Editors
Intracerebral Hemorrhage
Therapeutics
Concepts and Customs
Editors
Bruce Ovbiagele Adnan I. Qureshi
University of California, San Francisco University of Minnesota
Medical Center Minneapolis, MN
San Francisco, CA USA
USA
ISBN 978-3-319-77062-8 ISBN 978-3-319-77063-5 (eBook)

https://doi.org/10.1007/978-3-319-77063-5
Library of Congress Control Number: 2018952921
© Springer International Publishing AG, part of Springer Nature 2018

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Foreword
What a breath of fresh air, this book with 12 deeply researched chapters, focusing
on intracerebral hemorrhage therapeutics! It reflects a new mindset, emerging in the
past decade, with concepts and practices, indeed new medical care customs, about
treating a problem that had long eluded therapy.
For centuries, Galenic admonitions about the poor prognosis of “apoplexy,” or
the futility of treatment advocated in Avicenna’s Canon of Medicine (“Falej,
La’tAalej” translated as do not treat apoplectic stroke), had taken hold on our col-
lective mindsets. Surely, intracerebral hemorrhage, accounting for a small fraction
of strokes, has been recognized to exact disproportionate mortality, case disability,
cost of care, and lost productivity. It was best prevented, mostly by chronic blood
pressure control. But once blood was spilt in the brain or ventricles, it seemed to be
an insurmountable disease. A doctor seemed best able to explain and prognosticate
that the more blood spilt, the worse the outlook and provide comfort to patient and
family and advice about hospice or long-term nursing care. Many doctors were
taught, until recently, that survival may be worse than death, for patient, family, and
society, after a bad intracerebral hemorrhage. It seemed that all damage occurs
when the brain bleeds, and little could be done thereafter.
Yet new concepts emerged in the past decade, mostly with earlier diagnosis on
the coattail of rapid transport of all stroke victims to hospitals, driven by the “time
is brain” concepts of acute ischemic stroke management. It became clear that, in
many cases of intracerebral hemorrhage, the bleed is still expanding in the early
hours after symptom onset, with progressive clinical deterioration. Indeed, this
hemorrhagic expansion has a huge impact on outcome and is modifiable, especially
in the setting of coagulopathy and intractable blood pressure elevations. Limiting
eventual volume of the bleed with rapid reversal of coagulopathy and blood pres-
sure control can in fact improve outcome. Diagnostic studies now identify patients
at risk of further hematoma expansion, and rigorous clinical trials have provided
new guidelines for blood pressure control in the acute state. Other studies have
mandated a new stance on rapid reversal of coagulopathy. These have impacted
policies on the rapid transport, urgent diagnosis, and acute resuscitation of patients
with intracerebral hemorrhage. Treatment of hydrocephalus and elevated i ntracranial
v
vi Foreword
pressure offers another opportunity to prevent secondary deterioration. Etiologic

screening has come into play, as several special pathologies call for individualized
management stances (venous thrombosis, arteriovenous malformations, moyamoya
disease, cerebral aneurysms).
The concept of thrombotoxicity, modulating clinical decline over days rather
than hours after an intracerebral hemorrhage, has reinvigorated questions about the
value of evacuating the hematoma, not as much to reverse acute damage, but to
prevent secondary sequelae and enhance survival and recovery potential. Yes, clini-
cal trials of early and delayed hematoma evacuation by craniotomy have been disap-
pointing, but we must remember that countless young patients with impending
herniation, including expanding supratentorial lobar bleeds and cerebellar hemato-
mas, have always been excluded from such trials and many have benefited from
emergent surgery. Decompressive craniectomy has been deployed in many young
patients with tight cranial vault, and dramatic gratifying recoveries have been
recorded.
More recently, another glimmer of hope has emerged from the use of thromboly-
sis for enhanced evacuation of hematoma by intraventricular and intracerebral cath-
eters. Feasibility and safety have been demonstrated in randomized clinical trials,
protocols have been optimized, and the effectiveness of these therapies is being
assessed in ongoing studies. Other minimally invasive surgical tools are being
developed, with the same aim of injury-sparing hematoma evacuation. Indeed, peri-
hematoma edema is blunted by such interventions, a critical proof of concept, and
mortality is clearly improved. Effect on functional outcome, optimal patient selec-
tion and timing of intervention, and comparative techniques are motivating novel
hypotheses and a new therapeutic discourse.
Critical care of the brain-injured patient and other multisystem support contrib-
ute to the prevention of countless secondary sequelae. Ethical issues have reinvigo-
rated discussions regarding informed consent and the unresponsive patient, family
and social dynamics, disparities of care, the implementation of advanced directives,
or end of life management. And most exciting are new concepts about biomarkers
and medical modifications of secondary injury and potential restorative interven-
tions to enhance recovery.
This book cannot be more timely. It is edited by leaders in the field, with contri-
butions by innovators who helped shape the above “concepts and customs.” It tack-
les all the exciting innovations, and much more, with a mature pragmatic clinical
perspective and scientific rigor. Each of the 12 chapters contains pearls of wisdom,
likely to benefit actual patients. Students, novices, and experts can benefit from the
knowledge and experiences shared herein. Moreover, the book instills the new way
of thinking about intracerebral hemorrhage therapeutics in its new age.
Issam A. Awad, MD,MSc,FACS,FAANS,FAHA,MA(hon)

The John Harper Seeley Professor of Neurological Sciences
Professor of Surgery (Neurosurgery) and Neurology
University of Chicago Medicine and Biological Sciences
Chicago, IL, USA
Preface
Intracerebral hemorrhage (ICH) is a serious condition for which early aggressive

care is often warranted. This book provides a framework for goal-targeted manage-
ment of the patient with spontaneous nontraumatic intracerebral hemorrhage, which
represents a major cause of morbidity and mortality throughout the world. While
ICH has unfortunately trailed behind ischemic stroke with regard to compelling
scientific evidence from clinical trials to guide management, over the past several
years, advances in brain imaging have resulted in a better understanding of the
pathophysiology of ICH, and there has been a welcome rise in the number of clini-
cal trials assessing the impact of various interventions to improve ICH outcomes.
With this backdrop, it is an opportune time to summarize current knowledge of ICH
and its management from a practical view.
Intracerebral Hemorrhage Therapeutics is a timely and consolidated resource
for clinicians, which captures novel strategies and the ever-increasing pace of dis-
covery that is transforming what we know about ICH and its treatment. Topics
addressed in a comprehensive yet practical manner in the book include prehospital/
emergency department care, early inpatient workup, antithrombotic- and thrombo-
lytic-related strokes, optimal blood pressure management, avoidance of medical
complications, surgical interventions, outcome prognostication, recurrence preven-
tion, rehabilitation/recovery, special situations, systems of care, and the design of
clinical trials for patients with ICH. Procedures, processes, and helpful decision-
making algorithms are presented with the aid of complementary illustrations that
facilitate understanding of practical aspects and enable the reader to promptly
retrieve relevant information. Prominent academicians with broad clinical practice
experience from all over the world present the underlying evidence (or lack thereof)
behind prevailing therapeutic strategies for treating ICH. Throughout, the style
delivered is both holistic and multidisciplinary. It should however be noted that the
book is primarily focused on ICH management in adults, and not necessarily in
children and neonates.
As appropriate, each chapter reviews currently available therapies, discusses key
controversial or unresolved management issues, and highlights promising future
areas of therapeutic focus under investigation. In areas, where evidence is limited or
vii
viii Preface
lacking, our expert contributors provide their own management recommendations.

Reference lists at the end of each chapter direct readers to important articles for
more thorough reading on a particular subject.
Intracerebral Hemorrhage Therapeutics will be of value to primary care physi-
cians, geriatricians, emergency care physicians, hospitalists, general neurologists,
neuro-hospitalists, vascular neurologists in training, and vascular neurology board
recertification candidates, because it provides a detailed review of the most current
evidence-based therapies for routine management of ICH patients and a glimpse of
promising future treatment strategies. Moreover, the book allows practitioners in
other disciplines to become more familiar with the terminology and techniques that
vascular neurologists and neurosurgeons frequently use to aid them in their ICH
management practice.
Finally, we are especially grateful to our contributors for lending their time and
expertise, our families for providing their moral support, as well as our patients and
trainees for teaching us so much.
San Francisco, CA, USA Bruce Ovbiagele

Minneapolis, MN, USA Adnan I. Qureshi
Contents
1 Prehospital and Emergency Department

Management of Intracerebral Hemorrhage�� 1
Muhammad Fawad Ishfaq, Nitin Goyal, Abhi Pandhi,
and Marc Malkoff
2 Early Inpatient Workup for Intracerebral Hemorrhage �� 17
Muhib Khan, Rushna Ali, Justin Singer, Paul Mazaris,
and Brian Silver
3 Antithrombotic- and Thrombolytic-Related
Intracerebral Hemorrhage�� 27
Jan C. Purrucker, Matthew L. Flaherty, Gustavo Rodriguez,
Saqib Chaudhry, Fazeel Siddiqui, and Thorsten Steiner
4 Blood Pressure Management in ICH �� 45
Shahram Majidi and Adnan I. Qureshi
5 Thromboprophylaxis and Seizure Management
in Intracerebral Hemorrhage �� 57
Odysseas Kargiotis, Georgios Tsivgoulis, and Jose I. Suarez
6 Surgical Treatment of Intracerebral Hemorrhage �� 81
Jan Vargas, Alejandro M. Spiotta, and Raymond D. Turner
7 Intracerebral Hemorrhage Prognosis�� 95
Craig A. Williamson and Venkatakrishna Rajajee
8 Prevention of Recurrent Intracerebral Hemorrhage �� 107
Chirantan Banerjee and Bruce Ovbiagele
9 Special Disease Management Considerations �� 121
Nabeel A. Herial and Magdy Selim
ix
x Contents
10 Special Systems of Care Considerations

in Intracerebral Haemorrhage �� 139
Aravind Ganesh and Michael D. Hill
11 ICH Rehabilitation and Recovery�� 161
Benjamin A. Abramoff, Nicole D. Mahdi,
Maria Beran, and Samir R. Belagaje
12 Clinical Trial Design in Subjects with Intracerebral
Hemorrhage�� 185
Adeola Olowu and Nicole R. Gonzales
Index�� 201
Contributors
Benjamin A. Abramoff, MD Physical Medicine and Rehabilitation, Emory

University Hospital, Atlanta, GA, USA
Rushna Ali, MD Department of Neurosurgery, Vanderbilt University, Nashville,
TN, USA
Chirantan Banerjee, MD, MPH Department of Neurology, Medical University
of South Carolina, Charleston, SC, USA
Samir R. Belagaje, MD, FAAN Neurology and Rehabiliation Medicine, Emory
University, Atlanta, GA, USA
Maria Beran, MD Physical Medicine and Rehabilitation, Emory University
Hospital, Atlanta, GA, USA
Saqib Chaudhry, MD Departments of Neurology and Neuro-critical Care,
University of Pennsylvania, Philadelphia, PA, USA
Matthew L. Flaherty, MD Department of Neurology and Rehabilitation Medicine,
University of Cincinnati Academic Health Center, Cincinnati, OH, USA
Aravind Ganesh, MD Calgary Stroke Program, Department of Clinical
Neurosciences, Cumming School of Medicine, University of Calgary, Calgary,
Canada
Centre for Prevention of Stroke and Dementia, Nuffield Department of Clinical
Neurosciences, University of Oxford, Oxford, UK
Nicole R. Gonzales, MS Department of Neurology, McGovern Medical School,
Houston, TX, USA
Nitin Goyal, MD Department of Neurology, University of Tennessee Health
Science Center, Memphis, TN, USA
xi
xii Contributors
Nabeel A. Herial, MD, MPH Departments of Neurology and Neurosurgery, Sidney

Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
Michael D. Hill, MD, MSc, FRCPC Calgary Stroke Program, Department of
Clinical Neurosciences, Cumming School of Medicine, University of Calgary,
Calgary, Canada
Department of Radiology, Department of Community Health Sciences, Department
of Medicine, Hotchkiss Brain Institute, Cumming School of Medicine, University
of Calgary, Calgary, AB, Canada
Muhammad Fawad Ishfaq, MD Department of Neurology, University of
Tennessee Health Science Center, Memphis, TN, USA
Odysseas Kargiotis, MD, PhD Stroke Unit, Metropolitan Hospital, Piraeus,
Greece
Muhib Khan, MD Spectrum Health Neuroscience Institute, Michigan State
University, Grand Rapids, MI, USA
Nicole D. Mahdi, MD Stroke Program, Northwest Hospital, The Sandra and
Malcolm Berman Brain and Spine Institute, Baltimore, MD, USA
Shahram Majidi, MD Department of Neurosurgery, Icahn School of Medicine at
Mount Sinai, New York, MD, USA
Marc Malkoff, MD Department of Neurology, University of Tennessee Health
Paul Mazaris, MD Spectrum Health Neuroscience Institute, Michigan State
Adeola Olowu, MD Department of Neurology, McGovern Medical School,
Houston, TX, USA
Bruce Ovbiagele, MD, MSc, MAS, MBA University of California, San Francisco
Medical Center, San Francisco, CA, USA
Abhi Pandhi, MD Department of Neurology, University of Tennessee Health
Jan C. Purrucker, MD Department of Neurology, Heidelberg University Hospital,
Heidelberg, Germany
Adnan I. Qureshi, MD University of Minnesota, Minneapolis, MN, USA
Venkatakrishna Rajajee, MBBS Departments of Neurology and Neurosurgery,
University of Michigan, Ann Arbor, MI, USA
Gustavo Rodriguez, MD, PhD Department of Neurology, Texas Tech University,
El Paso, TX, USA
Contributors xiii
Magdy Selim, MD, PhD Department of Neurology, Stroke Division, Beth Israel

Deaconess Medical Center, Boston, MA, USA
Fazeel Siddiqui, MD Department of Neurology, Southern Illinois University,
Springfield, IL, USA
Brian Silver, MD Department of Neurology, University of Massachusetts,
Worcester, MA, USA
Justin Singer, MD Spectrum Health Neuroscience Institute, Michigan State
Alejandro M. Spiotta, MD Department of Neurosurgery, Medical University of
South Carolina, Charleston, SC, USA
Thorsten Steiner, MD, MME Department of Neurology, Heidelberg University
Hospital, Heidelberg, Germany
Department of Neurology, Klinikum Frankfurt Höchst, Frankfurt a.M., Germany
Jose I. Suarez, MD Division of Neurosciences Critical Care, Departments of
Anesthesiology and Critical Care Medicine, Neurology, and Neurosurgery, The
Johns Hopkins University School of Medicine, Baltimore, MD, USA
Georgios Tsivgoulis, MD, FESO Second Department of Neurology, “Attikon”
Hospital, School of Medicine, University of Athens, Athens, Greece
Department of Neurology, The University of Tennessee Health Science Center,
Memphis, TN, USA
Raymond D. Turner, MD Department of Neurosurgery, Medical University of
South Carolina, Charleston, SC, USA
Jan Vargas, MD Department of Neurosurgery, Medical University of South
Carolina, Charleston, SC, USA
Craig A. Williamson, MD Departments of Neurology and Neurosurgery,
University of Michigan, Ann Arbor, MI, USA
Chapter 1
Prehospital and Emergency Department
Management of Intracerebral Hemorrhage
Muhammad Fawad Ishfaq, Nitin Goyal, Abhi Pandhi, and Marc Malkoff
Background
Stroke is a leading cause of death and disability worldwide and a very common
vascular disease prevalent globally spreading like a pandemic [1, 2]. Stroke can
be ischemic or hemorrhagic in nature. Intracerebral hemorrhage (ICH) is the
second most common subtype of stroke and a critical disease usually leading to
severe disability or death [3]. ICH is defined as bleeding in the brain paren-
chyma. Incidence of ICH is 12–15 cases per 100,000 individual or about 40,000
cases per year in the United States [4]. ICH can be defined as “deep” located
within the deep brain parenchyma such as the internal capsule, brain stem, or
thalamus, or it can be “lobar” located in cortical–subcortical areas and follows
a lobar pattern across one or multiple lobes of the brain. Deep ICH accounts for
about two third of spontaneous ICH cases, and lobar ICH accounts for the
remaining one third [5].
Hypertension is by far the most common risk factor. Other common risk factors
are cerebral amyloid angiopathy, hematological abnormality, anticoagulation use,
drug or alcohol abuse, and chronic kidney disease [6].
ICH mortality is about 40% at 30 days, making ICH one of the most deadly acute
medical events. At 1 year, the mortality is 50%. Around 50% of the deaths happen
in 48–72 h of ictus and are related to neurological complications (i.e., mass effect,
increased intracranial pressure, and/or herniation) [7]. Many deaths also occur in
the setting of withdrawal of support due to presumed poor prognosis. In the acute
setting, predictors of early mortality are hematoma size, hematoma expansion, older
age, coma, intraventricular hemorrhage (IVH), and infratentorial location [8].
M. F. Ishfaq · N. Goyal · A. Pandhi · M. Malkoff (*)

Department of Neurology, University of Tennessee Health Science Center,
Memphis, TN, USA
e-mail: [email protected]
© Springer International Publishing AG, part of Springer Nature 2018 1

B. Ovbiagele, A. I. Qureshi (eds.), Intracerebral Hemorrhage Therapeutics,
https://doi.org/10.1007/978-3-319-77063-5_1
2 M. F. Ishfaq et al.
ICH is a medical emergency and delays in treatment result in worse outcome.

Around 20% of patients will experience a decrease in the Glasgow Coma Scale of
two or more points between the prehospital assessment and the initial evaluation in
the emergency department [9]. Moreover, around 20% of patients demonstrate con-
tinued deterioration within the first hours after hospital arrival [10, 11]. Therefore
aggressive prehospital and emergency department treatment is cornerstone for
effective management of patients with ICH.
Initial management should focus on urgent stabilization of cardiorespiratory
variables and treatment of intracranial complications [12]. Recent advances such as
newer laboratory testing and rapid computed tomography for diagnosis, blood pres-
sure reduction to reduce hematoma expansion, and new anticoagulant reversal
agents may allow for improved outcomes. In this book chapter, we will discuss
about different aspects of prehospital and emergency management of ICH.
Prehospital Stroke Care
Recent technological innovations have opened new perspectives for stroke diagno-
sis and treatment before the patient arrives at the hospital. These include presumed
stroke diagnosis by paramedics, mobile telemedicine for remote clinical examina-
tion and imaging, mobile stroke units with integrated CT scanners, and point-of-
care laboratories in ambulances [13]. Algorithms for prehospital treatment for
either ischemic or hemorrhagic stroke are parallel to each other. In this section of
the manuscript, we will discuss several aspects of prehospital care for patients
with ICH.
Public Awareness
Time is saved if stroke symptoms are recognized early, and both the family and
bystanders play a major role. Early recognition leads to early 911 call and early
treatment and thus better outcomes not only for hemorrhagic but ischemic strokes
as well. Multiple modalities for increasing awareness have come along including
printed materials, audiovisual aids, and billboard advertisements targeting patient
population, family members including children and relatives [14–16]. The effects of
the campaigning were seen to be effective but for a short span only, and thus repeti-
tion and continuous promotion is the key [17]. Despite the continuous campaigning,
only 53% of the population is using EMS services. The National Hospital
Ambulatory Medical Care Survey (NHAMCS) reported that with use of 911 and
EMS services, prehospital delays are less and patient’s door to CT or MRI times are
shorter as well [ 18]. Early alarm has been associated with female gender, higher
education and socioeconomic status, presence of bystanders, family history of
stroke, and acute and severe symptoms [19, 20].
1 Prehospital and Emergency Department Management of Intracerebral Hemorrhage 3
Emergency Medical System Services
Emergency medical system (EMS) personal are involved since 911 activation and
dispatch, response to on site, triage and stabilization in field, patient transport
ground or air, and prehospital notification. The primary objective is to provide air-
way management if needed, provide cardiovascular support, and transport the
patient to the closest facility prepared to care for patients with acute stroke [21, 22].
The secondary objective for EMS personal is to obtain a focused history regarding
the symptom onset time; nature of clinical symptoms; relevant past medical and
surgical history, medication, and drug use; and contact information for family.
Another important role of EMS providers is the prehospital notification so that criti-
cal pathways can be initiated and consulting services alerted. Advance notice by
EMS has been shown to significantly shorten time to computed tomography (CT)
scanning in the ED [21, 23].
Accuracy of EMS in identifying stroke (ischemic or hemorrhagic) symptoms is
highly variable ranging from 30% to 83% [24, 25]. There are various scales avail-
able that can be used by EMS personal for identification of suspected stroke patients
including Cincinnati prehospital stroke scale [26], Los Angeles prehospital stroke
screen [27], or Face Arm Speech Test (FAST) scale assessment [28]. Certain clinical
features suggest the diagnosis of ICH over ischemic stroke are vomiting, systolic
blood pressure > 220 mmHg at onset, severe headache, coma or decreased level of
consciousness, and symptom progression over minutes or hours. However, none of
these clinical features are specific [29].
Several prehospital interventions known to influence outcomes, including admin-
istration of supplemental oxygen [30, 31], fluid resuscitation preferably with normal
saline (avoiding dextrose containing solutions as it can exacerbate cerebral injury),
keeping head of bed up for suspected hemorrhagic stroke, identifying hypo- or
hyperglycemia with a finger stick glucose testing and treating it promptly, and inser-
tion of angiography compatible IV lines, are routinely provided by EMS personal
en route to the hospital in suspected stroke patients.
Mobile Stroke Unit
The concept of taking stroke care to the patient by deployment of mobile stroke
units (MSU) is rapidly expanding. Mobile stroke units enable time-sensitive diag-
nosis and delivery of ultra-early stroke treatment. Walter and colleagues launched
the first MSU in 2010 in Saarland, Germany, with a Mercedes-Benz Vario 815D
ambulance that included conventional ambulance equipment; a small portable
8-slice CT scan; a telemedicine system for transmission of digital imaging, com-
munication, and real-time video of patient clinical examination; and a point-of-care
laboratory system [32].
Then came STEMO in Berlin with CT head and CT angiography capability, but
only one CT angiography was done [33–35]. The first MSU in the United States was
launched at University of Texas, Houston, followed by Cleveland Clinic MSU and

then University of Tennessee, Memphis, MSU [36–38].
The concept of MSU can be very useful for hyper-acute management of
ICH. Early detection of ICH on CT head on MSU allows EMS personal to triage
patient and to make sure patient is being transported to a tertiary care center with
services of neurology, neurosurgery, neurocritical care, and neurointerventional
specialist [13]. Hematoma expansion occurs early after ictus in ICH most com-
monly within 4.5–6 h from onset [21]. Whether very early aggressive reduction
systolic blood pressure in the MSU could effectively improve functional outcome in
ICH remains unknown, but the MSU provides a unique environment to test this
hypothesis. Other than blood pressure lowering, MSUs may serve as a powerful
platform for study of hemorrhage control agents as well as neuroprotective drugs in
the management of ICH [39]. The BEST-MSU study reported enrolling 4 ICH cases
from their first 26 patients, and aggressive BP lowering was provided within the first
hour of symptom onset [40]. Use of continuous infusion antihypertensive agents by
MSU teams promotes improved blood pressure control of these fragile cases while
ensuring provision of close hemodynamic monitoring. Additionally, MSU teams
that stock reversal agents for coagulopathic ICH are well suited to rapidly support
hemostasis alongside standard management while alerting both neurosurgery and
neurocritical care teams of CT/CT angiography findings and pending patient needs
[40, 41]. Administration of hyperosmolar agents including mannitol or hypertonic
saline, in consultation with neurocritical care team, can be carried out if clinical
signs of herniation are present while en route to avoid delay and preventing com-
plete herniation. Detailed prehospital workup with CT angiography allows the
determination of vessel leak (so-called spot sign) in ICH patients. However, the
cost-effectiveness of MSUs is still a concern.
Role of Mobile Telemedicine
Telemedicine-enabled ambulance-based evaluation reduces time to imaging and

treatment. Non-stroke-capable hospitals are also able to get stroke expertise from
stroke experts via telemedicine. Telemedicine has been shown to be safe and pro-
motes early triaging and treatment and better clinical outcome. Telemedicine also
helps in identifying severe patients which can benefit more by transferring to ter-
tiary stroke centers [42, 43].
Emergency Department Stroke Care
All the major stroke centers are working toward the concept of “Time is brain” which
holds true for both ischemic and hemorrhagic strokes [44, 45]. Timely evaluation,
diagnosis, and treatment of patients with ICH should be performed expeditiously in
emergency department (ED) because clinical deterioration is common in the first few
hours. In addition to prehospital notification provided by EMS, there should be an
effective and quick communication between EMS transport and ED staff as soon as
patient arrives in ED so that rapid clinical evaluation by adequately trained nurses
and physicians can be possible [46]. The hospitals without on-site presence of stroke
or neurosurgery consultants can also easily be benefited by the telemedicine which
allows rapid visualization of clinical and neurological data, providing neurosurgical
expertise within minutes to peripheral hospital. Telemedicine can also help to trans-
fer such patients to tertiary care centers when necessary [42, 43].
Primary management of ICH in ED include rapid clinical evaluation, laboratory
studies including blood glucose and coagulation defects, diagnostic imaging stud-
ies, management of blood pressure and early intracranial complications such as
hydrocephalus or impending herniation, and admission to stroke unit or neurosci-
ence intensive care unit (NICU).
Rapid Clinical Evaluation
Rapid clinical evaluation by trained nursing staff and physician is the most vital and
earliest part of management of ICH patients in the ED. History can help to evaluate
possible vascular risk factors and any triggering agents such as medicine, alcohol,
illicit drugs, or other underlying pathologies such as intracranial vascular malforma-
tion, cancer, or hematological disorders. Effective physical examination should
include vital sign, focused general and cardiovascular exam, and detailed neurologi-
cal exam including severity scale. Different severity scales are being used for the
assessment of ICH, and the most used is ICH score which provides clinical grading
scale for outcome after ICH [47]. When the patient arrives to ED, it is difficult to
predict that it is ischemic or hemorrhagic stroke; therefore commonly used ischemic
stroke scale known as the National Health Institute Stroke Scale may be helpful in
ICH as well to assess the severity of deficits. However these scales should be not be
used as solo measures to grade prognosis [48, 49].
Laboratory Studies
Laboratory studies include complete blood count, complete metabolic panel, toxi-
cology screen, coagulation profile, urine studies, and other relevant studies deemed
significant by history. Early diagnosis and reversal of any triggering factors such as
coagulation defects, blood glucose, etc. can play a vital role in better prognosis of
patients with ICH.
Neuroimaging Evaluation
In any patients with acute stroke symptoms, it’s impossible to know if stroke is
ischemic or hemorrhagic based on clinical symptoms alone; therefore rapid neuro-
imaging evaluation is a must to make the diagnosis and elucidate the etiology of
ICH. Neuroimaging usually comprises the combination of any of the following,
computerized tomography (CT) head, CT angiography, CT perfusion, magnetic

resonance (MR) brain, MR angiography, and MR venography or conventional angi-
ography. CTH without contrast is considered to be the gold standard due to its high
sensitivity for diagnosing ICH, rapidity, cost-effectiveness, and easy availability
[50, 51]. CT head also gives useful information about location, intraventricular
extension, hydrocephalus, presence and degree of edema, and midline shift or brain-
stem compression secondary to the mass effect from the hematoma [51]. Both CT
head and MR brain are equally sensitive to identify ICH, but CT head better visual-
izes intraventricular and subarachnoid bleed, and MR brain is better at identifying
prior hemorrhages, hemorrhagic transformation of ischemic stroke, and underlying
structural lesions (i.e., neoplasms and vascular malformations). Given the cost,
duration of the examination, and poor tolerability for some patients, MR is less
commonly used in the ED for workup of ICH [52].
ICH volume is a strong predictor of ICH outcome as larger hematomas have a
poorer prognosis. Intracerebral hematoma volume can be rapidly estimated in the
ED with the ABC/2 technique. A is the maximum ICH diameter (in cm) estimated
visually; B is the maximum ICH diameter perpendicular to A (in cm), and C is the
total number of CT slices with the ICH seen in the vertical plane multiplied by the
CT slice thickness (typically 5 mm or 0.5 cm). A, B, and C numbers are then multi-
plied together and divided by 2 [53, 54]. The location of ICH on CT head, along
with the patients’ age and medical history, provides important information about the
etiology of ICH. In general, deep ICHs are hypertensive, and lobar ICHs are caused
by secondary causes, such as cerebral amyloid angiopathy, coagulopathy, vascular
malformations, tumors, dural arteriovenous fistulas, and vasculitis, and warrant fur-
ther investigation such as contrasted MR, CT, or MR angiography or conventional
angiogram [55]. A small percentage of lobar ICH can be hypertensive as well [ 56].
A “spot” sign on post-contrast CT is a small enhancing foci within the hema-
toma, related to vascular leak at the point of enhancement; the presence of the “spot”
sign seems to independently predict hematoma enlargement [53]. The ICH patients
with spot sign are at risk of immediate worsening, and several ongoing studies are
investigating role of ultra-intensive blood pressure control or hemostatic therapy in
this subgroup of patients [53, 57–60].
Computed tomography angiography (CTA) is a useful diagnostic tool in the
acute setting of ICH. It is the most widely available noninvasive technique for the
detection of vascular abnormalities as secondary cause of ICH [60]. Prompt detec-
tion of these lesions is crucial and has a significant impact on patient management.
Although CTA is an excellent noninvasive screening tool, digital subtraction angi-
ography remains the gold standard investigation for diagnosis and for possible
endovascular treatment of cerebral vascular malformations. The main drawback of
CTA is contrast and the additional radiation exposure. Although some clinicians are
concerned about the risk of contrast-induced nephropathy, there is a debate in the
literature whether this entity exists. In patients with poor kidney function, contrast
allergies, or other contraindications to CTA, brain vessel imaging can be achieved
through MR angiography [53, 60]. Conventional digital subtraction angiography is
often indicated in patients with SAH and ICH with abnormal calcifications or blood
in atypical locations or presentation or in young patients with no obvious cause for

ICH. MRI is equally sensitive as is CTH to pick up ICH, but ICH evaluation on MRI
depends primarily on the age of the hematoma and the type of MR sequence (i.e.,
T1 or T2 weighted). The signal intensity on MR depends on the specific form of Hb
present, hyper-acute >24 h appear isointense on T1 and slightly hyperintense on T2;
acute 1–3 days appear slightly hypointense on T1 and very hypointense on T2; early
subacute >3 days appear very hyperintense on T1 and very hypointense on T2; late
subacute >7 days appear very hyperintense on T1 and very hyperintense on T2;
chronic center >14 days appear isointense on T1 and slightly hyperintense on T2;
and chronic rim >14 days appear slightly hypointense on T1 and very hypointense
on T2 [ 61].
After diagnosis, emergency providers should arrange for rapid admission to a
stroke unit or neuroscience intensive care unit (at their own hospital if available or
via transfer) and initiate early management, while the patient is awaiting this bed.
The following management procedures should be initiated in the ED rather than
waiting until after transfer to an intensive care unit, stroke unit, or other hospital.
Airway Protection
Generalized endotracheal intubation is indicated in patients with reduced conscious-

ness to protect airway, bulbar dysfunctional leading to inability to handle secretions,
or concomitant respiratory or cardiac problems leading to respiratory distress. In
these clinical situations, induction of GETA should be done as in a rapid sequence
technique with careful attention to minimize large hemodynamic fluctuations or
fluctuations in intracranial pressure if monitoring is being done [62].
Blood Pressure Management
The underlying reason for high blood pressure in stroke patients is not absolutely
clear. Most of patients with ICH have chronically uncontrolled hypertension and
elevation of blood pressure at time of presentation to hospital is merely a reflection
of the poorly controlled blood pressure. Cushing–Kocher response resulting from
compression from brain stem may also play a vital role for elevated blood pressure
to maintain cerebral perfusion. Acute stress response leading to abnormal neurohu-
moral mechanism may also cause acute high blood pressure during ICH. Blood
pressure increase is associated with higher risk of hematoma expansion, neurologi-
cal deterioration, poor outcome, and death. The pathophysiology behind hematoma
expansion is not well understood. It is not clear whether it reflects leakage, rebleed-
ing, or both. After vessel rupture, an initial hematoma forms, causing secondary
vessel rupture due to mass effect, and also triggers an avalanche of further vessel
ruptures, but the real mechanism leading to final hematoma volume remains unclear.
Hematoma expansion occurs early in the course of ICH, and early CT scan repeti-
tion is warranted to detect it [63, 64].
ATACH-I trial failed to find any significant relationship between SBP reduc-
tion and hematoma expansion, perihematomal edema, and 3-month outcome
among patients with ICH [65]. INTERACT1 (intensive blood pressure reduction
in acute cerebral hemorrhage trial-1) showed that patients within 6 h of ICH with
rapid reduction of SBP to <140 mmHg to be safe [66]; but INTERACT 2 (inten-
sive blood pressure reduction in acute cerebral hemorrhage trial-2) failed to meet
its primary end point, and did not definitively show improved outcome with inten-
sive BP treatment (SBP target <140 mmHg) [67–69]. The most robust and latest
data on BP management come from the ATACH-2 trial (antihypertensive treat-
ment of acute cerebral hemorrhage II), a large clinical trial randomizing patients
to one of two different systolic blood pressure (SBP) control strategies, SBP
110–139 mmHg vs SBP 140–179 mmHg, which showed that patients with ICH
and tight SBP control of 110–139 mmHg did not result in a lower rate of death or
disability than standard reduction to a target of 140–179 mmHg [70]. The main
limitation in ATACH-2 trial is that patient randomized to have intensive treatment
had ultra-intensive control of blood pressure, i.e., the mean minimum systolic
blood pressure during the first 2 h was 128.9 ± 16 mmHg versus 141.1 ± 14.8 mmHg
in the standard-treatment group. Such intense systolic blood pressure control led
to higher percentage of patients with any serious adverse events (25.6% vs.
20.0%).
The current American Heart Association guidelines suggest that the early lower-
ing of BP to 140 mmHg is safe and can be effective for patients with ICH presenting
with a 150–220 mmHg systolic blood pressure [21].
To avoid hypotension, short half-life antihypertensive, such as labetalol or nica-
rdipine, is recommended to control blood pressure in patients with ICH [21, 64].
Clevidipine monotherapy has recently shown promising effects in terms of safe
rapid blood pressure reduction in ICH patients leading to decreased hematoma
expansion [71].
Thromboprophylaxis in ICH Patients
Deep vein thrombosis (DVT) prophylaxis is tricky in patients with ICH as they
have tendency to bleed more with conventional medications used for DVT
prophylaxis; therefore intermittent pneumatic sequential compression devices
(SCDs) are indicated in such patients beginning the day of hospital admission.
DVT prophylaxis can be started with conventional low-dose molecular weight
heparin or unfractionated heparin once intracranial bleed has been stopped after
3–4 days of onset of the ICH [72–74]. ICH patients with symptomatic DVT or
PE can be given one of the following two options, systemic anticoagulation
or IVC filter placement, depending on various factors such as comorbidities
including prothrombotic conditions, cause of hemorrhage, time from hemor-
rhage onset, and hematoma stability.
Hemostatic Treatment
(a) Platelet function

Limited data is available to support the reversal strategy to improve platelet
function in patients with ICH who are taking antiplatelet medications. PATCH
trial failed to show beneficial effect of platelet transfusion over standard care for
people taking antiplatelet therapy before intracerebral hemorrhage [75].
However, patients with severe thrombocytopenia, 50,000–100,000, should
receive replacement therapy with platelet transfusion [72].
(b) Anticoagulant-Associated Coagulopathy
Anticoagulants and coagulation defect may lead to intracranial hematoma
expansion and subsequently clinical deterioration and death. In case of warfarin
coagulopathy, recommendations are to discontinue warfarin, administer intra-
venous vitamin K, and factor repletion [72–74]. INCH trial [76] showed that in
patients with vitamin K antagonist-related intracranial hemorrhage, prothrom-
bin complex concentrates (PCC) may be preferred over fresh frozen plasma
(FFP) due to rapid action causing INR normalization in short period of time and
leading to smaller hematoma expansion [67, 68]. The optimal INR target is still
debated, and proposed target value range less than 1.5. rFVIIa is not recom-
mended for reversal in ICH [77]. FAST trial failed to prove the beneficial effects
of hemostatic therapy with rFVIIa in terms of survival or functional outcome
after ICH, but it significantly reduced growth of the hematoma [78].
Protamine sulfate may be considered to reverse heparin in patients with
acute ICH at the dose of 1 mg per 100 units of heparin (maximum dose up to
50 mg).
Novel oral anticoagulants (NOACs) or direct oral anticoagulants (DOACs)
are increasingly being used as an alternative to warfarin. The most commonly
used are the factor Xa inhibitors apixaban, rivaroxaban, and edoxaban and the
direct thrombin inhibitor dabigatran. Functions of these agents do not need to
be monitored by laboratory studies such as INR. Limited data is available on
reversal of these newer agents by antagonists. Administration of vit K for rever-
sal of these newer agents is futile; however charcoal (<2 h intake of NOACs)
PCC, FEIBA, and rFVIIa have showed some promising effects which needed to
be further investigated [79, 80]. Idarucizumab has been recently licensed and
proved effective for reversal of dabigatran [81]. Andexanet alfa has also shown
promising effect in reversal of rivaroxaban, apixaban, and edoxaban and is
likely to be soon licensed for use in patients with ICH [82–84].
(c) Recombinant tissue plasminogen activator (rtPA)-associated coagulopathy may
lead to hemorrhagic conversion of ischemic stroke, symptomatic ICH being the
most dangerous complication. To prevent the hemorrhagic conversion of isch-
emic stroke, it is recommended to strictly control blood pressure and avoid anti-
thrombotic medication in the first 24 h following the infusion of rtPA. Limited
data is available to standardize the treatment of post rtPA ICH. It is recom-
mended to immediately discontinue rtPA and administer any of the following

compounds: cryoprecipitate, antifibrinolytic, aminocaproic acid, vitamin K,
FFP, PCC, platelet transfusion, or recombinant activated factor VII A [85].
Intracranial Pressure Management
Current AHA/ASA guidelines suggest ICP monitoring with parenchymal or ventricu-

lar devices in patients with coma, significant IVH with hydrocephalus, and evidence
of transtentorial herniation, with a cerebral perfusion pressure target of 50–70 mmHg.
ICP increase can be avoided or treated by elevation of the head to 30, adequate seda-
tion, or avoidance of hyponatremia [21]. ICH who are at risk of transtentorial hernia-
tion may also benefit from hyperosmolar therapy with mannitol or hypertonic saline.
Surgical Management of ICH
Surgery in patients with neurologically asymptomatic ICH is not clearly beneficial.

Supratentorial hematoma evacuation in deteriorating patients might be considered
as a life-saving measure. STICH and STICH II were undertaken to determine
whether early surgery reduces mortality and improve neurological outcome com-
pared with conservative management for supratentorial ICH [86, 87]. Both STICH
and STICH II failed to clearly identify the beneficial role of surgery in patients
supratentorial hemorrhages, but subgroup analysis of STICH [86] suggested that
patients with lobar hemorrhages within 1 cm of the cortical surface might benefit
from surgery which led to STICH II trial that specifically included the ICH patients
with superficial lobar hemorrhage.
Supratentorial ICH patients who are in a coma, have large hematomas with mid-
line shift, or have elevated ICP refractory to medical management may also have
mortality benefit from decompressive craniectomy with or without hematoma evac-
uation [ 86, 87].
The role of minimally invasive clot also is uncertain [88, 89]. The Minimally
Invasive Surgery Plus Recombinant Tissue-Type Plasminogen Activator for ICH
Evacuation Trial II (MISTIE II) showed a significant reduction in perihematomal
edema in the hematoma evacuation group. Such a promising effect in MISTIE II led
researchers to continue a randomized phase 3 clinical trial of minimally invasive
hematoma evacuation (MISTIE III) which is currently in progress [90]. Apollo
devices have also been studied for minimally invasive evacuation of ICH and intra-
ventricular hemorrhage, but further studies are required to prove benefit from this
promising technology [91].
Emergent surgical removal of the hemorrhage is also recommended in patient
with cerebellar hemorrhage who have neurological deterioration, brain stem com-
pression, or neurologically or hydrocephalus from ventricular obstruction [88, 89].
Intraventricular administrations of thrombolytics or any other endoscopic treat-
ment of IVH are clinically unproven in terms of efficacy [92].
Blood Glucose Management
No specific blood glucose target level is recommended, but tight glycemic control
has been shown to be associated with better outcome [ 93]. The AHA/ASA guide-
lines suggest to avoid both hyperglycemia and hypoglycemia [21].
Temperature Management
Optimal temperature management is still unclear, but it is recommended to treat

fever as it has been associated with poor outcome. The presence of fever is a com-
mon finding in patients with ICH, especially in those with extensive IVH [ 93].
More studies are needed to investigate the role of normothermia or hypothermia and
their effect on outcome in patients with ICH.
Seizures and Antiseizure Drugs
The prophylactic administration of antiseizure drug therapy is not recommended,

and even some data suggest that phenytoin may worsen outcomes in patients with
ICH. Antiseizure medications are administered in the patients with clinical or elec-
troencephalography (EEG) evidence of seizures [94]. The patients with ICH who
have impaired mental status that is disproportionate to the degree of brain damage
should be considered for continuous EEG monitoring to rule out nonconvulsive
seizures.
ransfer to an Intensive Care Unit, Stroke Unit, or Other

T
Hospital
There should be no delay in transfer of patients with ICH to a facility which is better
equipped to manage this devastating condition. Furthermore, studies have shown bet-
ter morbidity and mortality rates in patients who are admitted to dedicated stroke unit.
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Chapter 2
Early Inpatient Workup for Intracerebral
Hemorrhage
Muhib Khan, Rushna Ali, Justin Singer, Paul Mazaris, and Brian Silver
Spontaneous non-traumatic intracerebral hemorrhage (ICH) is a leading cause of

morbidity and mortality around the world. The mortality related to ICH has not
changed in the past three decades emphasizing the need for further improvement in
care of these patients [1]. In this chapter we will focus on the diagnostic workup of
ICH to determine the etiology. It is important to understand the various etiologies of
ICH to tailor the investigation accordingly. We have attempted to provide an evi-
dence-based approach using the available data at this time.
Clinical Evaluation
The initial evaluation is focused in the emergency department. However, this clini-
cal evaluation should continue onto the neuro-critical care unit and/or stroke unit [2,
3]. Since intracerebral hemorrhage can be a devastating condition, a baseline sever-
ity score should be performed as part of the initial evaluation of patients with
ICH. Various severity scales have been developed, but the most widely used scale is
ICH score [3–11] and should be used as a standardized severity score for communi-
cation between providers [10]. It should not be used as a singular indicator of prog-
nosis and decision for withdrawal of care. The National Institutes of Health Stroke
M. Khan (*) · J. Singer · P. Mazaris

Spectrum Health Neuroscience Institute, Michigan State University, Grand Rapids, MI, USA
R. Ali
Department of Neurosurgery, Vanderbilt University, Nashville, TN, USA
B. Silver
Department of Neurology, University of Massachussetts, Worcester, MA, USA

https://doi.org/10.1007/978-3-319-77063-5_2
18 M. Khan et al.
Scale (NIHSS) score, which is used for ischemic stroke, may also be useful for
continued bedside monitoring in ICH [12, 13].
A complete history is imperative in determining the need for further evaluation.
This includes time of symptom onset (or time the patient was last normal) and
progression of symptoms over time. Patient and/or family members should be
asked about history of prior ischemic stroke or ICH, seizures, liver disease, cancer
and hematological disorders, hypertension, diabetes mellitus, and smoking.
Current and prior prescribed and over-the-counter medications should be docu-
mented specially anticoagulants, antiplatelets, antihypertensives, stimulants
(including diet pills), and sympathomimetic drugs. It is important to know about
the recent trauma or surgery especially carotid endarterectomy or carotid stenting
as these can lead to ICH through hyperperfusion. An assessment of prior cognitive
function or dementia is helpful. A history of alcohol or illicit drug use such as
cocaine and other sympathomimetic drugs also needs to be evaluated, given that a
significant number of these patients with ICH have a past or current history of drug
abuse [14, 15].
Laboratory Tests
Laboratory investigation is important in both the evaluation of etiology of ICH and

continued care. Complete blood count, electrolytes, blood urea nitrogen, creatinine,
glucose, prothrombin time (with INR), activated partial thromboplastin time, car-
diac-specific troponin, electrocardiogram (ECG), urinalysis, urine culture, preg-
nancy test in a woman of childbearing age, and urine toxicology screening [3].
Classification of ICH
In order to efficiently investigate the etiology, it is important to characterize the ICH

into different classes. As mentioned earlier, a good system of classification is not
available, but some guidance can be sought from published literature.
Intracerebral hemorrhages can be classified according to location into deep,
lobar, supratentorial, and infratentorial. This location-based classification helps in
determining the severity and prognosis [16]. However, this location-based approach
alone is not helpful in determining the etiology and guide diagnostic workup.
Therefore, it needs to be combined with further demographic and clinical informa-
tion. A simple classification is provided by Meretoja et al. designated as SMASH-U
(structural vascular lesions, medication, cerebral amyloid angiopathy, systemic dis-
ease, hypertension, or undetermined) [17]. This classification provides a stepwise
approach to etiological assessment of ICH incorporating demographic, clinical, and
imaging context.
This approach provides a simple and practical means by which to classify the
pathogenesis of ICH as well as provide prognosis. However, like every other clas-
2 Early Inpatient Workup for Intracerebral Hemorrhage 19
sification system, SMASH-U is not accurate at all times and may misclassify ICH
especially when there are more than one possible etiologies [18]. Determining the
etiology of ICH is dependent on neuroimaging evaluation which we discuss
below.
Neuroimaging
Initial evaluation of ICH in the emergency department should include at least com-
puted tomography (CT). Although certain clinical features can point toward an ICH,
neuroimaging is the only definitive way to make a diagnosis [19].
Computed Tomography (CT)
CT is a sensitive and effective modality for identifying acute hemorrhage. It is con-

sidered the “gold standard” for initial evaluation of ICH [3]. CT is commonly used
in the emergency department due to its convenience and availability. As mentioned
earlier, hematoma volume plays a major role in ICH severity, and the ICH score
relies on volume calculation. CT is the main modality implied in quantifying the
hematoma volume and monitoring expansion [20]. Hemorrhage volume is calcu-
lated by the ABC/2 method, where A is the greatest hemorrhage diameter; B, the
diameter at 90° to A; and C, the approximate number of CT slices with hemorrhage
multiplied by slice thicknesses [21]. Recent studies question the reliability of the
ABC/2 method showing that it produces a larger percentage of error compared with
planimetry, particularly for irregular-shaped objects [22, 23]. However, ABC/2
method is easy to use assessment tool in the acute situation.
CT scan has the ability to approximate the age of hematomas based on the den-
sity measured in Hounsfield units. Hyperacute ICH is seen as a uniform and smooth
hyper-intense signal. Evolving hematomas start showing fluid levels as hypodense
bloody serum layered above hyperdense settled blood [24]. Further evolution leads
to a hypodense region around the hematoma, as a result of the edema that surrounds
the brain tissue. Consequently mass effect can be detected at this time. Subacutely,
the hematoma shrinks in about 20 days after onset becoming less intense. This pro-
cess can take up to 2 months and eventually a confined region of modest hypoden-
sity can be seen [25].
Magnetic Resonance Imaging
CT scan is highly sensitive in identifying intracerebral hemorrhage as mentioned

earlier. Multimodal magnetic resonance imaging (MRI) has excellent ability to
delineate hyperacute ischemia [26]. Stroke MRI protocols which include T1, T2,
20 M. Khan et al.
gradient echo (GE), fluid-attenuated inversion recovery, and diffusion-weighted

images are widely used nowadays [27]. T1- and T2-weighted MRI sequences are
able to detect subacute and chronic blood. However, with technological advance-
ment, gradient recalled echo (GRE) is sensitive in detecting hyperacute ICH [28–
32]. MRI is able to identify ICH from the blood degradation product deoxyhemoglobin
which has paramagnetic properties. GRE shows areas of hyperintensity in the ICH
core usually surrounded by hypointense boundaries. Hyperintense signals are found
bordering the central ICH on T2 images, whereas a hypointense signal is seen on T1
indicating vasogenic edema [27, 29–31]. MRI has shown comparable accuracy to
CT in detecting ICH in hyperacute phase.
MRI brain has its limitations as well. Patient factors such as critical illness, presence
of a pacemaker, metallic implants, and claustrophobia preclude some patients from
getting an MRI. Easy availability is another issue which is a factor in the acute situation
[33, 34]. MRI is superior to CT in detecting underlying causes of ICH, including vas-
cular malformations, tumors, and cerebral vein thrombosis [35]. MRI is highly sensi-
tive for detecting cavernomas which can lead to ICH [36]. Contrast-enhanced MR
venography shows the thrombosed segment of the venous sinus and correlates well
with conventional angiogram [37, 38]. Cerebral microhemorrhages (CMB) have been
shown to increase the risk of ICH [39] and point toward a diagnosis cerebral amyloid
angiopathy (CAA) [40]. MRI is superior to CT in detecting these silent lesions and
helps in etiological assessment. CMB have been shown to increase the risk of recurrent
ICH, and detecting these may be helpful in further management of these patients with
regard to antiplatelet and anticoagulation treatment [41]. Moreover, MRI helps in
quantifying the burden the small vessel disease in patients with ICH [42].
For the abovementioned reasons, it is important to carefully select patients with
ICH who should have evaluation by MRI. Although no established protocols are
available, a logical approach is suggested by Kamal et al. utilizing the Hong Kong
criteria which were originally developed for catheter angiography [35]. Kamal et al.
recommend an MRI brain for patients with ICH with age less than 45 years and no
history of hypertension or who present with lobar hemorrhage [35, 43].
Computed Tomographic Angiography
Computed tomographic angiography (CTA) in the initial phase can reveal a spot sign,
which is extravasation of contrast within the hematoma [44]. The spot sign is predic-
tive of hematoma enlargement with high sensitivity (63%) and specificity (90%) [45].
The spot sign is associated with a poor prognosis; however its impact on clinical
decision-making still needs further evaluation [46]. CTA performed in the initial
3–4 days from symptom onset has a high accuracy for detecting vascular lesions. Its
easy availability and noninvasive nature make it a promising modality in the initial
workup of ICH [47, 48]. However, it comes with its own risk of exposure to radiation,
contrast-induced nephropathy (CIN), and allergic reaction [49]. Cost is another issue
related to diagnostic studies and should be factored in. Therefore, it should be reserved
for patients in whom the suspicion for underlying vascular lesion is high.
Magnetic Resonance Angiography
Magnetic resonance angiography (MRA) is a noninvasive modality used to identify

vascular lesions responsible for ICH. MRA is useful in avoiding radiation and
iodinated-contrast. The sensitivity (0.98) and specificity (0.99) is comparable to
CTA [50]. Limitations are similar to MRI such as accessibility and patient-related
factors. It is a good alternative for patients who cannot undergo CTA.
Digital Subtraction Angiography (DSA)
Patients who have subarachnoid hemorrhage (SAH) in addition to ICH, noncircular

hematoma, edema out of proportion to the hemorrhagic mass seen on CT at admis-
sion, lobar ICH, and young age might point toward an underlying vascular lesion [3].
DSA should be considered in these cases. It can reveal underlying conditions such
as arteriovenous malformations, aneurysms, moyamoya disease, vasculitis, revers-
ible cerebral vasoconstriction syndrome, and cerebral vein thromboses. Factors such
as young age, absence of history of hypertension, and lobar hemorrhage can increase
the yield of angiogram [51]. Timing of DSA is important in improving yield as well
as diagnosing vascular lesions promptly to treat them. Repeat angiogram can
improve the yield in certain patients. DSA is associated with the risks of transient
and permanent neurological deficits and should be kept in mind. Therefore, careful
selection of patients for repeat angiogram is warranted [52, 53].
CTA vs MRA vs DSA
It is difficult to compare these modalities due to variation in studies evaluating each

modality [50]. Combining CTA with DSA or MRA with DSA improves the diag-
nostic yield. Patient selection should be based on demographics, known risk factors,
ICH location, and imaging features. A simplified approach to the diagnostic workup
is provided by Macellari et al. [54] They propose a stepwise approach to diagnostic
evaluation incorporating CT, CTA, MRI, and DSA. The choice of each modality is
guided by clinical and imaging findings [54].
Other Causes of ICH
Hematological disorders account for about 8% of all spontaneous ICH. Most of

these are attributed to coagulopathy caused by anticoagulant and antiplatelet use
[55]. However a significant number is due to clotting factor deficiencies, thrombo-
cytopenia and lymphoproliferative disorders.
22 M. Khan et al.
Thrombocytopenia has multiple causes with some general mechanism: (1)

decreased platelet production due to congenital disorders and bone marrow damage,
(2) increased platelet destruction as seen in idiopathic thrombocytopenic purpura
(ITP) and disseminated intravascular coagulation (DIC), (3) abnormal sequestration
in the spleen as seen in cirrhosis, and (4) toxins such as alcohol, drugs, and uremia
[56]. Idiopathic thrombocytopenic purpura (ITP) can lead to ICH in about 1% of the
patients with ITP. The risk is high with very low platelet counts of less than 20,000/
mm [3].
Cytotoxic drugs, antimalarial agents, antiepileptic medications, furosemide,
digoxin, and estrogens have been shown to cause thrombocytopenia [57]. Uremia
causes both a decrease in the number of platelets and dysfunction leading to ICH
[58]. Alcohol causes thrombocytopenia through folate deficiency, splenic sequestra-
tion, and direct toxic effects of alcohol on the bone marrow [59]. It also causes
platelet dysfunction. Therefore, a platelet count should always be tested in patients
with ICH. In addition, a select number of patients should have their platelet function
tested.
Coagulation factor deficiencies are rare conditions causing ICH in young patients
[56]. Hemophilia A and B are rare conditions caused by a deficiency of coagulation
factors VIII (hemophilia A) and IX (hemophilia B). Intracerebral hemorrhage is a
serious complication of hemophilia leading to mortality [60]. The incidence is
between 2.2% and 7.8% in hemophiliacs [61]. Most of these patients are young, and
the mean age of hemophiliacs presenting with ICH is 15 years [62]. Other congeni-
tal coagulation factor deficiencies such as vWF deficiency, congenital afibrinogen-
emia, and factors V, VII, and XIII can lead to ICH [63–67].
Hypercoagulable states such as antiphospholipid syndrome, prothrombin muta-
tion, and factor V Leiden deficiency can lead to ICH through mechanism cerebral
venous thrombosis [68–70]. Patients with leukemia have a high (15%) incidence
ICH. Of the subtypes, acute myeloid leukemia (AML) has a higher incidence of
22%. ICH is mediated through DIC, thrombocytopenia, and leukostasis [71].
Therefore, it is important to test for these coagulation factors both quantitative and
qualitatively specially in young patients with ICH.
Intracranial Vasculopathy
Approximately 12% of patients with Primary CNS Vasculitis (PCNSV) patients can
present with ICH [72]. The mean age of presentation is 50 years with a range
between 30 and 68 years. Headache, cognitive deficits, and systemic vasculitis man-
ifestations are presenting features. Therefore, when suspected diagnostic workup
should include MRI brain with contrast, lumbar puncture, cerebral angiogram, and
brain biopsy. Prompt diagnosis leads to a proper treatment with steroids and immu-
nosuppressive medications [72].
Reversible cerebral vasoconstriction syndrome (RCVS) can lead to ICH in 12%
of patients at presentation. Mean age of presentation is 43.5 years with a female
predominance. Sudden maximum intensity headache is a common presenting

symptom. Diagnostic evaluation should include extensive medication history
including over-the-counter medications, MRI brain, cerebral angiogram, and tran-
scranial Doppler ultrasound. A trial of magnesium and calcium channel blockers is
warranted to relieve headache [73].
Brain tumors have the potential to cause ICH with an overall incidence between
2% and 4%. Most of these brain tumors causing ICH are metastases of extracranial
origin (36%), followed by glioblastoma multiforme (30%) and benign primary
intracranial neoplasms (18%). A high number of these patients (58%) have ICH as
a presenting feature of neoplastic disease [74]. Therefore, patients with no risk fac-
tors of spontaneous ICH should undergo MRI brain with contrast and potential CT
chest, abdomen, and pelvis to look for neoplastic lesions. In some cases, a biopsy
might help with diagnosis [74].
Conclusion
ICH is a devastating disease with high morbidity and mortality. Proper diagnostic
workup is essential to effective management and should be guided by demograph-
ics, history, clinical features, imaging, and laboratory findings.
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Chapter 3
Antithrombotic- and Thrombolytic-Related
Intracerebral Hemorrhage
Jan C. Purrucker, Matthew L. Flaherty, Gustavo Rodriguez,

Saqib Chaudhry, Fazeel Siddiqui, and Thorsten Steiner
Antithrombotic- and Thrombolytic-Related ICH
Case Vignette
Only minutes after dining with her husband, a 77-year-old woman was found by
him vomiting and with reduced level of consciousness. She was immediately trans-
ported to the closest hospital, a tertiary care center. On admission, her Glasgow
Coma Scale score was 8, with no clear lateralizing signs of paresis, but bilateral
positive Babinski signs. Emergency medical services personnel reported use of riva-
roxaban due to atrial fibrillation, but the last time of intake and dose were unknown.
CT scan revealed a small left-sided thalamic intracerebral hemorrhage (ICH) with
J. C. Purrucker
Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany
M. L. Flaherty
Department of Neurology and Rehabilitation Medicine, University of Cincinnati,
Academic Health Center, Cincinnati, OH, USA
G. Rodriguez
Department of Neurology, Texas Tech University, El Paso, TX, USA
S. Chaudhry
Departments of Neurology and Neuro-critical Care, University of Pennsylvania,
Philadelphia, PA, USA
F. Siddiqui
Department of Neurology, Southern Illinois University, Springfield, IL, USA
T. Steiner (*)
Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany
Department of Neurology, Klinikum Frankfurt Höchst, Frankfurt a.M., Germany

https://doi.org/10.1007/978-3-319-77063-5_3
28 J. C. Purrucker et al.
intraventricular extension (Fig. 3.1). The third and fourth ventricles were nearly
occluded, but hydrocephalus had not developed. CT angiography revealed no vas-
cular pathology. Aware of rivaroxaban use, the attending neurologist and neurosur-
geon were immediately informed of the necessity of intubation of the patient,
preparation of a reversal treatment, and placement of an external ventricular drain-
age (EVD). However, both responded with several questions, “In the absence of a
definite time-window of ‘last intake of rivaroxaban,’ should one wait for laboratory
parameters confirming the effective intake before administration of a reversal treat-
ment?” and “Which dose of the reversal treatment should be administered?”, and
the neurosurgeon questioned “after reversal treatment, how can I be sure no antico-
agulant effect is present before placing an EVD?”
In the following chapter, knowledge about the clinical course and emergency
management of ICH related to vitamin K antagonists (VKA), non-vitamin K antag-
onist oral anticoagulants (NOAC), heparin, thrombolytic agents, and antiplatelet
treatment will be provided in order to offer sufficient background knowledge for
daily clinical practice.
Fig. 3.1 Illustrative CT scan showing left-sided thalamic intracerebral hemorrhage with intraven-
tricular extension (By courtesy of the Department of Neuroradiology, Heidelberg University
Hospital)
3 Antithrombotic- and Thrombolytic-Related Intracerebral Hemorrhage 29
Pathophysiology of OAC-Related ICH
Small vessel disorders account for approximately 85% of all ICH cases. Chronic
disorders such as hypertension can lead to fibrinoid necrosis (lipohyalinosis), char-
acterized by vessel wall thickening, endothelial dysfunction, and local inflamma-
tory processes [1]. Accumulation of beta-amyloid in basement membranes of
arterioles and capillaries in cases of cerebral amyloid angiopathy (CAA) causes
blood-brain barrier disruptions and microaneurysm formation [2, 3]. While ICH in
patients with hypertensive angiopathy occurs mainly in deep cerebral locations,
bleedings in CAA are mostly lobar. In contrast, primary ICH related to large vessel
disease including arterial aneurysms, arteriovenous malformations, dural fistulas,
and venous malformations may be deep or lobar.
Although the exact pathophysiology of ICH in orally anticoagulated patients is
not fully understood, it is currently assumed that spontaneous bleedings occur due
to mechanisms previously described. In non-anticoagulated patients, rapid coagula-
tion and thus cessation of bleeding lead to (asymptomatic) cerebral microbleed for-
mation in the vast majority of cases. However, in patients treated with antithrombotic
agents, bleeding continues, and symptomatic macrobleeds are more likely to form.
Therefore, anticoagulation presents a hemorrhagic diathesis (facilitates symptom-
atic ICH), but may not cause the bleeding itself. Notably, there are indirect hints that
formation of micro- and macrobleeds do comprise distinct pathophysiological pro-
cesses in the context of CAA [4]. Similarly, neuropathological observations ques-
tion a direct relation between microbleeds and CAA burden [5].
If the initial bleeding is not fatal, hematoma expansion may worsen outcome. In
anticoagulated patients, hematoma expansion is frequent and occurs during a longer
period compared to non-anticoagulated patients [6, 7]. Hematoma expansion is
influenced by at least two phenomena: 1 the pressure gradient between arterial
blood extravasating from an injured vessel and the pressure in surrounding tissue
and 2 shear forces which may injure adjacent vessels and produce further, second-
ary sources of bleeding [8]. Immediately after vessel rupture, the vessel-tissue-pres-
sure gradient is highest, but decreases with increasing hematoma volume. However,
if adjacent vessels or microaneurysms rupture due to shear forces, hematoma expan-
sion may continue [9]. The two processes build the rational for stringent blood pres-
sure management and immediate reversal of anticoagulation in order to prevent or
stem hematoma expansion.
Vitamin K Antagonist-Related ICH
In the pre-NOAC era, vitamin K antagonist-related ICH (VKA-ICH) accounted for

10–25% of all ICH [10, 11], with a rising annual incidence of >4/100,000 persons
in 1999 [12]. Although a decline in the incidence of VKA-ICH is expected due to
the increasing use of NOACs, VKAs are still widely used and therefore account for
a substantial number of ICH cases [13]. Baseline hematoma size is likely larger in
VKA-ICH compared to other cases of ICH; however in one study this effect was
only seen with supratherapeutic INR (>3) [14]. In contrast, hematoma expansion
occurs more frequently in VKA-ICH even when INR levels are within the therapeu-
tic range [6]. In a large retrospective observational study, hematoma expansion was
as frequent as 36% in VKA-ICH (Table 3.1) [7]. [Note: While in the latter study
hematoma expansion was defined as a relative increase of 33% compared to base-
line, the lack of a common agreed definition hampers direct comparison with other
studies [15].] In warfarin-related ICH, the period of hematoma growth is prolonged,
even beyond the initial 24 h [6] especially if anticoagulation is not reversed.
Intraventricular extension of ICH during anticoagulation with warfarin is also
more frequent compared to non-anticoagulated patients, and the risk of IVH is INR
dependent, with higher INR levels being associated with a greater risk [16].
Another potential prognostic factor is lobar location of ICH (defined as ICH
related to the cortex and cerebellar hemorrhage in the MUCH-Italy study) that was
recently found to occur more frequently in VKA-ICH compared to ICH in non-
anticoagulated patients [17]. Anticoagulant-related ICH was previously found to
preferentially affect the cerebellum, but supratentorial lobar ICH was not associated
with anticoagulant use [18]. In a large observational study including only VKA-
ICH, there was no relevant difference between patients with deep and lobar hemor-
rhage (according to the definition by Pezzini; n = 433 vs. n = 422). However,
distribution of hemorrhage was only available for patients with follow-up imaging;
thus patients with large lobar hemorrhage with early decision to palliate might not
have been included.
The potentially larger baseline hematoma volume and more frequent hematoma
expansion including ventricular extension contribute to a less favorable prognosis
compared to patients without anticoagulation [19]. VKA-ICH is associated with a
high in-hospital mortality (~ 31%) and an unfavorable long-term prognosis with the
majority of all patients (56%) being dead at 1-year follow-up [7]. Once discharged
with an unfavorable functional status (modified Rankin scale score of 4–5), the
chance of significant improvement at 1 year was only 6.3% [7].
Anticoagulation Reversal Treatment (VKA)
In VKA-anticoagulated patients, determination of anticoagulant status is performed

by measuring the INR [20]. Point-of-care devices allow for rapid bedside measure-
ments [21]. In contrast to the easy assessment of the anticoagulant activity, until
recently there was uncertainty about the best method of anticoagulant reversal. The
time-dependent nature of hematoma expansion makes the rapid correction of coag-
ulopathy intuitively attractive. Additionally, observational data suggests that the
rapid correction of INR to ≤1.3, coupled with reduction of systolic blood pressure
control to <160 mmHg, reduces hematoma expansion (see also Chap. 4) [5].
However, the associations were drawn from retrospective data and therefore might
be subject to bias.
Table 3.1 Summary of selected studies on intracerebral hemorrhage related to non-OAC and OAC
Non-OAC Mixed OAC
Reference Kazui Brott Davis Mayer Flibotte Flaherty Cucchi- Huhtakan- Horst- Kura- Purrucker Steiner Connolly Wilson
et al. et al. et al. et al. et al. et al. ara et al. gas et al. mann matsu et al. et al. et al. et al.
et al. et al.
# [49] [50] [51] [52] [6] [14] [53] [54] [10] [7] [31] [13] [42] [32]
Year 1996 1997 2006 2008 2004 2008 2008 2011 2013 2015 2016 2016 2016 2017
Study Retro- Prospec- Pooled RCT Prospec- Retro- RCT Retrospec- Prospec- Retro- Prospec- RCT Prospective Pooled
type spective tive meta- tive spective substudy tive tive spective tive (VKA) observa- analysis
analysis observa- analysis cohort cohort observa- observa- cohort observational (factor
tional study study tional tional study tional Xa
(VKA) (NOAC) antagonists
incl.
enoxaparin)
N 204 103 218 268 183 (70 258 303 982 206 (152 853 61 50 14 (ICH 91
(placebo expan- (285 expan- only) (NOAC),
arm) sion expansion 403
analy- sion analysis) (VKA)
sis) analy-
sis)
Age, 64 63 66 65 76 69 NR 69 74b 74 76 76 NR Median:
mean, (OAC: 80
years 75)
3 Antithrombotic- and Thrombolytic-Related Intracerebral Hemorrhage
Women, % 37.7% 36.0% 41.7% 37.0% NR 54.3% 33.9% 46.2% 47.6% 37.9% 41% 38% NR 45%
(NOAC),
51%
(VKA)
Oral 0 (0) 0 (0) 0 (0) 0 (0) 42 51 21 (6.9) 182 (18.5) 51 (24.8) 853 61 (100) 50 NR 500
anticoagu- (23.0) (19.8) (100) (100) (100)
lation, No.
(%)c
31
(continued)
Table 3.1 (continued)
32
Non-OAC Mixed OAC

Reversal – – (Placebo (Placebo VK + – Not Partly: VK + VK+/− Partly: PCC Andexanet Partly
therapy arms) arm) FFP speci- VK + PCC or PCC PCC vs. FFP alfa PCC
fied PCC FFP +-FFP
Hematoma volume (mL)
Median NR NR NR NR NR NR Non- NR Non- 19.3 10.8 FFP: NR NOAC
(IQR) OAC: OAC (6.9– (4.0–30.0) 13.2 14.4
14.4 14.3 52.8) (0.2– (3.6–
(7.9– (4.9– 43.9) 38.4);
30.9) 35.7) PCC: VKA
OAC: OAC: 13.0 10.6
30.6 20.0 (0.6– (4.0–
(7.4– (8.3– 78.1) 27.9)
70.1) 48.8)
Mean 20.1 26 (29) 25.3 22 (24) NR d NR Non-OAC: Non- NR 23.7 NR NR (8/14 ≤ NR
(SD) (18.0) (NR) 29.6 (37.0) OAC: (31.3) 10 ml;
OAC: 47.8 26.4 6/14
(58.0) (31.7) 11–60 mL)
OAC:
31.5
(30.2)
Hematoma expansion
Predefined 0–120 h 0–20 h 24 h 21–48 h 0–7 day – 0–72 h NR 24–48 h NR 3–72 h 3 h, 1 h, 12 h <72 h
time frame 24 h,
analyzed 72 h
J. C. Purrucker et al.
Definition >12.5 ml ≥33% >33% – ≥33% NR ≥33% NR ≥6 ml or ≥33% ≥6 ml ≥33% “effective ≥6 ml or
of or > 40% ≥ 33% or ≥ 33% or hemostasis: ≥ 33%
significant death ≤20%;
expansion good
hemostasis:
>20%
≤35%”
Proportion 19.6% 38.0% 31.6% NRe Non- NR Non- NR Non- 36% 38% 24 h: NR NOAC
of patients OAC OAC: OAC: FFP: (intracranial 40%,
with 23% 26% 11.7% 60% hemor- VKA
significant OAC: OAC: OAC: PCC: rhage, 34%
expansion 54% 56% 12.5% 30% effective/
good
hemostasis:
80%
(56–94%)
Modified and updated from Purrucker et al. [31]
Abbreviations: NR not reported, RCT randomized clinical trial, OAC oral anticoagulation
a
References within the main document
b
Median
c
Oral anticoagulation = treatment with vitamin K antagonists
d
Non-OAC (international normalized ratio (INR) < 1.2) 13.4 ml, OAC INR 2.1–3.0 14.0 ml, OAC INR > 3.0 33.2 ml
e
Estimated mean volume increase 26%
f
3 Antithrombotic- and Thrombolytic-Related Intracerebral Hemorrhage
Further secondary imaging endpoints included hematoma expansion ≥15% and/or death
33
Because VKA block a subunit of the vitamin K epoxide reductase and conse-
quently the synthesis of the vitamin K-dependent coagulation factors (II, VII, IX,
and X) [22], administration of vitamin K counteracts this mechanism. Nevertheless,
administration of vitamin K does not immediately reverse anticoagulation. Thus, it
should be used in order to avoid a rebound after administration of more rapid-acting
reversal agents.
Three agents are capable of INR normalization: activated factor VII (aFVII),
fresh frozen plasma (FFP), and prothrombin complex concentrate (PCC). According
to an international survey [23], all agents are currently in use in various combina-
tions depending on local standards and recommendations, which until recently were
not supported by prospective, multicenter, randomized data. PCC contains all vita-
min K-dependent coagulation factors, with variable amounts of factor VII. PCCs
with no or only little amounts of VII are classified as three-factor PCCs and PCCs
including factor VII, as four-factor PCCs. As the latter formulations provide a better
correlation with INR reversal, it should be preferentially used, if available [24]. In
2015, a pooled multicenter observational study found that the combination of FFP
and PCC was associated with the lowest case fatality and concluded that FFP might
be equivalent to PCC. However, in 2016 data from the randomized INCH trial (fresh
frozen plasma versus prothrombin complex concentrate in patients with intracranial
hemorrhage related to vitamin K antagonists) showed that (four-factor) PCC was
more efficient in normalizing the INR (≤1.2 at 3 h) and hematoma expansion seems
to occur less frequently in the PCC group [13]. However, due to safety concerns
(more hematoma expansion in the FFP group), the trial was halted early, and no
effect on clinical outcome was found. Importantly, in the INCH trial, 83% of the
patients initially treated with FFP had subsequently received PCC because INR was
not below 1.3 after 3 h. Potentially due to this delay, hematoma volumes were larger
in the FFP than in the PCC group, supporting an immediate start of reversal treat-
ment once the diagnosis is made by CT or MRI scan. In view of the low efficacy and
high doses (translating into high fluid volumes administered in a short time period)
necessary in attempting INR reversal with FFP, PCC should be used whenever
available. Due to scarce data supporting the use of recombinant factor VIIa and its
known risk of inducing thrombotic events, it is only recommended for exceptional
circumstances (e.g., Jehovah’s witness not accepting blood products) [25]. Although
rare, adverse thrombotic events might also occur with PCC. In patients with VKA-
ICH, 4.4% of adverse thrombotic events were rated as “possibly” or “probably
related” to PCC infusion in a retrospective observational study, but no event was
rated as “clearly related.” [26] In that study, high doses of PCC (>2000 IU) were
associated with occurrence of thrombotic events. Thus, titration of PCC to achieve
an INR below a certain threshold seems reasonable. However, the optimal INR tar-
get following VKA reversal is unknown. In the INCH trial, 1.2 was chosen [13],
while other prospective studies used a target INR value of 1.3 [27, 28].
Recommendations In cases of VKA-ICH, immediate reversal of INR to ≤1.3
should be targeted by administration of a PCC and intravenous vitamin K. For
patients in whom the INR is not corrected by the first dose of PCC, it is unknown
whether the benefit of repeat dosing outweighs potential risks. General treatment
recommendations, especially strict blood pressure control (<160 mmHg systolic),

are the same as for ICH not associated with anticoagulants. Future prospective stud-
ies will have to show whether a bundle of these measures will indeed help to improve
the dismal prognosis of VKA-ICH. Prevention of VKA-ICH by careful selection of
patients with an indication for VKA therapy and stringent INR controls to optimize
the time within the therapeutic range is necessary.
Non-vitamin K Antagonist Oral Anticoagulant-Related ICH
All NOACs have been shown to significantly reduce the relative risk of ICH com-
pared to warfarin [29]. However a greater acceptance of oral anticoagulation, along
with an increasing number of patients with indications for oral anticoagulation
caused by increasing numbers of patients with atrial fibrillation and a potential
extension of indications (e.g., embolic stroke of undetermined source), may ulti-
mately result in a greater absolute number of NOAC-related hemorrhages. Eighteen
to 25% of ICH patients are anticoagulated [10, 30], and according to recent German
registry data, 40% of anticoagulant-associated ICHs are now attributable to NOACs
[30]. In contrast to the long experience with VKA-related complications, less evi-
dence exists regarding the clinical and radiological course and optimal management
of NOAC-associated ICH (NOAC-ICH). The first prospective observational data
show a similar rate of hematoma expansion (38%) in NOAC-ICH and VKA-ICH,
and prognosis of NOAC-ICH seems unfavorable as well (Table 3.1) [31, 32].
In contrast to VKA-ICH, where INR measurements rapidly allow assessment of
the anticoagulation status, coagulation testing in NOAC-treated patients is less
straightforward. Sensitivity of routine global coagulation tests, such as INR or acti-
vated partial thromboplastin time (aPTT) for detection of relevant anticoagulant
activity of NOACs, largely depends on the reagent used, and thus results should be
interpreted with caution if the locally used reagent is not known [20, 33]. Thrombin
time (TT) – highly sensitive for dabigatran – can be used to rule out any dabigatran
effect if normal, but cannot provide a reliable estimate of the effective anticoagulant
activity [20]. NOAC-specific coagulation tests (e.g., drug-specific calibrated anti-
Xa tests for factor Xa inhibitors or diluted TT/hemoclot assay for dabigatran) should
thus be obtained directly at admission if available. Assessment of initial coagulation
status is important to clarify the etiology of the bleeding, to guide management of
reversal agents, and to provide a baseline for sequential measurements after admin-
istration of reversal agents.
Anticoagulation Reversal Treatment (NOAC)
The lack of specific antidotes to the NOACs has been perceived as a major disad-
vantage relative to VKAs and has limited their adoption by some clinicians. Data
from experimental settings suggest that PCC and FFP and activated factor VII are
effective in preventing hematoma expansion with rivaroxaban as well as dabigatran

[34–36]. In contrast, while a phase I clinical study involving 12 healthy male volun-
teers showed efficacy in reversal of rivaroxaban after PCC administration, no such
effect was observed with dabigatran [37]. According to the first prospective registry
data, no effect of PCC on hematoma expansion and functional outcome was
observed, but these data are clearly preliminary [31]. In 2015 however, the first
specific antidote for a NOAC, idarucizumab for reversal of dabigatran, gained
approval from the FDA. Idarucizumab is a humanized monoclonal antibody frag-
ment, which specifically reverses dabigatran, and it was shown effective in a phase
III case series replicating positive phase I data [38–40]. More recently the publica-
tion of the RE-VERSE AD study results confirmed the reversal of dabigatran in
patients with an uncontrolled hemorrhage or those requiring an urgent procedure
after the administration of intravenous idarucizumab 5 g. The primary endpoint was
the reversal of the anticoagulation effect of dabigatran within 4 h using thrombin
time or ecarin clotting time. In a total of 503 patients, the median maximum per-
centage reversal was 100% (95% CI, 100–100). Only 10 patients experienced recur-
rent or ongoing hemorrhage out of 114 that were found to have recurrent elevations
in the unbound-dabigatran levels between the 12 and 24 h. While only three of these
patients required an additional dose of idarucizumab, the explanation suggested for
the recurrent elevation in clotting time was redistribution of unbound dabigatran
from the extravascular to the intravascular compartment [41]. Another antidote
exists for reversal of the oral Xa inhibitors (apixaban, rivaroxaban, and edoxaban)
and low-molecular-weight heparin, termed andexanet alfa (a recombinant truncated
factor Xa). According to phase I data, it is capable of reversing the anti-factor Xa
activity within minutes. In contrast to idarucizumab, in which a single bolus infu-
sion showed long during activity, a rapid rebound after cessation of andexanet alfa
infusion is observed, resulting in equal activity levels of the drug vs. placebo group
after 1 h. Consequently, a continuous infusion may be needed as long as pharmaco-
logically relevant activity can be expected. The latter depends on individual factors,
such as dose, renal function, and concomitant medication, but usually after 24 h, a
concentration below 33 ng/ml, currently seen as the lower threshold of clinically
relevant activity [20], should be reached. An interim analysis of the prospective
multicenter open-label single-arm study ANNEXA-4 (clinicaltrials.gov
NCT02329327) evaluated the efficacy and safety of andexanet alfa in patients pre-
senting with major bleeding within 18 h of the last administration of a factor Xa
inhibitor (rivaroxaban, apixaban, edoxaban, or enoxaparin) [42]. Forty-seven
patients with baseline anti-factor Xa activity over 75 ng/mL were included in the
efficacy analysis. In 89% of rivaroxaban (95% CI, 58–94%) and 93% (95% CI,
87–94%) of apixaban-treated patients, anti-factor Xa activity was effectively
reduced by bolus administration of andexanet alfa, and levels remained stable dur-
ing a 2-h continuous infusion. Four hours after cessation of the andexanet alfa infu-
sion, a relevant rebound of the anti-factor Xa activity occurred, such that reductions
of 39% (rivaroxaban) and 30% (apixaban) were observed, compared to baseline.
Due to the interim nature of the report, patient numbers were small, with only 20
patients with intracranial hemorrhage included in the efficacy analysis (12 ICH, 7
subdural hematoma, 1 subarachnoid hemorrhage). Furthermore, patients with a sus-

pected unfavorable profile (GCS < 7 or estimated ICH volume > 60 mL) were
excluded. ICH volume increase after 12 h was ≤30% in 10 of the 12 patients (80%),
comparable to the larger study population, where effective hemostasis was reached
in 79%. As of October, 2017, andexanet alfa was not yet approved for clinical use
by regulatory authorities.
Further antidotes are in development, among them the “universal antidote” ari-
pazine (Ciraparantag or PER977), which may enable reversal of the oral factor Xa
inhibitors, the thrombin inhibitor dabigatran, unfractionated heparin, low-molecu-
lar-weight heparin, and fondaparinux [43].
Recommendations In view of the similar rate of hematoma expansions in NOAC-
ICH compared to VKA-ICH, immediate reversal of anticoagulation in acute NOAC-
ICH is prudent. After admission, standard procedures such as strict management of
blood pressure should be undertaken. When available, indicators of coagulation
status including thrombin time or ecarin clotting time (in the case of dabigatran) and
drug-specific concentrations can be obtained. For dabigatran-related ICH, intrave-
nous bolus administration of 5 g of idarucizumab is recommended. If idarucizumab
is not available, PCC might be administered, and/or the patient might undergo
immediate hemodialysis as dabigatran is dialyzable. In case of the factor Xa inhibi-
tors, in the absence of a specific antidote, PCC may be administered. If specific
reversal agents were used, drug-specific concentrations might be remeasured before
starting neurosurgical procedures (in case a short postponement is possible).
However, nonspecific reversal agents such as PCC do not reliably influence the drug
concentration measurements, and thus measurement of the efficacy of the reversal
treatment is not possible with standard coagulation tests.
Heparin-Related ICH
Data regarding the natural course of ICH during heparin therapy with either unfrac-
tionated heparin (UFH) or low-molecular-weight heparin (LMWH) is scarce.
Among patients receiving heparin for non-neurological indications, ICH occurs in
<0.1% of the patients [25]. Interestingly, a recent study examining the common
practice of “bridging” (i.e., in case of discontinuation of warfarin therapy due to
elective surgery, periprocedural use of LMWH until warfarin resumption) found a
higher incidence of bleedings among the bridging group compared to those with full
discontinuation of anticoagulation: Major bleeding (including ICH) occurred in
3.2% of bridged patients compared to 1.3% in the no-bridging group. In case of
UFH-induced ICH, continuous infusion should be stopped immediately, and prot-
amine sulfate (1 mg for every 100 units of heparin administered in the past 2–3 h)
should be administered (maximum single dose, 50 mg). If repeated aPTT measure-
ments indicate prolongation, a further 0.5 mg per 100 units heparin should be
administered [25]. Recommendations for reversal of subcutaneous LMWH depend
on the substance used and dosing: in patients not receiving therapeutic doses,
reversal is not generally recommended [25]. In case of enoxaparin, protamine at a

dose of 1 mg per mg enoxaparin should be administered (if the last dose of enoxa-
parin was >8–12 h, 0.5 mg protamine per mg enoxaparin; max. Single dose, 50 mg).
In cases of dalteparin, nadroparin, and tinzaparin, 1 mg protamine per 100 IU should
be administered (if time from last administration of LMWH is <25 h (~3–5 half-
lives)). If protamine is contraindicated or not available, factor VIIa can be consid-
ered, although evidence is poor [25]. Full therapeutic doses of fondaparinux might
be reversed by administration of PCC or recombinant factor VIIa. The availability
of a “universal antidote” might dramatically change recommendations in the near
future.
Thrombolytic-Related ICH
Intracerebral hemorrhage is the most feared complication of thrombolytic therapy.

Various definitions of (symptomatic) hemorrhage in relation to thrombolytic ther-
apy exist [44]. Recently, an updated anatomical classification set of secondary hem-
orrhage after ischemic stroke was proposed (the Heidelberg Bleeding Classification,
Table 3.2) [45].
A large meta-analysis of randomized trials comparing alteplase vs. placebo
found that parenchymal hemorrhage type 2 (Table 3.2) occurred in 6.8% of the
patients who received alteplase compared to 1.3% in patients who were not treated
(odds ratio (OR), 5.6) [46]. Fatal ICH occurred in 2.7% vs. 0.4% (OR 7.1) [46].
More severe stroke, but not age, increased the absolute risk of ICH [46]. Importantly,
rates of ICH are significantly lower in patients receiving thrombolytics in situations
other than ischemic stroke [25]. Thrombolytic therapy by plasminogen activators
Table 3.2 Description of secondary hemorrhage after ischemic stroke

Class Type Description
1 Hemorrhagic transformation of infarcted brain tissue
1a HI 1 Scattered small petechiae, no mass effect
1b HI 2 Confluent petechiae, no mass effect
1c PH 1 Hematoma within infarcted tissue, occupying <30%, no substantive mass effect
2 Intracerebral hemorrhage within and beyond infarcted brain tissue
PH 2 Hematoma occupying 30% or more of the infarcted tissue, with obvious mass
effect
3 Parenchymal hematoma remote from infarcted brain tissue
3 a Parenchymal hematoma remote from infarcted brain tissue
3 b Intraventricular hemorrhage
3 c Subarachnoid hemorrhage
3 d Subdural hemorrhage
HI indicates hemorrhagic infarction and PH, parenchymatous hematoma (According to the
Heidelberg Bleeding Classification; modified from Rüdiger von Kummer et al. [ [45]], Table 3.1
with permission from Wolters Kluwer Health, Inc.
disturbs coagulation for several hours (fibrinogen levels may not be recovered to
normal even after 24 h). Low fibrinogen levels (<150 mg/dL) were associated with
hematoma expansion in a retrospective analysis [47].
In every case of early neurologic deterioration, thrombolytic therapy should be
halted immediately, and follow-up brain imaging (CT scan) must be obtained. If
ICH is confirmed, guidelines recommend administration of cryoprecipitate (initial
dose, 10 IU). Cryoprecipitate is obtained from thawed and centrifuged FFPs and
contains factor VIII, fibronectin, factor XIII, and von Willebrand factor [25]. Target
fibrinogen levels are >150 mg/dL (although others still recommend >100 mg/dL).
Transfusion of 10 units of cryoprecipitate contains 2 g of fibrinogen, which may
raise fibrinogen levels by 70 mg/dL in a 70 kg patient [25]. However, cryoprecipitates
are not available at every site. If cryoprecipitate is unavailable, tranexamic acid
(10–15 mg/kg body weight) or ε-aminocaproic acid may be administered [25].
Fibrinogen levels should be measured after administration of a reversal agent.
Platelet infusions have been advocated in the past but are not recommended in the
recent guidelines from the Neurocritical Care Society and Society of Critical Care
Medicine [25].
Antiplatelet Medication-Related ICH
Conflicting data exists over the relevance of baseline antiplatelet therapy and risk of
hematoma expansion or poor functional outcome following ICH [25]. Nevertheless,
as a potential effect on hematoma expansion cannot be excluded by the data avail-
able today, discontinuation of antiplatelet therapy in cases of ICH is recommended.
After discontinuation of antiplatelet therapy, prolonged effects on thrombocyte
function can be observed. In agents producing a “nonreversible” platelet inhibition
(such as aspirin, clopidogrel, prasugrel, ticlopidine, or abciximab), effects last up to
several days until a relevant number of new thrombocytes are produced. For agents
acting as reversible inhibitors (such as ibuprofen, ticagrelor, tirofiban, or eptifiba-
tide), function is restored after 3–5 half-lives [25]. While platelet transfusion may
seem a logical treatment for ICH associated with antiplatelet drugs, the best avail-
able data does not support this routine practice. The PATCH trial randomized
patients with spontaneous acute ICH taking antiplatelet therapy (aspirin, clopido-
grel, and/or dipyridamole) to platelet transfusion therapy vs. standard therapy [48].
Platelet transfusion increased the likelihood of death or an unfavorable outcome
(OR, 2.05) [48]. While platelet transfusion cannot be recommended in acute spon-
taneous ICH with prior antiplatelet therapy, it should be noted that patients who
were likely to undergo surgical procedures were excluded from the PATCH trial. It
remains possible that platelet transfusion may provide a benefit if acute neurosurgi-
cal procedures are necessary. In patients requiring immediate surgery, administra-
tion of desmopressin can be considered, although higher-class evidence is lacking.
Desmopressin releases multimers of factor VIII/von Willebrand factor, supporting
platelet adhesion to the endothelium. Desmopressin should be administered as a
single dose (0.4 μg/kg body weight) [25].
Conclusion
ICH related to anticoagulant therapy represents a medical emergency and is associ-

ated with a high case fatality and unfavorable outcome. Prothrombin concentrate
can effectively reverse VKA therapy and should be immediately administered in
acute VKA-ICH. For NOAC-associated ICH, specific antidotes are either available
(idarucizumab for reversal of dabigatran) or in development (for factor Xa inhibi-
tors)). In cases of ICH associated with antiplatelet therapy, cessation of antiplatelet
therapy seems sufficient in most cases, and platelet infusions should not be given.
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Chapter 4
Blood Pressure Management in ICH
Shahram Majidi and Adnan I. Qureshi
Blood Pressure Management in ICH
Elevated blood pressure is a strong and independent risk factor for occurrence of
intracerebral hemorrhage (ICH) [1]. Elevated blood pressure (greater than
140/90 mmHg) in the first 24 h from symptom onset has been observed in approxi-
mately 80% of patients with primary ICH [2–4]. This high blood pressure in acute
phase following ICH, known as acute hypertensive response, is shown to be tran-
sient with spontaneous reduction even without antihypertensive therapy [5, 6]. The
mechanism of acute hypertensive response following ICH is not fully understood;
however, the high prevalence and self-limiting nature of this phenomenon suggest
possible hemorrhage specific etiology such as damage to the areas of the brain
involved in blood pressure regulation (for example the insula, cingulate cortex,
amygdala, prefrontal area, or brainstem compression and increased intracranial
pressure) with subsequent functional recovery [7–9].
The management of elevated systolic blood pressure (SBP) in patients with pri-
mary ICH has been subject of a long-lasting debate and controversy during the past
few decades. Approximately three decades ago, the standard approach was to not
treat elevated blood pressure in acute phase in order to avoid subsequent ischemic
changes in perihematoma areas. However, during the subsequent years, an alterna-
tive hypothesis gained attention which was advocating for aggressive acute blood
pressure management to improve patients’ outcome by reducing the magnitude of
hematoma expansion. Figure 4.1 shows the evolution of our understanding on blood
pressure management in patients with ICH.
S. Majidi (*)
Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA
A. I. Qureshi
University of Minnesota, Minneapolis, MN, USA

https://doi.org/10.1007/978-3-319-77063-5_4
46 S. Majidi and A. I. Qureshi
Concept: Concept: Concept: Concept:

Presence of Elevated SBP SBP reduction SBP reduction
peri- associated associated may improve
Management of acute hypertensive response
hematoma with with less clinical

pneumbra/ hematoma hematoma outcome/
based on expansion/ expansion/ phase 3
in intracerebral hemorrhage
experimental based on case based on pilot clinical trials

and clinical series studies
studies
Do not treat Moderate SBP Consider Consider

elevated SBP reduction to intensive SBP intensive SBP
to avoid peri- limit reduction to reduction to
hematoma hematoma decrease limit
ischemia expansion hematoma hematoma
expansion expansion and
improve
outcome
1985–1997 1998–2003 2004-2009 2010–2016
Time (year)
Fig. 4.1 Evolution in the management of elevated blood pressure in acute ICH during the past
three decades. (From Majidi et al. [41] with permission of Springer)
lood Pressure and Outcome in Patients with Intracerebral

B
Hemorrhage
Previous observational studies have identified SBP ≥ 200 mmHg as a predictor of

poor outcome and higher mortality rate, early hematoma expansion, and perihema-
toma edema in patients with primary ICH [10, 11]. In a retrospective analysis of 87
patients with hypertensive ICH, Dandapani et al. [12] found higher rate of mortality
and severe morbidity among patients with admission mean arterial pressure (MAP)
of >145 mmHg compared to those patient with MAP ≤ 145 mmHg. The Stroke
Acute Management with Urgent Risk-factor Assessment and Improvement
(SAMURAI)-ICH study [13] was a prospective multicenter observational study to
determine the safety and feasibility of early SBP reduction in patients with primary
ICH. They recruited 211 patients with primary ICH within 3 h from symptom onset
and initial SBP > 180 mmHg. All patients were treated with intravenous nicardipine
within 3 h from symptom onset and continued on treatment for 24 h with the SBP
goal of <160 mmHg and > 120 mmHg. Blood pressures were measured every
15 min during the initial 2 h and then every 1 h in the following 22 h. The mean SBP
during the first 24 h was calculated for each patient. The study demonstrated that the
higher mean SBP was independently associated with hematoma expansion (defined
as >33% increase in hematoma volume), neurological deterioration (defined as ≥4
points increase in National Institutes of Health Stroke Scale (NIHSS) score or ≥ 2
4 Blood Pressure Management in ICH 47
points decrease in Glasgow Coma Score (GCS) score), and unfavorable outcome
(defined as 90-day modified Rankin Scale (mRS) score of 4–6). Essentially, every
10 mmHg increment of mean SBP was associated with a 4.5-fold increase in neuro-
logical deterioration, 2-fold increase in unfavorable outcome, and 1.8-fold increase
in hematoma expansion. The study also demonstrated that the relative reduction of
SBP in first 24 h was inversely associated with higher rate of hematoma expansion,
neurological deterioration, and unfavorable outcome [14]. In a retrospective analy-
sis of 76 consecutive patients with hypertensive ICH, Ohwaki et al. [15] found
direct association between maximum SBP levels and the rate of hematoma expan-
sion. Only 9% hematoma expansion was observed in patients with SBP goal of less
than 150 mmHg whereas 30% hematoma expansion in those patients with SBP goal
of less than 160 mmHg. Analysis from secondary analysis from Factor Seven for
Acute Hemorrhagic Stroke Trial (FAST) revealed independent association between
higher mean arterial pressure (MAP) and presence of intraventricular hemorrhage
which is an independent predictor of poor outcome [16].
The primary target of blood pressure reduction in hypertensive ICH is to prevent
hematoma expansion and subsequently improve the patient’s outcome. Therefore,
the time window for blood pressure management in these patients is short and lim-
ited as majority of hematoma growth occur in the first few hours after symptom
onset. In a pooled analysis using placebo arms of three clinical trials studying dos-
ing, safety, and efficacy of recombinant factor VIIa (rFVIIa) [17–19] and also
Cincinnati ICH cohort [20], hematoma expansion reported in 73% of 218 patients
within 3 h from symptom onset [21]. In a retrospective analysis of 204 patients with
primary ICH, the highest rate of hematoma expansion observed within 3 h from
symptom onset which was 36% compared to 16% within 3–6 h and 15% within
6–12 h. Notably, none of the patients with first CT scan obtained within 24–48 h had
hematoma expansion (suggesting that hematoma expansion had preceded the first
scan) [22]. FAST trial was a randomized, double-blind, placebo-controlled study of
821 patients treated within 4 h of symptom onset with placebo, 20, or 80 μg/kg of
rFVIIa [23]. The study demonstrated significant reduction in hematoma expansion
in patients who received 80 μg/kg of rFVIIa; however, no improvement in 90-day
functional outcome or survival was noted. Pertinent to our current discussion is the
subgroup analysis from this study which showed that the reduction in hematoma
expansion rate in comparison to placebo group doubled when limiting symptom
onset to treatment to 2.5 h [24]. Finally, it should be noted that although the rate of
hematoma expansion is highest in the first 3 h, it may still occur in 12–30% of
patients between 3 and 24 h from symptom onset; therefore, it is reasonable to
maintain adequate blood pressure control during first 24 h [25, 26].
Safety of Early Intensive Blood Pressure Lowering Treatment
The safety of acute SBP reduction in patients with ICH has been confirmed in
numerous independent studies. The safety has been assessed by radiological bio-
markers or clinical outcomes. In an observational study of 19 patients with primary
supratentorial ICH who underwent positron emission tomography (PET) 5–22 h

from symptom onset, no evidence of ischemia in the perihematoma region was
detected [27]. In a prospective study, perihematoma edema and blood flow were
studied in 21 patients with primary ICH. All patients underwent perfusion-weighted
MRI and diffusion-weighted MRI study at baseline, 3–5 and 30 days after symptoms
onset and relative mean transit time (rMTT), relative cerebral blood flow (rCBF),
and relative cerebral blood volume (rCBV) were calculated in each perfusion study.
The study found perihematoma oligemia (rMTT>2 s) in patients with ICH vol-
ume > 15 ml. This phenomenon was self-limited with spontaneous resolution within
3–5 days after symptom onset, and there was no MRI marker of cerebral ischemia
[28]. In a randomized, multicenter, open-label clinical trial (ICH-ADAPT), Butcher
et al. studied the effect of blood pressure reduction on perihematoma CBF. They
recruited 75 patients with primary ICH with baseline SBP >150 mmHg and within
24 h from symptom onset and assigned the patients to intensive SBP reduction of
<150 mmHg or standard SBP reduction of <180 mmHg using intravenous antihy-
pertensive medication with SBP goal to be achieved in 1 h. All patients underwent
CT perfusion imaging 2 h after randomization. They found no significant change in
CBF in the perihematoma region related to acute blood pressure reduction [29].
In a prospective observational multicenter study, Qureshi et al. [30] studied the
feasibility and safety of intravenous antihypertensive treatment for acute hyperten-
sion in patients with primary ICH. Elevated blood pressure was defined as
SBP ≥ 160 mmHg and/or diastolic blood pressure (DBP) ≥ 110 mmHg documented
by at least two measurements 5 min apart. The treatment goal was to maintain SBP
<160 mmHg and DBP <100 mmHg for 24 h from onset of symptoms. The study
included total of 35 patients, 27 patients required antihypertensive treatment, and 8
other patients were used as control group. They demonstrated lower rate of neuro-
logical deterioration (defined as a decrease in initial GCS score ≥ 2) among patients
who required antihypertensive treatment (7% versus 26%). The study also found
lower rate of hematoma expansion among patients who required antihypertensive
treatment (9% versus 13%) and higher chance of functional independence (mRS
0–2) at 30 days among patients who were treated within 6 h from symptom onset
compared to those within 6–24 h. Antihypertensive Treatment of Acute Cerebral
Hemorrhage (ATACH)-I [31] was a National Institute of Neurological Disorders
and Stroke (NINDS)-funded open-labeled pilot trial which was conducted to deter-
mine the safety and tolerability of reducing SBP in the acute phase of ICH. A total
of 60 patients within 6 h of symptom onset and initial hematoma volume of less than
60 ml were recruited in three different SBP goals. The escalating SBP goals
(achieved using intravenous nicardipine) were as follows (1): 170–200 mmHg (2),
140–170 mmHg, and (3) 110–140 mmHg. The SBP goal was maintained for 24 h
from symptom onset, and the primary outcome of the study was first to assess the
feasibility of achieving and maintaining SBP goals for 18–24 h and to determine the
rate of neurological deterioration (defined as decline in the GCS score ≥2 or increase
in NIHSS score ≥4 points) within 24 h and serious adverse events within 72 h. The
SBP goals were achieved in 90% of the patient by 2 h. The observed proportions of
neurological deterioration and serious adverse events were below the pre-specified
safety thresholds, and the 3-month mortality rate was lower than expected among all
SBP tiers. The post hoc analysis of ATACH I study showed a trend toward lower
rates of hematoma expansion, perihematoma edema, and also poor outcome in
90 days among patients with more intensive SBP reduction; however the differences
were not statistically significant [32]. Intensive blood pressure reduction in acute
cerebral hemorrhage (INTERACT)-I [33] trial was another randomized clinical trial
that assessed the safety and efficacy of intensive SBP reduction in patients with
acute ICH. The study included patients ≥ 18 years old of age with primary ICH
within 6 h from symptom onset and elevated SBP which was defined as at least two
measurements of 150–220 mmHg recorded ≥ 2 min apart. A total of 404 subjects
were recruited and randomly assigned to either standard SBP reduction (with SBP
goal <180 mmHg) or intensive SBP reduction (with SBP goal <140 mmHg). The
SBP goal was to achieve within 1 h and maintained for 7 days or until discharge
from hospital. The primary efficacy outcome of study was proportional change in
hematoma volume at 24 h. There was no evidence of increased rate of adverse
events or worse outcome at 90 days among intensive SBP reduction group. They
also found 8% absolute risk reduction in the rate of hematoma expansion (defined
as an increase in volume > 33% or > 12.5 ml in the first 24 h) in intensive SBP
reduction group (15% versus 23%, p = 0.05). Notably, substantial reduction in the
rate of hematoma growth was observed among intensive SBP reduction group
recruited within 4 h from symptom onset (15 vs 30% in guideline group, relative
risk reduction 54%, 95% CI: 30–88%) and also among subjects with initial SBP
greater than 180 mmHg (17 vs 32% with relative risk reduction 47%, 95% CI:
6–70%).
fficacy of Early Intensive Blood Pressure Lowering

E
Treatment
Following promising observations from ATACH I and INTERACT I studies and

also other studies such as ICH-ADAPT and SAMURAI-ICH, two phase 3, random-
ized, double-blind, multicenter international clinical trials were launched to inde-
pendently determine the efficacy of intensive SBP reduction in patients with acute
primary ICH.
In the second intensive blood pressure reduction in acute cerebral hemorrhage
trial (INTERACT II) [34], a total of 2839 patients from 144 hospitals in 21 countries
with ICH within 6 h of symptom onset were randomized to either intensive SBP
reduction which was defined as target of <140 mmHg within 1 h or standard SBP
reduction which was target of <180 mmHg. Patients with primary hypertensive ICH
were required to have at least two SBP measurements between 150 and 220 mmHg
recorded at least 2 min apart to be eligible for enrollment. The target SBP goal in
each group was maintained for 7 days. The study did not show any significant dif-
ference in the rate of 90-day major disability and death (mRS: 3–6) between the two
treatment groups. Also, there was no significant reduction in the rate of hematoma
expansion among the intensive SBP reduction group. However, in the ordinal analy-
sis of 90 day mRS, higher rate of functional recovery was observed among intensive
SBP reduction group. Patients in the intensive SBP reduction group reported better
physical and mental health-related quality of life in the European Quality of Life 5
Dimension (EQ-5D) health utility score obtained at 90 days. The post hoc analysis
of INTERACT II study showed lowest rate of death and major disability at 90 days
(mRS 3–5) among patients who had larger SBP reduction (≥20 mmHg) which was
achieved within 1 h of randomization and maintained for 7 days [35]. As further
evidence on importance of faster and greater SBP reduction, sub-analysis of
INTERACT II study revealed the lowest mean absolute hematoma expansion in
patients who achieved SBP < 140 mmHg within 1 h compared to those who required
over 6 h (2.6 ml versus 5.4 ml) [36]. There are some issues and limitations which
need to be considered for the interpretation of INTERACT II study results including
1) patients with large hematoma volume and midline shift and low GCS score were
not included in the study. Indeed, 70% of the patients had baseline hematoma vol-
ume of <15 ml; therefore, the safety and efficacy of intensive SBP reduction in large
ICH and patients with unfavorable characteristics were not tested in this study. 2)
Substantial percentage (34%) of patients in the intensive SBP reduction group did
not achieve SBP goal, and only one third of the patients in the intensive SBP reduc-
tion group achieved SBP goal within 1 h. The benefit of intensive SBP reduction
might have been different if intensive SBP reduction goal had been achieved in a
larger proportion of the patients and in a faster time period.
Based on INTERACT II results, several organizations including European Stroke
Organization and American Heart Association/American Stroke Association (AHA/
ASA) updated their guideline for ICH management. In the updated 2015 AHA/ASA
guideline for management ICH, acute SBP reduction to <140 mmHg in ICH patients
presenting with SBP between 150 and 220 mmHg and without contraindication to
acute BP treatment is mentioned as safe and feasible which can be effective in
improving clinical outcome. However, it is highlighted that data pertaining to the
safety and efficacy of intensive SBP reduction in patients with higher SBP
(>220 mmHg) and larger hematoma volume and those who require decompressive
craniotomy is limited [37].
Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) II trial
was a NINDS-funded randomized double-blind controlled clinical trial which
recruited patients with primary supratentorial ICH from 2010 to 2015 in the United
States, Europe, and Asia [38]. ATACH II study was highly anticipated to solidify the
evidence for efficacy of intensive SBP reduction in acute ICH following promising
trends seen in INTERACT II study. However, ATACH II study was prematurely
terminated by Data Safety and Monitoring Board (DSMB) before reaching target
1280 subjects recruitment for futility after interim analysis revealed no significant
difference in outcome between the intensive SBP reduction group and standard SBP
reduction group. Briefly, ATACH II clinical trial recruited patients with primary
ICH within 4.5 h from symptom onset with initial SBP ≥180 mmHg. The patients
were randomly assigned to SBP target of 110–139 mmHg (intensive treatment) or a
target of 140–179 mmHg (standard treatment). The SBP goals were maintained for
24 h in both groups because the primary therapeutic target of SBP reduction mainly
occurs within this time frame. Nicardipine infusion was used for blood pressure
reduction in both groups, and the primary outcome of the study was defined as death
or major disability (mRS >3) at 90-day follow-up. A total of 1000 subjects were
recruited in the study, 500 patients in each group with mean admission SBP of
200 ± 27 and 201 ± 27 mmHg in intensive treatment group and standard treatment
group, respectively. There was no significant difference between the two groups in
regard to the rate of 90-day death or major disability (38.7% versus 37.7%), the
quality of life assessment via EQ-5D, or the rate of hematoma expansion. Moreover,
the rate of renal adverse events within 7 days after enrollment was significantly
higher among intensive SBP reduction group (9.0% versus 4.0%, p = 0.002). There
are several issues that need to be taken into consideration for proper interpretation
of ATACH II results: 1) only 10% of all subjects had initial hematoma volume
greater than 30 ml, and more than half of the patients had admission GCS score of
15; therefore, similar to INTERACT II, the result of ATACH II cannot be general-
ized to patients with unfavorable characteristics including larger hemorrhage and
low GCS score on admission. 2) primary treatment failure occurred in 12% of
patients in intensive SBP reduction group versus less than 1% of patients in standard
SBP reduction group. It can be argued that if higher proportion of the patients had
met the treatment goal, the outcome benefit could have been different. 3) consider-
ing the high rate of favorable outcome among both arms of ATACH II study in
comparison to previously published studies, it is also possible that standardized
intensity of medical care and monitoring provided throughout the study sites and
blunting of blood pressure fluctuations may have provided therapeutic benefits
independent of the magnitude of SBP reduction. Table 4.1. summarizes all clinical
trials addressing SBP management in patients with primary ICH.
In summary, ATACH II and INTERACT II, as two largest clinical trials address-
ing acute blood pressure treatment in patients with ICH, both failed to demonstrate
improved functional outcome with intensive SBP reduction to <140 mmHg in com-
parison to standard SBP goal of <180 mmHg in acute primary ICH. Figure 4.2 dem-
onstrates the blood pressure profile within the first 24 h among study arms in both
studies. As evident in this figure, the SBP profile of intensive SBP reduction group
in INTERACT II study is similar to standard SBP reduction group of ATACH II
study. The results of these two studies suggest that perhaps SBP reduction to 140–
150 mmHg in patients with acute ICH provides the maximum outcome benefit as
further reduction to less than 140 mmHg was associated with higher rate of adverse
events without further improvement of clinical outcome. However, the safety and
possible outcome benefits of intensive SBP reduction in certain groups of ICH
patients including patients with large hematoma volume, midline shift, increased
ICP, and lower admission GCS score remain unclear. Further sub-analysis from
ATACH II study and pooled analysis from these two trials might answer some of
these questions. Future studies should focus on utilization of MRI and MR perfu-
sion in acute ICH for better delineation of the pathophysiology, magnitude, and
natural history of secondary brain injury and its association with patient’s SBP pro-
file during the acute phase after ICH ictus. Prior studies of MRI in patients with
Table 4.1. Summary of completed prospective clinical trials that studied acute hypertensive response treatment in ICH patient
52
Mean
initial ICH
volume
(ml)
median No. of
Study Design Patient included (range) Intervention Primary outcome subjects Results
Intracerebral Multicenter, ICH within 24 h of 23.25 IV labetalol to Pre-hematomal 82 Perihematomal rCBF was
Hemorrhage Acutely open-label, symptom onset and (±24.82)a reduce SBP to rCBF measured not lower among patients
Decreasing Arterial randomized, SBP ≥150 mmHg <150 mmHg, with CT perfusion randomized to SBP
Pressure Trial blinded-point control group 2 h after treatment <150 mmHg (p = 0.18)
(ICH-ADAPT) [29] trial based on AHA
guideline
Antihypertensive Prospective, ICH within 6 h of 13.74 Stepwise BP [1] Neurological 60 Low rate of serious
Treatment in Acute multicenter, symptom onset and (±14.21)a control to test deterioration adverse events and
Cerebral Hemorrhage open-label, SBP ≥200 mmHg three tiers of SBP within 24 h [2]. neurological deterioration
(ATACH-1) [31] safety, and reduction: Serious adverse among all three tiers. No
tolerability study 170–200 mmHg events within 72 h difference in average SBP
140–170 mmHg from treatment change between patients
and 110– initiation with and those without
140 mmHg using neurological deterioration
IV nicardipine (p = 0.47)
Intensive Blood Randomized, ICH within 6 h of 13.45 Intensive SBP Proportional 400 Early intensive BP
Pressure Reduction in open-label, symptom onset and (±13.05)a lowering to change in reduction feasible, safe
Acute Cerebral active-control, SBP >150 <140 mmHg hematoma volume and reduces the rate of
Hemorrhage – parallel- and ≤ 200 mmHg within 1 h; control in 24 h and hematoma expansion by
(INTERACT I) Pilot assignment, group with SBP mortality and poor 8% (p = 0.05)
Study [33] safety/efficacy goal of outcome (defined
study <180 mmHg as mRS 3–6) at
90 days
S. Majidi and A. I. Qureshi
Intensive Blood Randomized, ICH within 6 h from 11 (6–20) Intensive SBP Death or major 2794 No significant change in
Pressure Reduction in open-treatment, symptom onset with lowering to disability (defined the rate of death or major
Acute Cerebral blinded at least two SBP <140 mmHg as mRS > 2) at disability. However,
Hemorrhage – end-point reads between 150 within 1 h; control 90 days ordinal analysis of mRS
INTERACT II [35] clinical trial and 220 mmHg group with SBP suggested improved
goal of outcome (OR: 0.87; 95%
<180 mmHg CI: 0.77–1.00; p = 0.04)
Antihypertensive Randomized ICH patients within 10 (1–79) Intensive SBP Death or severe 1000 No difference in the rate
Treatment in Acute multicenter, 4.5 h from symptom control with goal disability (defined of death or severe
Cerebral two-arm, onset with at least of 110– as mRS 4–6) at disability (p = 0.72).
Hemorrhage – open-label one SBP record of 139 mmHg, 90 days Higher rate of renal
ATACH II [38] clinical trial ≥180 mmHg control group complications in 7 day
4 Blood Pressure Management in ICH
with SBP goal of among intensive SBP

140–179 mmHg group (p = 0.002)
Abbreviations used: ICH intracerebral hemorrhage, rCBF relative cerebral blood flow, SBP systolic blood pressure, mRS modified Rankin Scale
a
Mean (±SD)
53
200
Systolic blood pressure (mm Hg)
180
ATACH-2 guideline treatment arm
INTERACT-2 guideline treatment arm
INTERACT-2 intensive treatment arm

140
ATACH-2 intensive treatment arm
110
1 6 24
Time (h)
Fig. 4.2 Comparison of mean SBP profile in the first 24 h after randomization in standard SBP
reduction and intensive SBP reduction group in INTERACT II (black dash lines) with mean mini-
mum SBP profile for same groups in ATACH II (gray lines). (From Majidi et al. [41] with permis-
sion of Springer)
acute ICH have shown remote areas of restricted diffusion and blood-brain barrier
disruption and suggested correlation with acute SBP reduction [39, 40]. Utilization
of more advanced imaging modalities in patients with acute ICH can potentially
assist the clinicians to identify a subset of ICH patients who may benefit from inten-
sive SBP reduction and therefore provide more individualized SBP goal for those
patients. Until future clinical trials provide further evidence on different aspects of
acute SBP reduction in patients with ICH, standard SBP reduction to 140–160 mmHg
seems safe and reasonable.
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Chapter 5
Thromboprophylaxis and Seizure
Management in Intracerebral Hemorrhage
Odysseas Kargiotis, Georgios Tsivgoulis, and Jose I. Suarez
Introduction
Intracerebral hemorrhage (ICH) is a common cause of death and disability in adults

with an overall annual incidence of 24.6 cases per 100,000 people. The incidence is
considerably higher in Asian populations (51.8 per 100,000 persons-years) and the
elderly [1]. Mortality after ICH is high, exceeding 40% the first month and reaches
60% 1 year after insult. Interestingly, more than 50% of deaths occur within the first
48 h [2]. At least 75% of the survivors remain dependent at 6 months, with half of
them having a modified Rankin score of 4 or 5 [3]. Surprisingly, mortality rates have
remained unchanged over the last three decades [1]. Up to 50% of patients have
advanced age and arterial hypertension as the most common risk factors for ICH
[4]. In the present section, we review the available data regarding the prevention and
treatment of common complications, namely, deep vein thrombosis (DVT), pulmo-
nary embolism (PE), and seizures.
O. Kargiotis
Stroke Unit, Metropolitan Hospital, Piraeus, Greece
G. Tsivgoulis (*)
Second Department of Neurology, “Attikon” Hospital, School of Medicine,
University of Athens, Athens, Greece
Department of Neurology, The University of Tennessee Health Science Center,
Memphis, TN, USA
J. I. Suarez
Division of Neurosciences Critical Care, Departments of Anesthesiology and Critical Care
Medicine, Neurology, and Neurosurgery, The Johns Hopkins University School of Medicine,
Baltimore, MD, USA

https://doi.org/10.1007/978-3-319-77063-5_5
58 O. Kargiotis et al.
Thromboprophylaxis
Incidence of Venous Thromboembolism and Risk Factors
Patients with acute neurological insults and those undergoing major neurosurgi-
cal procedures are at increased risk for DVT and subsequent PE. The reported
rates of these complications in different studies show substantial variation. The
incidence of DVT and PE in stroke patients ranges from 1% to 10% (including
asymptomatic patients) and from 0.5% to 1.6%, respectively [5–9]. It is esti-
mated that, without preventive measures, 53% and 16% of stroke patients suf-
fering from severe motor deficits will present with DVT or PE, respectively
[10]. Neurosurgical patients might develop venous thromboembolism (VTE)
even more often. Indeed, 16% to 25% of them suffer from such complications,
whereas PE is associated with a 60% mortality [11, 12]. Prolonged immobility
is a major risk factor that is determined mainly by the severity of the neurologi-
cal deficit [5]. In cases with residual lower limp paralysis and without thrombo-
prophylaxis, standard diagnostic tests may detect asymptomatic DVT in up to
75% of patients [13].
Among stroke patients, those with ICH have a fourfold increased risk of VTE
compared with those with ischemic stroke [14]. Less aggressive thromboprophy-
laxis and more severe motor deficits in ICH might account for the higher rates of
VTE compared with ischemic stroke [15]. The analysis of a large US-based national
hospital discharge database comprising 1,606,000 cases with ICH revealed VTE
rates of 1.93%, DVT of 1.37%, and PE of 0.68% [9]. In the FAST (Factor Seven for
Acute Hemorrhagic Stroke) trial, the incidence of DVT and PE was 3% and 1%,
respectively [16]. Smaller patient cohorts involving Asian patients have shown
higher rates of DVT. Fourteen days after admission, DVT was diagnosed in the 21%
of 81 Japanese patients, while 1 patient suffered PE. However it should be noted that
no specific antithrombotic preventive measure was administered in this Japanese
cohort of ICH patients [17]. Similarly, another study from Japan documented a
40.4% incidence of DVT among 52 ICH patients [18].
Eighty percent of DVTs develop between the second and the tenth day after ICH
[7]. In addition, PE is responsible for 5% of deaths after ICH [19]. The emboli caus-
ing PE originate in the lower limbs in more than 90% of cases [20]. Factors associ-
ated with increased risk for DVT include older age, female sex, complete lower
limb paralysis, severe neurological deficit with National Institute of Health Stroke
Scale (NIHSS) score of more than 12, large hematoma volume and lobar location,
obesity, cancer, prothrombotic state, hormonal therapy, and prolonged immobiliza-
tion [14, 17, 18, 21, 22].
Practitioners may use one of several clinical predictive scores to assess the risk
of developing DVT in hospitalized patients. The Padua Predictive Score (Table 5.1)
was evaluated in a cohort of 1180 consecutive patients admitted to a department of
internal medicine, with the most common diagnosis being active cancer, whereas
stroke patients composed less than 5% of the study group. The patients were cat-
5 Thromboprophylaxis and Seizure Management in Intracerebral Hemorrhage 59
Table 5.1 The Padua risk Risk assessment model (high risk of VTE: ≥ 4)
assessment model for the Baseline features Score
identification of hospitalized
medical patients at risk for Active cancera 3
venous thromboembolism [23] Previous VTE (with the exclusion of superficial 3
vein thrombosis)
Reduced mobilityb 3
Already known thrombophilic conditionc 3
Recent (< 1 month) trauma and/or surgery 2
Elderly age (≥ 70 years) 1
Heart and/or respiratory failure 1
Acute myocardial infarction or ischemic stroke 1
Acute infection and/or rheumatologic disorder 1
Obesity (BMI ≥30) 1
Ongoing hormonal treatment 1
a
Patients with local or distant metastases and/or in whom chemo-
therapy or radiotherapy had been performed in the previous
6 month
b
Bed rest with bathroom privileges (either due to patient’s limita-
tions or physicians order) for at least 3 days
c
Carriage of defects of antithrombin, protein C or S, factor V
Leiden, G20210A prothrombin mutation, and antiphospholipid
syndrome. From Barbar et al. [23], Table 1, with permission of
John Wiley and Sons
egorized as either low or high risk for VTE according to a cutoff value of 4. The
authors showed that only the 0.3% of low-risk patients developed VTE in compari-
son with the 11% of those at high risk but without thromboprophylaxis. Prophylactic
treatment reduced VTE to 2.2% in high-risk patients [23]. According to this score,
all patients with ICH and reduced mobility are at high thromboembolic risk.
Among the other two predictive scores, Rogers score is applicable only to surgical
patients, whereas Caprini’s assessment model (Table 5.2), although validated also
in surgical patients, appears practical and easy to use in nonsurgical patients, too,
with all stroke patients being again categorized as at high thromboembolic risk
[24–26].
Oral anticoagulant-related ICH is typically managed with the administration of
prothrombin complex concentrates (PCCs), fresh frozen plasma (FFP), and vitamin
K in order to reverse the anticoagulant effect [27]. Interestingly, these interventions
might further increase the risk for VTE and DVT. A meta-analysis of 27 studies with
1032 ICH patients receiving acutely PCC found an 1.8% (95% CI 1.0–3.0) inci-
dence of thromboembolic events in patients treated with 4-factor PCCs and 0.7%
(95% CI 0.0–2.4) in patients treated with 3-factor PCCs [28]. The retrospective
analysis of 54 ICH patients treated with rFVIIa (recombinant activated Factor VII)
reported VTE rates of 5% [29]. However, these patients were not routinely screened
for DVT, and the diagnosis was based on clinical suspicion. Of interest, the FAST
clinical trial investigating the effect of rFVIIa administration in spontaneous, non-
anticoagulation-related ICH found similar DVT and PE rates (3% and 1%, respec-
Table 5.2 The Caprini risk assessment model for the identification of hospitalized (surgical or
medical) patients at risk for venous thromboembolism [25]
Clinical characteristics Pointsa
Age
Age 41–60 1
Age 61–74 2
Age ≥ 75 3
Surgery
Minor surgery 1
Arthroscopic surgery 2
Major open surgery (> 45 min) 2
Laparoscopic surgery (> 45 min) 2
Elective arthroplasty 5
BMI > 25 kg/m2 1
Lower limb edema 1
Lower limb varicose 1
Pregnancy or postpartum 1
History of spontaneous abortion 1
Oral contraceptives use 1
Recent sepsis (< 1 month) 1
Obstructive pulmonary disease 1
Recent pneumonia (< 1 month) 1
Abnormal pulmonary function tests 1
Acute myocardial infarction 1
Congestive heart failure 1
Inflammatory bowel disease 1
Bed rest 1
Bedridden (> 72 h) 2
Cancer 2
Immobilizing cast 2
Central venous catheter 2
Previous venous thromboembolism 3
Factor V (Leiden) mutation 3
Presence of lupus anticoagulant 3
Anticardiolipin antibodies 3
Homocysteinemia 3
Heparin-induced thrombocytopenia 3
Other congenital or acquired thrombophilia 3
Recent stroke (< 1 month) 5
Lower limb fracture 5
Recent spinal cord injury (< 1 month) 5
Maximum score 60 (medical patients),
65 (surgery patients)
Adapted from Caprini [25]
a
The individual scores of each risk factor are summed to generate a cumulative risk score that
defined the patient’s venous thromboembolism risk level: very low risk 0–1, low risk 2, moderate
risk 3–4, and high risk ≥5
tively) in the placebo and treated patients [16]. It is important to stress that after
weighing all this evidence, patients presenting with anticoagulation-related ICH
should undergo anticoagulation reversal upon admission [29].
Physicians who manage patients with ICH usually undertake a less aggressive
approach concerning thromboprophylaxis, due to the possible enlargement of
parenchymal hematoma secondary to ongoing bleeding. Indeed, a meta-analysis of
218 ICH cases demonstrated some degree of hematoma growth in 72.9% of them,
which was associated with mortality and overall outcome [30]. Another prospective
observational study of 103 patients found a significant association between early
hematoma growth and clinical deterioration [31]. Thus, confirmation of bleeding
cessation and hematoma volume stabilization is necessary before initiation of phar-
macological thromboprophylaxis.
I nternational Recommendations on Thromboprophylaxis

Management in ICH
Since 2007, the American Heart Association/American Stroke Association (AHA/

ASA) guidelines recommend low-dose unfractionated heparin (UH) or low-molec-
ular-weight heparin (LMWH) after ICH for the prevention of VTE [32]. This initial
weak recommendation suggested the use of anticoagulants after documentation of
bleeding cessation in patients with hemiplegia but no earlier than 3–4 days after
insult (Class IIb, Level of Evidence B). For the rest of the patients suffering from
hemiparesis or hemiplegia, lower limb intermittent pneumatic compression (IPC)
use was strongly recommended (Class I, Level of Evidence B). In 2015, the revised
guidelines preserved the strong recommendation for IPC (Class I, Level of Evidence
A) and recommended against the use of graduated compression stockings (Class III,
Level of Evidence A). Moreover, the recommendation about low-dose anticoagu-
lants allows for an earlier institution of prophylactic medication, even after 1 day
from symptom onset, provided that bleeding cessation has been documented (Class
IIb, Level of Evidence B) [27]. Despite these recommendations, a recent study
depicted a less than 20% use of prophylactic anticoagulation in ICH patients (5395
out of 32,690), with almost half of them receiving treatment within 48 h [33].
Similarly, the most recent European Stroke Organization (ESO) guidelines for
the management of spontaneous ICH include a strong recommendation for the use
of IPC in immobile patients and overrule the application of short or long graduated
compression stockings. Regarding UH or LMWH, they state that there is insuffi-
cient evidence to guide decisions about the details of its indication, so the recom-
mendation for the prophylactic use of heparin is weak [34]. In line with AHA/ASA
and ESO, the Japanese guidelines support the consideration of prophylactic low-
dose anticoagulation [35]. The American College of Physicians and the American
College of Chest Physicians recommend also the use of DVT pharmacoprophylaxis
and discourage the application of graduated compression stockings [36, 37]. On the
contrary, the United Kingdom and Australian authorities recommend against the
prophylactic initiation of low-dose UH or LMWH in patients with ICH [38, 39].
Finally, the most recent guidelines from the Neurocritical Care Society regard-
ing thromboprophylaxis for ICH patients requiring intensive care were based in
the grade system [40]. The goal of this guideline was to provide clinicians with an
evidence-based framework for the appropriate administration of thromboprophy-
laxis in patients with neurologic illness, with a focus on those requiring neurocriti-
cal care. The authors recommended the use of IPC and/or graduated compression
stockings for VTE prophylaxis over no prophylaxis beginning at the time of hospi-
tal admission (strong recommendation and high-quality evidence). They also sug-
gested using prophylactic doses of subcutaneous UFH or LMWH to prevent VTE in
patients with stable hematomas and no ongoing coagulopathy beginning within 48 h
of hospital admission (weak recommendation and low-quality evidence). Moreover,
the authors recommended continuing mechanical VTE prophylaxis with IPCs in
patients started on pharmacologic prophylaxis (weak recommendation low-quality
evidence). As can be gathered from the evidence reviewed thus far, the inconsistency
between the different expert’s consensuses derives greatly from the lack of convinc-
ing, large-scale randomized trials on ICH pharmacologic thromboprophylaxis.
Studies on Non-pharmacologic Antithrombotic Measures
Calf IPC was originally investigated as a potential non-pharmacologic antithrom-

botic measure in surgical patients and in hospitalized patients with or without can-
cer in the early 1970s [41–43]. A few years later, the approach was studied on
neurosurgical patients, including non-operated ones, with impressive results con-
cerning VTE risk reduction [44, 45]. Subsequently, sequential compression devices
were added to heparin plus elastic stockings (ES) in patients with ischemic stroke
resulting in a significant 40-fold risk reduction of DVT [46]. The first strong evi-
dence about the efficacy of IPC in the prevention of DVT in ICH patients came from
a randomized trial by Lacut et al. The authors assigned 151 ICH patients to receive
ES alone or combined with IPC, and after 10 days, they documented a substantial
relative risk reduction of 71% in favor of the ES plus IPC treatment group [47].
Interestingly, asymptomatic DVT had a high incidence of 15.9% at 10 days in the
group receiving only ES. Similar prophylactic effect of IPC in patients with ICH
was also found in the CLOTS (Clots in Legs Or sTockings after Stroke) 3 trial,
where a subgroup analysis verified a 10% absolute risk reduction of DVT in the
group of patients randomized to IPC (6.7% versus 17.0%). CLOTS 3 trial was the
largest to date randomized controlled clinical trial (RCT) that evaluated the safety
and efficacy of IPC for DVT prophylaxis in a large sample of 2876 acute stroke
patients including 376 cases with ICH [48].
The current evidence for the application of graduated compression stockings sug-
gests that they do not afford substantial protection against DVT in stroke patients. In
a small cohort of 99 randomized individuals suffering from stroke, elastic stockings
did not reduce significantly the diagnosis of asymptomatic DVT (OR = 0.43, 95%
CI 0.14–1.36) [49]. Similarly, the large CLOTS 1 trial that was an outcome-blinded
randomized controlled study, after having randomized 2518 stroke patients, including
232 cases with ICH, confirmed the lack of efficacy of graduated compression stock-
ings for DVT prophylaxis in acute stroke. The nonsignificant absolute risk reduction
of 0.5% for DVT was accompanied by significant local complications, such as skin
breaks, ulcers, blisters, and skin necrosis, in the 5% of patients wearing stockings
[7]. However, in the similarly designed CLOTS 2 trial, which allocated 3114 stroke
patients, thigh-length graduated compression stockings were more efficient in reducing
DVT risk than below-knee stockings, with an absolute risk reduction of 2.5% (95% CI,
0.7–4.4; p = 0.008) [50]. Thus, IPC is strongly recommended immediately after ICH,
whereas graduated compression stockings should be avoided. In case of IPC unavail-
ability, thigh-length, graduated compression stockings could be an alternative option,
at least until the safe initiation of pharmacologic thromboprophylaxis treatment.
Studies on Pharmacologic Thromboprophylaxis
The prophylactic antithrombotic properties of low-dose UH or LMWH in hospital-

ized/immobilized patients have been investigated during the past 50 years. Initial
studies showed that low-dose anticoagulation was very effective in reducing DVT
occurrence in patients hospitalized for different etiologies, including myocardial
infarction, orthopedic operations and hip replacement, urological surgery, and gen-
eral surgery [51–56]. All studies used a control group and documented absolute
percentage reductions of DVT rates ranging from 12% to more than 40%.
In stroke medicine, low-dose UH at first and LMWH at a later stage were studied
as means of lower limb thromboprophylaxis [57]. In the initial studies, discrimina-
tion between ischemic and hemorrhagic stroke could only be made post-mortem.
One such study with 305 patients achieved absolute DVT reduction rates of 50%,
along with a significantly reduced mortality in the heparin group. Furthermore, PE
detection was less frequent in patients that died during the follow-up and had been
treated with heparin. Hemorrhagic stroke was subsequently found in 9.9% of the 84
deceased patients, with similar distribution between treatment groups [58]. Later, an
absolute reduction in DVT incidence of 26–30% was demonstrated by different
LMWH molecules compared to placebo in ischemic stroke patients [59, 60]. Again
in patients with ischemic stroke, LMWH were compared in randomized trials with
UH and were proven to be superior or non-inferior to UH in preventing DVT [61,
62]. The largest of these studies (PREVAIL Study) assigned 1762 patients with
ischemic stroke to either enoxaparin 40 mg or UH 5000iu twice per day and found
a risk reduction of DVT of 43% with enoxaparin (relative risk 0.57, 95% CI 0.44–
0.76, p = 0.0001), without increase in intracranial hemorrhage incidence [63].
Finally, in a mixed population with both ischemic and hemorrhagic stroke patients
in rehabilitation, the multivariate analysis showed that only therapeutic anticoagula-
tion (OR = 0.37; 95% CI, 0.15–0.88) and then low-dose heparin (OR = 0.48; 95%
CI, 0.23–0.98) protected against VTE, whereas antiplatelet agents had no effect
(OR = 0.79; 95% CI, 0.40–1.57) [64].
It is well-documented and supported that pharmacologic thromboprophylaxis is

warranted after ischemic stroke unless contraindications exist, whereas in cases
with ICH there is still some controversy due to the limited available evidence from
RCTs evaluating solely patients with acute ICH. The first prospective randomized
study was conducted by Dickmann et al. and found that heparin did not offer sub-
stantial protection against VTE but neither increased the risk of bleeding [65]. The
results of this study were incorporated to those of a subsequent randomized study,
in which, an additional group of 22 ICH patients received very early heparin pro-
phylaxis. Thus, the study compared the three groups of very early, early, and late
pharmacoprophylaxis with UF (3 × 5000 IU/day subcutaneous on day 2, 4, and 10,
respectively, after bleeding). There was a significant lowering of PE incidence in the
group of very early treatment (odds ratio 9.2), without bleeding complications.
DVTs were also reduced with very early heparin introduction, without the numbers
reaching statistical significance [66]. Conversely, the use of heparinoids in 219 out
of 988 ICH patients did not alter the risk of VTE [67].
The first report on the use of LMWH in ICH came from Kleindienst et al. that
treated 238 patients with intracranial hemorrhage using prophylactic certoparin
3000 IU and observed no intracranial bleeding and very low rate of DVT and/or PE
(0.8%) [68]. Subsequently, a retrospective analysis of 232 ICH patients treated with
20 mg of subcutaneous enoxaparin and 175 controls disclosed no difference in mor-
tality or hematoma enlargement but also low VTE complication rates in both groups
(3% and 2%, respectively) [69]. Heparin was also safe in another nonrandomized
study of 200 ICH patients that received pharmacoprophylaxis in addition to elastic
stockings and was compared with 258 patients that wore only elastic stockings [70].
Similar results were obtained from the randomization of 75 ICH patients to enoxa-
parin sodium 40 mg/day or compression stockings, 48 h after admission [71]. No
hematoma growth and no fatal PE were reported in another cohort of 97 ICH
patients receiving LMWH within 36 h after diagnosis [72]. Finally, two more stud-
ies verified the safety of early pharmacologic VTE prophylaxis after ICH [22, 73].
The only currently available meta-analysis of pharmacologic VTE prophylaxis in
acute ICH included data from only four available studies (two randomized and two
nonrandomized, total number of patients 1000) [66, 69–71]. The analysis found a
significant reduction of PE events with low-dose anticoagulation (1.7% versus 2.9%;
RR, 0.37; 95% CI, 0.17–0.80; p = 0.01). There was no difference in DVT rates
(4.2% vs. 3.3%) or hematoma enlargement (8.0% vs. 4.0%) rates. A marginally
nonsignificant reduction in mortality (16.1% vs. 20.9%; RR = 0.76; 95% CI, 0.57–
1.03; p = 0.07) was observed in patients treated with low-dose anticoagulation [74].
Early Mobilization and Hydration for VTE Prophylaxis
Adequate hydration and early mobilization also have been studied for the prevention
of VTE. Dehydration increases the risk for VTE in stroke patients, with odds ratios
of 4.7, 2.8, and 3.4 for serum osmolality of >297 mOsm/kg, urea >7.5 mmol/l, and
urea/creatinine ratio (mmol:mmol) >80, respectively [75]. The AHA/ASA guide-

lines for the management of spontaneous ICH adopt the same recommendations for
the prehospital management with the AHA/ASA guidelines for the early manage-
ment of ischemic stroke and state that euvolemia is desirable and hypovolemia
should be corrected with intravenous normal saline (Class I; Level of Evidence C)
[27, 76].
Early mobilization is considered an important element for the management of
stroke patients hospitalized in specialized stroke units, as it can potentially limit the
risk of complications, such as infections and thrombosis, and also accelerate clinical
recovery through early augmentation of brain plasticity [77–79]. However, there is
still uncertainty on the exact time of active physiotherapy initiation. A recent meta-
analysis of 3 RCTs with 159 patients showed that initiation of mobilization within
24 h versus 48 h was associated with a nonsignificant increase in mortality
(OR = 2.58; 95% CI, 0.98–6.79, p = 0.06), with no difference in other complications
or outcomes. On the other hand, earlier transfer to rehabilitation centers improved
outcomes in terms of physical independence [80]. Moreover, a small prospective
RCT enrolling 52 patients that were subjected to mobilization within 24 or 48 h
found no significant differences between groups with regard to month outcomes
[81]. The largest RCT to date (AVERT) assigned 2104 patients (258 with ICH) to
very early mobilization within 24 h or to standard care and reported worse func-
tional outcomes in the group assigned to very early mobilization (adjusted
OR = 0.73, 95% CI, 0.59–0.90; p = 0.004), but no significant differences in mortal-
ity or serious complications. Moreover, a subgroup analysis revealed that ICH
patients might even be more vulnerable to very early mobilization when considering
the 3-month outcome and death results [82]. Based mainly on the findings from
AVERT, the mobilization of ICH patients should be avoided for the first 24 h, and
physical rehabilitation should be applied with a progressively increased intensity
taking into account the patient’s clinical fragility. A simple algorithm referring our
own clinical experience (after taking into account international recommendations)
for ICH thromboprophylaxis is presented in Fig. 5.1.
Diagnosis of DVT and PE
Before the introduction of ultrasound, the diagnosis of DVT was based on venogra-
phy, which could even visualize the distal veins with adequate detail. The diagnostic
sensitivity of ultrasound for distal vein thrombosis is lower than that for proximal
vein thrombosis and depends on the examination protocol [83]. However, in the
hands of an experienced examiner, ultrasounds will miss only 0.5% of DVTs [84].
The diagnosis of PE frequently requires a high index of suspicion. Computed
tomography pulmonary angiography (CTPA) is the gold standard to diagnose
PE. Echocardiography, which can confirm right ventricular overload, as well as
lower limb Doppler ultrasounds might be used as alternatives when CTPA is contra-
indicated, since up to 70% of patients with symptomatic PE have DVT [85]. In
ICH diagnosis
OAC related non OAC related
reversal of anticoagulation effect
withhold antiplatelets & physical therapy

lower limb intermittent pneumatic compression
adequate hydration with normal saline
after 24 hours: clinical assessment, brain CT
patient stable and CT with bleeding cessation patient unstable and/or CT with hematoma enlargement
withhold initiation of mobilization and

begin low intensity physical therapy
anticoagulation
enoxaparin 0.4 ml sc or UH 5000UI BID
repeat assessment accordingly, no later than 24
hours
Fig. 5.1 A schematic algorithm of thromboprophylaxis in acute intracerebral hemorrhage (ICH).

This algorithm reflects our clinical experience after taking into account current international rec-
ommendations. CT, computed tomography; ICH, intracerebral hemorrhage; LMWH, low-molecu-
lar-weight heparin; OAC, oral anticoagulation; UH, unfractionated heparin
addition, there are several clinical prediction scales for the diagnosis of PE, with
sensitivity ranging from 88 to 96% [86]. The modified Wells score may distinguish
between “likely PE” and “unlikely PE” and when combined with a D-dimer
level < 0.50 μg/mL has a negative predictive value of 99.5% [87]. The score takes
into account variables such as the clinical symptoms/signs suggestive of DVT, heart
rate, duration of immobilization, and previous VTE [88].
D-dimers are very useful to exclude DVT, especially when applying a lower
cutoff threshold of 0.5 mg/L which results in a sensitivity of 100% but with a speci-
ficity of only 46.2% in stroke patients with symptoms suggestive of DVT [89]. In
low probability suspected PE, normal D-dimer values safely exclude PE, whereas
increased values necessitate further investigation with CTPA [85].
Treatment of VTE in ICH Patients
Despite all prophylactic measures, physicians might be confronted with difficult

treatment dilemmas when ICH is complicated by DVT or PE, especially early in
the course of hospitalization. Current AHA/ASA guidelines recommend full dose
anticoagulation or inferior vena cava (IVC) filter placement when ICH patients
present with symptomatic DVT or PE (Class IIa; Level of Evidence C). It is also
suggested that the decision to anticoagulated or place an IVC filter hinges on sev-
eral clinical factors, such as the time from initiation of intracranial bleeding, hem-
orrhage cessation, cause and location of bleeding, and patient comorbidities
(Class IIa; Level of Evidence C) [27]. For example, lobar hemorrhage has a two-
fold risk of rebleeding with the administration of therapeutic anticoagulation.
Data from historical, non-treated case series with PE and proximal DVT, compris-
ing of patients with various medical and surgical conditions, have shown mortal-
ity rates of 26.6% and 16.2%, respectively, whereas anticoagulation reduced the
risk to 2.6% and 0.7%, respectively [90]. In stroke patients, untreated proximal
DVT may be complicated by fatal PE in 10–20% of patients, and nonfatal PE may
recur in 12–15% of untreated cases [27, 90]. Thus, symptomatic VTE in ICH
patients should not be left untreated. However, there are no studies addressing
important aspects of VTE treatment, such as timing after hemorrhage for the safe
introduction of therapeutic anticoagulation, the indications of IVC filter place-
ment as an alternative to anticoagulation, as well as when to remove the IVC
filter.
Nieto et al. aimed to assess the effect of the location of a major hemorrhage to
the subsequent risk for rebleeding, after the introduction of anticoagulation for
symptomatic VTE. Their cohort included 94 ICH patients that had suffered VTE
after hemorrhagic stroke. The mean time elapsed since bleeding was 20 days (SD 20
+/−9), and the majority of patients received LMWH (88%), a few patients UH
(6.4%), and some IVC filter (30%). Surprisingly, there were no reports of rebleed-
ing, whereas recurrence of VTE was documented in 5.3% of cases [91]. Although in
this study VTE was a late complication after ICH, the results support the immediate
use of therapeutic anticoagulation, which received the majority of the patients
(94.4%) and underscores its safety and efficacy.
The main indications for IVC filter placement include a contraindication for anti-
coagulation and the recurrence of PE under therapeutic anticoagulation [92].
Although placement of IVC filters is a common practice, especially in high throm-
boembolic risk patients, a recent randomized open-label blinded end point trial
(PREPIC2) of patients with DVT-related severe PE failed to show an additive pro-
phylactic effect of IVC filter to anticoagulation during a 6-month follow-up period
[93]. An earlier randomized trial of 400 patients with DVT, with or without PE,
found a reduction of early PE occurrence in the group treated with both IVC filter
and anticoagulation versus only anticoagulation. However, when taking into account
only the symptomatic Pes, the difference was not significant [94]. More impor-
tantly, there is a lack of evidence from RCTs demonstrating the efficacy of IVC
filter placement in the absence of concomitant anticoagulation.
In the event of VTE complicating ICH, we recommend full dose LMWH as long
as the volume of hematoma has been stabilized on repeat brain imaging. IVC place-
ment without anticoagulation can be reserved for cases with no evidence of bleed-
ing cessation, VTEs occurring during the first 48 h following the index event and
perhaps recent (<7 days) lobar hemorrhages. In case of PE recurrence despite full
dose anticoagulation with documentation of adequate anticoagulant effect (anti-Xa
assay), the addition of IVC filter may be considered.
Management of Seizures
Incidence and Predisposing Factors
Seizures are an important complication of spontaneous ICH. The incidence of early

post-ICH seizures ranges from 2.7% to 7.3% and has been reported up to 12%–
17%. Early seizures are generally more frequent than late ones [95–98]. The largest
single center observational study of 1920 consecutive patients showed a 6.6% inci-
dence of seizures after ICH, with early seizures (4.3%) being more common than
late ones (2.3%). However, only the volume of hematoma increased the odds for
recurrent seizures [99]. In a study using the US Nationwide Inpatient Sample data-
base, there were 13,033 cases identified as ICH, of which 1430 (11%) received also
a diagnosis of seizures [100]. In another study, among 761 patients with ICH, early
seizures (at presentation or within 24 h) occurred in 32 cases (4.2%), whereas addi-
tional 25 (3.8%) patients had seizures after the first 24 h and within the first month.
The 30-day post-ICH risk for seizures was 8.1%. In addition, among survivors with
seizures, the risk of recurrence was 5.3% (95% CI, 1.6–8.9) in the first year and
27% (95% CI, 15.6–38.4) at 5 years [101]. Another prospective study of 562 con-
secutive ICH patients documented early seizures (within 1 week) in 71 patients
(14%) [102]. In a smaller cohort consisting of 112 patients with nontraumatic,
supratentorial ICH, early clinical seizures were reported in 19 cases (17%) [98].
Srinivasan et al. analyzed two different chronological cohorts comprising of 30 and
108 ICH patients and observed seizures in 6.6% and 13.0%, respectively [103].
Arntz et al. found a 31% cumulative risk of epilepsy and a 23% cumulative risk of
epilepsy with recurrent seizures in ICH patients, with their mixed cohort consisting
of 697 consecutive patients with ischemic stroke, transient ischemic attack, or ICH
[104]. Similarly, it has been shown that the cumulative annual risk of experiencing
a seizure after ICH was increased from 19.9% 1 year after insult to 26.1% after
5 years [105]. However, a minority of long-term ICH survivors suffer from chronic
epilepsy at 5 years (6.5%) [106]. In studies with continuous electroencephalo-
graphic monitoring, seizures were recorded in 18–28% of patients with ICH within
the first 48 and 72 h, respectively [107, 108]. The majority of seizures are simple
partial or focal with secondary generalization [95].
Clinical and radiological characteristics may predict the risk of seizure occur-
rence. Early seizures correlate with lobar location, rebleeding, brain ischemia,
hydrocephalus, and brain edema. In the study by Sung and Chu, 32% of patients
with lobar ICH had seizures, and 62% of the 42 patients with lobar hematomas
developed epilepsy [95]. Antiepileptic drugs (AEDs) reduce the risk of early sei-
zures, and alcohol abuse predisposes to status epilepticus [101]. Frontal lobar hema-
tomas are more epileptogenic, whereas individuals with seizures are younger and
more frequently undergo craniectomy (2.1% vs. 1.2%, p = 0.006), ventriculostomy
(8.5% vs. 6.0%, p < 0.001), intubation (32.2% vs. 25.9%, p < 0.001), and tracheos-
tomy (6.4% vs. 4.2%, p < 0.001), probably in the context of a more severe ICH
[100, 109]. Indeed, seizures are more frequent after neurological deterioration and
midline shift in brain imaging [108]. Factors predisposing to the presentation of

ICH with seizures include previous ICH (OR = 4.76; 95% CI, 1.53–14.84), cortical
involvement (OR = 2.21; 95% CI, 1.11–4.43), younger age (OR = 0.97 per 1-year
increase; 95% CI, 0.95–0.99), and increased NIHSS score at admission (OR:1.03
per 1 point increase; 95% CI, 1.01–1.06) [102]. Late onset seizures (2 weeks after
hemorrhage) might predispose to recurrent seizures [95, 104], whereas others found
only the volume of hematoma to be associated with recurrent seizures [99]. Higher
NIHSS scores are also reported to predict epilepsy and epilepsy with recurrent sei-
zures [104]. On the other hand, electrographic seizures are associated with more
than 30% hematoma enlargement between the admission and the 24-h follow-up CT
scan, whereas periodic epileptiform discharges (PEDs) are associated with hemato-
mas located at least 1 mm from the cortex [107]. Collectively, large hematomas
involving the cerebral cortex and those resulting in higher grades of neurological
deficits exhibit an increased epileptogenic potential.
Seizures and Outcome
There are conflicting data regarding the influence of early or late seizures on the
outcome of patients with ICH. Epilepsy might aggravate recovery of stroke survi-
vors and reduce quality of life [104]. Theoretically, early seizures might predispose
to hematoma enlargement due to transient increases of blood pressure and also
accelerate the loss of stressed peri-hematomal neurons from increased metabolic
demand or even cause aspiration-related infections. In addition, seizures after ICH
might lead to epilepsy due to the promotion of aberrant neuronal networks [110].
In the study by Vespa et al., seizures were associated with higher neurological
deficits and midline shift on CT scan but also with a nonstatistically significant
trend toward poor outcome (p < 0.06) [108]. Furthermore, among 6044 patients
with stroke, including 715 with ICH, those with early seizures had a twofold
increase in the risk of 30-day mortality (32.1% vs. 13.3%; p < 0.0001). However,
patients with early seizures had also higher NIHSS scores and lower Glasgow Coma
Scale scores, a correlation that was even more powerful for the 60 (8.4%) patients
with ICH and seizures. Further analysis did not confirm that seizures promote
clinical deterioration nor that they are an independent factor of poor outcome, but it
is rather argued that they reflect and are a consequence of severe brain damage
[111]. In a Canadian multicenter cohort study of 5027 stroke patients, again seizures
were associated with longer hospitalization, higher disability at discharge
(p < 0.001), and increased mortality at 30 days (36.2% vs. 16.8%, p < 0.0001) and
at 1-year poststroke (48.6% vs. 27.7%, p < 0.001) [112]. Also, among 1402 ICH
patients, those with status epilepticus (11 patients) had slightly higher mortality
rates (36%) than those without it (24%) [95]. Moreover, PEDs are shown to predict
poor outcome after ICH [107].
Of interest, not all studies have shown an unfavorable outcome of ICH patients
with seizures. Mortality of hospitalized patients was not affected by immediate or
early seizures in the studies by Passero et al. and Labivitz et al., whereas Mullen
et al. found that seizures were even associated with reduced odds of inhospital death
(OR, 0.62, 95% CI, 0.52–0.75) [96, 100, 101]. In another study, early seizures did
not affect outcome at 6 months after insult [102].
Based on the currently available data, it is not possible to draw safe conclusions
regarding the impact of seizures on ICH outcome. Given the fact that seizures are
more common in severely affected patients with less favorable prognosis due to the
characteristics of the hematoma itself, one would expect an association of seizures
with higher mortality and morbidity rates. This observation, however, is not suffi-
cient to support a possible role of seizures in the expansion of brain injury.
I nternational Recommendations on Prophylactic Antiepileptic

Treatment in ICH
Current clinical practice is not consistent among different stroke units regarding the
use of prophylactic AEDs in ICH patients. The most recent AHA/ASA guidelines
recommend against prophylactic AED administration (Class III; Level of Evidence
B) [27]. In contrast, the ESO guidelines do not make any recommendations on the
same issue based on the lack of currently available trials [34]. Many physicians
routinely prescribe preventive AEDs [27, 34].
veryday Clinical Practice on Prophylactic Antiepileptic

E
Treatment in ICH
Despite AHA recommendations advocating deferral of prophylactic AED, a large

number of stroke physicians is using antiepileptic treatment for primary seizure
prevention in patients with acute ICH. A prospective study of 744 ICH patients
disclosed rates of 39% in the use of prophylactic AEDs, with levetiracetam being
the most common treatment (89% of cases). Increased hematoma volume, lobar
localization, as well as craniotomy were associated with more frequent use of pre-
ventive AEDs. These patients were obviously more severely affected and exhibited
worse outcomes (OR, 1.40; 95% CI, 1.04–1.88; p = 0.03).. However, after adjusting
for clinical and demographic characteristics, AED treatment was no longer signifi-
cantly associated with outcome (odds ratio, 1.11; 95% confidence interval, 0.74–
1.65; p = 0.62) [113]. A retrospective analysis of two chronological cohorts of
patients with ICH, the first between 1/1/99 and 12/31/00 (30 patients) and the sec-
ond between 1/1/09 and 12/31/10 (108 patients), revealed AED use in the 53.3%
and 50%, respectively, although the 86.6% and 59.1% of patients discharged on
AEDs did not exhibit clinical or electrographic seizures neither had epileptiform
abnormalities in EEG [103]. A recent survey addressed to physicians managing ICH
patients found that prophylactic AEDs were never used by only one third of the
responders, whereas the rest of the physicians initiated treatment selectively, with
the minority (9%) using AEDs in nearly all ICH cases. The duration of the prophy-
lactic treatment was typically for less than 1 month, and levetiracetam was the most
common medication prescribed (60%) [110]. The study highlights the significant
heterogeneity that exists in the way different physicians approach and manage
issues concerning the prevention of seizures in ICH patients.
Studies on Prophylactic Antiepileptic Treatment in ICH
An updated Cochrane review on primary and secondary prevention of seizures after

stroke failed to provide sufficient evidence supporting the routine use of AEDs
[114]. The review was based on the results of one available randomized placebo-
controlled trial of valproic acid in 72 ICH patients. Treatment was maintained for
1 month, and follow-up was completed after 1 year. Valproic acid treatment failed
to reduce long-term seizures. However, it decreased early seizures and improved the
final neurological deficit, an effect that was not attributed to the antiepileptic action
[115]. Short-term preventive AED treatment in lobar hematomas is also supported
by another study of 761 ICH patients, 432 of whom received phenobarbital. The risk
of early seizures was significantly reduced only in patients with lobar hematomas
(OR, 0.62; 95% CI, 0.40–0.96; p = 0.033) [101].
However, the majority of the available studies conclude that prophylactic AEDs
are not warranted in ICH patients. A retrospective cohort of 157 patients (29% on
prophylactic AEDs) failed to demonstrate an association of treatment with the risk
of early seizures, long-term epilepsy, disability, and death [116]. Similarly, the
administration of prophylactic AED treatment in 216 ICH cases did not reduce the
risk of early or late seizures [117].
Regarding the association between prophylactic anticonvulsants and outcome,
the results of the available studies, the majority of which being nonrandomized, are
inconsistent.. In a cohort of 295 patients, preventive AED use (and in particular
phenytoin use) was associated with poor outcome, even after adjustment for other
known risk factors after ICH (age, initial hematoma volume, presence of
intraventricular blood, initial Glasgow Coma Scale score, and prior warfarin use)
[118]. Moreover, prescription of phenytoin after ICH was associated with fever,
worse NIHSS at 14 days, and worse modified Rankin Scale at 14 days, 28 days, and
3 months, whereas the exclusion of patients with seizures did not alter the results
making seizures an unlike risk factor for poor outcome [119]. In the study by Woo
et al., prophylactic AEDs were also linked to a worse modified Rankin score [117].
One randomized trial of 880 stroke patients treated with diazepam or placebo that
included 95 ICH cases concluded that the incidences of pneumonia and death were
increased in the diazepam group (35% versus 10% for pneumonia and 22% versus
12% for mortality, respectively) [120]. On the contrary, the randomized trial of
valproic acid by Gilad et al. found a protective effect of the drug, as mentioned
earlier [115]. Recently, the protocol of a randomized double-blind, placebo-con-

trolled trial (SPICH) of short-duration valproate in ICH patients has been published.
The trial will randomize 258 individuals and will assess seizure occurrence and
outcome [121].
In clinical practice, prophylactic AED treatment is more likely to be introduced
in patients with higher hematoma volumes and greater ICH scores, lobar hemato-
mas, and craniotomy [113, 122, 123]. Thus, the adjustment for clinical and demo-
graphic characteristics is necessary in order to estimate the influence of AEDs on
outcome. In this way, three recent studies that used mainly phenytoin and levetirace-
tam found an association of AEDs with poor outcome, but after multivariate adjust-
ment, the relation was no longer statistically significant [113, 123, 124]. Thus, we
cannot draw safe conclusions regarding the possible influence of anticonvulsants
and especially as prophylactic treatment, on the outcome of ICH patients. The rou-
tine prophylactic use of AEDs is not justified, especially in patients with absence of
cortical involvement [98]. In addition, and since nonconvulsive seizures may occur
in about 20% of cases, continuous EEG recordings are recommended for patients
with otherwise unexplained reduced level of consciousness [125].
Seizure Management in ICH
Current AHA recommendations advocate that patients with clinical seizures should
be treated with AEDs (Class I, Level of Evidence A). Antiepileptic therapy should
be also administered to patients with a change in mental status who are found to
have electrographic seizures on electroencephalogram (Class I, Level of Evidence
C) [27]. Since late seizures are related to increased risk of epilepsy, duration of
treatment should be longer after late seizures, and the decision on treatment discon-
tinuation should involve both clinical and electrophysiological data [27].
Regarding the choice of the AED, there are data supporting that levetiracetam
appears to have a safer profile in critically ill patients, including ICH [113, 123,
126]. In stroke patients with late seizures, levetiracetam is well tolerated and effec-
tive, achieving seizure-freedom in the 77.1% to 82.4% of cases [127, 128]. Finally,
a study comparing phenytoin and levetiracetam as prophylactic AEDs in ICH
patients found greater efficacy and better cognitive performance of patients treated
with levetiracetam [129]. A simple algorithm referring our own clinical experience
(after taking into account international recommendations) for seizure management
in ICH is shown in Fig. 5.2.
For those ICH patients experiencing status epilepticus (SE), prompt and emer-
gent treatment is recommended to reduce morbidity and mortality [130]. The
Neurocritical Care Society published guidelines for management of SE for all clini-
cal conditions including ICH [130]. These guidelines recommend that the treatment
of convulsive SE should occur rapidly and continue sequentially until clinical sei-
zures are halted (strong recommendation, high quality). Critical care treatment and
monitoring should be started simultaneously with emergent initial therapy and con-
ICH diagnosis
young age, lobar hematoma late clinical seizures unexplained low

with large volume > 1week level of
consciousness
no clinical or EEG seizures early clinical seizures

< 1week continuous EEG
monitoring
long-duration of AED*
treatment, min 1 year
consider short term AED*
treatment, max 1 month
further seizures
EEG seizures
short-duration of AED*
treatment, max 3 months no yes
*when AED treatment

yes no
is warranted, consider perform EEG: if no ED consider
levetiracetam as the treatment discontinuation continue AED*
first choice treatment
Fig. 5.2 A schematic algorithm of seizure prophylaxis and treatment in acute intracerebral hemor-
rhage (ICH). This algorithm reflects our clinical experience after taking into account current inter-
national recommendations. AED, antiepileptic drug; ED, epileptiform discharges; EEG,
electroencephalogram; ICH, intracerebral hemorrhage
tinued until further therapy is consider successful or futile (strong recommendation,

moderate quality). Benzodiazepines should be given as emergent initial therapy
(strong recommendation, high quality). Urgent control AED therapy recommenda-
tions include the use of IV fosphenytoin/phenytoin, valproate sodium, or levetirace-
tam (strong recommendation, moderate quality). Finally, refractory SE therapy
recommendations should consist of continuous infusion AEDs but vary by the
patient’s underlying condition (strong recommendation, low quality).
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improve acute stroke outcome: results of the early GABA-Ergic activation study in stroke
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study (SPICH): a randomized, double-blind, placebo-controlled trial of short-term sodium
valproate prophylaxis in patients with acute spontaneous supratentorial intracerebral hemor-
rhage. Int J Stroke. 2014;9:814–7.
122. Hemphill JC 3rd, Bonovich DC, Besmertis L, Manley GT, Johnston SC. The ICH score: a
simple, reliable grading scale for intracerebral hemorrhage. Stroke. 2001;32:891–7.
123. Zandieh A, Messé SR, Cucchiara B, Mullen MT, Kasner SE, VISTA-ICH Collaborators.
Prophylactic use of antiepileptic drugs in patients with spontaneous intracerebral hemor-
rhage. J Stroke Cerebrovasc Dis. 2016. pii: S1052-3057(16)30099-4.
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Neurocrit Care. 2012;17:3–23.
Chapter 6
Surgical Treatment of Intracerebral
Hemorrhage
Jan Vargas, Alejandro M. Spiotta, and Raymond D. Turner
Spontaneous Intracerebral Hemorrhage
Background and Demographics
Spontaneous intracerebral hemorrhage (ICH) is responsible for 10–15% of strokes,

with an annual incidence of 10–30 per 100,000 and a 1-year mortality rate of more
than 40% and a 5-year mortality rate of approximately 29.2% [1, 2]. When associ-
ated with intraventricular hemorrhage (IVH), the mortality rate increases to 50–80%
[3–5]. Functional independent outcome (defined as an mRS of 0–2) is estimated at
16.7–24.6% at 1 year following ICH [1]. The long-term rate of recurrence is esti-
mated to be 1.3–7.4% per year over an average follow-up of 1–7 years.
ICHs can be divided into supratentorial and infratentorial based on location, with
considerable controversy concerning outcomes in patients with primary supratento-
rial ICH compared to infratentorial ICH.
Craniotomy for Supratentorial Intracranial Hemorrhages
Most ICHs are supratentorial, and spontaneous supratentorial ICH can be further
subdivided into deep and superficial. Risk factors for mortality in the setting of ICH
are increasing age, decreasing Glasgow Coma Scale score, increasing ICH volume,
and presence of intraventricular hemorrhage [1]. The most recent guidelines for the
management of spontaneous ICH suggest considering a standard craniotomy for
J. Vargas · A. M. Spiotta (*) · R. D. Turner

Department of Neurosurgery, Medical University of South Carolina, Charleston, SC, USA

https://doi.org/10.1007/978-3-319-77063-5_6
82 J. Vargas et al.
patients with supratentorial lobar hemorrhages within 1 cm of the cortical surface,
with the goal being to prevent impending mortality [2].
For patients that do not meet these criteria, there is a lack of consensus on appropri-
ate treatment despite the theoretical benefits of early hematoma evacuation and pre-
vention of secondary insults following spontaneous ICH. The Surgical Trial in
Traumatic Intracerebral Hemorrhage (STITCH) trial was a multicenter, randomized
investigation that ultimately failed to show any overall benefit to early surgery versus
medical management for patients with spontaneous, supratentorial ICH, with favor-
able outcomes observed in 26% of the surgical group compared to 24% in the medical
group [6]. However, a subgroup analysis of the STITCH I data suggested that favor-
able outcomes were more likely with surgery performed on hematomas less than 1 cm
from the cortical surface [7]. These findings lead to the STITCH II trial, which dem-
onstrated similar results and did not show a benefit for the surgical evacuation of
superficial lobar hemorrhages [8]. A subsequent meta-analysis of 14 trials of surgery
for intracerebral hemorrhage demonstrated improved outcomes with surgery if ran-
domization was performed within 8 h of hemorrhage, if the volume of hematoma was
between 20 and 50 mL with a Glasgow Coma Scale of 9–12, or if patient age was
between 50 and 69 years [9]. When the results of STITCH II were pooled with this
data, the subgroup of patients with lobar intracranial hemorrhage and no IVH demon-
strated a trend toward benefit with surgery, but this trend was not significant [8].
The STITCH trials suggested that while surgery may improve outcomes in some
patients with superficial lobar hemorrhages, attempts at targeting deeper lesions
may disrupt viable tissue and overcome any benefits yielded by hematoma removal.
This has led to an interest in developing minimally invasive approaches for access-
ing and evacuating deep-seated hematomas.
Surgery for Infratentorial Intracranial Hemorrhages
The most recent guidelines for the management of spontaneous ICH published by
the American Stroke Association in 2015 recommend immediate surgery for cere-
bellar hemorrhages with evidence of brainstem compression or hydrocephalus [2].
Despite lack of high-quality evidence, there is data to suggest that suboccipital
decompressive craniectomy can reduce mortality when compared to medical ther-
apy alone [10, 11]. These studies advocate for early decompression despite a low
GCS in the setting of IVH and fourth ventricular obstruction, on the basis that non-
surgical intervention carries with it a high mortality.
Craniectomy for Spontaneous Intracranial Hemorrhage
The neurological injury caused by spontaneous intracranial hemorrhage is felt to

be not only due to the immediate mechanical disruption caused by the original
hemorrhage but also from the accumulation of perihematoma edema (PHE)
6 Surgical Treatment of Intracerebral Hemorrhage 83
secondary to an inflammatory reaction incited by hemoglobin breakdown prod-

ucts such as iron, and the presence of thrombin. Additionally, there is some evi-
dence that local mass effect limits regional perfusion, causing further secondary
ischemic injury. This delayed, second phase of injury results in the extension of
damage to potentially viable tissue [5, 12–18]. As a result, several studies have
postulated that the addition of a decompressive craniectomy to hematoma evacu-
ation can decrease ICP and increase cerebral blood perfusion, thus mitigating
some of the delayed secondary injury and decreasing the morbidity and mortality
[19–21]. There is limited evidence that hemicraniectomy can improve survival
and recovery in patients with aneurysmal and spontaneous intracerebral hemor-
rhages [22–24].
A recent prospective controlled trial involving 40 patients with hypertensive
ICHs randomized to hematoma evacuation with decompressive craniectomy with
expansile duroplasty versus hematoma evacuation only found that adding decom-
pressive craniectomy and duroplasty improved outcomes at 6 months (Fig. 6.1)
[25]. In this study, patients with a hematoma volume of at least 60 ml and a GCS of
8 or less were included or if neurological deterioration resulted in surgical evacua-
tion. The authors report that at 6 months, 70% of patients who underwent decom-
pressive craniectomy and expansile duroplasty had a favorable outcome (mRS of 3
or less), compared to 20% in the hematoma-only group, a statistically significant
difference. As a result of these data, the most recent American Stroke Association
guidelines from 2015 state that craniectomy with or without hematoma evacuation
might reduce mortality for patients with supratentorial ICH who are in a coma, have
large hematomas with significant midline shift, or have elevated ICP refractory to
medical management [2].
16
14
12
10
Patients
Favorable
8
Moderate
6 Poor
0
Group A Group B
Fig. 6.1 Adapted from Moussa and Kheder, 2017. Group A received decompressive craniectomy
and expansile duroplasty in addition to hematoma evacuation, whereas Group B only underwent
hematoma evacuation. (From Moussa and Khedr [25], with permission of Springer)
84 J. Vargas et al.
inimally Invasive Surgery for Spontaneous Intracranial

M
Hemorrhage
History
A minimally invasive approach to the evacuation of intracranial hematomas has

been a topic of interest for some time. In 1989, Auer et al. published their experi-
ences in with early endoscopic irrigation and aspiration-based evacuation of
ICH. This trial demonstrated a significant improvement in a 6-month mortality rate
when compared to medical management [26].
There are several reports of the use of stereotactic minimally invasive techniques
such as direct aspiration or mechanical clot disruption to safely remove deeper hem-
orrhages [26–30]. More recently, newer methods for hematoma disruption have
been introduced, such as ultrasound or injection of recombinant tissue plasminogen
activator directly into the hematoma [31, 32].
CLEAR Trials
The Clot Lysis Evaluating Accelerated Resolution of IVH Phase II (CLEAR II)
trial aimed to investigate the benefit of clearing intraventricular blood in the
setting of spontaneous ICH or subarachnoid hemorrhage [33]. IVH has been
shown to be an independent risk factor for poor outcome and occurs in about
40–45% of ICH [7, 34, 35]. The patients who received intraventricular rtPA via
an external ventricular drain showed a trend toward lower mortality at 30 days
(18% vs. 23% in placebo groups); however this was not statistically significant.
There was a significant relationship observed with respect to the rate of clot
resolution and clinical improvement at 96 h. In addition, a greater percentage of
patients treated with intraventricular tPA demonstrated mRS ≤ 4 (52% vs. 27%)
and NIHSS <10 (54% vs. 29%) at 30 days. While the trial was not powered to
assess functional outcomes, it demonstrated the safety of a minimally invasive
approach to the treatment of IVH and paved the way for the launch of the
CLEAR III trial.
MISTIE
The Minimally Invasive Surgery Plus Tissue-Type Plasminogen Activator for ICH
Evacuation (MISTIE II) investigation was a controlled, phase II trial which included
123 patients randomized between medical management and minimally invasive
Fig. 6.2 The results of the Day 365 modified Rankin Scale (mRS)
MISTIE trial suggested N = 25 N = 23
100
improved outcomes and 0
1
shorted hospital stay 2
following minimally 14% 3
80
invasive catheter 4
placement. Modified 5
6
60
% Subjects
ranking shift at 1 year
40 20
0
Medical Surgery
surgery followed by catheter drainage with daily rtPA (recombinant tissue plas-
minogen activator) irrigation. The MISTIE II trial showed a strong trend toward
clinical benefit in patients with ICH treated with minimally invasive surgery versus
those which received medical management (Fig. 6.2). Surgical patients had a sig-
nificant reduction in perihematoma edema volume, shorter hospital length of stay
and reduced hospital costs, and greater gain activities of daily living scores on the
Stroke Impact Scale [31].
New Techniques for MIS Evacuations
Apollo
The Penumbra Apollo (Penumbra Inc., Alameda CA) is an aspiration-irrigation

system which allows the removal of hemorrhage via a wand with controlled
aspiration. A vibrational element housed within the wand vibrates at high fre-
quency to break down the hemorrhagic products inside of the wand and prevent
clogging. The wand can be used in conjunction with commercially available
endoscopes and is positioned in the hematoma under stereotactic guidance via a
cranial burr hole with a small dural incision (Figs. 6.3, 6.4, 6.5, 6.6, and 6.7).
Since its approval, the Apollo system has been used for the evacuation of both
intraventricular and intracerebral hemorrhages, including those associated with
ruptured aneurysms [36–39].
86 J. Vargas et al.
NICO
The NICO BrainPath system consists of a 13.5 mm sheath with an internal obturator
that is placed stereotactically through a small craniotomy into intracranial hemato-
mas. The obturator is designed to displace rather than disrupt brain parenchyma
during placement, minimizing damage to underlying functional tissue. Once placed,
the obturator is removed, allowing access to the hematoma which can be evacuated
using conventional suction and bipolar cautery under the operating microscope or
an exoscope which is aligned down the length of the BrainPath sheath. The NICO
BrainPath sheath has been approved for visualization of the surgical field during
brain and spinal surgery.
In addition to its BrainPath sheath, NICO also manufactures the Myriad hand-
piece, consisting of a wand with a side port equipped with a reciprocating cutting
blade. The handpiece has an aspiration mechanism that pulls tissue into the side
port. Using a foot pedal, the surgeon can both control the strength of aspiration
Red Vaccum
a Regulator Hole
Wand
Vibration
Irrigation Connector
Port
Wand-to-Canister
Aspiration Tube
Fig. 6.3 (a) Apollo wand. (With permission of Penumbra, Inc.), (b) Apollo system. (With permis-
sion of Penumbra, Inc.)
b
Saline Bag
Mounting Pole
Irrigation
Control Valve Clamp
Generator
Timer
Power Push
Button (ON/OFF) Wand
Red Vacuum Power Inlet
Regulator Hole Ground Stud
Irrigation Pump
Vibration Connector Foot Switch
Irrigation Tubing Pig Tail Power Cord
Connector
Pump-to-Canister
Vacuum Tube Ground Stud
Vacuum
Gauge
Vacuum
Vacuum Pump
Regulator
Dial
Wand-to-Canister
Aspiration Tube
Collection
Canister
Canister Power Cord

Holder
Foot Switch
Front Back
Fig. 6.3 (continued)
and turn the cutting blade on or off. The Myriad handpiece has been approved
for the morcellation and removal of tissue during pelviscopic, laparoscopic, per-
cutaneous, and open surgical procedures whenever access to the surgical site is
limited.
The NICO BrainPath has been successfully used for the evacuation of intracere-
bral hematomas, with reported at least 87% reduction in hematoma volume,
although 3 of the 11 patients (27%) suffered postoperative complications including
a fatal hemorrhage [40, 41] (Fig. 6.8).
Upcoming Trials
The encouraging findings of recent case series have led to the development of sev-
eral randomized controlled trials to investigate MIS techniques.
88 J. Vargas et al.
Fig. 6.4 Setup with

endoscope
Fig. 6.5 Endoscopic view

of hematoma and/or ICH
evac cavity
a b
Fig. 6.6 (a, b) Pre-Apollo evac examples
a b
Fig. 6.7 (a, b) Post-Apollo evac samples
Minimally Invasive Endoscopic Surgical Treatment with Apollo Versus Medical

Management for Supratentorial ICH (INVEST) trial is a phase II trial which will
compare ICH evacuation using the Apollo system to medical management in 222
patients with moderate to large (30–80 cm3) spontaneous supratentorial hemor-
rhages [42]. The NICO BrainPath system will also be part of a randomized con-
trolled trial, which will include up to 10 centers.
90 J. Vargas et al.
a b
Fig. 6.8 (ICH pre and post MIS evacuation). (a) Large right ICH hemorrhage approaching the
cortical surface. (b) Post-NICO evacuation of the hemorrhage
Timing of Surgery
The current American Stroke Association guidelines from 2015 do not have any
recommendations regarding early evacuation versus waiting for a neurological
decline, reflecting the significant controversy regarding the timing of surgery for
spontaneous intracranial hemorrhage [2]. However, there is data suggesting that
approximately 50% of deaths from spontaneous ICH occur within the first 48 h
[43]. Although the STITCH I trial failed to demonstrate added benefit for early sur-
gery, a subgroup analysis of STITCH II demonstrated that there may be a benefit of
surgery if performed before 21 h of ictus [8]. Additionally, there is data suggesting
that surgery within the first 12–24 h improves neurologic function [44, 45]. A meta-
analysis performed by Gregson et al. suggested that operation on supratentorial
spontaneous ICH within 8 h of ictus was beneficial with an OR of 0.59 [9].
Despite the lack of evidence, currently guidelines suggest that supratentorial
hematoma evacuation in deteriorating patients might be considered as a life-saving
measure [37].
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44. Wang YF, Wu JS, Mao Y, Chen XC, Zhou LF, Zhang Y. The optimal time-window for sur-
gical treatment of spontaneous intracerebral hemorrhage: result of prospective randomized
controlled trial of 500 cases. Acta Neurochir Suppl. 2008;105:141–5.
45. Maila SK. Factors affecting the outcome of surgical evacuation of spontaneous deep intra
cerebral bleeds. Br J Neurosurg. 2015;29(5):668–71.
Chapter 7
Intracerebral Hemorrhage Prognosis
Craig A. Williamson and Venkatakrishna Rajajee
Clinical Case
A 78-year-old woman with a history of mild cognitive impairment, hypertension,

and chronic kidney disease is found down by her husband with altered mental status
and left-sided weakness. She is brought in by an ambulance to the emergency room
where, on initial examination, her Glasgow Coma Scale (GCS) is 13 (E3M6V4) and
National Institute of Health Stroke Scale (NIHSS) is 21, with a neurological exam
notable for disorientation, right gaze preference, dysarthria, left-sided neglect, left
facial droop, and hemiparesis. A head CT reveals an approximately 60 cc right pari-
etal intraparenchymal hematoma without intraventricular extension. As the treating
provider, you sit down for an initial meeting to review the physical exam and head
CT findings with the patient’s family. The patient’s husband asks about prognosis
and shows you an advance directive that states that “In the event of permanent coma
or vegetative state, as determined by the treating physician,” the patient would not
wish to receive life-prolonging treatments, such as mechanical ventilation and arti-
ficial nutrition.
Introduction
Outcomes for spontaneous intracerebral hemorrhage (ICH) remain stubbornly poor

in comparison with ischemic stroke, despite a possible reduction in 30-day mortal-
ity in the last three decades [1]. Addressing questions related to prognosis, within
the limits of accurate prediction, is a core component of ICH care. It is also one of
the most challenging tasks providers are called upon to do, with enormous potential
C. A. Williamson (*) · V. Rajajee

Departments of Neurosurgery and Neurology, University of Michigan, Ann Arbor, MI, USA

https://doi.org/10.1007/978-3-319-77063-5_7
96 C. A. Williamson and V. Rajajee
impact on patient outcome. Families use prognostic information to inform decision-

making about early treatment interventions, such as intubation, ventriculostomy
placement, and surgery, taking into consideration the known or inferred wishes of
patients who typically cannot speak for themselves. Advance directives sometimes
exist, but these are often too vaguely worded to directly apply to the complex situa-
tions providers and families confront.
There are numerous population- and hospital-based publications on short- and
long-term prognosis after ICH. Multiple predictive models have also been described,
the most widely used of which remains the ICH score. However, completely accu-
rate prognostic data remains elusive. The overwhelming majority of deaths in ICH
result from early withdrawal of life-sustaining treatment, therefore creating poten-
tial for a “self-fulfilling prophecy,” where perceived prognosis directly affects sur-
vival and thus confounds truly objective determination of prognosis [2, 3].
This chapter will first review epidemiological data in order to provide a general
overview of prognosis after ICH. It will then discuss individual factors that are
known to most strongly influence prognosis. Next, common prognostic models will
be reviewed, while being mindful of the limits of applying population-based models
to individual patients. Finally, current guidelines and recommendations for prog-
nostication will be covered.
Overview of ICH Prognosis
Most assessments of outcome following ICH estimate a substantial short-term

mortality rate, ranging from 28% to greater than 50%. One meta-analysis of 36
population-based studies from 1980 to 2008 identified a median 30-day mortality
rate of 40.4% and did not find that mortality rates were decreasing with time [4].
In contrast, Ovbiagele et al., in a US study using the Nationwide Inpatient
Sample, found that in-hospital mortality rates for ICH experienced a slight but
statistically significant decline between 1997 and 2006, from 30.4% to 28.3%
[5]. Using another US administrative database, Adeoye et al. identified a signifi-
cant decrease in in-hospital mortality from 34.5% in 2000 to 28.5% in 2008 [6].
Recent population-based assessments have shown similarly varying results. In a
study of stroke incidence and outcomes in Corpus Christi, TX, Zahuranec et al.
found that while ICH incidence declined between 2000 and 2010, there was no
decrease in 30-day case-adjusted mortality rate between 2000 and 2010 [7]. In
contrast, in the Dijon Stroke Registry, 30-day mortality rates were noted to
decrease significantly over time, from 48.9% during 1985–1993 to 29.6% during
2003–2011 [1]. In a national Dutch ICH registry, since 2003 ICH mortality was
found to substantially decrease for individuals less than 75, but no change was
noted in older patients [8].
Less data is available regarding long-term survival following ICH. However,
multiple studies have documented an increase in mortality rates among ICH survi-
vors. In a population-based study of all ICH patients in a region of Central Finland,
from 1985 to 1991, the 28-day mortality rate was 50.6%. Among survivors, the
7 Intracerebral Hemorrhage Prognosis 97
annual mortality rate was 4.5 times higher than the general population during the
first year and then 2.2 times higher between years 2 and 6 before declining to below
the population rate [9]. In a later Finnish study, among 3-month ICH survivors, the
7-year mortality was 32.9% versus 19.4% in age- and sex-matched controls, though
there was no difference among survivors with a good functional recovery at 3 months
[10]. Flaherty et al. assessed long-term survival in ICH patients in 1988 and then in
2002–2003. They reported 12-month mortality rates of 59% and 53%, respectively.
Ten-year survival in the 1988 cohort was 18%, and survival analysis did not find a
significant difference in mortality rate between the two cohorts [11]. In another
study of a predominantly rural Italian population, ICH mortality rate was 50.3% at
30 days and 59.0% at 1 year, with a 10-year survival rate of 24.1% [12]. A recent
meta-analysis of published cohort studies found pooled survival estimate of 46% at
1 year and 29% at 5 years [13].
In general, outcomes after ICH are thought to be significantly worse in compari-
son to those for ischemic stroke. There clearly is a higher mortality rate among ICH
patients, but studies differ regarding whether ICH independently leads to worse
long-term functional outcome. In a large multicenter neuroprotection trial that
enrolled both ischemic stroke and ICH patients, mortality rates were similar, but
ICH patients had significantly worse functional outcomes at 3 months [14]. In a
South London population-based stroke registry, ICH patients experienced worse
functional outcomes at 3 months and 1 year, but functional status was equivalent at
5 years [15]. However, other studies have reported similar functional outcomes
upon controlling for initial stroke severity [16, 17].
It is important to note that different pathophysiological mechanisms affect initial
severity in ICH and ischemic stroke patients. Whereas ischemia immediately leads
to bioenergetic failure causing cell dysfunction and rapid cell death, early neuronal
dysfunction in ICH is largely mediated by tissue displacement and direct compres-
sion. These pathophysiological differences may result in potential for a greater and
more rapid recovery among ICH survivors, as has been noted in several studies [18,
19]. For example, in a case-control study of 270 stroke patients admitted to a single
rehabilitation center, ICH patients showed larger and more rapid improvements than
ischemic stroke patients [20]. In another population-based stroke registry, ICH
patients had a significantly greater rate of improvement between baseline and
3 months in comparison to ischemic stroke patients [15].
In summary, ICH is associated with high overall mortality, with 1-month mortal-
ity rates ranging from 28 to over 50% in multiple studies. While some studies sug-
gest that the mortality rate may be declining over time, other studies have failed to
identify any trend toward decreasing mortality. Withdrawal of medical care is the
most common cause of death in ICH, and it is not possible to quantify the degree to
which the self-fulfilling prophecy may contribute to early mortality rates. When dis-
ability is present in ICH survivors, the mortality rate remains well above that of the
general population for many years. Overall functional outcomes appear to be worse
for ICH patients in comparison to ischemic stroke, but studies of whether this effect
is independent of baseline stroke severity differ. Among ICH survivors, there does
appear to be a more rapid early recovery in comparison to ischemic stroke sufferers,
along with potential for greater gains in rehabilitation.
Individual Factors Associated with Prognosis
Numerous factors have been reported to be associated with outcome after ICH, and
it is not our intention to review all of them. However, several key features have been
identified in multiple studies and are included as components of various predictive
models. Other predictors have been more recently identified and may be incorpo-
rated into future predictive models. Overall, in the absence of any definitive evi-
denced-based treatment, outcome is primarily determined by patient and disease
factors, with some emerging evidence that specialized care and the absence of care
limitations may improve outcome.
Imaging and Clinical Features
Numerous clinical studies have found a worse outcome to be significantly associ-

ated with increasing age and decreasing Glasgow Coma Scale (GCS). Coagulopathy,
iatrogenic and otherwise, is consistently associated with hematoma expansion and
worse outcome, while platelet dysfunction has also been implicated. Studies after
the widespread adoption of CT scans in routine practice showed a strong association
with ICH volume and outcome [21], and multiple more recent studies have con-
firmed this finding. Additional radiographic features with strong evidence for an
association with worse outcome include deep or infratentorial location, the presence
of intraventricular hemorrhage, and hematoma expansion. Visualization of contrast
extravasation on CT scans – the “spot sign” – has been shown to be associated with
greater likelihood of hematoma expansion and worse outcome [22]. Some studies
have also suggested that the presence of white matter lesions on CT scan is associ-
ated with greater initial severity and is an independent predictor of worse outcome
[23, 24]. Electroencephalography (EEG) is not widely utilized as a prognostic tool
in ICH, but an association between periodic discharges and worse outcomes has
been reported [25]. Whether seizures independently predict worse outcome is
unclear based on current studies.
Treatment Factors
Though there is no definitive treatment for ICH, the provision of high-quality sup-
portive care clearly has the potential to improve outcomes. Increasingly, ICH
patients are cared for in specialized neurocritical care and stroke units, which may
be associated with better outcomes. Multiple clinical trials have found that out-
comes improve when ischemic stroke patients receive care in specialized stroke
units [26]. A systematic review and meta-analysis of trials that include hemorrhagic
stroke patients suggest that hemorrhagic patients experience the same reduction in
death and disability as ischemic stroke patients, with a nonsignificant trend toward
a further mortality reduction [27].
Compared with ischemic stroke, hemorrhagic stroke patients are more likely to
be admitted to an intensive care unit (ICU). Increasingly, this care is provided in
specialized neurological ICUs. Several studies have evaluated whether outcomes
are better for patients treated in specialized neurocritical care units, in comparison
with general ICUs. Diringer and Edwards, in a 2001 study utilizing a prospectively
collected ICU database from multiple institutions, found that admission to a spe-
cialized neurological ICU was associated with a significantly lower inpatient mor-
tality rate [28]. Subsequent studies have had slightly differing results. Varelas et al.
found that introduction of a neurointensivist into an existing neuro ICU resulted in
significantly reduced LOS and overall significant increase in the percentage of
stroke patients well enough to be discharged home, although there was no statistical
difference in adjusted mortality for ICH patients [29]. In another recent study, spe-
cialized neurocritical care was associated with decreased ICU and hospital length of
stay but did not affect mortality rate or 3- and 12-month functional outcomes [30].
In contrast, Damian et al., using a national ICU database sample in England and
Wales, noted a temporal trend of increasing ICH admission to specialized neuro-
critical care units between 1996 and 2009. For ICH patients admitted to neurologi-
cal ICUs during this period, mean LOS was longer, but mortality was decreased,
and there was a significant decrease in the mortality rate over time in comparison to
patients admitted to non-neurological ICUs [31].
Impact of Withdrawal of Care and DNR Orders
As mentioned previously, the overwhelming majority of patients with ICH die

shortly after cessation of life-sustaining treatments, so decisions about withdrawal
of care can dramatically affect prognosis. This also results in difficulty obtaining a
truly objective understanding of clinical correlates of poor outcome that are truly
independent of goals-of-care decisions. Becker et al., in a 2001 study, were the first
to bring attention to the impact of a “self-fulfilling prophecy” on hospital mortality
following ICH. In their single-center ICH cohort, the overall mortality was 34.5%.
Twenty-three of 30 deaths occurred as a result of withdrawal of medical care. The
strength of association between withdrawal of care and mortality was such that
when introduced as a covariate in a logistic regression model, no other prognostic
factor achieved statistical significance. Based on a survey, the authors also con-
cluded that practitioners tended to be overly pessimistic about the prognosis for
functional recovery after ICH [32].
Since only a small minority of ICH patients die following unexpected cardiac
arrest, “do not resuscitate” (DNR) orders might reasonably be expected to have a
correspondingly low impact on mortality rates. However, in actual practice DNR
orders are often viewed as a waypoint on a continuum progressing toward with-
drawal of life-sustaining treatments and therefore may serve as a surrogate marker
for less aggressive care. Hemphill et al., in a statewide study of 234 California hos-
pitals, found that there were significant differences in the rate at which hospitals
implemented early (<24 h) DNR orders. Hospitals with a higher rate of early DNR
orders had a significantly higher case-adjusted mortality rate, and this effect
occurred independent of the DNR order itself, suggesting early DNR status may be
a proxy for less aggressive early resuscitation that then increases mortality [33].
These findings were corroborated by results from a study of a population-based
cohort of ICH patients, in which early limitations on treatment were associated with
a more than doubling of the hazard for short- and long-term mortality, independent
from other clinical predictors [34].
As described previously, survivors of ICH have increased overall mortality and
often significantly impaired quality of life. Therefore, it is very appropriate for prac-
titioners and families to be concerned about long-term prognosis and together arrive
at treatment goals that are consistent with a patient’s wishes, either spoken or unspo-
ken. Unwarranted early pessimism may, however, inadvertently result in a poor out-
come for a patient who might otherwise have potential for recovery [35–37]. Making
prognostication more difficult is the fact that patients with the most severe injury
may occasionally demonstrate delayed neurological recovery. In a single-center
study by Rajajee et al. of long-term recovery in patients whose surrogates decided
to pursue long-term supportive care following severe acute brain injury requiring
the placement of tracheostomy and percutaneous gastrostomy, 29 patients with ICH
were identified in a 5-year period [38]. Of these, 20 (71%) were unable to ambulate
1–3 months following injury. Of these 20, however, 5 (25%) were able to ambulate
independently, and 3 (15%) were able to independently perform activities of daily
living 6–12 months following injury. In select patients with a good premorbid func-
tional status whose families are inclined to pursue long-term supportive care, a
period of at least many months may be necessary before the full potential for recov-
ery is realized.
Prognostic Models
Multiple predictive models, most utilizing logistic regression, have been developed
to predict ICH prognosis. One early model in the post-CT era used GCS, hematoma
size, and intraventricular extension to predict outcome at last follow-up in a cohort
of 112 patient [39]. Another model used the combination of GCS, hematoma size,
and widened pulse pressure to predict 30-day mortality in a single-center cohort
with a high degree of accuracy [40]. In 2001, Hemphill et al. published the “ICH
score” – the first simple, numeric, prognostic grading system. In its first derivation,
the ICH score used GCS, hematoma volume, interventricular extension, posterior
fossae location, and age to predict 30-day mortality in a cohort of 152 patients.
Mortality was most strongly associated with GCS, so this factor was given the
greatest weight: 2 points for GCS 3–4 and 1 point for a GCS 5–12. For all other
factors, 1 point was assigned for a given binary outcome: hematoma volume ≥ 30 ml,
intraventricular extension, posterior fossae location, and age ≥ 80, for a maximum
score of 6 [41]. External validation was subsequently performed in multiple popula-
tions [42–45], and the ICH score remains the most widely used grading scale.
The ICH score was criticized because it was developed to predict early mortality,
rather than functional outcome, which is arguably of greater interest to families and
providers. In 2008, Rost et al. published the FUNC score, which was derived to
predict functional independence, defined as Glasgow Outcome Scale (GOS) ≥ 4
3 months after disease onset, in a large single-center prospective cohort. This
11-point scale uses the following components to predict increasing probability of
functional independence: hematoma volume, location (lobar, deep, infratentorial),
age, GCS, and presence of premorbid cognitive dysfunction [46]. With inclusion of
these variables, IVH was found to no longer be statistically significant and so was
not included in the final model. In a subsequent validation study, the ICH score was
tested and found to correlate with 12-month functional outcomes, in addition to
early mortality [47].
Several modifications of the ICH score have also been described. The modified
ICH score substitutes the NIHSS for GCS, with the primary intention of more accu-
rately stratifying aphasic patients [42]. The ICH grading score (ICH-GS) includes
the same components as the original ICH score but contains more numerous and
different cut points for scoring, as well as rating IVH volume and including different
volume cut points for infratentorial and supratentorial hemorrhages [48]. Chuang
et al. proposed a simplified ICH score (sICH), which includes only patient factors
such as age, GCS, serum glucose, as well a history of hypertension and dialysis
dependency [49]. Other scores with varying combinations of patient and imaging
factors have also been proposed [50, 51]. Bruce et al. confirmed that all of these
grading scales demonstrated excellent discrimination in predicting mortality and
that they generally performed well at predicting functional outcomes in a cohort of
97 patients with ICH [52]. In a larger comparison of >2500 patients from the multi-
center INTERACT 2 trial, the ICH score, modified ICH score, and ICH-GS scores
were compared. All scores showed good discrimination for 30-day mortality, with
the modified ICH score performing slightly better than the ICH score or ICH grad-
ing scale (c-statistic 0.78, 0.75, 0.75, respectively). The modified ICH score also
showed slightly better discrimination for predicting poor 3-month outcome (c-sta-
tistic 0.75) in comparison to the ICH score (0.68) and ICH-GS (0.69) [53].
Several investigators have further examined the impact of limitations of life-
sustaining treatment on various prognostic models. Zahuranec et al. examined the
performance of several commonly used predictive models after patients were strati-
fied based on the presence of DNR orders within the first 24 h. In general, there
were statistically significant deviations between observed and protected mortalities
for all models assessed. However, after stratification, the models substantially
underestimated mortality for patients with early DNR orders while overestimating
mortality when an early DNR order was not placed [54]. Creutzfeld et al. found
similar results in another cohort of ICH patients. They determined that their newly
developed logistic regression model and the ICH score became poorly calibrated
when stratifying by DNR status, again overestimating mortality when an early DNR
was not present and underestimating mortality when early DNR was placed [55].
These studies underscore the difficulties of applying prognostic models to patients
without considering the impact of decisions to limit treatment.
The Approach to Prognostication in ICH
Since current prognostic models cannot account for the influence of decisions to
limit life support and the self-fulfilling prophecy, the 2015 Emergency Neurological
Life Support (ENLS) module for management of ICH specifically recommends
against the use of grading scales to guide early decisions to limit the use of support-
ive care or therapeutic intervention [56]. The 2015 ENLS guidelines suggest that the
ICH score may be best utilized as a communication tool to convey severity of illness
between providers, as well as during discussions with patients and families.
Similarly, the American Heart Association’s (AHA) 2015 ICH guidelines recom-
mend that aggressive, guideline-concordant therapy be used in the early phase of
care (about the first 24 h), for all ICH patients without an advance directive that
specifically limits such treatment [57]. The optimal duration of observation while
aggressive supportive care is provided is unclear. Factors such as premorbid func-
tional status, surrogates’ recall of statements by patients on what might constitute an
acceptable quality of life, and the clinical course following admission often guide
subsequent conversations between providers and families. Providing accurate infor-
mation and supporting families struggling to make treatment decisions in the face of
prognostic uncertainty remains one of the most challenging aspects of ICH care. A
willingness to pursue early aggressive care, constant emotional support to families,
and objective, evidence-based estimates of the potential for recovery are all corner-
stones of the management of the patient with ICH.
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Chapter 8
Prevention of Recurrent Intracerebral
Hemorrhage
Chirantan Banerjee and Bruce Ovbiagele
Introduction
Spontaneous non-traumatic intracerebral hemorrhage (ICH) accounts for 10–15% of

strokes worldwide, with an annual incidence of 24.6 per 100,000 [1]. In low and mid-
dle-income countries, it accounts for ~20% of all strokes [2]. ICH is associated with a
high 30-day mortality rate that has remained unchanged over the past couple of
decades, hovering around ∼40% [1]. A recent meta-analysis found no improvement in
1-year survival between years 1983 and 2004, as well as no change in 5-year survival
rates between 1983 and 1997 either [3]. Similarly, the overall incidence of ICH has
disappointingly remained roughly constant over the past three decades, as observed in
data from community-based cohorts in the UK and France [4, 5]. However, a closer
look at these data revealed that while on one hand there was a reduction in hyperten-
sion-related ICH due to improved blood pressure control, on the other hand, this was
offset by an increase in cases of ICH among the elderly, which mainly comprised
amyloid-related lobar hemorrhages associated with use of antithrombotic drugs [4, 5].
Beyond its association with a high mortality rate, survivors of an initial ICH are also
at elevated risk of secondary strokes including recurrent ICH and ischemic stroke [6].
This chapter will focus on evidence-based strategies to prevent the occurrence of recur-
rent ICH, taking into consideration the challenge that several patients who survive a
first-time ICH are also at risk of a future ischemic stroke, which raises an important
question for providers taking care of ICH patients about the potential benefits and haz-
ards of antithrombotic (antiplatelet and anticoagulant) drugs in these high-risk patients.
C. Banerjee (*)
Department of Neurology, Medical University of South Carolina, Charleston, SC, USA
B. Ovbiagele
University of California, San Francisco Medical Center, San Francisco, CA, USA

https://doi.org/10.1007/978-3-319-77063-5_8
108 C. Banerjee and B. Ovbiagele
Table 8.1 Risk of recurrent intracerebral hemorrhage (ICH) after index ICH
Study Cohort size Mean duration (years) Recurrence risk/proportion
Passero et al. (1995) [11] 112 1 7.2
Arakawa et al. (1998) [12] 74 5.6 2.0
Bae et al. (1999) [13] 933 1 1.8
Hill et al. (2000) [14] 423 3.6 2.4
Vermeer et al. (2002) [15] 243 5.5 2.1
Inagawa et al. (2005) [10] 279 3 2.3
Cheung et al. (2007) [16] 108 1 7.4
Azarpazhooh et al. (2008) [17] 191 2 2.6
Zia et al. (2009) [18] 353 3 2.3
Schmidt et al. (2016) [8] 15,270 5 13.7
Risk of Stroke Recurrence After Intracerebral Hemorrhage
Risk of ICH recurrence has been assessed in both hospital-based and population-
based cohorts over the years. The proportion of patients having a recurrent ICH by
1 year varies from 1.8% to 8.9% in various studies, as listed in Table 8.1. This varia-
tion is likely secondary to differences in study methodology, population character-
istics, as well as different durations. A systematic review of the risks of recurrent
ICH and ischemic stroke among ICH survivors was conducted in 2007, which
pooled data from patients in heterogeneous studies and reported a higher annual risk
of recurrent ICH (2.3%) than ischemic stroke (1.1%) [7]. A more recent meta-anal-
ysis conducted in 2014 identified 13 studies which reported the risk of recurrent
ICH at 1 year. The annualized rate of ICH recurrence was 2.0–2.4%, and the propor-
tion of patients having a recurrent ICH in the first year varied from 1.8% to 7.4%
[3]. In this study, the authors analyzed data from four studies and found that isch-
emic stroke incidence was at least as common as recurrent ICH over 3 years [3]. A
Danish cohort of 15,270 primary ICH patients between 1996 and 2011 had 2053
recurrences, with a cumulative recurrence risk of 8.9% at 1 year and 13.7% after
5 years [8]. The risk of ICH recurrence is highest in the first year after the index
bleed but can extend several years out [7–9]. Table 8.1 summarizes the risk of recur-
rent ICH after index ICH in various studies. As far as location of ICH is concerned,
most of the initial and recurrent hemorrhages tend to be lobar among Caucasians.
On the other hand, deep hemorrhages (both initial and recurrent) are more common
in Asians [7, 10].
Risk Factors for Recurrence of ICH
The most important risk factors of ICH recurrence are hypertension, older age, and
location of the initial hemorrhage (lobar versus deep) [3, 7, 8]. Hypertension is
associated with an increase in the recurrence of ICH, irrespective of whether the
8 Prevention of Recurrent Intracerebral Hemorrhage 109
initial hemorrhage was deep or lobar [3, 7, 8, 19]. In a prospective study of Italian
ICH survivors, during follow-up, poor control of hypertension was found in 47% of
hypertensive patients with rebleeding, as opposed to 7% of hypertensive patients
without rebleeding [11].
Increased age is also attributed to a higher risk of recurrence. This may be sec-
ondary to higher prevalence of lobar ICH and cerebral amyloid angiopathy (CAA)
and increased use of antithrombotic medications with accumulating comorbidities
among the elderly [19, 20].
Lobar location has been associated with a higher risk of ICH recurrence as com-
pared to deep hemorrhages, with the recurrent ICH also more likely to occur in a
lobar location [7, 11, 14]. As compared to nonlobar index hemorrhages, patients
with lobar hemorrhage were 3.8–4.9 times more likely to have a recurrent bleed in
the first year in two distinct cohorts [11, 21]. In a prospective, longitudinal study of
consecutive elderly ICH survivors with lobar ICH, the 2-year cumulative rate of
ICH recurrence was 21% [22]. In the same study, apolipoprotein E genotype was
significantly associated with the risk of recurrence. Carriers of the ε2 or ε4 allele
had a 3.8 times higher risk of recurrence as compared to patients with the common
apolipoprotein E ε3/ε3 genotype (28% versus 10%) [22].
CAA is a recognized risk factor for recurrent ICH. Pooled data from ten studies
including 1306 patients were meta-analyzed to assess the significance of CAA [pre-
sumed based on lobar distribution of cerebral microbleeds (CMBs)], as well as the
number of CMBs [23]. The annual recurrent ICH risk was higher in CAA-related
ICH vs CAA-unrelated ICH (7.4% vs 1.1%). Among patients with lobar CMBs,
presence of ≥2 CMBs increased the risk of recurrent ICH. In CAA-unrelated ICH,
however, only >10 CMBs (versus none) were associated with recurrent ICH (OR
5.6).
Lacunar ischemic stroke has a shared pathophysiology with ICH. A history of
prior lacunar stroke has been found to be associated with ICH recurrence in a couple
of Caucasian cohorts [17, 24].
A significantly increased recurrence risk has also been observed for patients who
underwent surgical evacuation of the primary ICH compared to medically managed
patients, with 1-year cumulative recurrence risk of 21.2% for surgically treated
patients compared to 8.3% for conservatively managed patients [8]. In the same
cohort, patients with renal insufficiency had a significantly increased recurrence
risk with a 1-year cumulative recurrence risk of 16.1% versus 8.7% for other cohort
members [8]. Among the preceding risk factors, hypertension and the use of anti-
thrombotic agents are modifiable.
Management of Blood Pressure
As discussed briefly in the previous section, hypertension is a key risk factor for
ICH and ICH recurrence, with hypertensive patients having a 5.7 times increased
risk of ICH compared with those without hypertension [25]. Untreated hypertension
further increases the risk of ICH, with these patients having a 2.5–3.5 times increased
risk of ICH when compared to persons on hypertension treatment [26, 27]. This
increased risk is also noted among patients who ceased taking their antihypertensive
treatment [27]. With regard to recurrent ICH risk, antihypertensive treatment is
associated with a significantly reduced risk (RR 0.82) with 1-year cumulative recur-
rence risk for patients treated for hypertension of 7.5% as compared to 9.7% for
others [8].
In the Perindopril Protection Against Recurrent Stroke Study (PROGRESS)
[28], patients with ischemic stroke or ICH and with or without hypertension were
randomized to antihypertensive medications perindopril (an angiotensin-converting
enzyme inhibitor) and indapamide (a thiazide diuretic) or placebo. Over 3.9 years of
follow-up, patients with ICH treated with the antihypertensive agents had a 50%
relative risk reduction in the absolute rates of recurrent ICH from 2% to 1%. This
effect was more robust than in patients with ischemic stroke where a 24% relative
risk reduction was achieved in the rate of recurrent stroke. This underscores the
notion that patients with ICH are particularly likely to benefit from blood pressure
reduction as a measure of secondary prevention, even more so than patients with
ischemic stroke. Combination therapy with perindopril and indapamide reduced
blood pressure by 12/5 mm Hg as compared to 5/3 mm Hg by single-drug therapy
in the trial. Only combination therapy produced a discernable reduction in risk of
stroke [29].
The SPS3 trial randomized patients with a recent lacunar infarct to a SBP target
of 130–149 mm Hg or less than 130 mm Hg [30]. The primary end point was reduc-
tion in occurrence of any stroke (ischemic stroke and intracranial hemorrhage).
After 1 year, the mean systolic blood pressure was 138 mm Hg in the higher-target
group and 127 mm Hg in the lower-target group. Nonsignificant rate reductions
were seen for all stroke and the composite outcome of myocardial infarction or
vascular death in the lower target group. But there was a robust and significant
reduction in the rate of ICH (HR 0.37, 95% CI 0.15–0.95) [30]. As lacunar strokes
and most ICH share a pathogenesis, this would suggest that ICH patients should
have their BP lowered to or beyond the targets currently recommended in other
high-risk groups (<130 mm Hg SBP and 80 mm Hg DBP in the presence of diabetes
mellitus, heart failure, or chronic kidney disease) [31].
In a retrospective analysis of prospectively collected data on a cohort consisting
of 15,270 individuals diagnosed with a primary ICH in Denmark between 1996 and
2011, antihypertensive treatment was associated with a significantly reduced recur-
rence risk (RR 0.82, 95% CI 0.74–0.91). The 1-year cumulative recurrence risk for
patients treated for hypertension was 7.5% compared to 9.7% for others [8].
In a single-site observational study of 2197 consecutive patients with ICH pre-
senting between July 1994 and December 2013 [32], 1145 patients with ICH sur-
vived at least 90 days and were followed up for a mean duration of 36.8 months. The
event rates for both lobar and nonlobar ICHs were significantly higher among
patients with inadequate BP control as compared to patients with adequate BP con-
trol (84 versus 49 per 1000 person-years for lobar and 52 versus 27 per 1000 person-
years for nonlobar ICH). Both systolic and diastolic BP during follow-up were
associated with increased risk of lobar ICH recurrence, but only diastolic BP was
associated with increased risk of nonlobar ICH recurrence. Inadequate BP control
was associated with higher risk of recurrence of both lobar ICH (HR 3.53, 95% CI
1.65–7.54]) and nonlobar ICH (HR 4.23, 95% CI 1.02–17.52) [32].
An ongoing English pilot trial, Prevention of Hypertensive Injury to the Brain by
Intensive Treatment after Intracerebral Hemorrhage (PROHIBIT-ICH), will assess
whether home telemetry-guided treatment can improve ICH recurrence rates by
randomly allocating ICH survivors to either home BP monitoring using telemetry
(sending BP information to a study coordinating center) to allow treatment adjust-
ments to improve BP control or to standard care [33].
Finally, the actual optimal timing for initiating BP lowering after ICH to prevent
recurrence is unknown, but post hoc analyses of the CATIS [34] and COSSACS
[35] trials suggested that early initiation of antihypertensives was associated with
better BP control at 2 weeks.
Antithrombotic Medications
Oral anticoagulants (OAC) are increasingly used for long-term primary and second-
ary prevention of stroke and systemic embolism in patients with atrial fibrillation
and mechanical heart valves due to proven efficacy [36]. ICH is probably the most
feared complication of OAC and accounts for >50% of all deaths associated with
hemorrhage in anticoagulated patients [37]. One fourth of all ICH were related to
OAC in a German prospective cohort study [38]. Also, OAC-related ICHs have
higher hematoma volume, worse functional outcome [39], and higher mortality [40]
as compared to non-OAC ICH. Novel OACs (NOACs) such as dabigatran, rivaroxa-
ban, apixaban, and edoxaban are safer than vitamin K antagonists (VKA) in terms
of risk of major hemorrhage and have half the risk of intracranial hemorrhage com-
pared to VKA [41]. Furthermore, NOAC-associated ICH has smaller hematoma
volume and better functional outcome as compared to warfarin-associated ICH [42,
43].
There have been no randomized clinical trials or prospective cohort studies to
assess the risk of ICH recurrence with anticoagulation post-ICH versus the benefit
toward lowering risk of thromboembolism. A nationwide observational cohort
study among patients with atrial fibrillation and warfarin-related ICH in Denmark
between 1998 and 2016 found that resuming warfarin therapy was associated with
a lower rate of ischemic stroke or systemic embolism (adjusted HR 0.49; 0.24–
1.02) and an increased rate of recurrent ICH (adjusted HR, 1.31; 0.68–2.50) com-
pared with not resuming warfarin therapy, but these differences did not reach
statistical significance [44]. A systematic review and meta-analysis to summarize
the associations of anticoagulation resumption with the subsequent risk of ICH
recurrence and thromboembolism were published in 2017 [45]. It included 5306
ICH patients from 8 retrospective cohort studies. 1899 (35.8%) patients were
restarted on anticoagulation therapy, with a total follow-up for 3494 person-years,
and 3407 patients (64.2%) were not, who were followed for a total of 7030 person-
years. Recurrence of ICH was observed in 166 (8.7%) patients on anticoagulation
and in 267 (7.8%) not on antithrombotic agents (pooled RR, 1.01; 0.58–1.77).
There was heterogeneity however between the included studies. Sensitivity analy-
ses were carried out, and significant heterogeneity was found with the inclusion of
studies that used NOACs. After the exclusion of these studies, the pooled RR was
1.18 (0.83–1.70). Thus, there was no significant difference in ICH recurrence
between the two groups. To assess the risk of thromboembolic events, data from 6
of the 8 retrospective studies with 2044 patients were analyzed. The rate of throm-
boembolic events in patients on anticoagulation therapy was 6.7% compared with
17.6% for patients not restarted on anticoagulation therapy (pooled RR, 0.34; 0.25–
0.45). There are several inherent limitations of this analysis, however, the main one
being the lack of detailed data on hematoma location and volume, as it may have
been a possibility that anticoagulation was more likely to be reinstated in patients
with smaller hematomas. Also, ICHs were not classified as being index or recur-
rent, as recurrent hemorrhages are more likely to be lobar and secondary to amyloid
angiopathy. The reason this is important is because a prior Markov decision analy-
sis [46] stratified by ICH location estimated a 1-year risk of ICH recurrence of 15%
after lobar ICH versus 2.1% for deep ICH and found that withholding anticoagula-
tion improved quality-adjusted life year (QALY) expectancy by 1.9 QALYs after
lobar ICH and 0.3 QALYs after deep ICH. The authors concluded that anticoagula-
tion should be avoided after lobar ICH but can be considered in patients with deep
hemorrhage if the risk of thromboembolism is particularly high [46]. Another sys-
tematic review and meta-analysis of studies reporting recurrent ICH and ischemic
stroke in ICH survivors with atrial fibrillation compared recurrent ICH and isch-
emic stroke risk among patients restarted on VKA versus antiplatelet agents (APAs)
and no antithrombotic agents. The pooled RR estimates for ischemic stroke were
lower for VKA compared to APAs (RR 0.45; 0.27–0.74) and no antithrombotic (RR
0.47; 0.29–0.77). At the same time, pooled RR estimates for ICH recurrence were
not significantly increased across treatment groups (VKA vs APA: RR 1.34; 0.79–
2.30, VKA vs no antithrombotic: RR 0.93; 0.45–1.90) [47]. There is no data to
evaluate the utility of use of NOACs among warfarin-related ICH survivors with
atrial fibrillation.
Among patients where resumption of anticoagulation after ICH is necessary, the
optimal timing is also uncertain. The above meta-analysis found a wide variation in
the timing of anticoagulation resumption in the included studies, with a range from
10 days up to 6 months [45]. Two single-center retrospective studies with small
sample sizes between 1998 and 2001 reported low rates of cardioembolic events
among patients with prosthetic heart valves while not receiving anticoagulation
therapy or recurrent ICH when anticoagulation was reinitiated at median 7 and
15 days, respectively, and the patients were followed for 23.5 months and 6 months
[48, 49]. A study of patients with warfarin-related ICH were followed up for a
median of 69 weeks found that the combined risk of recurrent intracranial hemor-
rhage or ischemic stroke reached a nadir if warfarin was resumed after approxi-
mately 10–30 weeks [50].
Resumption of antiplatelet agents (APAs) after ICH has never been evaluated in
a randomized clinical trial. The ongoing randomized controlled REstart or STop
Antithrombotic Randomized Trial (NCT02966119, http://www.RESTARTtrial.
org/) is assessing whether a policy of starting APA after ICH results in a net reduc-
tion in serious vascular events compared with a policy of avoiding APA. Meta-
analyses evaluating the efficacy of aspirin for primary and secondary prevention of
ischemic stroke and myocardial infarction have noted a significant increase in the
risk of ICH (12 events per 10,000 persons), but this is superseded by a larger
15–34% reduction in risk of stroke, myocardial infarction, and death [51, 52]. A
Chinese study found a twofold reduction (52 per 1000 patient-aspirin years versus
113 per 1000 patient-years; P = 0.04) in all vascular events (combined ischemic and
hemorrhagic) among patients who restarted aspirin after any ICH [53]. There was
no difference in the risk of recurrent ICH alone (22.7/1000 patient-aspirin years vs
22.4/1000 patient-aspirin years, P = 70) as well.
About one third of non-anticoagulated ICH patients in the Get with the Guideline
Database were already taking a single or dual antiplatelet agent [54], and those on
combination antiplatelet therapy had higher in-hospital mortality (adjusted OR
1.50; 1.39–1.63), but not those on single APA. In a multivariable analysis of patients
in the placebo arm of the randomized Cerebral Hemorrhage and NXY-059 Treatment
(CHANT) trial, there was no association of use of APAs with ICH expansion or
clinical outcome at 90 days [55].
In a prospective German study of 496 ICH patients followed for 2 years, APAs
were used in 28.4% and were not associated with increased risk of ICH recurrence
[9]. Another single-center prospective study found that antiplatelet use in 22% of
ICH survivors was not associated with an increase in the risk of ICH recurrence
among both lobar and deep hemorrhage patients [56]. In a subsequent study by the
same group that focused solely on lobar ICH, aspirin was not associated with ICH
recurrence in univariate analysis, but after adjusting for baseline clinical predictors,
it independently increased the risk of recurrent ICH (adjusted HR 3.95; 1.6–8.3)
[20]. This, however, may have been secondary to overfitting of the multivariable
model [57].
In the same Markov decision analysis described above, aspirin was found to be
the preferred treatment among patients with deep ICH who had moderate ischemic
stroke risk and recurrent ICH relative risk less than ~1.3. Among patients with lobar
ICH, aspirin was preferred when the risk of ischemic stroke was average (4.5% per
year) and the relative risk of recurrent ICH was less than ~1.04 [46].
Statins
Conflicting data exists pertaining to use of statins post-ICH. A number of studies

have found an inverse relationship between total and LDL cholesterol and the risk
of ICH [58]. In the Stroke Prevention by Aggressive Reduction in Cholesterol
Levels (SPARCL) trial, the benefit of high-dose atorvastatin in reducing ischemic
stroke recurrence was accompanied by an increased risk of ICH, without differ-

ences in overall mortality [59]. In a subsequent sub-analysis of the trial, in addition
to atorvastatin, ICH was more frequent in those with ICH as entry event, men, those
with increased age, and those with stage 2 hypertension [60]. An increase in the rate
of hemorrhagic stroke was not observed in the previously conducted Heart Protection
Study, which included patients with prior stroke randomized to simvastatin or pla-
cebo [61]. A Markov decision analysis evaluated the risks and benefits of statin
therapy in patients with prior ICH and found that in survivors of lobar ICH without
prior cardiovascular events, avoiding statins yielded a life expectancy gain of 2.2
QALYs compared with statin use. In patients with lobar ICH who had prior cardio-
vascular events, the annual recurrence risk of myocardial infarction would have to
exceed 90% to favor statin therapy [62]. Avoiding statin therapy was also favored,
although by a smaller margin, in secondary prevention for survivors of deep ICH
[62]. On the other hand, a meta-analysis of 31 randomized controlled trials which
included 91,588 statin-treated patients found no significant association between
statin use and ICH (OR 1.08; 0.88–1.32); all strokes and all-cause mortality were in
fact significantly reduced with statin therapy [63]. Continued statin use after ICH
was associated with early neurological improvement and reduced 6-month mortal-
ity in a small retrospective study [64]. Hydrophilic statin therapy was associated
with a reduced risk of recurrent ICH in post-ICH patients in a Taiwanese cohort
[65]. It therefore remains unclear whether statins should be continued or discontin-
ued in ICH patients, and the decision should be individualized based on the patient’s
cardiovascular profile, ICH location, and presence of CMBs.
Other Risk Factors
Several other factors, such as the presence of obstructive sleep apnea (OSA), alco-
hol use, smoking, recreational drug abuse, and other lifestyle modifications, should
also be considered in prevention of ICH recurrence despite the lack of systematic
data regarding their effect on ICH secondary prevention.
As discussed above, untreated hypertension is a robust predictor of recurrent
ICH. Hypertension is considered resistant when the blood pressure remains above
goal despite lifestyle modification and administration of three antihypertensive
agents of different classes including a diuretic. Large population-based studies have
suggested that OSA is a risk factor for resistant hypertension [66]. In a small study
among noncomatose hypertensive ICH patients, OSA occurred acutely in >50% of
patients and was associated with perihematoma edema [67].
An Australian case-control study reported an increase in ICH risk (OR 3.4; 1.4–
8.4) with heavy drinking (>60 g/day of alcohol for men and >40 g/day of alcohol for
women) [68]. Similarly, a Japanese study documented an increased risk of ICH in
those who drink heavily (defined as drinking 450 g of alcohol or more per week), a
finding that was significant despite controlling for hypertension (RR 2.07; 1.12–
3.83) [69]. In the standardized INTERSTROKE case-control study in 22 countries,
>30 drinks per month was associated with ICH (OR 1.51; 1.18–1.92), as was binge
drinking [70].
Tobacco use is also associated with increased ICH risk in several epidemiologic
studies [70, 71]. Data from the Women’s Health Study showed that as compared to
nonsmokers, women who smoked ≥15 cigarettes/day had 2.67 times higher risk of
ICH [72]. Current male smokers of ≥20 cigarettes/day had a relative risk for ICH of
2.06 (1.08–3.96) as compared to never smokers in the Physician’s Health Study
over 17.8 years of follow-up [73].
Several recreational drugs, including cocaine, methamphetamine, and dimethyl-
amylamine (DMAA), have been associated with ICH [74–76]. Drug cessation
counseling and treatment is very important for secondary prevention of ICH in
patients with identified drug abuse.
Nonmodifiable risk factors such as apolipoprotein E2 or E4 [77] as well as modi-
fiable lifestyle risk factors such as body mass index, waist hip ratio, diet (vegetable
consumption), and physical activity [70, 78] have been associated with ICH in epi-
demiological studies.
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Chapter 9
Special Disease Management
Considerations
Nabeel A. Herial and Magdy Selim
Intraventricular Hemorrhage (IVH)
Case A 76-year-old woman with history of untreated hypertension developed sud-

den vomiting and loss of consciousness. She was intubated at the scene for airway
protection. Blood pressure upon arrival to the hospital was 222/125 mm Hg. Plain
head CT scan (Fig. 9.1a) showed a large left basal ganglionic hemorrhage extending
into both lateral, third, fourth ventricles and obstructive hydrocephalus with enlarge-
ment of the occipital and temporal horns of the left lateral ventricle. She was started
on nicardipine infusion. Routine laboratory studies were all within normal limits,
and toxicology screen was negative. On examination, eyes were closed. There were
no spontaneous movements or response to voice. Pupils were equal and minimally
reactive to light. Eyes were down in the resting position. Corneal and gag reflexes
were active. She withdrew the left side and has extensor posturing of the right arm
to painful stimulation. Toes were upgoing bilaterally. Neurosurgery was consulted.
A right frontal external ventricular drain (EVD) terminating near the right foramen
of Monroe was placed (Fig. 9.1b), and 1 mg of intraventricular t-PA was adminis-
tered. The patient’s exam remained unchanged without evidence of radiological
improvement of hydrocephalus after 4 doses of t-PA. A second left frontal EVD was
N. A. Herial (*)
Departments of Neurology and Neurosurgery, Sidney Kimmel Medical College,
Thomas Jefferson University, Philadelphia, PA, USA
M. Selim
Department of Neurology, Stroke Division, Beth Israel Deaconess Medical Center,
Boston, MA, USA

https://doi.org/10.1007/978-3-319-77063-5_9
122 N. A. Herial and M. Selim
a b
c d
Fig. 9.1 (a) Non-contrast CT head showing large left basal ganglionic hemorrhage extending into
both lateral and ventricles with enlarged occipital horns. (b) A right frontal external ventricular
drain entering the right lateral ventricle. (c) CT head without contrast with evidence of bilateral
external ventricular drains in the lateral ventricles. (d) A follow-up CT head showing improvement
in ventricular hemorrhage
placed (Fig. 9.1c) with some radiological improvement (Fig. 9.1d). The patient’s

examination remained unchanged. Family ultimately decided to withdraw support-
ive care, and the patient died.
Discussion
The management of patients with IVH involves two important steps that should be
carried out in parallel: (1) identifying the underlying etiology of IVH and (2) pre-
vention and management of complications, in particular the development of
9 Special Disease Management Considerations 123
obstructive hydrocephalus and associated risks of increased intracranial pressure

and herniation, which could be potentially fatal. Intraventricular hemorrhage com-
monly occurs in the setting of deep intracerebral hemorrhage (ICH), which is often
attributed to hypertension, or aneurysmal subarachnoid hemorrhage, and is referred
to as secondary IVH, in contrast to primary IVH, where IVH is isolated, not associ-
ated with ICH or SAH, and confined to the ventricles. Primary IVH is relatively
uncommon; it may complicate traumatic head injury or use of anticoagulant ther-
apy, but the most common etiology is vascular malformations.
Secondary IVH is an independent risk factor for poor outcomes. It is associated
with high morbidity and mortality [1, 2]. Mortality is reported to be greater than
50%, and more than 75% of survivors have poor functional outcomes [1, 2].
Patients with IVH are at risk of neurological deterioration as a result of hydro-
cephalus and its sequelae. The presence of blood in the 3rd or 4th ventricles is often
associated with higher risk for the development of obstructive hydrocephalus,
which can be potentially fatal [3]. Patients may also develop a delayed communi-
cating hydrocephalus after IVH. IVH expansion/extension may also occur, particu-
larly in patients with an underlying vascular lesion or in the setting of a
coagulopathy.
Although plain head CT scan is often sufficient to determine the presence and
extent of IVH, to monitor its progression, and to identify hydrocephalus, we recom-
mend that patients with IVH undergo further imaging with MRI and MRA or CTA
during the early days of hospitalization to rule out an underlying vascular malfor-
mation particularly when an obvious cause such as trauma, concomitant use of anti-
coagulation therapy, or a hypertensive deep ICH is absent. Repeat imaging including
MRI with gadolinium and/or a conventional cerebral angiogram may be warranted
in some cases [4], where the suspicion for an underlying lesion is high, after approx-
imately 4–8 weeks to allow for reabsorption of the IVH.
The treatment of IVH should focus on prevention of IVH expansion, early detec-
tion and treatment of hydrocephalus and high intracranial pressure, and prevention
and treatment of medical complications of ICH such as aspiration and deep vein
thrombosis. The latter conforms to the general recommendations of the American
Heart Association/American Stroke Association Guidelines for management of
spontaneous ICH [5]. The insertion of an EVD to facilitate the drainage of blood
and cerebrospinal fluid has been the standard initial treatment strategy for acute
hydrocephalus resulting from IVH. However, difficulty in maintaining EVD patency
led to a rising interest in the use of intraventricular thrombolysis, i.e., administration
of thrombolytic agents such as tissue plasminogen activator (t-PA) through EVD, as
an effective way to maintain EVD patency to remove IVH in order to relieve
obstructive hydrocephalus and to reduce the toxic effects of blood product in the
ventricles with the hope of improving survival and long-term functional outcomes.
Indeed, animal studies and small clinical series, largely open-label or retrospective,
have reported that intraventricular administration of fibrinolytic agents, including
t-PA, is safe and may reduce morbidity and mortality after IVH by accelerating
blood clearance and clot lysis [6–10].
The efficacy of intraventricular fibrinolysis in IVH, however, has been debatable.
While a Cochrane review in 2002 found no sufficient good quality evidence from
randomized trials to determine whether this approach does more good than harm
[11], a subsequent meta-analysis in 2014 of 8 randomized and 16 observational
studies found that intraventricular thrombolysis reduces mortality, decreases the
need for ventriculoperitoneal (VP) shunt placement, and improves functional out-
come after IVH [12]. However, the included trials were underpowered to support
concrete recommendations about the use of intraventricular t-PA in IVH. Most
recently, the largest, randomized, placebo-controlled trial of intraventricular t-PA in
IVH (CLEAR III trial) was completed [13].
In this trial, 500 patients with stable, non-traumatic, spontaneous ICH less than
30 ml with secondary IVH obstructing the 3rd or 4th ventricles were randomized
to receive up to 12 doses (8 h apart) of 1 mg of t-PA or normal saline via an EVD.
It is important to point out that patients with coagulopathy-associated ICH/IVH
and those with suspected underlying vascular malformation were not included in
this trial. Expectedly, treatment with t-PA led to greater end-of-treatment IVH
removal compared with saline; 33% of t-PA vs. 10% of the saline-treated patients
had 80% of the IVH removed by the end of treatment. However, there was a wide
variability in the number and location of EVDs and number of treatment doses
within the trial, which may have impacted the removal of IVH. The primary effi-
cacy outcome was good functional outcome, defined as modified Rankin Scale
score (mRS) of ≤3 after 6 months. The primary efficacy outcome was similar in
the t-PA- and saline-treated groups; 48% of t-PA-treated patients vs. 45% of
saline-treated patients achieved good outcome at 6 months (risk ratio 1.06; 95%
CI 0.88–1.28; p = 0.55), even after adjustment for IVH volume and thalamic loca-
tion of ICH (risk ratio 1.98; 95% CI 0.90–1.29; p = 0.42). However, a reduction in
the odds of death after 6 months by 50% was noted in the group treated with t-PA
(adjusted odds ratio 0.50; 95% CI 0.31–0.80; p = 0.55). Mortality at 6 months was
significantly lower (18% vs. 29%) in the t-PA treated group compared to the
saline-treated group (hazard ratio 0.60; 95% CI 0.41–0.86; p = 0.006). In second-
ary post hoc analyses, faster and greater removal of IVH with t-PA was associated
with mRS ≤3 (adjusted odds ratio 0.96; 95% CI 0.94–0.97; p < 0.0001) and lower
case fatality (adjusted hazard ratio 1.03; 95% CI 1.02–1.04; p < 0.0001). Patients
with initial IVH volume ≥ 20 ml also achieved better functional outcomes with
t-PA, and the probability of good functional recovery increased when IVH clear-
ance was >80%.
Most recently, we conducted a meta-analysis of six randomized-controlled trials,
including CLEAR III, involving a total of 607 IVH patients, and found similar
results; the use of intraventricular thrombolysis in IVH patients reduced all-cause
mortality (risk ratio 0.63; 95% CI 0.47–0.83). However, the use of t-PA did not
reduce the proportion of survivors with poor functional outcome (risk ratio 1.39;
95% CI 1.04–1.77), the composite end point of death and poor functional outcome
(risk ratio 0.96; 95% CI 0.83–1.11), and the need for VP shunt placement (risk ratio
1.06; 95% CI 0.75–1.49) after secondary IVH [14].
Conclusion
The above data suggest that in most patients with IVH, local administration of t-PA
(1 mg up to 12 doses 8 h apart) via an EVD is unlikely to benefit their functional
recovery. While IVF appears to be safe, its benefit is limited to a reduction in mor-
tality at the expense of increased number of survivors with moderately severe to
severe disability. There is insufficient data to determine if this approach is more
beneficial in a subset of IVH patients with thalamic ICH or IVH ≥20 ml. There is
also no data to determine whether t-PA doses >1 ml or > 12 doses are safe. The
decision to use intraventricular thrombolysis in IVH patients should take into
account the patients’/family’s attributes toward survival and dependency.
Obviously, the use of t-PA should be restricted to patients who do not have an
underlying vascular malformation and cautiously considered or if not avoided in
patients with a large ICH or an associated coagulopathy. If the decision is made to
use t-PA, experience from CLEAR III provides some helpful insights: (1) greater
clot clearance is achieved with EVD placed ipsilateral to the dominant IVH; (2) in
patients with IVH ≥20 ml, greater clot removal is achieved with multiple EVDs
than with a single EVD; and (3) higher number of t-PA doses (up to 12) facilitates
better IVH removal.
The Use of Recombinant Factor VII A (rFVIIa) in ICH
Case A 63-year-old man presented with sudden onset of aphasia and right-sided
weakness within 3 h of symptom onset. Head CT scan revealed a 20 ml left fronto-
temporal ICH and subdural hemorrhage. Head CTA was noted for the presence of a
“spot sign” within the hematoma. His past medical history was noted for coronary
artery disease. His medications included aspirin and atorvastatin. Routine labora-
tory studies, including coagulation studies, were within normal limits. He was
treated with rFVIIa at a dose of 80 μg per kilogram.
Discussion
Early hematoma expansion is one of the most consistent predictors of poor outcome
and mortality after ICH [15]. Hematoma growth after ICH is a common phenome-
non; an increase in ICH volume > 33% is noted in approximately 38% of ICH
patients initially scanned within 3 h of ICH onset [16]. This is attributed to contin-
ued bleeding or re-bleeding within the hematoma region or in its vicinity.
Recombinant activated factor VII (rFVIIa), which is used to treat hemophilia, has
eluded us since the early 2000s as a potential hemostatic therapeutic strategy to stop
bleeding in order to limit ICH growth. In 2005, a phase 2A trial of 399 patients with
spontaneous ICH randomized patients to receive placebo or 40 μg of rFVIIa per
kilogram of body weight, 80 μg per kilogram, or 160 μg per kilogram within 4 h
after ICH onset [17]. The primary outcome measure was the percent change in the
volume of ICH at 24 h. Clinical outcomes were assessed at 90 days. Treatment with
rFVIIa limited the growth of the hematoma, reduced mortality, and improved func-
tional outcomes at 90 days relative to placebo. The mean increase in ICH volume
after 24 h was 29% in the placebo group, compared with 16%, 14%, and 11% in the
rFVIIa groups (p = 0.01). At day 90, 61% of placebo-treated patients died or were
severely disabled (as defined by mRS score of 4–6), compared with 55%, 49%, and
54% of the patients who were treated with rFVIIa (p = 0.004). In a subsequent phase
3 trial involving 841 patients with spontaneous ICH, treatment with rFVIIa did not
improve survival or functional outcome despite reducing hematoma expansion [18].
The mean increase in ICH volume at 24 h was 26% in the placebo group, compared
with 18% in the group receiving 20 μg of rFVIIa per kilogram (p = 0.09) and 11%
in the group receiving 80 μg (p < 0.001). However, there was no significant differ-
ence among the three groups in the proportion of patients with mRS <4 between the
three groups. Furthermore, arterial thromboembolic and myocardial adverse events
were more frequent in the group receiving 80 μg/kg of rFVIIa than in the placebo
group (9% vs. 4%; p = 0.04). A subsequent post hoc subgroup analysis of the trials’
datasets investigated whether rFVIIa might be beneficial in a particular subset of
ICH patients. This analysis indicated that patients ≤70 years of age with baseline
ICH volume < 60 ml and IVH volume < 5 ml who were treated with 80 μg of rFVIIa
within ≤2.5 h of ICH onset had an adjusted odds ratio of 0.28 (95% CI 0.08–1.06)
for poor outcome and doubling in the reduction of ICH growth (7.3 ± 3.2 vs.
3.8 ± 1.5 ml; p = 0.02) [19].
Most recently, two collaborative trials, the SPOTLIGHT trial in Canada and
STOP-IT in the United States, utilized contrast extravasation on CT angiogram,
termed “the spot sign,” to improve patient selection and to identify ICH patients
at greater risk for hematoma expansion for treatment with rFVIIa [20]. A total of
69 spot sign-positive patients were randomly assigned within 6.5 h of ICH onset
to receive 80 μg/kg of rFVIIa or placebo, while 73 spot sign-negative patients
were enrolled into a prospective observational cohort with the same inclusion
criteria. The primary outcome was the ICH volume on 24-h CT scan. In spot sign-
positive patients, the median baseline ICH volume in rFVIIa-treated group was
16 ml and 22 ml on 24 h scan vs. 20 and 29 ml, respectively, in placebo-treated
patients (p = 0.9). At 90 days, there was no difference in the proportion of patients
with mRS 5–6 between rFVIIa and placebo groups (20% vs. 21%; p = 0.6). It has
been argued, however, that poor enrollment which led to a small sample size and
late ICH onset to treatment time might have contributed to these disappointing
results.
Conclusion
In light of the above data, we do not recommend the use of rFVIIa as a treatment for
spontaneous ICH at this time. Although its use can limit hematoma growth, it is also
associated with an increase, albeit small, in thromboembolic and myocardial adverse
events with no benefit on functional outcome. We also do not recommend routine
use of rFVIIa as the sole hemostatic agent for reversal of coagulopathy in warfarin-
associated ICH. Although rFVIIa can rapidly normalize international normalized
ratio (INR), it does not replenish all vitamin K-dependent factors and may not
restore thrombin generation and clotting despite lowering INR [21].
I CH Related to Brain Arteriovenous Malformation (BAVM)

and Dural Arteriovenous Fistula (DAVF)
Case A 50-year-old woman presented with headache of sudden onset with associ-
ated nausea and vomiting. Headache was reported as left frontal in location and
severity of pain rated as 10 (on a 10-point scale). She had no associated visual dis-
turbance, weakness, tingling or numbness, or speech impairment at headache onset.
Patient had a long-standing history of headaches diagnosed as migraines, occurring
in the left frontal area, associated with nausea and blurred vision. Duration of head-
aches reported as several hours to a day. Headache frequency has decreased over the
years to 1 headache day every 3–4 months. At current presentation, characteristics
of headache reported as different include sudden onset of headache and severity
worse than any of her prior episodes. She also had a history of an untreated brain
arteriovenous malformation (bAVM), first diagnosed approximately 24 years ago.
Initial CT head without contrast revealed acute left parieto-occipital intraparen-
chymal hemorrhage measuring about 2.7 cm in diameter, subdural hematoma in the
left frontal convexity measuring 9 mm, and a midline shift to the right measuring
8.3 mm (Fig. 9.2a). Extra-axial extension of hemorrhage was noted along the inter-
hemispheric fissure and left tentorial leaflet to overly the frontal and temporal lobes.
CT angiogram of the head indicated a large arteriovenous malformation in the left
parietal-occipital region with arterial feeders from the left posterior cerebral artery
(PCA), left anterior cerebral artery (ACA), and left middle cerebral artery (MCA).
Venous drainage involved both the superficial and the deep cortical veins. A repeat
neurological examination revealed no focal deficits except for a new right homony-
mous hemianopsia. The ICH score was 0 with hemorrhage volume < 30 cc. Blood
pressure goal of SBP <160 was maintained with intravenous nicardipine infusion;
headache was managed with acetaminophen 500 mg q 12 h and seizure prophylaxis
with levetiracetam 500 mg q 12 h. Euvolemia and euglycemia were maintained (tar-
get glucose 100–180 mg/dL). Patient underwent conventional cerebral angiogram
b c
Fig. 9.2 (a) CT head without contrast showing intraparenchymal (left parieto-occipital) and left
subdural hematoma (left frontal convexity). (b, c) Angiographic image of the arteriovenous mal-
formation with anterior, middle, and posterior cerebral arteries (ACA, MCA, PCA). A small aneu-
rysm (white arrow) from proximal segment of the PCA. (d, e) Angiographic image showing
arterial feeders from the left PCA before (d) and after (e) embolization and aneurysm coiling
(white arrow). (f) An image showing a large flow-related aneurysm (white arrow) of left posterior
inferior cerebellar artery supplying the arteriovenous malformation
d e
Fig. 9.2 (continued)
which demonstrated a Spetzler-Martin grade IV AVM (Fig. 9.2b, c). The size of the
nidus measured 5.9 cm anterioposteriorly, 3.9 cm horizontally, and 4.7 cm cranio-
caudally. The left PCA had a small aneurysm measuring 2.5 mm (Fig. 9.2c) in the
proximal segment at the basilar tip and a dysplastic segment distally. There was
evidence of azygos ACA with large pedicle feeding the superior aspect of the
AVM. Venous drainage involved cortical veins draining into the superior sagittal
sinus and deep drainage into the vein of Galen and straight sinus. Also evident were
small feeding arteries from the left MCA feeders. Patient underwent left-sided burr
hole craniotomy and evacuation of subdural hematoma. After a stable hospital
course, the patient was discharged with a treatment plan of staged embolization fol-
lowed by surgical resection and/or stereotactic radiosurgery (SRS). She underwent
initial primary coiling of the feeding artery aneurysm of the left PCA and emboliza-
tion to occlude the two feeders of the left PCA (Fig. 9.2d, e) using Onyx® liquid
embolic agent (ev3, Irvine, CA).
Discussion
Brain AVMs represent an abnormal connection between the arterial and venous sys-
tem in the brain without a well-defined intermediate capillary network. The term
nidus is used to describe the entangled blood vessel of the AVM, and the size of
which has significant treatment and prognostic implications. Incidence of bAVMs
ranges from 0.7 to 1.3 per 100,000 population [21–23]. Although uncertain, the
etiology of bAVMs is considered congenital, and these lesions may remain asymp-
tomatic for decades (similar to case presented). Brain AVMs account for 2–4% of
all hemorrhagic strokes [24]. Spontaneous intracranial hemorrhage, intraparenchy-
mal and/or subarachnoid, accounts for as high as 40% of the clinical presentations
in patients with bAVMs [25]. Apart from intracranial hemorrhage and chronic head-
aches (similar to case presented), patients may present with seizures, stroke, or tran-
sient ischemic attack and non-focal neurological symptoms. In unruptured bAVMs,
the risk of hemorrhage is estimated to range approximately from 2% to 5% per year,
and the risk is higher in bAMV patients with Spetzler-Martin grade IV or V and is
associated with poor outcomes [26]. Mortality associated with ruptured AVMs
ranges from 10% to 29% with initial hemorrhage and could reach 50% with poste-
rior fossa involvement, particularly if involved with ruptured intranidal or flow-
related arterial aneurysms [27]. In ruptured AVMs, risk of subsequent hemorrhage
is high in the first year after hemorrhage (6–17%) [28].
Diagnostic evaluation starts in most cases after an incidental finding of hyper-
dense lesions on non-contrast CT head with focal areas of calcification or presence
of “flow voids” on MRI brain T2-weighted sequence. Scientific evidence on man-
agement of bAVMs recommends tailored treatment of these unique vascular lesions
based on patient’s age, clinical presentation, characteristics associated with high
risk of hemorrhage and/or mortality such as large intranidal or flow-related aneu-
rysms (Fig. 9.2f), deep venous drainage, venous outflow stenosis, single draining
vein, involvement of vertebrobasilar system, periventricular or ventricular area of
AVM location, etc. [29, 30]. While there is relative clarity on the role of intervention
in ruptured bAVMs, there are no widely accepted guidelines for unruptured AVMs.
A randomized trial of unruptured bAVMs comparing medical management to medi-
cal and intervention with embolization, radiosurgery, and/or surgery showed signifi-
cantly more adverse events of stroke or death in the interventional arm [31].
Concerns raised about this clinical trial include underrepresentation of surgical
treatment (4% surgery, 26% embolization, 27% radiosurgery), majority of Spetzler-
Martin grade I–II lesions undergoing embolization, incomplete treatment with non-
obliteration of AVM, and inadequate follow-up posttreatment. Treatment of bAVMs
has inherent risks and may result in permanent neurological deficits [32]. The risk
associated with surgical treatment in patients with Spetzler-Martin grades I–III is
reported as low [33] and utilizing this grading system for estimating the morbidity
and mortality associated with surgical intervention of bAVMs is recommended [34].
Brain AVM is a dynamic vascular condition, and in cases with partial embolization,
neuroangiogenesis and growth of the bAVM after embolization are reported [35].
Therefore, it is conceivable that partial treatment with incomplete embolization of

the nidus does not eliminate the risk of hemorrhage.
Endovascular treatment of AVMs frequently involves use of liquid embolic
agents such as nBCA (n-butylcyanoacrylate) labelled as Trufill (Codman
Neurovascular, Rayman, MA), an ethylene-vinyl alcohol polymer labelled as Onyx
(ev3, Irvine, CA) and administered with dimethyl-sulfoxide (DMSO), or less fre-
quently coils to decrease the flow in the feeding arteries followed by use of liquid
embolic material for controlled and effective treatment. Embolization of arterial
feeders and/or aneurysms of the AVM is frequently done prior to surgical resection
to decrease intraoperative bleeding. Alternatively, embolization can be followed by
stereotactic radiosurgery (SRS) or used independently to achieve angiographic cure
in select cases. For acute ruptured AVMs, embolization procedure should be delayed
by 1–2 weeks to allow for resolution of any edema or mass effect. Post-embolization,
blood pressure management in the ICU is critical, particularly in situations such as
early venous penetration and/or occlusion of venous drainage during embolization
or after embolization of large nidus which may incite autoregulatory failure and
breakthrough hemorrhage. Stereotactic radiosurgery (SRS) is considered a potential
option in the management of Spetzler-Martin grade I–III AVMs that are small in
size (< 3 cm of nidus) and deep seated and involve eloquent areas of the brain [36–
38]. Treatment response is expected several years after the SRS (approximately
3–5 years), and the risk of hemorrhage during the early period may match the
expected natural history of AVMs and is reduced overtime [31, 39, 40].
Conclusion
Brain AVMs frequently present with intracranial hemorrhage and carry a significant
mortality and morbidity. Management of bAVMs is complex due to the dynamic
nature of the disease. Conclusive evidence or consensus on the best management
strategy for bAVMs is currently not available. As there is an inherent risk of lifetime
hemorrhage in patients with bAVMs, a thorough diagnostic workup and therapeutic
evaluation are recommended. A multimodality treatment approach with a goal of
complete elimination of the AVM and balanced by a clinical benefit overtime is
most preferred. Long-term angiographic follow-up may be essential to confirm sta-
bility of these vascular lesions.
Dural Arteriovenous Fistulas (DAVF)
Case A 62-year-old male presented with mild headache and visual disturbance.
He had left homonymous hemianopsia and no other focal neurological deficits on
exam. Initial non-contrast CT revealed a small right occipital intraparenchymal
hemorrhage (Fig. 9.3a). Further investigations included a MRI brain with and
a b
c d
e f
Fig. 9.3 (a, b) Non-contrast CT and MR imaging (FLAIR sequence) of head showing small right
occipital hemorrhage with surrounding edema. (c, d) Angiography in anterior-posterior projection
showing fistulous drainage from right external carotid artery branches to superior sagittal sinus and
venous reflux. (e, f) Arterial and venous phases of angiography done post-embolization of occipital
and superficial temporal artery branches connecting to the fistula
ithout contrast and MRA head. Again, occipital hemorrhage with surrounding
w
edema and mild regional mass effect was noted (Fig. 9.3b). No clear abnormal
vasculature was seen on MR angiography, but there was overabundance of flow
voids within the region of hemorrhage on T2-weighted imaging suspicious for an
underlying arteriovenous malformation. A conventional cerebral angiogram was
performed which revealed evidence of Borden type III dural arteriovenous fistula
(dAVF) with venous drainage directly into cortical veins and then into anterior
and middle third of the superior sagittal sinus. Arterial connections of the dAVF
were from bilateral external carotid arteries, mainly the right occipital artery
(OA), middle meningeal artery (MMA), superficial temporal artery (STA), and
the left MMA (Fig. 9.3c). Evidence of leptomeningeal venous drainage was noted,
and patient underwent embolization of the OA, STA, and MMA feeders to shut
down a significant number of fistulous connections (Fig. 9.3d–f). On follow-up
cerebral angiography, previously noted meningeal venous reflux was no longer
seen.
Discussion
Abnormal communications within the dura between dural arteries and, less fre-
quently, the pial arteries and the dural venous sinuses are termed as dural arteriove-
nous fistulas (dAVFs). These vascular lesions in adults are frequently acquired
unlike the other arteriovenous malformations. Different etiologies such as sinus
thrombosis or surgery have been implicated in this phenomenon [41, 42]. In the
pediatric population, the abnormal dural arteriovenous connections are associated
with structural venous abnormalities and represent a distinct clinical group of vas-
cular anomalies. Traumatic lesions involving the skull base and leading to intracra-
nial arteriovenous shunts in previously normal vascular substrate, such as
carotid-cavernous fistula, represents a distinct clinical subset and not discussed in
this chapter. Clinical presentation of the dAVFs is commonly based on the location
of fistulous connection and type of venous drainage. The widely used classifications
of dAVFs are also based on the venous drainage in relationship to clinical presenta-
tion [43–45]. The two commonly involved venous sinuses are the transverse-sig-
moid sinus and the cavernous sinus. Symptoms such as pulsatile tinnitus and/or
headache are associated with transverse-sigmoid sinus and cranial nerve deficits
and ocular symptoms with cavernous sinus. DAVFs may also present with many
different signs and symptoms such as exophthalmos, papilledema from raised intra-
cranial pressure, and focal neurological deficits. The most feared clinical presenta-
tion of DAVFs is spontaneous intracranial hemorrhage. The major determinant of
hemorrhagic risk is the venous drainage pattern and severity of cortical venous
reflux if present. In patients with dAVF, the incidence of ICH is reported as high as
42%, and commonly the hemorrhage is intraparenchymal [43, 46]. The annual risk
of hemorrhage is reported as 8% and non-hemorrhagic neurological deficits as 7%
[46, 47]. Patients with dAVF and initial presentation of ICH have a 35% risk of
re-hemorrhage within the first few weeks [48]. Therefore, treatment is recom-
mended in patients with leptomeningeal or cortical venous reflux, and conservative
management is proposed for dAVFs without such drainage pattern.
Diagnostic evaluation of patients with neurological complaints frequently starts
with non-contrast CT head, and presence of hemorrhage may warrant further evalu-
ation with MRI of the brain. Prominent vasculature in the vicinity of the hemor-
rhage or along the cerebral or cerebellar convexities may be evident raising the
possibility of AVM or dural-based AVF. Cerebral catheter angiography is essential
to confirm the presence or absence of underlying dAVF and associated pattern of
venous drainage with or without dangerous features such as venous ectasia or aneu-
rysms [49].
Management of dAVFs depends on the type of venous drainage and lesions
draining directly into the venous sinuses with antegrade flow, and no evidence of
cortical venous reflux can be managed conservatively [41, 50, 51]. In cases with a
high flow across the shunt affecting normal venous drainage of the brain or presence
of clinical symptoms such as bruits, tinnitus, vision abnormalities, etc., intervention
may be reasonable after weighing the benefits with the risks involved with treat-
ment. Treatment of dAVFs could be performed in several stages if the lesions are
multifocal or extensive [51]. If there is involvement of cavernous sinus with pro-
gressive visual impairment, then intervention would be needed urgently. Treatment
may involve arterial approach to the AVF or retrograde venous approach after
excluding venous obstruction, stenosis, or thrombosis [52]. Goal of treatment in
cases with leptomeningeal or cortical venous reflux should be curative due to the
aggressive nature of the disease and in select cases may require surgical disconnec-
tion of the shunting lesion post-endovascular therapy. Arterial embolization for
treatment of dAVFs is beneficial in majority of the cases and cure achieved with
endovascular approach in up to 88% of the cases [46, 47, 52]. Embolic materials
regularly used for arterial approaches include nBCA and Onyx. Transvenous
approach to shut off the cortical venous reflux by maintaining a patent venous sinus
may be occasionally needed to cure the dAVFs. Surgical approaches such as intra-
operative embolization, dural resection, etc. are reserved for failed endovascular
treatments.
Conclusion
Dural arteriovenous fistulas in adults are acquired lesions involving the dural arter-
ies, and their clinical presentation is often based on the venous drainage patterns.
Lesions with cortical or leptomeningeal venous reflux have a relatively higher risk
of hemorrhage or neurological deficits, and curative treatment of these lesions is
recommended. Management of dAVFs mainly involves endovascular embolization
via transarterial approach and in select cases transvenously using embolic materials
with or without coils to obliterate the fistulous connections.
Acknowledgments Authors would like to thank Dr. Reid Gooch from the Department of
Neurosurgery, Thomas Jefferson University for sharing a case of brain arteriovenous malformation
for presentation in this chapter.
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Chapter 10
Special Systems of Care Considerations
in Intracerebral Haemorrhage
Aravind Ganesh and Michael D. Hill
Case Example
Mrs. Retiree was a 65-year-old smoker with a history of hypertension, living inde-
pendently at home. She presented to the emergency department of a regional hospi-
tal with a new moderate-intensity headache accompanied by mild right arm
numbness and weakness that had begun fairly suddenly 5 h ago. Her presentation
was triaged as a “headache”, and consequently she waited for an hour before being
examined by an emergency physician, by which point her weakness had worsened
and she had developed word-finding difficulties. A CT head was obtained within the
next hour, which demonstrated a left frontal lobar haemorrhage with an estimated
volume of 10 mL but no mass effect. A telephone referral was made to the neurosur-
gery team at the nearest tertiary hospital (7 h after onset), who reviewed the images
remotely and declined the request to transfer the patient as there was no apparent
indication for neurosurgical intervention. In the meantime, the patient was admitted
to a busy general medical ward, where hourly blood pressure readings remained
A. Ganesh (*)
Calgary Stroke Program, Department of Clinical Neurosciences, Cumming School
of Medicine, University of Calgary, Calgary, Canada
Centre for Prevention of Stroke and Dementia, Nuffield Department of Clinical
Neurosciences, University of Oxford, Oxford, UK
M. D. Hill
Calgary Stroke Program, Department of Clinical Neurosciences, Cumming School
of Medicine, University of Calgary, Calgary, Canada
Department of Radiology, Department of Community Health Sciences, Department
of Medicine, and Hotchkiss Brain Institute, Cumming School of Medicine,
University of Calgary, Calgary, Canada

https://doi.org/10.1007/978-3-319-77063-5_10
140 A. Ganesh and M. D. Hill
elevated (170–180 systolic). The ward did not have a protocol for neurological mon-
itoring. She continued to complain about her headache. Fourteen hours after symp-
tom onset, the nurse noticed that the patient was no longer responding to questions.
The on-call medical resident found her to have dense right hemiparesis and global
aphasia, and repeated the CT head which showed marked hematoma expansion with
1.5 cm midline shift and intraventricular extension. The neurosurgical team was
contacted again, and arrangements were made to transfer her to the tertiary hospital.
She suffered from severe generalized tonic-clonic seizures in the ambulance, which
did not settle with intravenous lorazepam. She was unable to protect her airway,
could not be intubated en route, and was pronounced dead upon her arrival to the
tertiary hospital.
The Case for Integrated Stroke Systems of Care
As Mrs. Retiree’s unfortunate case demonstrates, the management of intracerebral

haemorrhage (ICH) presents a variety of complex challenges all along the contin-
uum of care and is profoundly impacted by the availability and utilization of spe-
cialized healthcare resources. Given the specialized resources required to deliver
high-quality stroke care, the Canadian Stroke Best Practice Recommendations, the
American Stroke Association (ASA), and the World Stroke Organization’s Global
Stroke Services Guidelines have recommended the implementation of organized
systems of stroke care delivery [1–3].
To have a stroke system of care means that care is coordinated and optimized
along the entire stroke care continuum, from primary prevention to rehabilitation
[2]. These include the designation of comprehensive stroke centres [4], develop-
ment of regional strategies to guarantee appropriate interventions like emergency
medical services (EMS) routing policies, pre- and in-hospital care protocols, stroke
unit care, as well as inter-provider collaboration, the use of telemedicine to aid
patient care in remote facilities, access to post-stroke rehabilitation, and the integra-
tion of quality of improvement programs [1]. Mrs. Retiree’s case demonstrates sev-
eral examples of mishaps along the stroke continuum of care that can be addressed
by specific strategies; these are summarized in Table 10.1, with references to the
relevant chapter section where such strategies are discussed.
Stroke systems of care apply to all stroke types, haemorrhagic and ischemic,
though the largest effect of such systems will apply to ischemic stroke, simply
because it is more prevalent. However, ICH is currently orphaned as a stroke type
with a distinct lack of clearly proven acute interventions. Stroke unit care is the
only intervention applicable to all stroke types including haemorrhage that is
proven to result in reduced morbidity and mortality. Evidence for stroke systems
of care arises from consideration of stroke as a whole, and this overview will
assume that this evidence applies well to both ischemic and haemorrhagic stroke
types.
10 Special Systems of Care Considerations in Intracerebral Haemorrhage 141
Table 10.1 Potential issues along the stroke care continuum highlighted by Mrs. Retiree’sa case
and the relevant system-of-care strategy discussed in this chapter
Relevant chapter
Continuum of care issue System-of-care strategy section
Smoking Smoking cessation campaigns Prevention and
Hypertension Early identification and control of Public Awareness:
hypertension Modifiable Risk
Factors for ICH
5 h from onset to seeking help Public education about stroke Public Awareness of
symptoms and urgency of treatment Stroke Symptoms
(e.g. FAST campaign)
Triaged as “headache” owing to Acute onset of focal neurological Hyper-acute and
this being the main complaint symptoms should trigger a stroke Acute ICH
code and rapid assessment Management
Admitted to a regional centre Stroke code should trigger pre- Pre-hospital
without stroke expertise hospital protocols like EMS routing Protocols: EMS
to comprehensive stroke centres Routing Protocols
CT head obtained 2 h after Stroke code should trigger emergent In-hospital Care
presentation. No follow-up CT neuroimaging (<25 min). Protocols Protocols
obtained until severe deterioration, for early follow-up imaging in
despite clinical signs of potential high-risk or clinically deteriorating
hematoma expansion patients should be in place
Admitted to general medical ward ICH patients should be cared for on a Care on Stroke
and not stroke unit; neurological stroke/neurocritical unit with Units or Neurologic
monitoring not performed. ICU multidisciplinary team input and Intensive Care Units
admission not considered, given specialized nursing care ICH-Specific
potential for airway compromise Intensity of Care
Quality Metrics
BPs elevations not adequately Pre-hospital and in-hospital care ICH-Specific
treated protocols should aim for early BP Intensity of Care
control Quality Metrics
Inter-hospital transfer refused ICH patients should be redirected to Inter-hospital
owing to no neurosurgical appropriate centres to ensure complex transfers
indication; transfer undertaken care needs are met; inter-hospital
without adequate stabilization of transfer protocols should be in place
the patient to ensure safe transfers
Mock patient based on an aggregation of real cases
a
Stroke Systems of Care as an Intervention
The systematic organization of stroke care is a population-level intervention that

applies to all stroke types. A recent ASA policy statement estimated that a 2–3%
reduction in annual stroke mortality by such a system could translate into 20,000
fewer deaths in the United States and roughly 400,000 fewer deaths worldwide [5].
Although it is challenging to objectively demonstrate a causal benefit of such large-
scale, multi-faceted interventions, there is compelling evidence favouring the imple-
mentation of integrated systems of stroke care.
A 2013 study demonstrated that implementation of the Ontario Stroke System

in Ontario, Canada, in 2005 was associated with improved processes of care – in
particular, a higher rate of care at designated stroke centres (from 40.0% to
46.5%) – as well as in stroke outcomes, including lower rates of discharge to
long-term care facilities (from 16.9% to 14.8%) and decreased 30-day mortality,
including for haemorrhagic stroke (from 38.3% to 34.4%) [6]. This study used
piecewise regression analyses to distinguish the effect of the provincial stroke
system from underlying temporal trends in care and outcomes between 2001 and
2010. Evidence on a national scale was provided by a 2016 study which found a
15% relative reduction in 30-day in-hospital mortality in Canadian provinces with
integrated systems of stroke care, which was not observed in those without such
systems, starting in the 2009/2010 fiscal year and sustained through to the
2013/2014 fiscal year [7]. The establishment of stroke systems was also associ-
ated with an increased availability of resources including stroke units, stroke pre-
vention clinics, and telestroke services. Although these findings are most
generalizable to the Canadian healthcare system, this general observation of
decreased mortality in association with a multifactorial stroke system intervention
can help inform policy decisions in other healthcare jurisdictions. Optimizing
stroke care is likely to be cost-effective; it has been estimated that optimal stroke
care in Canada would result in a cost avoidance of $682 million annually in direct
and indirect healthcare costs [8].
Stroke systems of care are likely to evolve differently in different healthcare
systems and geographies, particularly in single- versus multi-payer settings. The
contrast between the American and Canadian healthcare systems is illustrative. The
Canadian healthcare system is a collection of similar systems organized and funded
by each province or territory [9]. Because of this centralization (essentially a single
payer which is the province/territory), each province/territory can choose to region-
alize stroke services to curtail cost and promote efficiency. These might include
restricting the number of hospitals providing stroke care by geographical need and
directing EMS to triage stroke patients preferentially to designated regional stroke
centres. The multi-payer American system is decentralized, with much less federal
or state-level coordination, meaning that allocation of resources is not directed nec-
essarily at efficiency of population-level services but instead at maximizing effi-
ciency at the level of the hospital or the hospital network; this may affect quality and
raise stroke-specific costs at the population level [10]. This absence of a centralized
structure can create barriers to monitoring and addressing regional issues to ensure
that stroke systems act in the best interest of the all patients in a given region [11].
Stroke systems of care can also be expected to follow different development trajec-
tories in lower- and middle-income countries, where a lack of adequate funds and
expertise may mean a greater focus on certain aspects of stroke systems – like
telestroke for rapid remote access to expert advice/evaluation, or rapid land/air
patient transport protocols – to compensate for a dearth of resource-intensive stroke
facilities.
Allowing for such inevitable heterogeneity, there are some core features and
operating principles along the continuum of stroke care that can frame the organiza-
tion of systems of care for ICH, each of which we will examine in turn: (a) prevention
and public awareness, (b) hyper-acute and acute management, and (c) rehabilitation
and community reintegration.
Prevention and Public Awareness
Modifiable Risk Factors for ICH
Globally, over 90% of the stroke burden is attributable to modifiable risk factors,
with nearly three quarters related to behavioural factors [12]. Stroke systems of care
can play a key upstream role in the prevention of ICH. Hypertension is the single
most important risk factor for ICH [13]; while most hypertension-related ICH
occurs in deep brain parenchymal nuclei, hypertension is also a risk factor for lobar
ICH [14]. Meta-analyses have reported a 3.5-fold increased risk of ICH with hyper-
tension [15], and more than a ninefold increase with blood pressures over 160/90
[16]. A recent report from the Trials of Hypertension Prevention (TOHP) found a
direct linear association between average sodium intake, a modifiable risk factor,
and mortality. Diabetes mellitus is associated with a 1.6-fold risk increase in ICH
[17], but it remains unclear if treatment of diabetes mellitus reduces ICH risk.
Smoking has been consistently shown to be a risk factor for ICH, with studies dem-
onstrating a dose-response relationship with the number of cigarettes smoked and
the risk of ICH [18, 19]. The relative risk for current versus non-smokers has been
reported to be around 1.5 [15, 16]. Excessive alcohol consumption, including binge
drinking, is a risk factor for ICH. Addressing these risk factors is both the function
of the stroke prevention clinic, within a stroke system of care, and general public
education with mass media campaigns [20–22].
The Role of Stroke Prevention Clinics
Following ICH, as with care following transient ischaemic attack (TIA) or isch-
aemic stroke (given shared risk factors), identifying the likely mechanism or cause
of ICH is important to secondary prevention strategies. While hypertension is the
most important risk factor for ICH, it can be well treated with currently available
medication. Anticoagulant use may need review, and individual level decision-mak-
ing may be required to decide if antithrombotic therapy continues to be indicated.
Venous sinus thrombosis associated with ICH will require long-term anticoagula-
tion, which appears to be safe in this setting [23]. In contrast, anticoagulants may be
contraindicated after lobar haemorrhage with associated microbleeds in the brain

suggestive of amyloid angiopathy [24]. Identification of structural arterial or venous
lesions (arteriovenous malformations, arteriovenous fistulas, or aneurysms) has
potential implications for subsequent neurosurgical, endovascular, or radiotherapy
interventions.
Public Awareness of Stroke Symptoms
Early recognition of stroke symptoms and early medical attention is critical for
maximizing the chance of a favourable outcome after stroke [25]. Because stroke is
typically painless and therefore does not uniformly engender a sense of urgency
[26] and many people do not know how to recognize stroke in another person and to
seek help [27], stroke systems of care should take an active role in promoting public
education about rapid recognition of stroke symptoms to optimize the hyper-acute
presentation of stroke cases to medical attention. The Face-Arm-Speech-Time
(FAST) campaign is an example of a highly successful international public aware-
ness campaign that has been shown to have a sustained reduction on the time to first
seeking medical attention after stroke [28]. In particular, the campaign appears to
have promoted a shift towards directly contacting EMS (versus other sources of
medical help like a general practitioner); increase in use of emergency services has
repeatedly been cited as a critical factor in facilitating rapid assessment following
stroke [29]. Importantly, such campaigns play a role not only in improving symp-
tom recognition in patients at risk but also in improving stroke awareness in rela-
tives, acquaintances, or other bystanders who are responsible for the actual call for
medical assistance in almost 90% of major stroke cases [28]. Surveys of the general
population in the United Kingdom have shown an increased ability to name stroke
warning signs following the FAST campaign, suggesting that such improved initial
diagnostic impressions in bystanders has likely contributed to the positive effects of
the campaign on response times [30].
Hyper-acute and Acute ICH Management
The concept of “time is brain” that has permeated the care of hyper-acute isch-
aemic stroke applies equally to ICH, where different mechanisms of secondary
brain damage also occur within the first few hours of symptom onset [25].
Hematoma growth >33% has been observed in one quarter of patients within the
first hour and in roughly 40% within the first 20 h [31], with more than 70% of
patients having some degree of hematoma expansion in the first day [32]. Hematoma
expansion is associated with worse functional outcomes and increased mortality
from ICH [32]. Perihaematomal oedema and intraventricular haemorrhage (IVH)
are additional mechanisms of secondary damage; oedema grows rapidly in the first
day but continues at a slower pace for 2 weeks [33], whereas IVH develops within
the first few hours and is clearly associated with worse short- and long-term out-
comes [34, 35].
Pre-hospital Protocols
EMS Routing Protocols
A recent analysis of pre-hospital delay times in patients with major stroke from the
Oxford Vascular Study found that two-thirds of pre-hospital delay in those who
sought emergency medical attention consisted of paramedic assessment and ambu-
lance transport time [28]. This highlights the importance of pre-hospital protocols
to rapidly identify and transport stroke patients to the correct emergency centre,
which involves coordinated efforts among emergency departments as well as ground
and air emergency transportation.
Pre-hospital identification of potential stroke cases is improved by adopting stan-
dardized tools like FAST, the Los Angeles Prehospital Stroke Screen, the Cincinnati
Prehospital Stroke Scale, or the Hospital Evaluation Criteria [36] to rapidly identify
and initiate a “code stroke” pathway. Protocols to allow EMS bypass to the most
appropriate centre without pressures or incentives to stop at a less optimal hospital
has been demonstrated to increase access to stroke centre care [1, 37]. Encouraging
progress has been made in this area; in 2010, 49% of stroke hospitalizations in the
United States occurred in jurisdictions with established EMS regional systems of
acute stroke care, versus just 1% in 2004 [38].
Designation of Primary and Comprehensive Stroke Centres
Selection of appropriate centres for stroke care is facilitated by the designation of

specific hospitals as comprehensive stroke centres (CSCs) and primary stroke cen-
tres (PSCs), as recommended by the Brain Attack Coalition (criteria summarized in
Table 10.2) [4, 39]. It remains unclear if preferential routing of suspected ICH
patients to CSCs improves outcomes. Clinical grading scales to identify ICH (e.g.
the Siriraj score [40]) have been proposed but are simply not discriminative enough
to identify ICH accurately. Pre-hospital clinical screening tools to identify ICH with
a high degree of accuracy are still needed. Mobile Stroke CT ambulances may pro-
vide the best immediate option for early diagnosis and testing of field-based thera-
pies; these are only available in selected cities around the world [41–44].
Development and certification of CSCs and PSCs must occur in parallel to the
development of pre-hospital protocols; lack of access to such facilities, particularly
in scarcely populated regions, can be a barrier to instituting acute stroke routing
protocols [45]. However, adoption of EMS routing policies may itself provide
incentive for more centres to achieve PSC accreditation, improving access to stroke
Table 10.2 Characteristics of comprehensive and primary stroke centres, with features compared
or contrasted where appropriate [4, 39]
Comprehensive stroke centre (CSC) Primary stroke centre (PSC)
Neurosurgical and endovascular capability,
including clipping and coiling of intracranial
aneurysms
Advanced thrombolytic capability, including Capability to provide acute medical
endovascular treatment thrombolysis
Stroke unit care as well as intensive care unit Stroke unit care (with telemetry monitoring)
Inter-disciplinary stroke team Inter-disciplinary stroke team but may not be as
complete or available as in a CSC
Advanced neurovascular imaging capability, Computed tomography on site
such as MRI and various types of cerebral
angiography
Responsibility for stroke service coordination Responsibility for stroke service within a site
across a region and maintenance of a stroke
registry
care: the yearly rate of eligible hospital conversion to PSC designation accelerated
from 3.8% to 16.2% during the implementation of EMS routing policies in California
[46]. From the healthcare system’s perspective, this raises the question of how to
optimize the number of stroke centres in a given region. Directing high case volume
to a smaller number of institutions can help hone stroke-specific competencies
among staff improving outcomes but may also result in the loss of skills at non-
designated centres. Stroke patients may also be forced to deal with increased trans-
port times to designated centres owing to restricted access. Alternately, if more
hospitals gain CSC designation and increase their stroke admission volume, this can
mean faster access to care for patients. The cost of CSC designation is a stretching
of hospital resources such as neuroimaging and critical care nursing [47]. This situ-
ation poses a challenge for stakeholders charged with PSC/CSC designation crite-
ria, who must strike an optimal balance between the healthcare establishment’s need
to sustainably invest limited resources and the public or consumer’s need for timely
access to certified stroke centres.
Evolving Pre-hospital Treatment Protocols
The additional availability of point-of-care laboratory testing for clotting parame-

ters in mobile stroke CT ambulances means that ICH patients can have platelet or
coagulation deficits treated even before they arrive in hospital. This can be espe-
cially valuable in cases of warfarin-related ICH, where rapid reversal (within 2 h of
onset) has been advocated but significant delays are common [48]. The Cleveland
mobile stroke unit reported rapid reversal of international normalized ratio (INR)
with four-factor prothrombin complex concentrate in a case of warfarin-related ICH
within 57 min of EMS dispatch [49], compared to the median onset-to-therapy time
of 15 h in a recent haemorrhage registry [50].
Another emerging pre-hospital treatment consideration for ICH is blood pressure
lowering in the field. While data from the ICH-ADAPT, INTERACT, and
INTERACT-2 RCTs have shown the safety of rapid BP lowering in ICH to a sys-
tolic target of 140 mmHg [51–53], the ATACH-2 study failed to show benefit of
rapid lowering of BP in hospital using intravenous nicardipine [54]. Still, there is a
physiological reason to believe that if blood pressure lowering is to work, it will
have to be done extremely early after stroke onset. The feasibility of a definitive
pre-hospital BP-lowering RCT in acute stroke has recently been demonstrated by
the PIL-FAST pilot study of paramedic-initiated lisinopril [55]. The FAST-MAG
trial, while negative for its primary outcome, has also demonstrated the feasibility
of large-scale pre-hospital administration of a potentially neuroprotective agent in
acute stroke [56]. By making their EMS provision amenable to large-scale trials or
imminent in-the-field treatment options, stroke systems of care can stand to gain
much from the advancement of pre-hospital stroke care.
In-Hospital Care Protocols
Once the patient with suspected stroke has arrived in the hospital, an in-hospital
“code stroke” or “STAT stroke” pathway should kick into effect, with the immedi-
ate priority being to definitively establish the diagnosis of ischaemic or haemor-
rhagic stroke, if not already done. Once the patient has been definitively identified
as having ICH, then their care should proceed along an ICH-specific pathway.
Protocol-based care is associated with decreased length of stay and hospitalization
costs [57].
Neurosurgical intervention is relevant for only a small minority of ICH patients;
most patients with ICH should be admitted to a medical stroke unit. There is sim-
ply no evidence for benefit of early (emergency) craniotomy and haematoma
evacuation. Stroke systems should facilitate relevant neurosurgical consultation in
ICH patients where ventriculostomy for obstructive hydrocephalus and surgical
evacuation of a cerebellar haemorrhage could be life-saving [5]. Early manage-
ment priorities for in-hospital protocols should include emergency reversal of
coagulopathies for which there is some modest evidence of benefit [58, 59],
administration of anti-epileptic medications when seizures have complicated the
patient’s early clinical course, measures to control elevated intracranial pressure,
deep venous thrombosis prophylaxis, and early mobilization and rehabilitation
therapy [60–62].
ICH-Specific Intensity of Care Quality Metrics
A valuable framework for the organization of in-hospital protocols has recently

been provided by the ICH-specific intensity of care quality metrics. These metrics
were developed through a review of the available scientific evidence on quality
indicators in ICH, or stroke in general or other directly relevant disease processes
(like hyperglycemia) where ICH-specific data were lacking; 26 quality indicators
related to 18 facets of care with thresholds for quality response for identified (sum-
marized in Table 10.3) [63].
Table 10.3 ICH-specific quality of care metrics and proposed performance thresholds (Adapted
from Qureshi et al. 2011 and 2013). To calculate intensity of care quality score, 1 point is assigned
to each threshold met [64]
Variable Definition Proposed threshold(s) for performance
Emergency Time to physician contact and Performed within 10 min of ED
department (ED) hemodynamic monitoring arrival
evaluation time
Rapid acquisition of Time interval between ED arrival Acquired within 25 min of ED arrival
neuroimaging and CT scan or MRI
ICU-type Neurological and hemodynamic Initiated within 10 min of ED arrival
monitoring monitoring within 30-min
intervals
Avoidance of DNR Appropriate causes include No DNR/withdrawal of care status
(do-not-resuscitate) severe stroke, life-threatening within 24 days of ED arrival, or not
or withdrawal of brain damage, and significant applicable
care status in first comorbidities No DNR/withdrawal of care status
24 h and DNR between 24 days and 7 days of ED
without cause arrival, unless there is a documented
within first 7 days change in patient status
Treatment of acute Systolic blood pressure (SBP) Achieved target range within 2.5 h of
hypertensive ≥180 mmHg per initial the second of two consecutive
response definition; following recent trials, measurements, or not applicable
SBP >140 may be more
appropriate
Early intubation and Indications: decreased level of Intubation initiated within 30 min of
mechanical consciousness (GCS < 10); identification of risk, or not applicable
ventilation hypoventilation or apnoea or
decreased or ineffective
respiratory effort; hypoxemia or
hypercarbia; impaired airway
protection; airway obstruction;
recurrent aspiration; seizures
>5 min; or craniotomy.
Treatment of Unilateral or bilateral pupillary Clinical reversal of herniation or
clinically significant enlargement or two spontaneous attainment of ICP <20 mmHg within
intracranial mass ICP readings >20 mmHg 60 min of detection, or not applicable
effect or trans- persisting for >5 min (if ICP No brain death status within 7 days of
tentorial herniation monitoring is available) herniation or ICP elevation
Treatment of Continuous or repetitive seizure All motor seizure activity ceased
repetitive seizures activity >5 min without recovery within 20 min after the first recorded
and status of consciousness seizure and no return of seizure
epilepticus (clinical) activity during next 40 min, or not
applicable
Treatment of Seizures seen only on All motor and
repetitive seizures electroencephalography or subtle electroencephalographic seizure
and status signs at the bedside activity ceased within 20 min after the
epilepticus first recorded seizure and no return of
(subclinical) seizure activity during the next
40 min, or not applicable
No recurrence of overt or subtle
seizure within 12 h after first seizure
or not applicable
Variable Definition Proposed threshold(s) for performance
Rapid reversal of INR >1.4 at admission INR reversal (INR <1.4) within 2 h of
elevated INR first elevated INR >1.4, or not
applicable
At least two reversal agents
administered within 2 h of first
elevated INR >1.4, or not applicable
Treatment of Serum glucose >200 mg/dL Target glucose achieved within 4 h of
elevated serum within 72 h detection of elevated glucose or not
glucose applicable
concentration No recurrent hyperglycemia within
72 h of admission
Treatment of Temperature ≥ 38.3 °C on two Time to normothermia (first
hyperpyrexia consecutive measurements 1 h T < 37.2 °C) <4 h, or not applicable
apart within 72 h No recurrent hyperpyrexia within 72 h
of admission
Deep vein Low-molecular-weight heparin, Administered in the first 48 h of
thrombosis heparin, or intermittent arrival, or not applicable
prophylaxis pneumatic compression
Dysphagia Bedside evaluations, Performed within 72 h of arrival, or
screening videofluoroscopic assessment, or not applicable
fiber-optic endoscopy
Nutrition initiation Enteric route preferred Enteral feeding started within 72 h of
arrival, or not applicable
Gastric ulcer H2 blockers, proton blockers, or Administered within 48 h of symptom
prophylaxis sucralfate onset, or not applicable
Treatment of SBP ≥160 mmHg within 7 days; Initiated within 7 days of arrival, or
persistently elevated following recent trials, SBP >140 not applicable or contraindication
blood pressure may be more appropriate documented
Tracheostomy for Early percutaneous or surgical Performed within 7 days of arrival, or
persistent intubation tracheostomy not applicable or contraindication
or poor airway documented
protection
Treatment of New or progressive radiographic Institution of intravenous antibiotics
hospital-acquired or infiltrate and at least two of fever, within 24 h of first persistent fever
ventilator-associated leucocytosis, or purulent tracheal (≥38.3 °C on consecutive
pneumonia secretions, during ICU stay measurements 1 h apart)
No new antibiotic substituted or added
within 10 days of initiating first
antibiotic
When a pilot study using these indicators was performed in 25 patients, the low-
est performance scores were observed for early intubation and mechanical ventila-
tion, treatment of significant mass effect or trans-tentorial herniation, and timely
acquisition of neuroimaging, whereas the highest scores were seen for the treatment
of status epilepticus or any seizure within 2 weeks of admission and prevention of
gastric ulcers [63]. A validation study was then undertaken in 50 consecutive
patients with ICH admitted within 24 h of symptom onset, with each patient’s care
scored from 0 to 26 based on the attainment of the threshold for appropriate perfor-
mance for each parameter [64]. Higher scores correlated with lower in-hospital
mortality, and the receiver operating characteristic curve demonstrated a high dis-
criminating ability of these metrics for that outcome (c-statistic of 0.91); the asso-
ciation was evident even after adjusting for known prognostic variables like initial
GCS score, haematoma volume, and intraventricular haemorrhage [64]. These find-
ings support the broader use of these metrics for standardizing in-hospital care for
ICH. Ultimately, these metrics provide a template that is amenable to modification
based on new evidence; for example, the originally proposed BP targets can be
modified based on recent RCT studies in ICH (Table 10.3).
Care on Stroke Units or Neurologic Intensive Care Units
Organized stroke unit care provided by specialized multidisciplinary teams on a

discrete ward dedicated to stroke patients has been found to have a robust, demon-
strably stable effect in reducing stroke mortality, when compared to alternative
forms of care delivery [65, 66].
A review of 31 trials, involving 6936 participants, compared stroke unit care with
alternative service provision and found that stroke unit care was consistently associ-
ated with improved outcomes; such patients are more likely to be alive and indepen-
dently living at home at 1 year post-stroke [65]. Centralization of acute stroke care
into hyper-acute stroke units increases the likelihood that patients will receive evi-
dence-based clinical interventions [67].
Similar benefits have been observed in ICH patients. A Spanish study of ICH
patients at a facility before and after the introduction of integrated care on a stroke
unit observed a significant reduction in average stay, with improved scores on the
Rankin scale at discharge, more patients discharged to rehabilitation centres, and
fewer sent to long-term care facilities [68]. There were also fewer complications
like hydrocephalus, re-bleeding, sepsis, and renal failure. Evidence of a mortality
benefit in ICH was provided by a Norwegian prospective controlled study of 56 ICH
patients admitted to an acute stroke unit, versus 65 ICH patients treated on general
medical wards, and found that the 30-day mortality was 39% in the acute stroke unit
compared to 63% in the general medical ward, while 1-year mortality rates were
52% and 69%, respectively (both statistically significant) [69]. This difference in
1-year mortality was driven by the large difference in 30-day survival, as there was
no difference in survival between 30 and 365 days.
For ICH patients in particular, admission to a dedicated neurologic intensive care
unit (ICU) with stroke expertise – versus just a stroke unit – for at least 24 h after
the clinic event may be a reasonable protocol. The AHA/ASA Stroke Council have
recommended that monitoring and management of ICH patients should take place
in an ICU setting, given the high risk of neurological deterioration, frequent eleva-
tions in intracranial pressure, cardiovascular instability (including frequent BP ele-
vations), the frequent need for intubation and ventilation, and multiple complicating
medical issues within the first 24 h [70–72]. Investing in such neuro-specific critical
care resources can have a meaningful impact on care. For instance, the introduction
of a neurocritical team, including a full-time neuro-intensivist, and implementation
of intensive-care protocol for key aspects of care like mechanical ventilation, deep
vein thrombosis treatment, gastrointestinal prophylaxis, infection control, sedation,
glucose control, core body temperature, and BP control were associated with sig-
nificantly lower in-hospital mortality and length of stay but without changes in read-
mission rates or long-term mortality in one ICU-based study [73]. In addition, a
multivariable analysis of prospectively collected data over 3 years by Project Impact
from 52 participating ICUs and two neurocritical ICUs (around 40,000 patient
records) found that not being on a neuro-ICU was associated with an increase in
hospital mortality (OR 3.4) after adjustment for patient demographics, ICH severity,
and ICU/institutional characteristics [74]. The added benefits of neurocritical care
may be related to different approaches to BP management, withdrawal of care,
coagulopathy correction, caregiver experience, comorbidity or complication man-
agement, and general supportive care [63].
Ultimately, whether ICH patients are housed on a stroke unit or neurologic ICU,
they should receive close and specialized nursing care that involves careful monitor-
ing for the possibility of clinical worsening from various complications.
Inter-hospital Protocols
Inter-hospital Transfers
Getting patients with suspected stroke to the right facility the first time must be a
priority in a stroke system, given that time delays may exclude ischemic stroke
patients from some acute therapies once they finally arrive at a PSC/CSC [75–77].
The secondary transfer of such patients to a PSC/CSC to initiate treatment can
greatly worsen the delay from symptom onset to acute therapy [78]. With ICH, the
urgency of transfer is dampened by the absence of proven acute interventions; how-
ever, transfers may help facilitate appropriate care in a stroke unit or neurologic
ICU. To navigate such situations, it is important for stroke systems to have transfer
protocols in place.
Inter-hospital transfer of ICH patients to receive neuro-ICU care may improve
the quality of care but may also be associated with complications, particularly if
transfer times are not optimized. A New York-based prospective single-centre study
of patients with haemorrhagic stroke (including ICH) found that while complica-
tions generally did not differ between patients who were transferred to the neuro-
ICU versus those directly admitted, longer transfer time among transferred patients
was associated with a significantly greater risk of aneurysm re-bleed and tracheos-
tomy [79]. Transferred patients had worse cognitive outcome at 3 months but there
were no differences in death, disability, or length of stay.
The adequacy of the ICH patient’s vital signs – airway, breathing, and circulation
status – must be rapidly assessed and stabilized before inter-hospital transfer occurs
[80–82]. During the initial management and transport, aforementioned measures to

prevent or minimize mechanisms of secondary injury should still be undertaken. A
single-centre prospective study in Taiwan found that inter-hospital transfer neuro-
logical deterioration – defined as a GCS score drop of two or more points from last
measure at the first facility to first measure at the second facility – occurred in
36/217 patients (16.6%) and was predicted by arrival SBP ≥180 mmHg, in addition
to the known prognostic factors of infratentorial ICH, presence of intraventricular
haemorrhage, and larger ICH [83]. This further highlights the need for pre-transfer
treatment of critical parameters like BP.
One question that remains is whether observed potential benefits of inter-hospital
transfer simply reflect the favourable baseline characteristics of those patients
selected for transfer. For example, a study of 760 consecutive ICH admissions to a
designated stroke centre in Connecticut, of which 321 (42.2%) were inter-hospital
transfers, found that transferred patients were younger, had lower ICH scores,
higher GCS, and lower SBP than direct admissions [84]. A retrospective cohort
study of 1364 consecutive ICH patients admitted to 14 acute and specialist hospitals
in Salford (United Kingdom), of whom 140 were transferred, also found that the
decision to transfer was more likely with younger patients but also in women, brain-
stem or cerebellar bleeds, and larger haematomas [85]. However, independent of
other prognostic factors, transferred patients had a significantly lower risk of death
versus those remaining at the referring centre, whether they or not they ended up
having a surgical intervention. This suggests that aggressive supportive care at spe-
cialized centres (i.e. CSCs) can improve survival in ICH. If observed estimates of
neuro-ICU-based functional outcome distributions are proven accurate, then there is
a strong cost-effectiveness argument for stroke systems to invest in the transfer of
ICH patients to specialized neuro-ICUs according to a recently published decision
analytic model [86].
For selected patients, early neurosurgical consultation is warranted, and inter-
hospital transfers may be undertaken to ensure this. Patients with large cerebellar
ICH or evidence of hydrocephalus will benefit from consideration of surgical inter-
vention. Inter-hospital transfer should include the establishment of written proto-
cols identifying criteria for such transfers, individuals responsible for coordinating
the transfer, patient monitoring during the transfer, and communication of transfer
outcome [5].
The Role of Telestroke Services
Telestroke – the use of voice and video telecommunications technology in stroke

care – offers further opportunities for both pre-hospital and collaborative inter-hos-
pital diagnosis and management in acute stroke. Pilot studies have explored the
concept of ambulance-based telemedicine to facilitate rapid and accurate pre-hospi-
tal stroke triage; whereas older studies were limited by earlier-generation broad-
band [87–89], more recent studies using modern cellular connectivity have shown
greater reliability [90, 91]. A recent study using standardized patients has also
demonstrated the reliability of a low-cost, tablet-based platform and commercial

cellular networks to perform pre-hospital neurological assessments in rural and
urban settings [92]. Such remote assessments can also be valuable when consider-
ing inter-hospital transfers to ensure appropriate preparation and pre-transfer stabi-
lization of the patients. Telestroke services can also be used by allied health
professionals. Speech therapists recently reported use of remote videofluoroscopy
to direct their examination of dysphagia with the aid of on-site clinicians, finding
moderate agreement with on-site assessors and good agreement in treatment recom-
mendations [93].
A systematic review of 18 telestroke studies found that such services can lead to
better functional health outcomes including reduced mortality, compared with con-
ventional care [94]. Telestroke services also appear to be cost-effective. For exam-
ple, in the Telemedical Project for Integrative Stroke Care (TEMPiS) network,
30-month costs were calculated for patients treated in hospitals with telestroke units
versus those without specialized care; whereas inpatient costs were higher in
TEMPiS hospitals, costs of aftercare were lower compared with conventional hos-
pitals, resulting in equal absolute costs by 30 months [95]. Costs of aftercare per
year survived were lower in TEMPiS patients, making long-term cost savings very
likely. Two other studies using decision-analytic models based on data from hospi-
tals in the United States calculated the effects of increased numbers of ischaemic
stroke patients treated with intravenous thrombolysis and estimated relevant cost
savings in the long term as a result of decreased disability [96, 97]. ICH-specific
models have not been published.
Rehabilitation and Community Reintegration
Successful rehabilitation after stroke consists of six main areas of focus: (1) train-
ing for maximum recovery, (2) prevention and treatment of co-morbid conditions,
(3) enhancement of psychosocial coping, (4) promotion of integration into the
community, (5) prevention of recurrent strokes or other vascular events, and (6)
enhancement of quality of life [98]. Rehabilitation of stroke survivors should begin
early but should not be started overly aggressively; the AVERT trial recently found
that a higher-dose, very early (<24 h) mobilization protocol was associated with a
lower odds of favourable outcome at 3 months [99]. Several studies have demon-
strated that organized multidisciplinary stroke rehabilitation reduces death, dis-
ability, and institutionalization [98]. Such services should be directed by a
physiatrist or neurologist experienced in stroke rehabilitation, and CSCs should
have physical, occupational, and speech therapists readily available for patient
assessment and therapy during the acute hospitalization [4]. Post-stroke care
should also include assessment and support for cognitive decline, depression, and
social consequences of stroke [100].
There have been a few different organized approaches to post-stroke rehabilita-
tion following acute care: (1) acute stroke units that discharge patients early, usually
within 7 days, for further inpatient or outpatient rehabilitation; (2) rehabilitation

stroke units that accept such patients after 7 days and focus on rehabilitation; and
(3) comprehensive stroke units that accept patients acutely and also provide reha-
bilitation for many weeks if needed [101]. Comprehensive units have demonstrated
the greatest overall benefit, achieving both a significant reduction in length of stay
and the greatest reduction in combined death/disability outcomes [101]. Cross-
sectional, “before-and-after” comparisons, and randomized controlled studies have
indicated that co-located acute/rehabilitation stroke care promotes better length-of-
stay and/or functional outcome when compared to the acute or rehabilitation stroke
unit models [102–104]. Outpatient rehabilitation programs can also improve out-
comes and prevent deterioration in stroke survivors [105].
Integrated models of community reintegration and secondary prevention, such as
the ICARUSS (Integrated Care for the Reduction of Secondary Stroke) model in
Australia, can reduce recurrent events. ICARUSS is a multimodal program involv-
ing collaboration between a specialist stroke service, a hospital coordinator, and the
patient’s general practitioner to promote the management of vascular risk factors
through ongoing patient contact and education. This model has been shown to be
associated with a successful reduction in systolic blood pressure, modification of
body mass index, greater exercise engagement, and reduced disability in the
12 months post-stroke versus usual care in an RCT; 10% of these patients had ICH
[106].
Conclusion
Stroke systems of care play an essential role in good ICH patient care. They have a
central role in education, infrastructure and protocol development, institutional
accreditation, and continuous quality improvement across the continuum of stroke
care. An integrated approach to stroke care, with carefully designed policies that
address the complex challenges and care needs along each step of the continuum
from prevention and public awareness to hyper-acute/acute management and ulti-
mately rehabilitation and community reintegration, can help ensure that patients
with ICH have the best chance at disability-free survival.
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Chapter 11
ICH Rehabilitation and Recovery
Benjamin A. Abramoff, Nicole D. Mahdi, Maria Beran,

and Samir R. Belagaje
Case
A 47-year-old African-American male with a past medical history of uncontrolled
hypertension presented with new-onset dysarthria and decreased response time.
Initial head CT showed a large right frontoparietal intraparenchymal hemorrhage
with midline shift of 9 mm, as well as a thin right convexity subdural hematoma. His
systolic blood pressure was greater than 200. The patient was taken urgently to the
OR for surgical decompression. Follow-up CT showed improvement of mass effect.
During the hospitalization, he had a witnessed seizure and was started on
levetiracetam.
Eighteen days following admission, he was discharged from the acute hospital
and transferred to a rehabilitation hospital. At that point, he was requiring moder-
ate to maximal assistance. Deficits included left hemiplegia and development of
spasticity. His rehabilitation stay was complicated by right common femoral vein
deep vein thrombosis requiring inferior vena cava filter placement and a Klebsiella
urinary tract infection leading to increased fatigue during therapy sessions which
was ultimately treated with antibiotics.
Despite these setbacks, the patient made progress during his rehab course. His
increased tone and spasticity was treated with baclofen and daily range of motion
B. A. Abramoff · M. Beran
Physical Medicine and Rehabilitation, Emory University Hospital, Atlanta, GA, USA
N. D. Mahdi
Stroke Program, Northwest Hospital, The Sandra and Malcolm Berman Brain and Spine
Institute, Baltimore, MD, USA
S. R. Belagaje (*)
Neurology and Rehabiliation Medicine, Emory University, Atlanta, GA, USA
e-mail: [email protected]; [email protected]

https://doi.org/10.1007/978-3-319-77063-5_11
162 B. A. Abramoff et al.
exercises. With physical and occupational therapy, he worked on mobility, upper

and lower extremity dressing, transfers, self-care, toileting, bathing, as well as
range of motion, strength, and gait. Speech language pathologists addressed his
speech, swallowing, and cognitive deficits. Diet was ultimately progressed from
nothing by mouth to regular consistency. His functional independence measure
(FIM) score improved to a minimal assistance at time of discharge. He had no sei-
zure-like events while in rehabilitation, and his family is wondering if the levetirace-
tam may be stopped.
The above case illustrates the typical rehabilitation course that a patient with
hemorrhagic stroke goes through after their initial hospitalization. Despite receiving
appropriate acute treatment in the hospital, the patient continued to have functional
deficits preventing his return home. With a dedicated team of professionals, he was
able to have significant recovery. This chapter will introduce the key statistics, con-
cepts, issues, and techniques surrounding rehabilitation of the hemorrhagic stroke
survivor with a focus on the evidence behind them.
The chapter begins by examining the statistics, factors, and trends in hemorrhage
stroke rehabilitation followed by an overview of key principles underlying stroke
rehabilitation. In addition, the chapter will focus on the issues and considerations
more specifically associated with hemorrhagic stroke rehabilitation. It concludes
with a discussion on future trends.
Outcomes and Prognosis
Mortality
There is a high rate of mortality following intracerebral hemorrhage (ICH) particu-

larly within the first 2 days [1]. As seen in Table 11.1, the mortality rate following
ICH is greatest in the first month and subsequently decreases.
Alternative survival figures place the 1-year survival rate at 46% and 5-year
survival rate at 29% [3]. In a population-based cohort study consisting of 140
patients beginning 3 months following a spontaneous ICH, the 7-year mortality in
ICH patients was 32.9% versus 19.4% in age- and sex-matched controls who had
not suffered an ICH [4]. The mortality after recurrent ICH has been shown to be
worse than after the initial ICH with in-hospital mortality reported to be between
32% and 56% [4]. A more detailed discussion on prognosis is found in a prior
chapter.
Table 11.1 Mortality following ICH over time [1, 2]

Time since ICH onset 24 h 2 days 28 days 1 year
Mortality rate 16% 24% 50% 53%
11 ICH Rehabilitation and Recovery 163
Functional Outcomes in Ischemic Vs Hemorrhagic Strokes
There is conflicting evidence as to whether prognosis differs in ischemic compared

to hemorrhagic strokes when controlling for other stroke factors. Barber et al.
found that mortality rates were similar in ICH compared to ischemic strokes when
both groups were matched on age, level of consciousness (as measured by GCS),
and handicap (as measured by modified Rankin score (mRS)) [5]. In another study
of patients who survived the first 2 days following ICH, patients were matched
with those with ischemic strokes on age, level of consciousness (as measured by
GCS), and handicap (as measured by mRS). There were not any differences
between the two groups in terms of survival and handicap at 1 year which led the
authors to conclude that the extent of the brain lesion, not the type of stroke, deter-
mined the outcome after a 2-day survival [1]. Andersen et al. found ICH was asso-
ciated with an overall higher mortality risk compared to ischemic strokes as a
result of both the higher severity level and the classification as hemorrhagic. The
mortality risk gradually decreased, and after 3 months the stroke type did not cor-
relate with mortality [6].
Paolucci et al. assessed the influence of stroke type on rehabilitation outcomes by
matching hemorrhagic and ischemic patients for stroke severity, age, disability, sex,
and time between onset and inpatient rehabilitation admission. At the time of dis-
charge from inpatient rehabilitation, better functional recovery and mobility status
was seen in the ICH patients compared to the ischemic stroke patients. The authors
speculated the difference could potentially be due to better neurological recovery as
hematomas resolve and brain compression improves in the ICH group. They also
found a lower percentage of persistent urinary incontinence in the ICH stroke
patients (4.7%) compared to ischemic stroke patients (12.4%). However the length
of stay and percent of discharges to home were similar between the groups [7].
Other studies have shown ICH patients were more disabled on admission to reha-
bilitation compared to ischemic stroke patients, based on lower motor function
scores and lower total, cognitive, and motor functional independence measure
(FIM) scores [8, 9]. The ICH patients had a greater functional improvement after
rehabilitation according to their functional independence measure (FIM) and motor
function scores, even after adjustment for admission FIM, length of stay, age, and
time from stroke onset to rehabilitation admission [8, 9].
General Stroke Rehabilitation Principles
Clinical Rehabilitation Principles and Pathways
The recovery team and rehabilitation pathways following an ICH are varied. The
most recent guidelines for the management of a spontaneous ICH published
jointly by the American Heart Association and American Stroke Association
provide a Level IA recommendation that patients with ICH have access to inter-
disciplinary rehabilitation and a Level IB recommendation that patients begin
rehabilitation as early as possible and continue their rehabilitation into the com-
munity setting [10].
The Stroke Patient Care Continuum
A recent Cochrane review outlined the various patient pathways following a stroke
with different levels of interdisciplinary team involvement (Table 11.2) [11].
Including patients with hemorrhagic strokes, patients who received orga-
nized stroke unit care have higher survival, independence, and return to home
with continued benefits potentially sustained up to 10 years. Dedicated stroke
wards have demonstrated improved outcomes compared to mobile stroke teams
as well as a trend toward improved outcomes compared to mixed rehabilitation
wards [11].
In a meta-analysis comparing the different types of stroke wards (acute stroke
units, rehabilitation units, and comprehensive units), Chan et al. found that compre-
hensive units led to reduced lengths of stay, decreased death and dependency, and
improved functional outcomes compared to acute stroke and rehabilitation units
[12]. Langhorne et al. found in a review of eight clinical trials that stroke units pre-
vent death and disability in those with hemorrhagic stroke at least as much as those
with ischemic strokes [13].
Rehabilitation efforts are not limited to the inpatient setting. A review of 14 trials
found that stroke survivors discharged from an inpatient setting and continuing
home-based rehabilitation improved their ability to perform activities of daily living
[14]. Other potential patient settings include outpatient clinics, transitional/long-
term acute care hospitals, home-health-based care, day treatment programs, assisted
living facilities, and skilled nursing facilities.
Table 11.2 Inpatient rehabilitation settings

Type Admission Discharge Features
Acute, intensive Acute (hours) Days High nurse staffing; life-support facilities
Acute, Acute (hours) Days Close physiological monitoring
semi-intensive
Comprehensive Acute (hours) Days to weeks Acute care/rehabilitation; conventional staffing
Integrated TCM Acute (hours) Days Comprehensive stroke unit with integrated
TCM (e.g., acupuncture)
Rehabilitation Delayed (days) Weeks Rehabilitation
Mobile team Variable Days to weeks Medical/rehabilitation advice
Mixed Variable Weeks Mixed patient group; rehabilitation
rehabilitation
From John Wiley and Sons, Stroke Unit Trialists’ Collaboration [11], Table 1
TCM traditional Chinese medicine
Members of the Rehabilitation Team
Comprehensive, organized, interdisciplinary, team-based care is a key component

of rehabilitation, and evidence shows that it enhances recovery and independence
while decreasing mortality [11, 15, 16]. The members of the rehabilitation team are
varied and have different roles (Table 11.3).
The patient’s family also becomes a critical part of the patient care team follow-
ing an ICH as they are often responsible for the long-term care of the patient and can
assist in functional recovery.
Table 11.3 Members of the Stroke Rehabilitation Team.

World Wide
Discipline Web site Description
Certified www. Assist individuals with disabilities to maximize their
rehabilitation vocational and avocational living goals in the most
crccertification.
counselors com integrated setting possible through the application of the
counseling process, including vocational and counseling,
case management, referral, and service coordination;
identifying and addressing employment and attitudinal
barriers; and job analysis, development, and placement
services.
Neuropsychologists www.apa.org Specialize in brain-behavior relationships and have
extensive training in anatomy, physiology, and
neuropathology. They identify and treat cognitive and
neurobehavioral dysfunction and through assessment
also monitor recovery and thereby enhance community
reintegration.
Occupational www.aota.org Focus on the “skills of living” necessary for independent
therapists and satisfying living. OT services include customized
treatment programs to perform daily activities,
comprehensive home and job site evaluations and
adaptation recommendation, performance skills assessment
and interventions, adaptive equipment recommendations
and training, and family and caregiver education.
Rehabilitation www. Manage complex medical issues, provide ongoing patient
nurses (RNs) rehabnurse.org and caregiver education, and establish care plans to
maintain optimal wellness. RNs use a holistic approach
to fulfill patients’ medical, environmental, spiritual,
vocational, and educational needs via principles from
other disciplines and their own unique medical expertise
(bowel, bladder, and skin management). In all care
settings, RNs function as coordinators/case managers,
collaborators, and counselors. A registered nurse with at
least 2 years of practice in rehabilitation who passes the
Association of Rehabilitation Nurses examination can
earn the Certified Rehabilitation Nurse distinction.
(continued)
World Wide
Discipline Web site Description
Physical therapists www.apta.org Experts in examining and treating neuromuscular
problems that affect the abilities of individuals to move.
PTs practice in many settings and with all age groups.
Physicians www.aapmr. Usually coordinate the rehabilitation team and manage
org medical conditions pertaining to stroke and
comorbidities. A physician may be a physiatrist (i.e.,
specializing in physical medicine and rehabilitation and
thus restoration of function in individuals with problems
that range from simple physical mobility to more
complex cognitive issues).
Recreational www. Provide treatment services and recreation activities to
therapists atra-online.com individuals with disabilities to facilitate independent
physical, cognitive, emotional, and social functioning by
enhancing individuals’ current skills and assisting new
skill development for daily living and community
function. Besides discharge planning for community
reintegration, they help individuals develop or redevelop
social, discretionary time, decision-making, coping,
self-advocacy, and basic skills to enhance overall quality
of life.
Social workers’ www.naswdc. Assist individuals, groups, or communities restore or
org enhance their capacity for social functioning, while
creating societal conditions favorable to their goals.
Requires knowledge of human development and
behavior; social, economic, and cultural institutions; and
interactions among these factors. Social workers help
prevent crises; counsel individuals, families, and
communities to facilitate coping with everyday stresses;
and identify resources to allow individuals with
disabilities to remain in the community.
SLPs www.asha.org Assess speech, language, and other cognitive functions,
as well as swallowing, and provide interventions and
counseling/education to address language and speech
disorders (e.g., aphasia, apraxia of speech, dysarthria,
and cognitive-communication impairment).
SLPs also intervene when swallowing and cognitive
disorders exist. They provide services to all age groups
and in all care settings.
From Miller et al. [15], Table 3, http://stroke.ahajournals.org/content/41/10/2402.long, with per-
mission of Wolters Kluwer Health, Inc
RN indicates rehabilitation nurse
Mechanisms of Recovery
Primary injury occurs in hemorrhagic stroke due to disruption of the brain’s cellular
architecture and mass effect. Secondary injuries include the adverse effects of
thrombin, inflammation, complement activation, free radicals, and glutamate-
induced excitotoxicity [17, 18]. These mechanisms can potentially continue to
cause damage days to weeks after initial injury [19–21].
Less research in the field of the recovery has been done with respect to hemor-
rhagic injuries compared to ischemic injury [22]. Nonetheless, the limited research
to date suggests that reduction in edema and neuroplasticity are the main recovery
mechanisms from hemorrhagic injury: there is evidence in rodents that the time
course of the formation and resolution of edema closely matches the neurological
deficits [20]. Efforts to reduce the mass effect from clot and/or edema may thus help
to improve recovery by reducing perihematomal ischemia and improving cerebral
blood flow [23]. Neuroplasticity is the ability of the brain and its synaptic connec-
tions to change in response to internal or external stimuli. It is a widely accepted
mechanism for recovery after stroke.
At the cellular level, following ICH, there is increased proliferation of neural
stem cells in the perihematomal region within 1–3 days [24]. There is also evidence
of possible increase in dendritic branching indicating the formation of new synapses
[20, 21]. From rodent models, there is evidence that rehabilitation may enhance
dendritic growth and reduce tissue loss following ICH [20].
Factors Impacting Functional Recovery
Numerous factors play a role in stroke recovery and subsequent improvement in

function (Fig. 11.1).
From: [25]
Age: Older patients who have had ICH have been found to have worse disability at
90 days compared to younger patients. A patient over 75 was four times more
likely to be dependent at 90 days compared to those less than 52 years old. Pain,
Genetic
factors
Rehabilitation therapeutics
Initial Stroke
injury recovery
Fig. 11.1 The factors
involved in stroke recovery. Post-stroke depression
Age
(From Feng and Belagaje race
[25], Fig. 1, © Georg gender
Thieme Verlag KG) comorbidities
mobility, self-care, participation in activities, and depression were all noted to

increase with patient age [26].
Race: Racial disparities have been noted in some studies investigating rehabilita-
tion therapies from stroke although the evidence is mixed. There is also evi-
dence that black patients have worse functional outcomes compared to white
patients [27].
Socioeconomic Status: Poor socioeconomic status has also been tied to impaired
recovery outcomes [25, 27].
Gender: Women tend to have worse functional outcomes following strokes com-
pared to men in multiple domains including physical impairments, limitations
in ADLs, quality of life, and depression. They are also more likely to be insti-
tutionalized [28, 29]. In ICH, there is evidence that female sex may be an
independent predictor of worse outcome, particularly in the early poststroke
period [30, 31].
Stroke Location: Lobar intracerebral hemorrhages are more likely to lead to poor
functional outcome compared to non-lobar ICH. There are no clear differences
in functional outcome based on laterality. These studies have been limited by
focus on motor outcomes and not precisely defining the neuroanatomical loca-
tions of the ICH. There is some evidence for poorer outcomes with thalamic
bleeds [32]. Ventricular extension of blood is another poor sign of functional
outcome [33].
Stroke Volume: Hemorrhage volume is one of the most important predictors of
short- and long-term functional outcome in patients with ICH. A volume of hem-
orrhage greater than 30 ml is generally associated with worse functional out-
comes, while a volume less than 20 ml is associated with better functional
outcomes. A volume between 20 and 30 ml has less clear implication of func-
tional recovery [33].
Outcome Scoring Systems: Numerous grading systems have been developed to eval-
uate the functional outcomes of patients with intracerebral hemorrhage. The
ICH-GS (composed of age, initial GCS, ICH location, ICH volume (dichoto-
mized by location of bleed)), and intraventricular extension have been used to
predict functional outcome at 30 days [34]. The mEDICH has also been used to
evaluate functional outcome at hospital discharge and is made up of initial GCS,
ICH volume, INR, IVH, and location [35]. The FUNC score is comprised of ICH
volume, age, ICH location, GCS, and pre-ICH cognitive impairment and is able
to accurately predict functional independence at 90 days. Figure 11.2 demon-
strates the percent of patients who became functionally independent at different
time points following ICH according to their initial FUNC score. None (0%) of
the patients with a FUNC score less than 4 had functional independence at
90 days. Eighty-two percent of patients with a FUNC score of 11 achieved
functional independence [36]. A comparison of the different methods at hospital
discharge found the mEDICH as the most reliable at predicting good functional
outcome at hospital discharge [37].
ICH volume (∞) FUNC score prediction tool

< 30 4
30-60 2
> 60 0
Age (yrs) 100
< 70 2
70-79 1
≥ 80 0 80
ICH location
Lobar 2
Deep 1 60
Infratentorial 0
GCS
≥9 2 40
≤8 0
Pre-ICH cognitive
impairment 20
No 1
Yes 0
0
FUNC score [0-4] [5-7] [8] [9-10] [11]
Entire cohort 0 13 42 66 82
Survivors only 0 29 48 75 95
% functionally independent at 90 days
Fig. 11.2 Predictive ability of FUNC score. (From Rost et al. [36], Fig. 1, http://stroke.ahajour-
nals.org/content/39/8/2304, with permission of Wolters Kluwer Health, Inc.)
iming, Intensity, and Safety of Intracerebral Hemorrhage

T
Rehabilitation
For all strokes, certain aspects of rehabilitation remain unknown. These questions
include timing, intensity, and dosing of rehabilitation. These questions are even
more apparent in the hemorrhagic stroke population as very few studies have inves-
tigated these questions specifically in this population.
As specific guidelines for early mobilization do not exist, one common concern
is starting therapy very early may raise blood pressures which may lead to worsen-
ing hemorrhage and outcomes. To further complicate matters, there are not clear
blood pressure parameters that are deemed safe to initiate therapy. In surveys of
stroke care professionals, patients with hemorrhagic strokes were felt to start later
mobilization than those with ischemic strokes [38, 39]. However, prolonged bedrest
increases the risk of complications related to immobility including pressure sores,
aspiration pneumonia, and deep vein thrombosis.
In the only dedicated large study specific to ICH to date, 243 subjects with ICH
at multiple centers in China were randomized to very early rehabilitation compared
to standard care. Survival and functional outcomes were measured. The intensity
between the very early rehabilitation (starting rehabilitation within 48 h) and the
standard of care group (rehabilitation starting on day 7) were comparable. At
6 months, patients receiving the standard of care were more likely to have died
(adjusted hazard ratio, 4.44; 95% confidence interval [CI], 1.24–15.87) [40]. The
generalizability of this study is uncertain given the standard of care group started
therapy on day 7 which is usually later than therapy is started in the Western hemi-
sphere, including US centers. Nevertheless, it suggests that patients may benefit
from early rehabilitation. This is supported by other studies showing patients with
hemorrhagic strokes undergoing early rehabilitation (starting within 24 h of their
stroke) have been found to have better recovery of ADLs and motor functioning
compared to patients undergoing more standard rehabilitation without an increase
in mortality [41].
In contrast to these findings, the A Very Early Rehabilitation Trial (AVERT),
2104 hospitalized stroke subjects (258 of whom had intracerebral hemorrhages)
were randomized to receive customary therapy or a very early intervention. In the
intervention arm, first mobilization aimed to begin within 24 h following stroke
onset with the additional goals of being upright and out of bed at least twice daily.
This intervention was for the first 14 days poststroke or until discharge from the
acute stroke unit and delivered by a physiotherapy team including a trained nurse.
Those who were mobilized had worse outcomes defined as a modified Rankin
Score <3 compared to standard care (46% vs 50%; adjusted odds ratio [OR] = 0·73,
p = 0·004) [42]. In a prespecified dose response analysis of the trial, patients who
were mobilized earlier and had more frequent sessions were more likely to have
favorable outcomes compared to those who had increased length of out of bed activ-
ity, thereby suggesting more frequent, shorter out of bed activity is possibly the
preferred dosing of rehabilitation [43].
In the ICARE trial, 361 subjects were given rehabilitation in one of three arms:
Accelerated Skill Acquisition Program (ASAP), dose-equivalent occupational
therapy (DEUCC), or monitoring-only occupational therapy (UCC). Motor out-
comes were not significantly different between the three groups. Twelve percent
(n = 43) of the subjects had intracerebral hemorrhage with equal numbers among
the three interventions. There are no further subsequent analysis on this subgroup
to date [44].
In the Locomotor Experience Applied Post-Stroke (LEAPS) trial, Duncan et al.
tested the role of body-weight-supported treadmill against standard home physical
therapy program and also attempted to provide further answers into the timing of
rehabilitation. In this single-blinded trial, 408 subjects, 70 (17.2%) of which had
hemorrhagic strokes, were randomly assigned to 1 of 3 arms lasting 12 to 16 weeks:
a home-based exercise starting 2 months after the stroke or the body-weight-
supported treadmill locomotor program, starting either at 2 or 6 months after the
stroke.
The primary outcome of the study was the proportion of participants with
improved walking function 1 year after the stroke. Most participants (52%)
improved their walking function, but there were no significant differences between
the three arms (change of 0.23 m/s in early locomotor group vs. 0.24 m/s in late
locomotor group vs. 0.25 m/s for home exercise group). Serious adverse events
were similar in all three arms, as were minor events, except that there was signifi-
cantly more d izziness or faintness (p = 0.008) in the locomotor groups [45]. These
results suggest that there is not a difference in poststroke walking improvement
between body-weight-supported treadmill devices and a home-based physical

therapy program.
Special Rehabilitation Considerations for ICH
For those patients who survive the acute phase of ICH, there are a variety of post-
stroke complications that pose a significant impact on recovery and rehabilitation.
This section will describe a variety of special considerations specific to ICH reha-
bilitation and how they impact long-term outcomes. As a summary, Table 11.4 con-
sists of common post-ICH sequelae along with possible pharmacologic and
non-pharmacologic treatments. These treatments have varying levels of evidence in
stroke, and particularly post-ICH patients, and primary sources should be reviewed
prior to prescribing.
Table 11.4 Common post-ICH sequelae and proposed treatment options

Common post-ICH sequelae Proposed and accepted treatment options
Hemiparesis Pharmacologic:
Selective serotonin reuptake inhibitors Amphetamines
Non-pharmacologic:
Physical and occupational therapy (constraint therapy, mirror
therapy)
Functional electrical stimulation
Specialized equipment
Spasticity Pharmacologic:
Botulinum toxin
Phenol/alcohol neurolysis
Intrathecal therapy (Baclofen)
Baclofen
Tizanidine
Dantrolene
Benzodiazpines
Non-Pharmacologic:
Daily stretching
Physical therapy
Splinting [77]
Seizures Prophylactic seizure medications are not recommended if no prior
history of seizures [72]
Dysphagia/aspiration Pharmacologic:
Cilostazol
Angiotensin-converting enzyme inhibitors
Amantadine
Non-pharmacologic: Exercises/swallowing rehabilitation
Postural and behavioral compensatory strategies
Texture/consistency of food
Nutrition consult
Nasogastric/orogastric feeding tubes, gastrostomy, jejunostomy [78]
(continued)
Neurogenic bladder Pharmacologic:
Anticholinergics (oxybutynin) and botulinum toxin for detrusor
overactivity
Cholinergics (Bethanechol) for urinary retention
Adrenergic antagonists (Tamsulosin) for sphincter dyssynergy/
urinary outlet obstruction
Non-pharmacologic:
Behavioral techniques: timed voiding, manual maneuvers, fluid
restriction, physical therapy
External, indwelling, and intermittent catheterizations
Surgical procedures
Consider urodynamic testing for further evaluation of bladder
function [79]
Neurogenic bowel Pharmacologic:
Fiber
Laxatives
Rectal stimulants
Non-pharmacologic:
Abdominal massage
Manual evacuation
Toilet transfer training
Bathroom equipment (bedside commode)
Timed toileting [80]
Falls Pharmacologic:
Avoid polypharmacy, sedating alcohol, and medications
Non-pharmacologic:
Exercise, balance, cognitive and safety training, supervision
Assistive devices (visual aids)
Environmental hazard removal
Prevention and treatment of osteopenia/osteoporosis to prevent
fractures [81]
Psychiatric issues: Pharmacologic:
depression, anxiety, Selective serotonin reuptake inhibitors
emotionalism, relationship Tricyclic antidepressants
difficulties Monoamine oxidase inhibitors
Buspirone
Non-pharmacologic:
Electroconvulsive therapy
Peer support
Recreational therapy
Psychotherapy (counseling, cognitive behavioral therapy,
motivational interviewing)
Family counseling [82, 83]
Sexual dysfunction Pharmacologic:
Phosphodiesterase-5 inhibitors
Intracavernosal
Intraurethral suppositories
Hormonal therapy
Avoid medications that can worsen sexual function:
antidepressants, SSRIs, anticholinergics, opioids
Non-pharmacologic:
Physical therapy
Mechanical devices, Counseling/psychotherapy [84]
Hemiplegic shoulder pain Pharmacologic:
Corticosteroid injections
Platelet-rich plasmin
Stem cells
Suprascapular nerve blocks
Botulinum toxin
Non-pharmacologic:
Physical therapy
Massaging
Support devices (slings, arm board)
Electrical stimulation [85]
Other causes of pain Pharmacologic:
following stroke: complex Topical Agents
regional pain syndrome, NSAIDs
spasticity-related pain, Opioids
poststroke pain, neuropathic Antiepileptic
pain Antidepressant
Lidocaine
Ketamine
Systemic corticosteroids
Intrathecal therapy: opioids, ziconotide, baclofen
Non-pharmacologic:
Neurostimulatory techniques
Transcutaneous electrical stimulation
Acupuncture
Desensitization
Contrast baths
Ultrasound
Sympathectomy
Pain psychology [86]
Fatigue Pharmacologic:
Antidepressants
Neurostimulants (methylphenidate, modafinil)
Non-pharmacologic:
Treatment of sleep apnea
Psychosocial therapy (education, CBT)
Physical therapy
Aerobic exercise [87]
(continued)
Visual and visuospatial Pharmacologic:
issues Dopamine agonists
Neurostimulants
Non-pharmacologic:
Visual therapy
Eye patching
Mirror therapy
Prisms [88]
Aphasia Pharmacologic:
Amantadine
Amphetamines
Acetylcholinesterase inhibitors (donepezil, galantamine)
Memantine
Piracetam
Bromocriptine
Non-pharmacologic:
Speech and language therapy
Transcranial magnetic/electrical stimulation [89]
Cognitive and attention Pharmacologic:
impairment, vascular Acetylcholinesterase inhibitors
dementia NMDA receptor antagonists
Calcium channel blockers
Non-pharmacologic:
Cognitive therapy
Treatment of depression
Control risk factors for vascular dementia
Seizures and ICH
It is well recognized that seizures commonly occur after stroke, with varying inci-
dences reported from 2% to 33% depending on the type of study, time windows
described, and stroke type analyzed [46–52]. This incidence may actually be under-
reported given subclinical electrographic seizures are not included in most studies.
Predictive factors that have been found to be independently associated with poststroke
seizures include hemorrhagic stroke, lobar or cortical location of stroke, and 10-point
increase in stroke severity on the Scandinavian Stroke Scale [46, 48]. For hemorrhagic
strokes, the local mass effect from edema, development of hydrocephalus, and pres-
ence of blood products can be a nidus for epileptogenic activity. Later onset seizures
are suspected to be due to gliosis and scarring that may become an epileptogenic focus
during the healing process after both ischemic and hemorrhagic stroke.
One controversial issue is the impact of seizures on early and long-term progno-
sis in ICH patients. De Herdt et al. explored the risk of early seizures in ICH and did
not show any influence of their occurrence on hospital mortality or functional out-
come at 6 months [49]. This finding contrasts results of a study by Szaflarski et al.
who showed that early post-ICH seizures occurring within the first 24 h were asso-
ciated with a higher incidence of 30-day mortality [47]. A more recent study by
Madzar et al. showed a trend favoring an association of post-ICH seizures with
poorer outcomes, but this data did not reach statistical significance [52]. With
respect to late-onset seizures, Rossi et al. found an association with worse func-
tional outcome after 3 years of follow-up [50]. There remains limited definitive
evidence of a direct correlation of post-ICH seizures with poor outcomes as the
association may be related to the inherent increased mortality seen in ICH patients
that may not be greatly altered by the development of seizures in either the acute or
late phase of ICH recovery.
Hydrocephalus and ICH
Another complication associated with ICH is intraventricular hemorrhage (IVH)

extension, which reportedly occurs in 30–50% of patients and has been shown to be
an independent predictor of poor outcomes and carries an overall mortality rate of
up to 75% [53]. Subsequently, the development of acute hydrocephalus is reported
in up to 50–67% of patients with ICH and most often seen with thalamic hemor-
rhages due to the close proximity to the third ventricle [53–55]. Hydrocephalus
management often involves placement of an external ventricular drainage (EVD) in
up to 30–50% of patients which can lead to further complications due to prolonged
hospital stays, increased infection risk, and immobility. The increased intracranial
pressure (ICP) due to hydrocephalus leads to rapid clinical deterioration including
death from brain herniation. Patients may require placement of a VP shunt for per-
manent diversion of CSF to reduce hydrocephalus recurrence if the EVD is unable
to be removed.
Studies have suggested that the presence of hydrocephalus with ICH an indepen-
dent predictor of poor outcomes [53, 54]. Diringer et al. showed that each 1 point
increase in hydrocephalus severity, as measured using a 24-point score grading the
degree of hydrocephalus within the various regions of the ventricular system, was
associated with a 1.64-fold increase in mortality risk [56].. In the study, fewer
patients with hydrocephalus were discharged to rehab or home, and over 60% of
patients required admission to a nursing home or did not survive hospitalization
[56]. Of those patients who survived, there was no difference in FIM scores at
3 months between patients with and without hydrocephalus. The study concluded
that hydrocephalus is an independent predictor of mortality after ICH.
Spasticity in ICH
It is well recognized that surviving stroke patients suffer from residual upper motor
neuron symptoms including muscle spasticity with prevalence ranging from 19% to
42% [57]. Spasticity can limit mobility and cause discomfort, all of which can impact
poststroke recovery, efficacy of rehabilitation, and performance of activities of daily
living. Hemorrhagic stroke is a predictor of poststroke spasticity [58]. One can
hypothesize that given the degree of disability in ICH patients which is often higher
than ischemic stroke patients, as well as tendency to sustain longer hospital stays and
subsequent delays to early and aggressive poststroke therapy, these patients may
have a higher prevalence of poststroke spasticity. Rehabilitation techniques for post-
stroke spasticity are currently generalized to help with functional outcomes for all
stroke types. A variety of techniques used for poststroke spasticity include muscle
strengthening exercises, treadmill training, use of orthotics, oral antispasmodics,
nerve blockade, botulinum toxin injections, and intrathecal baclofen therapy.
Neuropsychiatric Complications of ICH
The proposed etiologies of poststroke mood disorders specifically in ICH may be

attributed to the mass effect on various brain structures involved in emotion and
behavior such as the amygdala and prefrontal cortex by the primary injury [59]. The
subsequent inflammatory response on affected areas can therefore result in second-
ary injury [59]. An even simpler explanation would be a psychological reaction to
one suffering a devastating neurological injury resulting in physical impairment
affecting one’s prior functional independence [59, 60]. Regardless, the profound
complexity of ICH makes defining the exact mechanisms involved in poststroke
mental illness difficult.
Poststroke depression (PSD) is a well-recognized complication of stroke, regard-
less of type, location, or severity. It has a prevalence ranging anywhere from 11% to
78% depending on study design [60, 61]. There are many confounders that affect
PSD prevalence such as the incidence of pre-stroke depression, which is seen in up
to 16% of the general elderly population. Pre-stroke depression likely influences the
subsequent development of depression after stroke [60]. A recent systematic review
showed that depression had a negative effect on functional outcomes after stroke,
with associations of PSD with decreased quality of life, poor life satisfaction, less
efficient use of rehab services, increased need for institutional services, and higher
mortality. Individuals suffering from PSD are likely less motivated or physically
able, especially in severely impaired patients, to participate and engage in rehabili-
tation, in both the acute and long-term stroke recovery period. Given the negative
impact of depression on the ability to effectively rehabilitate from a stroke, it is
important to identify those patients at risk for PSD and therefore initiate early inter-
ventions to aid in successful stroke recovery.
Dementia and ICH
Cognitive impairment following stroke is a contribution to the worldwide burden of

new-onset dementia, which occurs in approximately 10% of patients after their first
stroke and increases to 30% after recurrent stroke [62]. Although various studies
exploring the prevalence of and risk factors for poststroke dementia, only a minority
of them include ICH patients. A small cross-sectional study first reported a preva-
lence of post-ICH dementia of 23% after 3 years [63]. A larger prospective cohort
study of ICH patients without preexisting dementia showed an incidence of demen-
tia of 14% at 1-year follow-up and an incidence of 28% at 4-year follow-up. Risk
factors associated with new-onset dementia included superficial siderosis, higher
number of cerebral microbleeds, and increased cortical atrophy [64, 65]. In addi-
tion, the incidence of post-ICH dementia was two times higher in those with lobar
hemorrhages, which may correlate with the known association of cortically located
ICH with cerebral amyloid angiopathy (CAA) [65]. CAA has been reported in over
40% of patients with ICH and subsequent cognitive decline, although CAA has
been independently associated with cognitive impairment, even in the absence of
extensive Alzheimer’s disease pathology [65, 66].
Thus, poststroke dementia poses a challenge to successful rehabilitation not only
in the acute but in the long-term poststroke period. Cognitive impairment has been
shown to be a powerful predictor for functional outcomes after stroke, with evi-
dence suggesting that these individuals have reduced recovery potential due to
reduced optimism, memory impairment, and deficiencies in performance of activi-
ties of daily living [66]. Further research on how dementia impacts stroke survivors
is needed as well as more treatments to guide rehabilitation techniques in this patient
population.
Medications in ICH Rehabilitation
Patients often suffer from depressed level of consciousness or impaired attention

following ICH, both of which can limit effective poststroke rehabilitation. Thus,
neurostimulants are often used to enhance arousal in order for patients to participate
in more aggressive rehabilitation in both the short- and long-term recovery period
and possibly even prevent extended care facility placement [67]. Despite the wide-
spread use and potential of these medications, evidence of clear efficacy is lacking.
In small studies, methylphenidate and dextroamphetamine, two commonly studied
neurostimulants, improved function and speech [67]. Unfortunately, these agents
carry the risk of hypertension; as blood pressure often needs to be strictly controlled
in ICH patients, they may not be the ideal choices used in this patient population.
Alternative neurostimulants include modafinil and amantadine, which are also used
to aid in increased alertness in poststroke patients. More studies directly studying
neurostimulant use in stroke patients are needed to make conclusive recommenda-
tions on which agents may in fact be beneficial and positively impact poststroke
rehabilitation.
As mentioned earlier, depression is a well-recognized complication of stroke; con-
sequently, antidepressants are commonly prescribed to patients after stroke to help
during the rehabilitation process. There have been some studies specifically looking at
selective serotonin reuptake inhibitors (SSRIs) and the risk of hemorrhagic stroke, and
they demonstrate that SSRIs inhibit platelet aggregation [68, 69]. Other studies have
not shown such a correlation, even with concomitant antiplatelet or anticoagulant use
[69]. The controversy in SSRI risk needs to be weighed against evidence from multi-
ple studies demonstrating benefit from SSRI. Both ischemic and hemorrhagic stroke
patients have been found to have less dependency, improved motor recovery, and
reduced depression with SSRIs [70]. Basic science research has demonstrated that
SSRIs play a role in inhibiting pro-inflammatory cytokine production, thus positively
impacting stroke recovery given its potential to augment neurogenesis and synaptic
plasticity [71].
Given the increased incidence of seizures following ICH as compared to isch-
emic stroke, many patients are placed on antiepileptic drugs (AEDs) for seizure
prophylaxis in the acute period. There is evidence showing that brief prophylaxis
may reduce the risk of early seizures with lobar hemorrhage [72]. However, AEDs
commonly have several side effects that may impact effective rehabilitation partici-
pation such as dizziness, drowsiness, and cognitive impairment [73]. In the Cerebral
Hemorrhage and NXY-059 Trial (CHANT), early use of AEDs was strongly inde-
pendently associated with severe disability and death in ICH; hypothesized mecha-
nisms included both the sedative and cardiovascular effects of AEDs [74]. In
particular, prophylactic use of phenytoin has been associated with fever and worse
functional outcomes after ICH while not reducing the risk of seizures [75].
There are a variety of pharmacologic treatments available to manage poststroke
spasticity including muscle relaxers and benzodiazepines, all of which have cen-
trally acting side effects. Some of the common side effects of these agents share are
dizziness, sedation, and cognitive slowing, which can negatively impact the efficacy
of poststroke rehabilitation [76]. In addition, consistent use of these agents can be
associated with withdrawal seizures if dependency is achieved, particularly with
frequent baclofen and benzodiazepine use. Therefore, a need exists to find a balance
between the benefits of lowering muscle tone with these medications while at the
same time minimizing side effects. Alternatives, such as botulinum toxin, should
also be considered in order to most benefit patients in the rehabilitation period.
Summary
Rehabilitation is an important component of care of hemorrhagic stroke patients.

Despite the advances in prevention and acute treatment, stroke survivors will con-
tinue to need rehabilitation. Recovery begins as soon as the patient enters the health-
care system. Despite having worse deficits than ischemic stroke patients,
hemorrhagic patients make larger gains in formal rehabilitation. Future recovery
and rehabilitation studies need to focus specifically on the hemorrhagic stroke pop-
ulation to better understand their care. By understanding the general trends of hem-
orrhagic stroke recovery, incorporating and applying general rehabilitation
principles, and recognizing and managing the special rehabilitation issues associ-
ated with hemorrhagic strokes, one can optimize outcomes.
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Chapter 12
Clinical Trial Design in Subjects
with Intracerebral Hemorrhage
Adeola Olowu and Nicole R. Gonzales
Introduction
Intracerebral hemorrhage imparts a high degree of disability and death. The greatest
impact in decreasing the devastating nature of ICH is to prevent the disease alto-
gether. Thus, screening, prevention, genetic, epidemiologic, and treatment trials are
all equally important in decreasing the burden of this disease; however, the lack of
effective treatment in the acute setting lends itself to a focus on clinical trials target-
ing acute treatment of ICH. Many aspects of clinical trial design in patients with
ICH will draw from our successful experiences with ischemic stroke; however, the
ICH patient population also offers unique considerations which will be discussed in
this chapter. Lastly, the results of several large randomized controlled trials in
patients with ICH have been reported over the last decade which provide important
lessons that can be carried forward as we continue our efforts to develop treatment
for this debilitating disease.
The last decade of clinical research in ICH has given us therapies which have
achieved their physiologic goal, i.e., decreased hematoma expansion; however, this
did not translate to improved clinical outcome based on the primary outcome mea-
sures [1–4]. While we have made considerable progress, definitive treatment which
improves outcomes remains elusive. Heterogeneity of the patient population,
patient recruitment and retention, finding the appropriate outcome measure, and
timing at which to acquire this information all contribute to the challenges in find-
ing efficacious treatment for ICH. In addition, there is a continued lack of under-
standing of the complex pathophysiology of disease which likely hampers our
ability to detect treatment effect in our current clinical trial paradigm. In order to
develop treatment, we need to more intimately understand the disease and recovery
A. Olowu · N. R. Gonzales (*)

Department of Neurology, McGovern Medical School, Houston, TX, USA

https://doi.org/10.1007/978-3-319-77063-5_12
186 A. Olowu and N. R. Gonzales
process. In order to prove treatment efficacy, we need to adjust our clinical trial
design to minimize known challenges and utilize our current technological and
computational tools to develop new and efficient methods of evaluating investiga-
tional treatment.
General Concepts
Phase 1 trials are designed to establish a safe dose in humans and evaluate toxicity
of a drug. Often, a specific aim is to estimate the maximum tolerated dose [5, 6].
Phase 2 studies examine feasibility, best dose, toxicity, and surrogate outcome
markers of drug efficacy. In addition, phase 2 trials can be used to assess futility
and can provide important information regarding the practical aspects of carrying
out a larger clinical trial such as treatment administration and trial costs [5, 6]. In a
phase 3 randomized controlled efficacy trial, participants are randomly assigned to
an intervention or control group. The goal of the randomized controlled trial (RCT)
evaluating therapy is to determine whether the treatment under evaluation is associ-
ated with an outcome. RCTs establish whether treatment is clinically efficacious
[5, 7, 8].
With this framework in mind, there are several challenges in clinical trial design
that are present in many conditions where patients present acutely with life-threat-
ening illness. In these situations, rapid diagnostic evaluation and management deci-
sions are made quickly with seemingly very little time for the additional processes
that are necessary for clinical trial enrollment.
Ethical Considerations
Informed Consent
The challenges with informed consent in acute ICH treatment trials are similar to
those in acute ischemic stroke (AIS) and other diseases in which patients present
emergently with life-threatening conditions. Namely, can patients with this type
of acute neurologic injury truly provide informed consent? When there is a time-
sensitive aspect to treatment, can patients or their surrogate decision-makers
really process the information needed to provide true informed consent [8]? What
is the role of the clinician versus the clinical researcher and how does each influ-
ence informed consent [9]? On the other side of the coin, we also know that in
acute stroke, the sooner treatment begins, the higher the chances for improved
outcomes, in general. We know from our own work that when a surrogate is
needed to provide informed consent it takes almost 20 min longer to obtain
informed consent compared to cases where the patient can provide consent [10].
While there is no perfect scenario for the informed consent process in the
12 Clinical Trial Design in Subjects with Intracerebral Hemorrhage 187
emergent setting, clinical trial design can be sensitive to these issues with appro-
priate planning and training.
Patients with acute ICH may present with alteration in consciousness, aphasia,
neglect, or other disabling deficit. In the acute setting of stroke, time is brain.
Emergency responders aim to gather information necessary to initiate treatment as
rapidly as possible. In most facilities, if the patient is not able to provide consent for
participation in clinical research, a legally authorized representative (LAR) must be
physically present to provide consent. Telephone consent is not typically allowed in
most institutions. If there is no LAR at the bedside, then the patient will not be eli-
gible for investigational studies; if the LAR subsequently arrives in the window for
enrollment, then study-related procedures have been delayed [11]. Both scenarios
can bias study results. In the best scenario, the LAR is at the bedside and, many
times, discussion about clinical research begins in the hectic emergency department
when the patient and family have just been delivered devastating news. Informed
consent forms (ICFs) are lengthy and contain research, clinical, and legal informa-
tion which can be overwhelming. The investigator must balance delivery of infor-
mation and adjust discussion with each scenario and family dynamic. In this
vulnerable state, patients may place all trust in their caregivers [9] or medical team
for decision-making. There may be confusion in understanding what is standard of
care and what is investigational when the clinician and researcher are the same per-
son or part of the same team [9]. These are daunting responsibilities for patients,
families, and investigators, and they must all be addressed in order for clinical
research to be successful.
There is no single solution to the challenges of obtaining informed consent dur-
ing emergent situations. Rather, it is important for investigators to be aware of these
issues when designing clinical research trials so that the informed consent process
happens correctly. Some potential approaches to these issues include ongoing dis-
cussion about consent even after enrollment and allowing the patient to provide
consent once she has recovered well enough to do so [8]. To address the lengthy
ICF, researchers can develop a short-form ICF [12] or a one-page summary of the
trial [8] to accompany the complete ICF, with important points if the trial can be
summarized succinctly and relevant institutional review board (IRB) is amenable to
this process. Delay in obtaining consent for transferred or disabled patients requir-
ing LAR consent or complete ineligibility of patients for clinical research without a
LAR present can potentially be addressed with telemedicine and exemption from
informed consent (EFIC).
Telemedicine provides the infrastructure to allow patients presenting to a hospi-
tal in a spoke/hub model to be offered participation in clinical research trials.
Moreover, investigators can consent patients and their families for clinical trial
enrollment remotely and begin study-related procedures either at the transferring
facility [13, 14] or immediately upon arrival to the primary study site [15]. In addi-
tion, the FDA has provided guidance for exception from informed consent (EFIC)
in emergency research when patients have a life-threatening medical condition
necessitating urgent intervention and cannot provide consent due to their condition
[16]. The circumstances under which EFIC is allowed are limited in scope but could
be applicable to acute treatment trials evaluating therapy in patients with ICH in

which the treatment is time-limited. EFIC also requires that available treatments are
unsatisfactory; there must be the potential for direct benefit to the patient, and in
order to provide benefit, treatment must be initiated before ICF can be obtained
from the patient or the patient’s LAR. The regulations also require community con-
sultation and public disclosure in the communities where the research will take
place. A summary of the regulations in the context of stroke-related research has
been reported [17]. In addition, the American Heart Association Emergency
Cardiovascular Care Committee and Council on Cardiopulmonary, Perioperative,
and Critical Care have provided a template to assist with ensuring appropriate
implementation of community consultation and public disclosure [18]. Lastly,
researchers have reported on the views of patients and families enrolled in a RCT of
an investigational agent for traumatic brain injury [19]. The majority of patients had
positive attitudes toward the study inclusion and found their inclusion under EFIC
acceptable [20].
The issue of obtaining true informed consent will always be a challenge in
clinical trials for acute ICH therapy. Balancing the distribution of information
for patients and families with rapid initiation of investigational treatment is an
important responsibility of investigators. Continual reassessment and refine-
ment of our informed consent processes will remain a focus of clinical trial
design.
Clinical Trial Design Considerations
Patient Population
When developing inclusion and exclusion criteria for a clinical trial, the dilemma is
whether to be inclusive or exclusive. If enrollment criteria are broad, then results
will be generalizable and applicable to a larger number of patients. On the other
hand, nonresponders may dampen treatment effect [9]. In contrast, if enrollment
criteria are selective, this helps to minimize the heterogeneity of the patient popula-
tion, may identify patients most likely to respond to treatment, and makes it more
likely that a treatment effect will be seen if one truly exists. The trade-offs for selec-
tive inclusion/exclusion criteria are that the trial results may not be generalizable [5,
21], it may be difficult to enroll patients, and it may take longer to complete the trial.
Development of new clinical, radiographic, and laboratory biomarkers can be incor-
porated into the patient selection algorithm to address the heterogeneity of this
patient population [21, 22] (Fig. 12.1).
Clinical investigators are in search of treatment that will be applicable to all
patients with a particular condition; however, the reality is that treatment may affect
patients differently. Some patients may experience a large treatment benefit and oth-
ers, a more modest effect, if any at all. Identification of the patient population which
might respond to treatment may not be obvious in the initial phases of treatment
Age 46 59 57
ICH Volume 13.9 5.6 9.0
IVH? Yes Yes No
GCS 14 14 14
NIHSS 16 10 7
Baseline mRS 0 0 0
180 Day mRS 3 2 1
Fig. 12.1 Clinical and Radiographic Heterogeneity in Patients with Intracerebral Hemorrhage.
MRI images at presentation demonstrating the heterogeneity of patients with intracerebral hemor-
rhage even when the injury is in the same anatomic location. All three patients have a left thalamic
hematoma; however, clinical and radiographic differences are apparent. ICH, intracerebral hemor-
rhage; IVH, intraventricular hemorrhage; GCS, Glasgow Coma Scale; NIHSS, National Institutes
of Health Stroke Scale; mRS, modified Rankin Scale
development. We have seen this pattern in AIS where the treatment effect of IV tpa
diminishes with time [23]. Thus, a larger treatment effect is present in patients who
are treated with thrombolysis sooner after symptom onset. Similarly, if we consider
recent endovascular trials in AIS as examples, after decades of not being able to
demonstrate superiority of endovascular therapy over standard care, updated treat-
ment devices, creation of a more homogeneous group of patients by limiting enroll-
ment criteria by time, imaging, or lesion location, investigators were better able to
accurately identify a group of responders to endovascular therapy [11, 24–27]. In
the Factor Seven for Acute Hemorrhagic Stroke (FAST) trial, recombinant activated
Factor VII (rFVIIa) demonstrated a dose-related decrease in hematoma expansion
which did not translate to a clinical benefit [1]. Patient selection in this case may
have played a role [3]. Since only about one third of patients are expected to have
acute hematoma expansion [28], the treatment effects of rFVIIa may have been
dampened by the enrollment of patients who were not likely to have hematoma
enlargement and thus would not be expected to benefit from treatment. Identifying
the subgroup of patients most likely to have hematoma expansion, e.g., with the spot
sign, could identify the group of patients most likely to benefit from therapy trials
targeting hematoma expansion [29]. While responder-based selection for enroll-

ment criteria may limit generalizability [21], it may be a necessary step in demon-
strating that acute treatment in ICH can affect outcomes.
Until recently, in-person or faxed consent was the only way to enroll a patient
into a clinical trial. Depending on the time frame for enrollment, this limits the
potential pool of study eligible patients to those presenting directly to the enrolling
center. Patients who are transferred from an outside hospital may not be eligible for
enrollment depending on the treatment window. Even if there is a prolonged time
for enrollment, e.g., 24 h, transferred patients can potentially bias the study results
if they are all enrolled and treated toward the end of the treatment window. As men-
tioned previously, telemedicine provides a mechanism by which study-related pro-
cedures can begin sooner when patients present to a facility with a spoke/hub model
of telemedicine coverage. Clinical researchers have the opportunity to consent
patients and/or their families for clinical trial enrollment remotely and begin study-
related procedures, either at the transferring facility [13, 14] or immediately upon
arrival to the primary study site [15]. The overall benefits of telemedicine are the
following: (1) the investigational treatment is offered to patients who otherwise
would not have been offered enrollment simply because of distance from an enroll-
ing center, (2) increased enrollment helps to complete the trial faster, (3) there is
increased generalizability as the geographic pool is enlarged, and (4) video consent
avoids delay in treatment if family is not transported with the patient (e.g., air trans-
port) who may not be able to provide consent. Incorporation of telemedicine into the
clinical trial workflow will require additional resources and personnel for training,
monitoring, in-servicing, and regulatory-related issues. In addition, depending on
the intervention being evaluated, pharmacy and laboratory facilities may need to be
involved [13]. The additional time and infrastructure development may be worth the
investment if clinical trials are completed sooner and investigational studies are
available to a greater number of patients.
Comparison Group
Single-arm studies can be completed quickly and require less resources than a clini-
cal trial which includes a control group. Many phase 2 safety or dose-finding studies
are single-arm studies. Even though we do not have a specific treatment approved
for ICH, modernization of medicine is such that the development of stroke units and
neurocritical care units may have an impact on outcomes and quality of care [30–
32]. Thus, the use of historical estimates for outcomes could underestimate how
well a control group actually does and overestimate the expected benefit of treat-
ment [21, 33]. Since sample size estimation depends on the expected outcomes of a
control group and anticipated benefit of the treatment [21], miscalculation can lead
to an underpowered study. When possible, it is ideal to include a parallel control
group in a randomized, controlled fashion.
Choice of Study Endpoint
Choosing the appropriate outcome at the right time is a critically important part of
the clinical trial design. Outcomes measured in ICH typically include neurologic
impairment, disability, and functional status. In addition, quality of life, resource
utilization, and patient/caregiver feelings are also important outcome measures.
Indirect measures of treatment effect such as biomarkers (e.g., radiographic or labo-
ratory) can also be assessed [34, 35]. The choice of outcome measure depends on
the phase of the investigation and the anticipated treatment effect. For example, in a
phase 2 trial, safety, adverse events, or biomarkers might be primary outcome mea-
sures, and clinical or functional outcomes may be secondary outcome measures.
Phase 3 clinical trials tend to use functional outcome as the primary outcome mea-
sure of drug efficacy. In addition, if treatment is expected to have a large impact on
recovery, one might choose to dichotomize between good and bad outcome; for
example, good outcome might be defined by modified Rankin scale score 0–1. On
the other hand, if treatment is expected to have a more mild effect on outcomes, a
researcher may choose to evaluate the entire range of the modified Rankin scale
score (shift analyses) [36]. Clinical trials also evaluate quality of life and resource
utilization outcomes. Incorporation of patient preferences and how outcomes are
weighted in analyses is a current focus in cardiovascular disease and can be evalu-
ated in the ICH population as well [37].
The most commonly used outcomes in clinical trials for ICH include mortality,
functional outcome measured by the Barthel index (BI), modified Rankin scale
score (mRS), Glasgow outcome scale (GOS), and the Stroke Impact Scale (SIS).
The mRS and GOS are used to measure degree of disability. They are both ordered
scales, and the main difference between the two measures is that the mRS has
slightly more distinction between degree of “good” outcome [38]. The BI is a mea-
sure of ability to perform basic activities of daily living and mobility. The SIS mea-
sures patient or caregiver feelings and perspectives about residual deficits. Resource
utilization and patient/caregiver perspectives will become a more common outcome
measure in future trials. If a potential treatment is resource intensive but does not
demonstrate improved outcomes compared with standard care, then cost utilization
information and patient and family perspective can provide valuable information on
whether the treatment should be pursued further. There may be other important
outcomes which are valued by patients and families even if improved function is not
demonstrated.
The best time point at which to measure outcome for ICH is unclear. The time
point of 90 days after stroke onset is commonly used as the time at which to mea-
sure outcomes with the rationale that outcomes captured at a later time can be
affected by late medical complications, rehabilitation therapy or other confounders
which are not related to the investigational treatment [35]. Phase 3 clinical trials
evaluating medical treatment for ICH have adopted a 3-month time point for
assessment of clinical and functional outcomes, similar to clinical trials in AIS [1,
2, 39–41]. Phase 3 clinical trials evaluating surgical therapy measure functional
outcomes at 6 months [42–44]. There is data which suggest that medically man-
aged patients continue to have improvement measurable by the mRS score up to
6 months [45]. Thus, additional study is necessary to determine the ideal outcome
measure(s) and timing at which to obtain this information in patients with ICH. Due
to the complexity involved in anticipating treatment effect, choice of outcome
measure, and method of evaluating the outcome measure, clinical researchers must
work closely with an experienced statistical team who understands the patient pop-
ulation and disease.
ICH Therapy Trial Challenges and Unique Considerations
There are several challenges in patients with ICH which can directly impact clinical
research trial design. ICH patients have clinical and radiographic features which
contribute to a more severely affected patient population than AIS. These character-
istics, e.g., IVH and coagulopathy-related ICH, introduce a higher in-hospital mor-
tality and long-term disability rate which impacts sample size estimation, inclusion
and exclusion criteria, and retention of patients in clinical trials. Given the high in-
hospital mortality rate of ICH, predictors of early mortality would be useful to
include in the randomization process. In contrast to AIS where standard care has
been protocolized with standard metrics which are monitored [46], similar treat-
ment standards are not as consistent for ICH. Routine care for patients with ICH is
variable despite the guidelines [47], and it is unclear how variable treatment in a
control group might affect outcomes. Clinical research protocols in patients with
ICH must strictly define “standard care” for the control group or study designs
which can accommodate the variability in clinical practice such as the use of hyper-
osmolar therapy, platelet transfusion, emergent surgery for herniating patients, and/
or type of epileptic drugs for seizure prophylaxis should be explored (Table 12.1).
Combined Interventions
ICH causes both primary and secondary injuries. The primary insult is due to dis-
ruption of adjacent tissue with deposition of blood and subsequent mass effect [48].
Secondary injury occurs with development of edema, the inflammatory cascade,
and direct cytotoxicity of red blood cell (RBC) breakdown products. The damage
caused by ICH is multifactorial. It is intuitive that successful treatment might be
multifaceted. Current treatment targets in ICH include prevention of hematoma
expansion, removal of the toxic RBC breakdown products either surgically or phar-
macologically, and cytoprotection [49]. Clinical trial designs which allow combined
therapy should be explored. Evaluation of combined interventions reflects the real-
world practice of medicine and could take into account the variability in our current
“standard of care” for patients with ICH.
Table 12.1 Challenges in clinical trial design in acute intracerebral hemorrhage (ICH)
Challenges in ICH Considerations
Severely affected Increased mortality and Adaptive design, development of novel
patient disability rates biomarkers for better risk stratification
population Inclusion of dying patients in Novel endpoints including patient- and
clinical trials family-centered outcomes
Consent in the Not enough time for true Short form or summary of important
emergent setting informed consent in the acute clinical trial points
setting Ongoing discussion with family and
patient even after initial consent
Consenting Ineligibility of patients for Telemedicine consent
impaired patients clinical trial enrollment without Exemption from informed consent in the
a surrogate present appropriate setting
Delayed initiation of study-
related procedures if surrogate
shows up in a delayed fashion
Variable Unclear interpretation of control Exploration of study designs which can
“standard care” group outcomes if treatment is incorporate common variable clinical
in ICH variable practice (e.g., adaptive design, factorial
design)
Clearly define “standard care” in protocol
Enrollment Nonresponders may dampen Responder-based selection for enrollment
inclusion/ treatment effect criteria
exclusion criteria Patient population heterogeneity
Single-arm Can overestimate treatment Randomized, parallel control group
studies, historical effect
controls
Retention in Transportation difficulty due to Limit number of in-person follow-up
clinical trial finances or disability visits
Distance and time for travel Allow for transportation accommodations
Patient in a facility during in the protocol and budget
short-term follow-up time point Study team can travel to the patient
Telephone, telemedicine, or
teleconferencing to obtain outcome data
ICH patients tend to be more severely disabled, and retention can be an issue.
Due to new disability, patients sometimes have to move to be closer to family mem-
bers who can participate in their care. Challenges for patients and families include
transportation of a disabled patient, sometimes over long distances. At short-term
follow-up (e.g., 30 days), some patients may still be in a facility (skilled nursing,
long-term acute care, or rehabilitation). In order to improve data collection, long-
term follow-up should accommodate this change in location by limiting the number
of in-person follow-up visits or incorporating accommodations for this possibility
in the protocol and budget. Some solutions include budgeting for transportation
costs. In addition, patients can be transported to the primary study site. In such
cases, sites may have to contract with a basic life support certified provider.
Alternatively, the study team can travel to the patient. If the study team is following
up with a patient in another facility, issues regarding credentialing may come into
play. In order to improve retention, researchers should consider telemedicine or

teleconferencing to obtain information [21, 50]. These “virtual visits” [22] can facil-
itate retention of patients who cannot travel due to financial hardship or disability. It
is also reasonable to consider outcome measures that do not require in-person visits
and can be obtained by telephone. Any accommodation that can minimize the need
for travel or in-person visits is likely to improve data collection.
Novel Aspects in Clinical Trial Designs
Given the challenges in designing clinical research trials for patients with ICH,
increasing limitations on funding, and the time it takes to complete trials, there is an
urgent need to develop more efficient trial designs. It is difficult to do so within our
traditional RCT framework, and it is imperative that clinical researchers explore
ways to avoid the same pitfalls of prior trials. Ultimately, the way we carry out clini-
cal trials in patients with ICH must adapt to the patient population, natural history
of disease, and complexity of recovery. We have new computational power and new
technology which make change possible. Efficiency can be incorporated in the pre-
trial planning phase as well as in the trial design. We have decades of clinical trials
to learn from. Overestimating treatment effect or underestimating control group
outcomes can lead to underpowered studies. Imbalances in baseline prognostic vari-
ables can make interpretation of results difficult. Inclusion of nonresponders damp-
ens potential treatment effect. These are just some of the challenges which can be
addressed with pretrial planning, adaptive methods of dose finding, randomization,
and study monitoring. In addition, the incorporation of telemedicine into our work-
flow allows us to broaden our geographic reach and thus our patient population.
The US FDA Draft Guidance defines adaptive clinical trial as a study that modi-
fies one or more aspects of the trial design based on prospectively planned evalua-
tion of accumulating study data [51]. Adaptive design can be incorporated in dose
escalation, randomization algorithms, study monitoring, determination of futility,
and evaluation of outcome data. Indeed, some of these design aspects have already
been utilized in stroke trials [52–57]. Adaptive design provides the ability to effi-
ciently dose escalate, to adjust sample size estimates, and to make meaningful inter-
pretations of available information in the absence of “statistical significance.” It is
important to understand the circumstances under which adaptive analyses are
appropriate and their limitations [6, 58]; thus, an experienced statistical team is
imperative.
Computer simulation utilizes mathematical models that mimic a real-world
situation. Experiments can then be conducted to investigate or predict outcomes
in this situation [59]. In clinical trials, simulation can be used at various points
in trial design. Simulation can model disease progression and identify factors
that contribute to variance in outcomes [22, 53]. In addition, simulation can be
used to validate performance of randomization programming to ensure equal
distribution of important prognostic variables among treatment groups [52].
Simulation is being utilized more in evaluation of neurologic treatment [22].

For example, the Stroke Hyperglycemia Insulin Network Effort (SHINE) trial
utilized clinical trial simulation to better understand and address potential sta-
tistical limitations of their adaptive trial design [53]. The argatroban in combi-
nation with TPA Stroke Study used simulation to validate performance of the
randomization program [52].
Regulatory and Financial Considerations
Keeping up with recruitment goals and adhering to a timeline for study completion
within a fixed time is a herculean undertaking, especially in multicenter trials. When
developing a timeline, keep in mind possible delays for IRB approval, developing
and negotiating a budget and determination of “standard of care” costs vs. study-
related costs. Investigators conducting a multicenter trial of surgical treatment for
patients with ICH have reported delay in study initiation due to vastly different
times in obtaining regulatory approval across institutions and countries [7]. As men-
tioned previously, because standard treatment for ICH can be variable, it can be
difficult to adhere to one budget for each participating center. For example, if center
A looks for a spot sign on all patients with ICH, then center A’s standard of care is
to perform a CT angiogram and post-contrast head CT on all their patients with
ICH. Center B may only perform a non-contrast head CT and additional vascular
imaging only when clinically indicated. Center B has a different “standard of care.”
One can imagine that in an ICH clinical trial where CTA is part of the study proto-
col, it may be more expensive to include center B because the budget would need to
bear the financial burden of the CTA for each enrolled patient since it would not be
considered standard of care for center B.
Conclusion
Thus far, identification of a treatment for ICH which improves outcomes has been
elusive. In order to develop treatment, clinical researchers must continue to better
understand the disease as well as adjust our clinical trial design to accommodate the
complexities of the patient population and recovery process. Several well-designed
clinical trials achieved the goal of limiting hematoma expansion, yet, this did not
translate to improved outcomes. Our experience from these trials will inform our
patient selection and stratification plans in future clinical trials. The smaller, sicker,
and heterogeneous population of ICH patients warrants careful consideration of
additional biomarkers which can help identify treatment responders. For future
clinical trials in ICH, incorporation of adaptive design, computer simulation, and
different types of outcome measures may be useful in identifying a meaningful
effect of treatment.
A quick perusal of clinical trials in ICH listed on clinicaltrials.gov (accessed

November 2016) demonstrated that almost 2/3 of registered clinical trials were
focused on acute treatment. Less than 1/3 of listed studies reviewed were observa-
tional in nature and less than 1/10 targeted primary or secondary prevention of
ICH. While there is an urgent need to develop acute treatment for ICH, the most
dramatic impact for patients and families would be prevention of ICH altogether.
We continue to better understand the pathophysiology of ICH through our pre-
clinical work and advancing technology. Technology also allows us to broaden the
scope of clinical trials in ICH, figuratively and literally. As we apply these tools to
our current practices, we remain hopeful that improved outcome in ICH is within
reach.
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Index
A Antiseizure drug, 11
Accelerated Skill Acquisition Program Antithrombotic- and thrombolytic-related
(ASAP), 170 intracerebral hemorrhage, 27–28, 35
Activated factor VII (aFVII), 34, 35 antiplatelet medication-related ICH, 39
Activated partial thromboplastin time (aPTT), heparin-related ICH, 37–38
35, 37 NOAC-ICH (see Non-vitamin K
Acute hypertensive response antagonists oral anticoagulant-
clinical trials, 52–53 related ICH)
mechanism of, 45 OAC-Related ICH, pathophysiology of, 29
Acute ischemic stroke (AIS), 186, 189, 191, VKA-ICH (see Vitamin K antagonist-
192 related ICH)
Acute myeloid leukemia (AML), 22 Antithrombotic medications, 111
Adaptive design, 194, 195 Apollo, 85–86, 89
American Heart Association, 8, 102, 123, 163 A Very Early Rehabilitation Trial (AVERT),
American Heart Association Emergency 153, 170
Cardiovascular Care Committee and
Council, 188
American Heart Association/American Stroke B
Association (AHA/ASA) Barthel index (BI), 191
guidelines, 61 BEST-MSU study, 4
Amyloid angiopathy, 112, 144 Bleeding, 29, 35–37
Andexanet alfa, 9, 36 Blood pressure management, in ICH
Anterior cerebral artery (ACA), 127, 129 early intensive blood pressure lowering
Anticoagulant-associated coagulopathy, 9 treatment
Anticoagulation reversal treatment efficacy of, 49–54
NOAC-ICH, –, 35, 37 safety of, 47–49
VKA-ICH, 30, 34–35 patient outcomes, 46–47
Antiepileptic drugs (AEDs), 68, 70–73, 178 recurrent intracerebral hemorrhage,
Antihypertensive treatment, 8, 48, 110 109–111
Antihypertensive Treatment of Acute Cerebral Brain arteriovenous malformation (bAVM)
Hemorrhage (ATACH) I, 8, 48, 49 etiology of, 130
Antihypertensive Treatment of Acute Cerebral incidence of, 130
Hemorrhage (ATACH) II trial, 8, management of, 130, 131
50, 51 patient history, 127
Antiplatelet agents (APAs), 112, 113 surgical intervention of, 130
Antiplatelet medication-related ICH, 39

https://doi.org/10.1007/978-3-319-77063-5
202 Index
C diagnosis of, 65, 66

Canadian healthcare system, 142 incidence of, 58
Caprini risk assessment model, 60 prophylaxis, 8
Care quality metrics, 147–150 risk reduction, 63
Cerebral amyloid angiopathy (CAA), 20, 29, Dementia, 176
109, 177 Digital subtraction angiography (DSA), 21
Cerebral Hemorrhage and NXY-059 Treatment Direct oral anticoagulants (DOACs), 9
(CHANT) trial, 113, 178 Disseminated intravascular coagulation (DIC),
Cerebral microbleeds (CMBs), 29, 109, 114 22
Cerebral microhemorrhages, 20 Do not resuscitate (DNR) orders, 99–101
Chronic hypertension, 7 Dose-equivalent occupational therapy
Clevidipine monotherapy, 8 (DEUCC), 170
Clinical trial design, ICH Dural arteriovenous fistulas (DAVF)
adaptive clinical trial, 194 classifications of, 133
challenges, 192, 193 clinical presentation of, 133
combined interventions, 192–194 diagnostic evaluation, 134
computer simulation, 194 management of, 134
ethical considerations, 186–188 patient history, 131–133
functional outcomes, 191–192 signs and symptoms, 133
medical treatment, 191 treatment of, 134
patient population, 188–190
phase 1 trials, 186
phase 2 trials, 186 E
quality of life, resource utilization and Early inpatient workup, ICH
patient/caregiver feelings, 191 clinical evaluation, 17–18
regulatory and financial considerations, computed tomography, 19
195 CTA, 20, 21
safety, adverse events/biomarkers, 191 DSA, 21
single-arm studies, 190 intracranial vasculopathy, 22–23
Clot Lysis Evaluating Accelerated Resolution laboratory tests, 18
of IVH Phase II (CLEAR II) trial, magnetic resonance imaging, 19–20
84 MRA, 21
CLOTS 2 trial, 63 Electroencephalography (EEG), 11, 70, 72, 98
Comprehensive stroke centres (CSCs), Elevated blood pressure, 45, 48
145–146 Emergency department (ED), ICH
Computed tomography (CT), 3, 6, 19 airway protection, 7
Computed tomography angiography (CTA), 6, blood glucose management, 11
20, 21 blood pressure management, 7–8
Computed tomography pulmonary hemostatic treatment
angiography (CTPA), 65 anticoagulant-associated coagulopathy,
Continuum of stroke care, 143, 154 9
Contrast-induced nephropathy (CIN), 20 platelet function, 9
Craniotomy rtPA-associated coagulopathy, 9–10
for spontaneous intracranial hemorrhage, intracranial pressure management, 10
82–83 laboratory studies, 5
for supratentorial intracranial hemorrhages, neuroimaging evaluation
81–82 computerized tomography, 6
Cushing–Kocher response, 7 CTA, 6
MRI, 7
rapid clinical evaluation, 5
D seizures and antiseizure drugs, 11
Dabigatran, 9, 35–37 surgical management, 10
Deep vein thrombosis (DVT) temperature management, 11
asymptomatic, 62 thromboprophylaxis, 8
Index 203
Emergency medical services (EMS), 2, 3, 145 Hypertension, 108–110, 114

Emergency Neurological Life Support (ENLS)
module, 102
European Stroke Organization (ESO) I
guidelines, 61 ICARE trial, 170
Exception from informed consent (EFIC), 187 ICH grading score (ICH-GS), 101
External ventricular drain (EVD), 28, 121, Idarucizumab, 36
123–125, 175 Idiopathic thrombocytopenic purpura (ITP),
22
INCH trial, 9, 34
F Inferior vena cava (IVC) filter placement, 66,
Face Arm Speech Test (FAST) scale, 3 67
Factor Seven for Acute Hemorrhagic Stroke Informed consent, 186–188
(FAST) trial, 9, 47, 58, 59, 189 Informed consent forms (ICFs), 187
FAST-MAG trial, 147 Infratentorial intracranial hemorrhages, 82
Fresh frozen plasma (FFP), 9, 34, 35 Institutional review board (IRB), 187
FUNC score, 168 Integrated Care for the Reduction of
Functional independent measure (FIM), 162, Secondary Stroke (ICARUSS)
163 model, 154
Integrated stroke systems of care, 140
Intensive blood pressure reduction in acute
G cerebral hemorrhage trial-1
Generalized endotracheal intubation, 7 (INTERACT1), 8, 49
Glasgow Coma Scale (GCS), 2, 69, 95, 98, Intensive blood pressure reduction in acute
100, 101 cerebral hemorrhage trial-2
Glasgow outcome scale (GOS), 101, 191 (INTERACT2), 8
Gradient recalled echo (GRE), 20 Intensive care unit (ICU), 99
Inter-hospital transfers, 151–152
Intermittent pneumatic compression (IPC), 61
H efficacy of, 62
Heart Protection Study, 114 prophylactic effect of, 62
Hematoma, 1, 4, 6–8, 10 International normalized ratio (INR), 127, 146
expansion, 45, 46, 50 Intracerebral hemorrhage (ICH), 2, 4, 31–33,
highest rate of, 47 57, 72, 96, 107, 125, 185
lower rates of, 49 causes of, 21–22
reduction in, 47 classification of, 18–19
growth, 9 clinical trial design (see Clinical trial
Heparin-related ICH, 37–38 design, ICH)
Hydrocephalus, 175 definition, 1
Hyper-acute and acute ICH management ED stroke care (see Emergency department
in-hospital care protocols (ED), ICH)
care on stroke units/neurologic hyper-acute and acute (see Hyper-acute
intensive care units, 150–151 and acute ICH management)
ICH-specific intensity of care quality ICH score, 17
metrics, 147–150 incidence of, 1
inter-hospital protocols integrated stroke systems of care, 140
inter-hospital transfers, 151–152 intensive care unit, stroke unit/hospital,
telestroke services, role of, 152–153 transfer to, 11
pre-hospital protocols ischemic vs. hemorrhagic strokes,
EMS routing protocols, 145 functional outcomes in, 163
primary and comprehensive stroke mortality, 1, 162
centres, 145–146 prehospital stroke care (see Prehospital
treatment, 146–147 stroke care, ICH)
Hyperacute ICH, 19, 20 prevention and public awareness
204 Index
Intracerebral hemorrhage (ICH) (cont.) for spontaneous intracranial hemorrhage

modifiable risk factors for, 143 CLEAR trials, 84
stroke prevention clinics, role of, history, 84
143–144 MISTIE, 84–85
stroke symptoms, public awareness of, Minimally Invasive Surgery Plus Tissue-Type
144 Plasminogen Activator for ICH
prognosis (see Prognosis, ICH) Evacuation (MISTIE II), 10, 84
recurrent ICH, prevention of (see Mobile stroke units (MSUs), 3–4
Recurrent intracerebral hemorrhage) Mobile telemedicine, 4
rehabilitation (see Rehabilitation, ICH) Modified Rankin scale score (mRS), 124, 191
rFVIIa in (see Recombinant factor VII A) Mortality, 162
seizures (see Seizures)
thromboprophylaxis (see
Thromboprophylaxis) N
Intracranial hemorrhage, 34, 36 National Institutes of Health Stroke Scale
Intracranial pressure (ICP), 10, 175 (NIHSS) score, 17–18, 58, 69, 95,
Intracranial vasculopathy, 22–23 101
Intraventricular hemorrhage (IVH) Neurological deterioration, 46, 48
CLEAR III, 125 Neuroplasticity, 167
CT scan, 123 NICO BrainPath system, 86–87, 89
CTA, 123 Non-vitamin K antagonists oral anticoagulant-
etiology of, 122 related ICH (NOAC-ICH)
intraventricular fibrinolysis in, 123 anticoagulation reversal treatment, 35–37
intraventricular thrombolysis in, 124 hematoma expansion, 35
mortality, 123 Novel oral anticoagulants (NOACs), 9
MRA, 123
MRI, 123
patient history, 121–122 O
patient management, 122 Obstructive sleep apnea (OSA), 114
primary, 123 Oral anticoagulants (OAC), 111
secondary, 123, 124
treatment of, 123
INVEST trial, 89 P
Padua risk assessment model, 59
PATCH trial, 9, 39
L Penumbra Apollo, 85
Legally authorized representative (LAR), 187, Perihematoma edema (PHE), 82
188 Perindopril Protection Against Recurrent
Locomotor Experience Applied Post-Stroke Stroke Study (PROGRESS), 110
(LEAPS) trial, 170 Periodic epileptiform discharges (PEDs), 69
Low-molecular-weight heparin (LMWH), 37, Pharmacologic thromboprophylaxis, 63
61–64, 67 Platelet function, 9
Positron emission tomography (PET), 48
Posterior cerebral artery (PCA), 127, 129
M Poststroke depression (PSD), 176, 177
Magnetic resonance angiography (MRA), 21 Prehospital stroke care, ICH
Magnetic resonance imaging (MRI), 19–20 EMS services, 3
Mean arterial pressure (MAP), 46, 47 mobile telemedicine, role of, 4
mEDICH, 168 MSU, 3–4
Middle cerebral artery (MCA), 127, 129 public awareness, 2
Minimally invasive surgery (MIS) Prevention of Hypertensive Injury to the Brain
evacuations by Intensive Treatment after
Apollo, 85 Intracerebral Hemorrhage
NICO BrainPath system, 86–87 (PROHIBIT-ICH), 111
Index 205
Primary CNS vasculitis (PCNSV), 22 OSA, 114

Primary stroke centres (PSCs), 145–146 recreational drugs, 115
Prognosis, ICH surgical evacuation, 109
case-control study, 97 tobacco use, 115
ENLS module, 102 risk of stroke, 108
individual factors statins, 113–114
imaging and clinical features, 98 Red blood cell (RBC), 192
treatment factors, 98–99 Rehabilitation, ICH
in-hospital mortality rates, 96 and community reintegration, 153–154
meta-analysis, 96 general stroke rehabilitation principles
pathophysiological mechanisms, 97 clinical rehabilitation principles and
prognostic models, 100–101 pathways, 163
withdrawal of care and DNR Orders, functional recovery, 167–168
impact of, 99–100 mechanisms of recovery, 167
Prophylactic antiepileptic treatment, in ICH rehabilitation team, members of, 165
clinical practice on, 70–71 stroke patient care continuum, 164
international recommendations on, 70 inpatient rehabilitation settings, 164
studies on, 71–72 rehabilitation team, 165–166
Protamine sulfate, 9 special rehabilitation considerations
Prothrombin complex concentrate (PCC), 9, dementia, 176–177
34, 35, 37, 38, 59 hydrocephalus, 175
Public awareness, 2 medications in, 177–178
Pulmonary embolism (PE) neuropsychiatric complications, 176
diagnosis of, 65–66 seizures, 174–175
incidence of, 58 spasticity, 175–176
timing, intensity and safety of, 169–171
Relative cerebral blood flow (rCBF), 48
Q Relative cerebral blood volume (rCBV), 48
Quality-adjusted life year (QALY), 112 Relative mean transit time (rMTT), 48
Retrospective analysis, 110
Reversible cerebral vasoconstriction
R syndrome (RCVS), 21, 22
Randomized controlled trial (RCT), 62, 188,
194
BP-lowering, 147 S
goal of, 186 Scandinavian Stroke Scale, 174
Recombinant factor VII A (rFVIIa), 9, 126 Second intensive blood pressure reduction in
arterial thromboembolic and myocardial acute cerebral hemorrhage trial
adverse events, 126 (INTERACT II), 49–51
clinical outcomes, 126 Secondary hemorrhage, 38
patient history, 125 Seizures, 11, 70, 174
treatment with, 126, 189 incidence and predisposing factors, 68–69
Recombinant tissue plasminogen activator management, 72–73
(rtPA), 9–10 and outcome, 69–70
Recurrent intracerebral hemorrhage prophylactic antiepileptic treatment
antithrombotic medications, 111–113 (see Prophylactic antiepileptic
blood pressure management, 109–111 treatment, in ICH)
risk factors Selective serotonin reuptake inhibitors
age, 109 (SSRIs), 177
alcohol use, 114 Sequential compression
CAA, 109 devices (SCDs), 8
hypertension, 108 Simplified ICH score (sICH), 101
lobar location, 109 SMASH-U, 18
nonmodifiable risk factors, 115 Spasticity, 175
206 Index
Spontaneous intracranial hemorrhage maximum, 47

craniectomy for, 82 mean, 46, 54
minimally invasive surgery for observational studies, 46
CLEAR trials, 84 relative reduction of, 47
history, 84 safety and tolerability, 48
MISTIE, 84–85 standard SBP reduction, 49
SPOTLIGHT trial, 126 treatment goal, 48
SPS3 trial, 110
Statins, 113–114
Stereotactic radiosurgery (SRS), 131 T
STICH II trial, 10 Telemedical Project for Integrative Stroke
Stroke Acute Management with Urgent Care (TEMPiS) network, 153
Risk-factor Assessment and Telemedicine, 4, 5, 187, 190, 194
Improvement (SAMURAI)-ICH Telestroke, 152–153
study, 46 Thrombin time (TT), 35
Stroke Impact Scale (SIS), 191 Thrombocytopenia, 22
Stroke Prevention by Aggressive Reduction in Thromboprophylaxis, 8, 58
Cholesterol Levels (SPARCL) trial, AHA/ASA guidelines, 61, 65
113 ESO guidelines, 61
Stroke rehabilitation Neurocritical Care Society, 62
clinical rehabilitation principles and studies on
pathways, 163–164 non-pharmacologic antithrombotic
functional recovery measures, 62–63
age, 167 pharmacologic thromboprophylaxis,
gender, 168 63–64
outcome scoring systems, 168 VTE (see Venous thromboembolism)
race, 168 Transient ischaemic attack (TIA), 143
socioeconomic status, 168 Trials of Hypertension Prevention (TOHP), 143
stroke location, 168
stroke volume, 168
mechanisms of recovery, 167 U
rehabilitation team, members of, 165 Unfractionated heparin (UH), 37, 61–63, 67
stroke patient care continuum, 164 Uremia, 22
Stroke systems of care US FDA Draft Guidance, 194
integrated, 140
as an intervention, 141–143
Stroke unit care, 140, 150–151 V
Subarachnoid hemorrhage (SAH), 21 Venous thromboembolism (VTE)
Supratentorial intracranial hemorrhages, 81 early mobilization and hydration, for VTE
Surgical treatment, of ICH prophylaxis, 64–65
minimally invasive surgery incidence and risk factors, 58–61
evacuations, 85–90 treatment of, 66–67
for spontaneous intracranial Vitamin K antagonist-related ICH (VKA-ICH)
hemorrhage, 84–85 anticoagulation reversal treatment, 30, 34–35
spontaneous intracerebral hemorrhage, hematoma expansion, 30
81–83 incidence of, 29
timing of, 90 in-hospital mortality, 30
Surgical Trial in Traumatic Intracerebral observational study, 30
Hemorrhage (STITCH) trial, 82, 90 prevention of, 35
Systolic blood pressure (SBP)
acute SBP reduction, 47, 50
baseline, 48 W
goal, 46, 48–50 Warfarin coagulopathy, 9
intensive SBP reduction, 49–51, 54 Warfarin-related ICH, 30

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Intracerebral

Concepts and Customs

ISBN 978-3-319-77062-8 ISBN 978-3-319-77063-5 (eBook)

Library of Congress Control Number: 2018952921

© Springer International Publishing AG, part of Springer Nature 2018

pressure offers another opportunity to prevent secondary deterioration. Etiologic

Issam A. Awad, MD,MSc,FACS,FAANS,FAHA,MA(hon)

Intracerebral hemorrhage (ICH) is a serious condition for which early aggressive

lacking, our expert contributors provide their own management recommendations.

San Francisco, CA, USA Bruce Ovbiagele

1 Prehospital and Emergency Department

10 Special Systems of Care Considerations

Benjamin A. Abramoff, MD Physical Medicine and Rehabilitation, Emory

Nabeel A. Herial, MD, MPH Departments of Neurology and Neurosurgery, Sidney

Magdy Selim, MD, PhD Department of Neurology, Stroke Division, Beth Israel

Muhammad Fawad Ishfaq, Nitin Goyal, Abhi Pandhi, and Marc Malkoff

M. F. Ishfaq · N. Goyal · A. Pandhi · M. Malkoff (*)

© Springer International Publishing AG, part of Springer Nature 2018 1

ICH is a medical emergency and delays in treatment result in worse outcome.

Prehospital Stroke Care

Emergency Medical System Services

Mobile Stroke Unit

launched at University of Texas, Houston, followed by Cleveland Clinic MSU and

Role of Mobile Telemedicine

Telemedicine-enabled ambulance-based evaluation reduces time to imaging and

Emergency Department Stroke Care

Rapid Clinical Evaluation

computerized tomography (CT) head, CT angiography, CT perfusion, magnetic

in atypical locations or presentation or in young patients with no obvious cause for

Generalized endotracheal intubation is indicated in patients with reduced conscious-

Blood Pressure Management

Thromboprophylaxis in ICH Patients

(a) Platelet function

mended to immediately discontinue rtPA and administer any of the following

Intracranial Pressure Management

Current AHA/ASA guidelines suggest ICP monitoring with parenchymal or ventricu-

Surgical Management of ICH

Surgery in patients with neurologically asymptomatic ICH is not clearly beneficial.

Blood Glucose Management

Optimal temperature management is still unclear, but it is recommended to treat

Seizures and Antiseizure Drugs

The prophylactic administration of antiseizure drug therapy is not recommended,

 ransfer to an Intensive Care Unit, Stroke Unit, or Other

4. Gebel JM, Broderick JP. Intracerebral hemorrhage. Neurol Clin. 2000;18(2):419–38.

investigation to solve longstanding controversy over the most appropriate management of

Muhib Khan, Rushna Ali, Justin Singer, Paul Mazaris, and Brian Silver

Spontaneous non-traumatic intracerebral hemorrhage (ICH) is a leading cause of

M. Khan (*) · J. Singer · P. Mazaris

© Springer International Publishing AG, part of Springer Nature 2018 17

Laboratory investigation is important in both the evaluation of etiology of ICH and

In order to efficiently investigate the etiology, it is important to characterize the ICH

Computed Tomography (CT)

CT is a sensitive and effective modality for identifying acute hemorrhage. It is con-

Magnetic Resonance Imaging

CT scan is highly sensitive in identifying intracerebral hemorrhage as mentioned

gradient echo (GE), fluid-attenuated inversion recovery, and diffusion-weighted

Computed Tomographic Angiography

Magnetic Resonance Angiography

Magnetic resonance angiography (MRA) is a noninvasive modality used to identify

San Francisco, CA, USA Bruce Ovbiagele

1 Prehospital and Emergency Department

10 Special Systems of Care Considerations

Prehospital Stroke Care

Emergency Medical System Services

Mobile Stroke Unit

Role of Mobile Telemedicine

Emergency Department Stroke Care

Rapid Clinical Evaluation

Blood Pressure Management

Thromboprophylaxis in ICH Patients

Intracranial Pressure Management

Surgical Management of ICH

Blood Glucose Management

Seizures and Antiseizure Drugs

ransfer to an Intensive Care Unit, Stroke Unit, or Other

Computed Tomography (CT)

Magnetic Resonance Imaging

Computed Tomographic Angiography

Magnetic Resonance Angiography

Digital Subtraction Angiography (DSA)

CTA vs MRA vs DSA

Other Causes of ICH

Antithrombotic- and Thrombolytic-Related ICH

Pathophysiology of OAC-Related ICH

Vitamin K Antagonist-Related ICH

Anticoagulation Reversal Treatment (VKA)

Non-vitamin K Antagonist Oral Anticoagulant-Related ICH

Anticoagulation Reversal Treatment (NOAC)

Antiplatelet Medication-Related ICH

Blood Pressure Management in ICH

lood Pressure and Outcome in Patients with Intracerebral

Safety of Early Intensive Blood Pressure Lowering Treatment

fficacy of Early Intensive Blood Pressure Lowering

Incidence of Venous Thromboembolism and Risk Factors

I nternational Recommendations on Thromboprophylaxis

Studies on Non-pharmacologic Antithrombotic Measures

Studies on Pharmacologic Thromboprophylaxis

Early Mobilization and Hydration for VTE Prophylaxis

Diagnosis of DVT and PE

Treatment of VTE in ICH Patients