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Intracerebral Hemorrhage
Intracerebral Hemorrhage

Edited by
J. R. Carhuapoma
Johns Hopkins University Hospital, Baltimore, MD, USA

S. A. Mayer
Columbia University Medical Center, New York, NY, USA

D. F. Hanley
Johns Hopkins University Hospital, Baltimore, MD, USA
CAMBRIDGE UNIVERSITY PRESS
Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore,
São Paulo, Delhi, Dubai, Tokyo

Cambridge University Press

The Edinburgh Building, Cambridge CB2 8RU, UK

Published in the United States of America by Cambridge University Press, New York

www.cambridge.org
Information on this title: www.cambridge.org/9780521873314
© J. R. Carhuapoma, S. A. Mayer, and D. F. Hanley 2010

This publication is in copyright. Subject to statutory exception and to the

provision of relevant collective licensing agreements, no reproduction of any part
may take place without the written permission of Cambridge University Press.
First published in print format 2009

ISBN-13 978-0-511-69131-7 eBook (NetLibrary)

ISBN-13 978-0-521-87331-4 Hardback

Cambridge University Press has no responsibility for the persistence or accuracy

of urls for external or third-party internet websites referred to in this publication,
and does not guarantee that any content on such websites is, or will remain,
accurate or appropriate.
Every effort has been made in preparing this publication to provide accurate and
up-to-date information which is in accord with accepted standards and practice at
the time of publication. Although case histories are drawn from actual cases, every
effort has been made to disguise the identities of the individuals involved.
Nevertheless, the authors, editors, and publishers can make no warranties that the
information contained herein is totally free from error, not least because clinical
standards are constantly changing through research and regulation. The authors,
editors, and publishers therefore disclaim all liability for direct or consequential
damages resulting from the use of material contained in this publication. Readers
are strongly advised to pay careful attention to information provided by the
manufacturer if any drugs or equipment that they plan to use.
To my son Ethan and my family for their unconditional support JRC
To Catherine, Philip and Elizabeth SAM
To my wife and family who have supported my career DFH

v
Contents
List of contributors ix
Foreword by Thomas Brott xii

Section 1 – Epidemiology Section 4 – Diagnostic investigations

1. The epidemiology of intracerebral 9. Computerized tomography and
hemorrhage 1 CT angiography in intracerebral
Matthew L. Flaherty, Daniel Woo, and Joseph hemorrhage 121
P. Broderick Rush H. Chewning and Kieran P. Murphy

10. MRI of intracerebral hemorrhage 125

Section 2 – Etiology of non-traumatic Ken Butcher and Stephen M. Davis
intracerebral hemorrhage 11. Cerebral angiography 139
2. Acute hypertensive response in intracerebral Rush H. Chewning and Kieran P. Murphy
hemorrhage 17
12. Laboratory and other ancillary
Ameer E. Hassan, Haralabos Zacharatos, testing in intracerebral
and Adnan I. Qureshi hemorrhage: an algorithmic
3. Etiology of tumor-related intracranial approach 149
hemorrhage 31 Michael Chen and Louis R. Caplan
Andreas F. Hottinger and Lisa M. DeAngelis
4. Cerebral amyloid angiopathy
Steven M. Greenberg
41
Section 5 – Management
5. Coagulopathy-related intracerebral
and critical care
hemorrhage 58 13. Medical management of
Hagen B. Huttner and Thorsten Steiner intracerebral hemorrhage 159
Neeraj S. Naval, Paul A. Nyquist,
6. Vascular malformations of the brain 71
and J. Ricardo Carhuapoma
Christian Stapf and J. P. Mohr
7. Cerebral venous thrombosis and intracerebral 14. Surgical management of
hemorrhage 84 intracerebral hemorrhage 165
Isabelle Crassard and Marie-Germaine Bousser A. David Mendelow

15. Future therapy in intracerebral

Section 3 – Clinical presentation hemorrhage and intraventricular
hemorrhage: aspiration and
8. Clinical presentation of intracerebral thrombolysis 176
hemorrhage 101 Paul A. Nyquist, Neeraj S. Naval,
Carlos S. Kase and J. Ricardo Carhuapoma

vii
 Contents

Section 6 – Prognosis and outcome 19. Cytoprotection strategies for experimental

intracerebral hemorrhage 217
16. Mathematical models of intracerebral Crystal MacLellan, James Peeling, and Frederick
hemorrhage and intraventricular Colbourne
hemorrhage outcomes prediction:
their comparison, advantages,
and limitations 187 Section 8 – Advances in pathogenesis
Stanley Tuhrim
and treatment of intracerebral
hemorrhage: clinical
Section 7 – Advances in
20. Natural history of perihematomal brain
pathogenesis and treatment edema 229
of intracerebral hemorrhage: Manuel Rodríguez-Yáñez, Antoni Dávalos, and
José Castillo
experimental
21. Hemostatic therapy for intracerebral
17. Animal models and experimental hemorrhage 238
treatments of intracerebral Wendy C. Ziai and Stephan A. Mayer
hemorrhage 193
Kenneth R. Wagner and Mario Zuccarello
18. Thrombin and secondary brain damage
following intracerebral hemorrhage 206 Index 254
Guohua Xi, Richard F. Keep, and Julian T. Hoff Color plate section between pp. 158 and 159.

viii
Contributors

Marie-Germaine Bousser MD Frederick Colbourne PhD

Department of Neurology, Department of Psychology,
Lariboisière Hospital, Paris, France University of Alberta, Edmonton, Alberta,
Canada
Joseph P. Broderick MD
Department of Neurology, Isabelle Crassard MD
University of Cincinnati, Department of Neurology,
Cincinnati, OH, USA Lariboisière Hospital, Paris, France

Ken Butcher MD PhD FRCPC Antoni Dávalos MD PhD

Division of Neurology, Department of Neurosciences,
University of Alberta, Hospital Germans Trias i Pujol,
Edmonton, Alberta, Canada Barcelona, Spain

Louis R. Caplan MD Stephen M. Davis MD FRACP

Department of Neurology, Department of Neurology,
Beth Israel Deaconess Medical Center, Royal Melbourne Hospital,
Boston, MA, USA Melbourne, Victoria, Australia

Lisa M. DeAngelis MD
J. Ricardo Carhuapoma MD FAHA
Department of Neurology,
Departments of Neurology, Neurosurgery,
Memorial Sloan-Kettering Cancer Center,
and Anesthesiology & Critical Care Medicine,
New York, NY, USA
Division of Neurosciences Critical Care,
The Johns Hopkins Medical Institutions, Matthew L. Flaherty MD
Baltimore, MD, USA Department of Neurology,
University of Cincinnati, Cincinnati, OH, USA
José Castillo MD PhD
Department of Neurology, Steven M. Greenberg MD PhD
Hospital Clínico Universitario, Neurology Stroke Service,
University of Santiago de Compostela, Massachusetts General Hospital,
Santiago de Compostela, Spain Boston, MA, USA
Michael Chen MD Daniel F. Hanley MD
Departments of Neurology and Radiology, Departments of Neurology, Neurosurgery,
Rush University Medical Center, and Anesthesiology & Critical Care Medicine,
Chicago, IL, USA Division of Brain Injury Outcomes Research,
The Johns Hopkins Hospital,
Rush H. Chewning BA Baltimore, MD, USA
Department of Radiology,
The Johns Hopkins Hospital, Ameer E. Hassan DO ix
Baltimore, MD, USA Department of Neurology,
 List of contributors

University of Minnesota Medical Center, Neeraj S. Naval MD

Minneapolis, MN, USA Department of Neurology, Neurosurgery,
and Anesthesia Critical Care Medicine,
Julian T. Hoff MD Neurosciences Critical Care Division,
Formerly Department of Neurosurgery, Oregon Health Sciences University School of Medicine,
University of Michigan, Oregon, USA
Ann Arbor, MI, USA
Paul A. Nyquist MD
Andreas F. Hottinger Department of Neurology, Neurosurgery,
Department of Neurology, and Anesthesiology & Critical Care Medicine,
Memorial Sloan-Kettering Cancer Center, Division of Neurosciences Critical Care,
New York, NY, USA Johns Hopkins Medical Institutions,
Baltimore, MD, USA
Hagen B. Huttner MD
Department of Neurology, James Peeling PhD
University of Heidelberg, Heidelberg, Department of Chemistry,
Germany University of Winnipeg, Winnipeg,
Manitoba, Canada
Carlos S. Kase MD
Department of Neurology, Adnan I. Qureshi MD
Boston Medical Center, Boston, MA, USA Department of Neurology,
University of Minnesota Medical Center,
Richard F. Keep PhD Minneapolis, MN, USA
Department of Neurosurgery,
University of Michigan, Manuel Rodriguez-Yáñez MD
Ann Arbor, MI, USA Department of Neurology,
Hospital Clínico Universitario,
Crystal MacLellan PhD University of Santiago de Compostela,
Department of Psychology, Santiago de Compostela, Spain
University of Alberta, Edmonton, Alberta, Canada
Christian Stapf MD
Stephan A. Mayer MD Department of Neurology,
Department of Neurology, Lariboisière Hospital, Paris, France
Columbia University Medical Center, Thorsten Steiner MD
New York, NY, USA
Department of Neurology,
A. David Mendelow PhD FRCSEd University of Heidelberg, Heidelberg, Germany
Department of Neurosurgery, Stanley Tuhrim MD
Newcastle General Hospital, Department of Neurology,
Newcastle upon Tyne, UK Mt Sinai Medical Center, New York, NY, USA
J. P. Mohr MD PhD Kenneth R. Wagner PhD
Department of Neurology, Department of Neurology,
Columbia University Medical Center, University of Cincinnati, Cincinnati,
New York, NY, USA OH, USA
Kieran P. Murphy MD Daniel Woo MD
Department of Radiology, Department of Neurology,
The Johns Hopkins Hospital, University of Cincinnati, Cincinnati,
x Baltimore, MD, USA OH, USA
 List of contributors

Guohua Xi MD Wendy C. Ziai MD

Department of Neurosurgery, Department of Neurology,
University of Michigan, The Johns Hopkins Hospital,
Ann Arbor, MI, USA Baltimore, MD, USA

Haralabos Zacharatos DO Mario Zuccarello MD

Department of Neurology, Department of Neurology,
University of Minnesota Medical Center, University of Cincinnati, Cincinnati,
Minneapolis, MN, USA OH, USA

xi
 Foreword

Intracerebral Hemorrhage is the first major text administered intravenously within 3 hours of symp-
devoted to non-traumatic intracerebral hemorrhage tom onset. Medical centers engaged in administration
(ICH) to appear in almost 20 years. The 21 chapters of rt-PA as urgent treatment geared-up for a similar
detail a generation of progress since the introduction emergency approach to ICH. Complex multi-
of brain computerized tomography (CT) in 1973. At departmental systems for urgent patient transport,
that time, and for the first time, the phenotype of diagnosis, and treatment were already in place at these
non-traumatic ICH could be clarified. The Polaroid- centers. Active bleeding during the first minutes and
print images of ICH pasted into patient medical hours after ICH onset provides a logical therapeutic
records were understandable in all languages. The target. The 40%-plus major morbidity and mortality
distinction between ICH and territorial cerebral following ICH has provided opportunity for firm
infarction was no longer fuzzy, to await the final clinical end points to evaluate treatment outcomes.
verdict at the autopsy table. Testable hypotheses Accordingly, attempts at very early surgery via crani-
replaced speculation. otomy or endoscopic techniques were initiated
During the next two decades, faster and more (Section 5). Thrombolytic agents including instilla-
accurate CT scanning and then magnetic resonance tion of rt-PA were utilized in several trials. Unfortu-
imaging (MRI) allowed rigorous clinical-radiographic nately, these attempts at treatment within 3–12 hours
studies (Chapters 8–10). Publications related to ICH suffered from slow enrollment and from disappoint-
sky-rocketed in number. In 1991, the National Insti- ing therapeutic results. Surgical evacuation of ICH
tutes of Health funded the first investigator-initiated within 90 minutes, or even 3 hours, was not an
R01 research grant to study ICH in emergency achievable goal, and complete surgical evacuation
departments. The US federal funding of additional has been difficult to achieve. Fortunately, encouraging
studies of ICH surged. Worldwide, CT-based clinical technical results were observed following catheter-
studies described the dynamic profile of ICH. The based techniques for clot removal in the setting of
pivotal role of ICH volume growth in clinical deteri- intraventricular hemorrhage, particularly when
oration during the first minutes and hours after employed in combination with locally instilled
symptom onset was established. In parallel with the thrombolytic drugs. Controlled studies of these tech-
studies of ICH in the emergency department setting, niques for parenchymal and intraventricular hemor-
experimental (Chapters 17, 18) and clinical studies rhage are currently underway (Chapter 15).
proceeded (Chapters 1–8). Subtypes of ICH were In 2005, the long-awaited results of the Inter-
identified with greater precision, facilitating epidemi- national Surgical Trial in Intracerebral Haemorrhage
ological studies, mechanistic experimental studies, (STICH) were published, the results of which are
and, more recently, genetic studies by subtype. discussed in Chapter 14 by the principal investigator,
Outcomes research has clearly shown that survival David Mendelow. The STICH trial was a major
and recovery after ICH is improved when patients are accomplishment as 1033 patients were randomized
cared for in specialized neurological intensive care at 83 centers from 27 countries. Overall, the operated
units, with a focus on aggressive medical support patients did not benefit, though subgroup analysis
and best medical practices. The search for a “magic suggested that early surgery may improve outcomes
bullet” has been more elusive. In 1995, recombinant for patients with lobar ICH. The STICH II trial,
tissue plasminogen activator (rt-PA) was shown to be designed to answer that question, is also described
xii safe and effective as treatment for ischemic stroke, if by Dr. Mendelow in Chapter 14.
 Foreword

Medical treatments for ICH are detailed in Perhaps most importantly, the biggest transform-
Sections 5, 6, and 7. General supportive treatments ation over the past 20 years has been widespread
in intensive care units and rehabilitation treatments acceptance of the concept that ICH is a treatable
in dedicated units have improved outcomes. For medical illness. Historically ICH was viewed as a
specific medical treatment, ongoing bleeding hopeless, life-negating event for which caregivers
following onset of ICH is the logical target for inter- had nothing to offer other than prayers and compas-
vention. Optimal management of blood pressure, sion. What has become dramatically clear, however,
and perhaps even acute lowering of blood pressure, is that many ICH patients die as a result of self-
may be shown to influence outcome (Chapter 13). fulfilling prophecies of doom. As caregivers have
Of particular interest, the recent randomized trials of been more aggressive with their interventions and
procoagulant therapy have shown promise in persistent with their support, the biggest surprise
slowing bleeding (Chapter 21). Both the phase II has been how often functional recovery far exceeds
and phase III studies of recombinant factor VIIa as what we once thought was possible. This is the key
very early treatment for ICH demonstrated lower insight that has served as the ultimate motivation for
ICH volumes in the actively treated patients com- the contributors to this book, who have devoted their
pared to those treated with placebo. Clinical out- careers to finding effective treatments for this devas-
comes were improved in the phase II trial but not tating disease.
in the phase III trial. In the future, initiation of
Thomas Brott, MD
procoagulant treatment even earlier and with
Mayo Clinic
improved patient selection may be shown to enhance
Jacksonville, FL
clinical outcomes after ICH.

xiii
 Section 1 Epidemiology
Chapter

1
The epidemiology of intracerebral
hemorrhage
Matthew L. Flaherty, Daniel Woo, and Joseph P. Broderick

Introduction [2–11]. Intracerebral hemorrhage incidence rates are

higher in eastern Asia, where ICH has historically
Advances in brain imaging have dramatically changed accounted for a larger percentage of all strokes than
our understanding of intracerebral hemorrhage in Western populations [12–14]. This balance may be
(ICH). In the pre-CT era, many small ICHs were changing due to declining rates of ICH in the East
misclassified as ischemic strokes and patients with [12,15,16].
massive ICH or subarachnoid hemorrhage (SAH) The incidence of ICH declined between the 1950s
were often difficult to correctly classify. This chapter and the 1980s [17–19]. Studies of incidence trends
reviews the epidemiology of non-traumatic ICH in in subsequent years have produced mixed results.
light of modern neuroimaging and includes discus- There was a trend toward a reduction in ICH inci-
sions of the incidence, etiology, clinical presentation, dence in Oxfordshire, England between 1981 and
and natural history of this condition. 2006 [20]. Intracerebral hemorrhage incidence also
declined during the 1990s in several Chinese cities
Incidence of intracerebral hemorrhage [12]. However, similar declines have not been seen
Intracerebral hemorrhage accounts for 10–15% of all in other studies [2,8,21,22]. The stabilization of ICH
strokes in Western populations and is defined as incidence in the last two decades is at least partially
the non-traumatic, abrupt onset of severe headache, attributable to the detection and proper classification
altered level of consciousness, or focal neurological of small hemorrhages with modern neuroimaging
deficit associated with a focal collection of blood [8,23,24].
within the brain parenchyma on neuroimaging or at Risk for ICH appears to be marginally greater in
autopsy which is not due to trauma or hemorrhagic men than in women, driven by an excess of deep
conversion of a cerebral infarction [1]. hemorrhages [11,25,26]. In the United States blacks
The incidence of ICH is defined as the percentage and Hispanics have significantly higher rates of ICH
of a population experiencing a first ICH in a given than whites [11,27]. Among blacks and Hispanics, the
time period (usually a year). When reviewing studies excess risk of ICH is most notable in young and
of ICH incidence it is important to consider the middle-aged persons (Table 1.1) [11,27,28].
criteria utilized, as investigators may include or exclude The predominant location of ICH within the brain
hemorrhages associated with vascular malformations, varies in different populations (Table 1.2). In the
anticoagulants, thrombolytic agents, or illicit drugs. United States, Europe, and Australia, deep cerebral
Comparisons of incidence rates are further comp- ICH (hemorrhage originating in the periventricular
licated by methodological differences in case ascer- white matter, caudate nucleus, internal capsule, puta-
tainment, imaging rates, variations in population men, globus pallidus, or thalamus) is most common,
structure, and the range of ages reported. followed closely by lobar hemorrhages originating in
Given these limitations, incidence rates of ICH in the gray matter or subcortical white matter. In a large
the Western hemisphere during the CT era have gen- population-based study in Japan, however, lobar
erally ranged from 10 to 30 cases per 100 000 persons hemorrhage accounted for only 15% of ICHs [13].

Intracerebral Hemorrhage, ed. J. R. Carhuapoma, S. A. Mayer, and D. F. Hanley. Published by Cambridge University Press. 1
# J. R. Carhuapoma, S. A. Mayer, and D. F. Hanley 2010.
 Section 1: Epidemiology

Table 1.1. Age-specific risk ratios for ICH defined by location in the Greater Cincinnati Area, black vs. white*

Age Lobar Deep Brainstem Cerebellum

RR 95% CI RR 95% CI RR 95% CI RR 95% CI

20–34 2.1 0.5–9.3 2.1 0.5–9.3 0 0–20.1 0 0.67
35–54 3.7 2.1–6.7 4.5 3.0–6.8 9.8 4.2–23.0 4.0 1.5–10.8
55–74 1.7 1.1–2.7 2.3 1.7–3.3 3.0 1.2–7.4 0.8 0.2–2.4
75–84 1.2 0.7–2.0 1.1 0.7–1.8 3.6 1.2–11.1 0.7 0.2–2.1
85þ 1.0 0.4–2.2 0.9 0.4–1.9 0 0–3.3 0.6 0.1–3.7
All 1.4 1.0–1.8 1.7 1.4–2.1 3.3 2.0–5.5 0.9 0.5–1.6
Notes: *Risk ratio calculated from unadjusted incidence rates.
RR ¼ risk ratio, RR > 1 indicates greater risk among blacks.
Source: From [11].

Table 1.2. Proportional distribution of ICH in different studies

Total ICH Lobar (%) Deep (%) Brainstem (%) Cerebellum (%)
Greater Cincinnati [11] 1038 359 (35) 512 (49) 65 (6) 102 (10)
Izumo City, Japan [13] 350 53 (15) 242 (69) 30 (9) 25 (7)
Southern Sweden [148] 341 176 (52) 121 (36) 15 (4) 29 (9)
{
Jyvaskyla region, Finland [9] 158 53 (34) 77 (49) 11 (7) 17 (11)
Dijon, France [149] 87 16 (18) 58 (67) 5 (6) 8 (9)
Perth, Australia [150] 60* 19 (32) 31 (52) 4 (7) 6 (10)
{
Notes: Includes 9 intraventricular hemorrhages, here included in the deep group.
*Includes 13 “massive cortical” hemorrhages, here included in the deep group.
Source: From [11].

In most populations, cerebellar hemorrhage accounts factors or whether there are additional factors, possibly
for approximately 10% of ICH and brainstem hemor- genetic, which remain undiscovered.
rhage for 5–10% of ICH (Table 1.2). In the United
States, the greatest excess risk of ICH in blacks and
Hispanics as compared to whites occurs in deep cere- Hypertension
bral and brainstem locations (Table 1.1) [11,28]. Hypertension is the most important and prevalent
modifiable risk factor for ICH. In the biracial popula-
tion of Greater Cincinnati during 1988, the presence
Risk factors for intracerebral of hypertension among patients with ICH was remark-
hemorrhage ably similar for whites (73%), African-Americans
(71%), men (72%), and women (73%) [29]. Untreated
Age and race hypertension is a greater risk factor than treated
Age is the greatest risk factor for ICH. Incidence hypertension, and hypertensive patients who discon-
rates increase dramatically among persons older tinue their medications have greater risk than those
than 60 (Fig. 1.1). As discussed previously, there are who continue them [30,31].
geographic and racial variations in ICH incidence. Among modifiable risk factors for ICH, hyper-
2 Studies to date have not determined whether these tension accounts for the greatest attributable risk
variations can be explained entirely by known risk for hemorrhage in deep hemispheric and brainstem
 Chapter 1: Epidemiology of intracerebral hemorrhage

locations [32]. The role of hypertension in lobar ICH 15–54 years to 1.3 among those aged 65–74 years
is less clear, but accumulating evidence suggests [31]. Treatment trials for hypertension have shown
hypertension is also a risk factor for hemorrhage in reduced ICH risk with improved blood pressure
this location (albeit less potent) [31,33]. The relative control [35,36].
effect of hypertension as a risk factor for ICH is The use of illicit sympathomimetic drugs, particu-
greater in younger patients than the elderly [31,34]. larly cocaine and amphetamines, has been associated
In one case-control study the odds ratio for hyper- with hemorrhagic stroke in some (but not all) studies
tension in ICH fell from 7.7 among patients age [37–39]. This relationship may be due to drug-induced
hypertension or drug-induced cerebral vasculitis.
200
Black
180
White
Cerebral amyloid angiopathy
Once thought to be a rare cause of ICH, cerebral
Incidence rate / 100 000 persons

160

140
amyloid angiopathy (CAA) is now considered an
important cause of lobar hemorrhage in the elderly
120 (Fig. 1.2) [40–42]. Its principal pathological feature
100 is the deposition of amyloid protein in the media and
adventitia of leptomeningeal arteries, arterioles, capil-
80
laries, and, less often, veins [40–44]. The hypothesized
60 pathogenesis of ICH due to CAA involves destruction
of the normal vascular structure by deposition of
40
amyloid in the media and adventitia and subsequent
20 miliary aneurysm formation or double barreling and
0
fibrinoid necrosis [40–42]. The brittle blood vessels
20–34 35–54 55–74 75–84 85+ and microaneurysms may then be prone to rupture in
Age response to minor trauma or sudden changes in blood
pressure [19]. Cerebral amyloid angiopathy may also
Fig. 1.1 Annual age-specific, race-stratified incidence rates of ICH
per 100 000 persons in the Greater Cincinnati/Northern Kentucky be responsible for transient neurological symptoms
region, 1998–2003 (author’s unpublished data). and dementia with leukoencephalopathy [45].

(a) (b) (c)

Fig. 1.2 Gradient echo MRI of a patient with previous microhemorrhages in multifocal regions typical of cerebral amyloid angiopathy.
(a) T1-weighted image demonstrating an old lesion in the left frontal lobe. (b) T2-weighted image demonstrates a hemosiderin ring around 3
the left frontal lesion. (c) Gradient echo imaging reveals microbleeds in the right frontal and parietal lobes.
 Section 1: Epidemiology

Amyloid protein becomes increasingly frequent in Table 1.3. Comparison of the frequency of vascular
malformations in autopsy series vs. series of symptomatic
cortical blood vessels with advancing age, affecting ICH patients
only 5–8% of persons age 60–69 years but 57–58%
of those age 90 years or older [46, 47]. The deposition Population-based ICH patients
of amyloid is most prominent in the parieto-occipital autopsy [151] autopsy [152]
regions and is rarely found in the basal ganglia or Venous 105 (63%) 2 (1.3%)
brainstem [40–43]. Cerebral amyloid angiopathy
Telangiectasia 28 (17%) 1 (0.6%)
equally affects men and women [41].
Arteriovenous 24 (14%) 159 (88%)
Cavernous 16 (10%) 6 (3%)
Apolipoprotein E and CAA
Mixed type N/A 11 (6%)
The relationshiop of Apolipoprotein E and CAA is
discussed in more detail in Chapter 4. Several studies Note: Some patients had more than one type of malformation.
N/A ¼ not reported.
have examined the relationship of Apolipoprotein E
E2 and E4 with lobar ICH and CAA [32,33,48–51].
In a population-based, case-control study of contrasts starkly with lesions that cause hemorrhage
hemorrhagic stroke in Greater Cincinnati/Northern as reported by autopsy (Table 1.3). While venous
Kentucky (the Genetic and Environmental Risk Factors malformations are the most common lesions in the
for Hemorrhagic Stroke, or GERFHS, study), cases general population, they are associated with only a
of lobar ICH were age-, race-, and gender-matched to small percentage of ICH cases. Similarly, cerebral tel-
controls from the same population, allowing investiga- angiectasias are more common at autopsy than AVMs
tors to control for putative ICH risk factors and deter- or cavernous malformations but rarely hemorrhage.
mine the prevalence of Apolipoprotein E genotype in The natural history, clinical evaluation, and manage-
the population from which cases were identified. ment options for intracranial vascular malformations
After controlling for the presence of hypertension, have been recently reviewed [53].
hypercholesterolemia, frequent alcohol use, smoking
history, and other risk factors, Apolipoprotein E E4
was found to be an independent risk factor for lobar Anticoagulant- and thrombolytic-
ICH but not non-lobar ICH. In addition, haplotypes
inferred using 12 markers over the 50 untranslated associated ICH
region, promoter region, and exons of the Apolipo- The use of warfarin for prevention of ischemic stroke
protein E gene identified significant association with among patients with atrial fibrillation increased signifi-
lobar ICH, which suggests that regulation of the gene cantly during the late 1980s and 1990s following pub-
may affect the risk of disease [33]. lication of the Stroke Prevention in Atrial Fibrillation
(SPAF) trials, European Atrial Fibrillation Trial,
and other important studies on this topic [57–60].
Aneurysms and vascular malformations Warfarin distribution in the United States quadrupled
Although ruptured berry aneurysms typically cause on a per-capita basis during the 1990s [61]. During
SAH, on occasion bleeding is directed into the brain the same period, the incidence of anticoagulant-
parenchyma without significant subarachnoid exten- associated intracerebral hemorrhage (AAICH) quintu-
sion [52]. Vascular malformations associated with pled in the Greater Cincinnati region [61]. Studies from
ICH include arteriovenous malformations (AVMs), other regions have shown similar trends [62,63].
cavernous malformations, dural arteriovenous fistulae, In most trials of warfarin for treatment of atrial
venous malformations, and capillary telangiectasias fibrillation or myocardial infarction the risk of
[53]. Reports of ICH mechanism suggest that aneur- AAICH has ranged from 0.3% to 1.0% per patient-
ysms and vascular malformations are particularly year, with risk on the lower end of this spectrum in
important as a cause of ICH among young people more recent studies [64,65]. Several trials have tested
[52,54–56]. In a prospective autopsy series, 4% of all warfarin for secondary stroke prevention in patients
4 brains were found to have vascular malformations, with cerebral ischemia of non-cardiac origin. The
of which 63% were venous malformations. This Warfarin-Aspirin Recurrent Stroke Study (WARSS)
 Chapter 1: Epidemiology of intracerebral hemorrhage

compared aspirin to warfarin (goal INR 1.4–2.8), and Antiplatelet drugs

found no difference between groups in effectiveness
Antiplatelet drugs probably increase the risk of ICH
or risk of major hemorrhage (including ICH) [66].
by a small amount [79]. The absolute risk of intracra-
The Stroke Prevention in Reversible Ischemia Trial
nial hemorrhage among elderly persons taking aspirin
(SPIRIT) compared aspirin to high intensity warfarin
has been estimated at 0.2–0.3% annually (vs. 0.15% in
(goal INR 3.0–4.5) [67]. It was stopped before com-
similar persons not taking antiplatelets or anticoagu-
pletion because of a 7.0% annual risk of major hem-
lants) [65]. This risk increases with age and aspirin
orrhage in the warfarin group, including a 3.7%
doses > 325 mg daily [79,80]. In trials comparing the
annual risk of intracranial bleeding [68].
antiplatelet agents clopidogrel or ticlopidine to aspirin
Studies of anticoagulation outside of clinical trials
among patients at high risk of vascular events, rates of
show that well-managed warfarin at conventional
intracranial hemorrhage were similar between groups
INRs can produce acceptable rates of ICH (similar
[81]. However, the combination of aspirin plus clopi-
to or slightly higher than in trials); however, the
dogrel led to more intracranial hemorrhages than
hemorrhage risk must be balanced against the benefit
clopidogrel alone when used for secondary stroke
of anticoagulation for each patient [64,69–72]. The
prevention in the MATCH trial [65,82]. A meta-
relative risk of ICH in anticoagulated patients as
analysis of trials using dipyridamole for secondary
compared to the general population is approximately
stroke prevention found the combination of aspirin
7–10 [64,69]. Data from clinical trials and community
and dipyridamole did not cause more bleeding than
surveillance suggest that clinical factors that increase
aspirin alone, although specific rates for intracranial
the risk of AAICH are advanced age, prior ischemic
hemorrhage were not reported [83].
stroke, hypertension, leukoaraiosis, and higher inten-
sity of anticoagulation [64,65,68]. The addition
of antiplatelet agents to warfarin probably increases Cerebral microbleeds
the risk compared to warfarin alone [64,65,73]. The use of gradient echo MRI to detect small, asymp-
Strict management of blood pressure and INR tomatic hemorrhages in the brain parenchyma
in anticoagulated patients reduces the risk of (“microbleeds”) has received considerable recent
hemorrhage [65]. attention. Gradient echo MRI accentuates signal
Thrombolysis for myocardial infarction carries a dropout from chronic blood products and is more
small but definite risk of intracranial hemorrhage. sensitive at detecting small hemorrhages than stand-
Rates of intracranial hemorrhage in this setting have ard T2 sequences [84,85]. The prevalence of micro-
generally ranged from 0.4% to 1.5% of patients treated bleeds in the general population is best estimated
with various regimens of thrombolytic agents and from two studies of middle-aged and elderly adults
anticoagulants [74–76]. Risk factors for hemorrhage without known cerebrovascular disease or dementia,
after thrombolysis for myocardial infarction include in which microbleeds were found in 6.4% and 4.7%
older age, female sex, black race, hypertension, prior of the respective populations [86,87]. Microbleeds are
stroke, excessive anticoagulation, and lower body associated with both ischemic (especially lacunar)
weight [74,76,77]. In the large GUSTO-1 trial, the and hemorrhagic cerebrovascular disease as well as
majority of such hemorrhages were intraparenchymal hypertension, leukoaraiosis, advancing age, and male
(81%) or intraparenchymal plus subdural (15%), with gender [86–89]. Microbleeds are common in hemor-
relatively few pure subdural (3%) or pure intraventri- rhagic stroke, occurring in 54–71% of ICH patients
cular (1%) bleeds [75]. Among intraparenchymal (Fig. 1.2) [90]. They appear to be equally prevalent
hemorrhages, the majority (77%) occurred in lobar in cases of deep cerebral and lobar hemorrhage, and
regions of the brain [75]. Intraventricular (49%) are therefore not specific for amyloid angiopathy
and subarachnoid (11%) extension of bleeding was or hypertensive ICH; however, in some studies the
relatively common [75]. location of microbleeds has correlated with the site of
Thrombolytic treatment of ischemic stroke symptomatic hemorrhage (i.e., deep cerebral micro-
carries a greater risk of intracranial hemorrhage bleeds are associated with deep cerebral ICH while lobar
than thrombolysis for myocardial infarction, but microbleeds are associated with lobar ICH) [91,92].
discussion of this matter is beyond the scope of this Many clinicians consider microbleeds to be markers 5
chapter [78]. of small-vessel disease and a hemorrhage-prone state.
 Section 1: Epidemiology

Although microbleeds have been associated with a Large randomized trials of statin drugs for primary
variety of demographic variables and disease states, and secondary prevention of cardiovascular disease
their practical value in predicting hemorrhage risk is have not shown increased ICH rates [103,104]. How-
less clear. A small, prospective Chinese study scanned ever, a randomized trial of high-dose atorvastatin
121 acute stroke patients with gradient echo MRI versus placebo for patients with transient ischemic
and found that 35.5% had microbleeds. Over a mean attack or stroke did find a trend toward more hemor-
follow-up of 27.2 months, 4 patients (9.3%) with rhagic strokes among the atorvastatin group during
microbleeds had a subsequent ICH, compared to 1 follow-up [105].
patient (1.3%) without microbleeds (p ¼ 0.053) [93].
Additionally, in a referral-based study of lobar ICH
patients, increasing burden of microbleeds was shown
Heavy alcohol use
to predict recurrent hemorrhage [94]. However, these Numerous studies have identified a relationship
studies are too small to guide patient management between alcohol use and the risk of hemorrhagic
at present. The power of microbleeds to predict sub- stroke [26,37,106,107]. There is probably a dose–
sequent hemorrhagic and ischemic cerebrovascular response relationship with increased risk among
disease and the value they might add to risk–benefit heavy but not light drinkers [26,107]. Heavy alcohol
analyses for antiplatelet or anticoagulant use are use has also been implicated in early hematoma
important questions which remain unanswered. expansion, possibly due to adverse effects upon platelet
and liver function [108].
Prior cerebral infarction
Prior cerebral infarction is associated with a 5- to Tobacco use
22-fold increased risk of ICH [32,95,96]. The strong There may be a weak association between tobacco
relationship between ICH and cerebral infarction is use and ICH but data have been conflicting [26,37].
not surprising since hemorrhage and infarction share Several recent studies suggest that current smoking
similar risk factors, such as hypertension. In the (as opposed to past smoking or never smoking)
GERFHS case-control study in Greater Cincinnati increases the risk of ICH in a dose-dependent manner
15% of ICH patients had a history of previous ische- [38,109,110].
mic stroke; the multivariate odds ratio for ICH in
patients with prior stroke compared to controls was
7.0 [32].
Diabetes
Diabetes is associated with greater risk of ICH in
some case-control studies. A review of available data
Hypocholesterolemia produced an overall risk ratio of 1.3 with borderline
While hypercholesterolemia is a risk factor for cardiac statistical significance [26]. The association of dia-
disease and ischemic stroke, hypocholesterolemia betes and ICH may vary by age group and location
appears to increase risk of ICH. Data from case-control of hemorrhage [38]. Clarification of the role of dia-
studies have been mixed, but the preponderance of betes as a “minor risk factor” for ICH will require
evidence supports an inverse relationship between larger studies [111].
cholesterol levels and ICH risk [26,97–102]. This
relationship is also supported by several cohort stud-
ies [26]. Potential explanations for the association Heritability
of low cholesterol and ICH include reduced platelet There is a genetic component to ICH risk but its
aggregation, increased fragility of the cerebral vascu- absolute value is small. Among probands in the
lature, and confounding by medical illness or nutri- GERFHS case-control study, 6% of patients had an
tional deficiencies [98]. Given these findings, there is affected first-degree relative and 6% an affected
theoretical concern that widespread use of cholesterol second-degree relative. Among cases the odds ratio
lowering medications may increase rates of ICH. for an affected first-degree relative was high (6.3) but
Analysis of the GERFHS study showed that hypercho- the population attributable risk was low (0.05) [32].
6 lesterolemia was protective for ICH, but that statin The association of apolipoprotein genotypes with
use was not associated with increased ICH risk [97]. lobar ICH was previously discussed.
 Chapter 1: Epidemiology of intracerebral hemorrhage

Clinical presentation and naturalhistory followed by increasing edema and clinical deterior-
ation. This view is no longer accepted. A prospective,
of intracerebral hemorrhage population-based study of spontaneous ICH in
The Harvard Cooperative Stroke Registry reported 1993 showed that among hemorrhages imaged within
on the clinical findings associated with stroke [112]. 3 hours of onset 26% increased by > 33% in volume
The clinical features used to define ICH were presen- in the next hour and 38% increased by > 33% volume
tation with a gradual progression (over minutes or within the first day (Fig. 1.3) [113]. The importance
days) or sudden onset of focal neurological deficit, of ICH expansion has been confirmed by other stud-
usually accompanied by signs of increased intracranial ies which demonstrate that most hematoma growth
pressure such as vomiting or diminished conscious- occurs within six hours of onset, and that growth
ness. As many as 91% of patients were hypertensive is associated with worse outcomes [108,114–116].
(blood pressure 160/100 mmHg or higher) at the onset Based upon these findings, the use of ultra-early
of their stroke. hemostatic therapy to reduce hematoma growth and
Vomiting was far more common in ICH and SAH potentially improve outcome following ICH has
(51% and 47% respectively) than for ischemic stroke become an active area of research [117]. Clinical
(4–10% of cases). While SAH presented with head- predictors of early hematoma growth have been diffi-
ache at onset in 78% of cases, 33% of cases of ICH cult to consistently identify. In one retrospective study
also had a headache at onset compared to 3–12% of hypertension (systolic blood pressure  160) was
ischemic stroke subtypes. Finally, SAH and ICH both associated with enlargement [116]. This finding has
presented with coma in 24% of cases compared to
0–4% of ischemic stroke subtypes. A particular charac-
Table 1.4. Clinical presentation of symptoms by subtype
teristic of ICH was the smooth or gradual progression of stroke
of stroke in 63% of cases, with sudden onset in 34% of
cases (Table 1.4). A smooth or gradual onset of stroke Thrombosis Lacune Embolus ICH SAH
was seen in only 5–20% of ischemic stroke subtypes Maximal 40% 38% 79% 34% 80%
and 14% of SAH. Thus, ICH is the stroke subtype most at onset
likely to worsen significantly in the first 24 hours.
Stepwise 34% 32% 11% 3% 3%
Gradual 13% 20% 5% 63% 14%
Hematoma growth Fluctuating 13% 10% 5% 0% 3%
Intracerebral hemorrhage was traditionally viewed as
Source: From [112].
a monophasic event with a brief episode of bleeding

(a) (b) Fig. 1.3 Increase in hemorrhage size.

A thalamic ICH (a) is seen in this patient
06:50 with a history of hypertension. The
patient’s condition deteriorated over
05:22 the next hour and repeat imaging
(b) demonstrates enlargement of the
hematoma and rupture into the ventricles.

7
 Section 1: Epidemiology

(a) (b) Fig. 1.4 (a) Spontaneous ICH

with perihematomal edema.
(b) Coagulopathy-associated ICH with
minimal perihematomal edema despite
greater hemorrhage size.

not been prospectively confirmed [113,118]. Another edema, while lysis of red blood cells contributes to
retrospective study identified earlier patient presenta- edema at approximately 72 hours [125,126]. Studies
tion, heavy alcohol consumption, reduced level of con- have subsequently demonstrated that edema forma-
sciousness, and an irregularly shaped hematoma as tion can occur when clotting factors alone (without
predictors of enlargement [108]. The authors did not serum or red blood cells) are injected into animal
include hypertension after admission in their multi- brains [127,128]. Thrombin and the fibrinogen cas-
variate model because of concern that hypertension cade have been implicated in edema formation [127].
was an effect rather than a cause of hematoma growth In humans, most hemorrhages due to thromboly-
[108]. Serum factors associated with hematoma growth sis are large and have little perihematomal edema
have included low fibrinogen levels and elevated levels [75]. Thrombolysis-related ICH has visible perihe-
of interleukin-6 and cellular fibronectin [108,119]. matoma less often than spontaneous ICH and has
Conflicting reports have compared the size of lower absolute and relative volumes of edema [129].
AAICH and bland ICH at presentation to medical care; Figure 1.4 compares a case of spontaneous ICH to a
some find no difference in size and some find larger case of ICH with coagulopathy.
hemorrhages in anticoagulated patients [120–122]. Among patients not receiving anticoagulants, abso-
After presentation, hematoma enlargement and clini- lute edema volume generally doubles within the first
cal deterioration are more common in anticoagulated day, while relative edema volume (defined as absolute
patients [64,120,123]. Failure to promptly correct edema volume divided by hematoma size) increases by
elevated INRs has been associated with hematoma a lesser amount [130]. One study found that greater
enlargement [124]. relative edema volume in the hyperacute period para-
doxically predicted better clinical outcomes, possibly
Perihematomal edema because such edema resulted from successful hema-
toma clotting, but this finding has not been replicated
With the advent of CT technology, much has been
[115,131]. Significant delayed edema may occur days
learned about perihematomal edema. When whole
to a week after initial bleeding and has been associated
blood is infused into the cerebral lobes of pigs,
with neurological deterioration [132].
perihematomal edema develops within one hour of
infusion [125]. Yet when packed red blood cells (no
serum) are injected, edema does not develop for Morbidity and mortality
8 nearly 72 hours. This suggests that factors within Intracerebral hemorrhage is often clinically devasta-
serum are responsible for acute perihematomal ting. Thirty-day case fatality rates in most studies
 Chapter 1: Epidemiology of intracerebral hemorrhage

Table 1.5. Mortality of ICH based on volume and location of hematoma

Overall 30-day mortality (n ¼ 188)  30 cm3 ICH 30–60 cm3 ICH  60 cm3 ICH
Lobar (n ¼ 66) 39% 23% 60% 71%
Deep (n ¼ 76) 48% 7% 64% 93%
Pontine (n ¼ 9) 44% 43% 100% N/A
Cerebellum (n ¼ 11) 64% 57% 75% N/A
Note: N/A ¼ not applicable.
Source: From [137].

range from 40% to 50%, with approximately half of approach (68%) than progression to brain death
deaths occurring within two days of onset [133–135]. (29%) or medical complications (3%) [139]. The
Patients with ICH fare worse than those with ische- “self-fulfilling prophecy” in neurological catastrophes
mic stroke, and few are left without disability [133, like ICH has been described as the preconceived
134]. Mortality after ICH was reportedly as high notion that medical care is futile, followed by
as 90% in the pre-CT area [17]. The lower mortality withdrawal of care and death of the patient [140].
in more recent studies likely reflect a combination The complicated determinants of morbidity and mor-
of identification bias in the pre-CT era (with mild tality following ICH, together with expectations of
hemorrhages misclassified as ischemic infarcts) and the patient, family, and physicians require careful
improved supportive care [23,135]. A study compar- consideration in each case.
ing mortality after ICH in 1988 and the late 1990s
found no improvement in outcomes during that
period [135]. Risk of ICH recurrence
Because ICH is less common and more deadly than
ischemic stroke, studies estimating ICH recurrence
Prognostic indicators risk have been more difficult to perform. A review
A variety of reports have examined clinical and radio- of studies tracking ICH recurrence found an aggre-
graphic factors associated with prognosis after ICH. gate risk of 2.4% per patient-year [141]. The studies
Predictors of poor outcome include advanced age, selected excluded patients with “secondary” causes of
poor neurological status at presentation (as measured ICH such as vascular malformations or anticoagula-
by Glasgow Coma Scale [GCS] score), larger hema- tion. Most studies have found ICH recurrence is more
toma size, early hematoma growth, intraventricular common following lobar ICH than non-lobar ICH.
extension of hemorrhage, anticoagulant use, and In the cited review, risk of recurrence among patients
brainstem location of hemorrhage [13,121,135–138]. presenting with lobar ICH was 4.4% per year, com-
In a population-based study in Greater Cincinnati, pared to 2.1% annually for those with non-lobar
the volume of ICH in combination with the GCS hemorrhage [141]. Risk of new cerebral ischemia
predicted overall 30-day mortality with 96% sensi- (1.1% per year) was lower than the risk of recurrent
tivity and 98% specificity (Table 1.5). Patients with a ICH [141]. One study found that Apolipoprotein
volume of 60 cm3 and a GCS score  8 had a pre- E2 or E4 genotypes increase the risk of recurrence
dicted mortality of 91% while those with a volume following lobar ICH, presumably because of their
of  30 cm3 and a GCS score  9 had a predicted association with amyloid angiopathy [142]. The 21%
mortality rate of 19%. For ICH with a volume of two-year recurrence risk after lobar ICH in this study
 60 cm3, the 30-day mortality for deep hemorrhages was greater than other reports and likely reflects
was 93% and for lobar hemorrhages was 71% the highly selected patient cohort [142]. A recent
(Table 1.5) [137]. Several prediction models for out- population-based study of ICH in Izumo City, Japan,
come after ICH have been developed but have not documented an annual recurrence risk of 2.3% among
gained widespread clinical use [136,138]. Nonetheless, 279 patients [143]. Location of ICH did not predict
in a recent study more deaths caused by ICH were recurrence in this population, consistent with epi- 9
associated with withdrawal of care or a “comfort care” demiological data showing that lobar hemorrhage
 Section 1: Epidemiology

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15
 Section 2 Etiology of non-traumatic intracerebral hemorrhage
Chapter

2
Acute hypertensive response
in intracerebral hemorrhage
Ameer E. Hassan, Haralabos Zacharatos, and Adnan I. Qureshi

Acute hypertensive response is the elevation of blood drugs) and un-modifiable (increased age, male gender,
pressure above normal and premorbid values that and cerebral amyloid angiopathy) risk factors that
initially occurs within the first 24 hours of symptom contribute to ICH and its recurrence must be carried
onset in patients with intracerebral hemorrhage out due to the high morbidity and mortality associ-
(ICH). We reviewed the existing data pertinent to ated with it. Other risk factors include gender (3.7- to
acute hypertensive response derived from scientific 4.6-fold increase in men), age (almost twofold increase
guidelines, randomized trials, non-randomized con- every ten years), smoking (2.1- to 2.7-fold increase),
trolled studies, and selected observational studies. low cholesterol levels (< 150 mg/dl; increased twofold),
diabetes (1.3-fold), increased alcohol consumption
(moderate, 36–56 g/day: twofold increase; excessive,
Chronic hypertension and intracerebral > 56 g/day: fourfold increase), drugs (i.e., cocaine and
hemorrhage amphetamines) and coagulopathies [7–12].
The risk of ICH in one study showed that it
Incidence of intracerebral hemorrhage doubled every decade, in-line with the results of other
and hypertension studies [7,13–15]. Age, > 65 years old, and non-white
Spontaneous, non-traumatic ICH from intraparen- ethnicity have both been consistently positively asso-
chymal blood vessels makes up approximately 8–15% ciated with ICH [16,17]. In young patients in whom
of all strokes. Approximately 80–85% are primary other causes such as arteriovenous malformation
spontaneous ICH which are either secondary to arter- or trauma have been excluded illicit drug use, which
ial hypertension or cerebral amyloid angiopathy [1]. leads to elevated systolic blood pressure, such as
It is estimated that 70% of the primary spontaneous amphetamines, cocaine, and phenylpropanolamine
ICH cases are attributed to arterial hypertension while should be excluded [18,19].
roughly 5–20% are secondary to cerebral amyloid There are large racial variations with increased
angiopathy. A total of 15–20% of stroke cases are rates of intracerebral hemorrhage in Hispanic, Asian
attributed to secondary spontaneous ICH, related to and African-American populations in comparison
oral anticoagulation (~ 4–20%), tumors (~ 5%), vas- with the white population [2,4,20–24]. The relative
cular malformations (~ 1–2%) and more uncommon rate of 1.89 for African Americans versus whites was
reasons, such as sinus venous thrombosis, cerebral also similar to estimates reported in the literature
vasculitis, drugs, eclampsia, and others (~1 %) [2–6]. [4,13,14,25–27]. Qureshi et al. examined the relation
between ethnicity and ICH in NHANES I (First
National Health and Nutrition Examination Survey
Risk factors for intracerebral hemorrhage Epidemiological Follow-up Study) and reported that
Hypertension is the most frequent and most import- much of the association with ethnicity was mediated
ant risk factor for ICH [1]. A rigorous identification through hypertension and education [26].
of modifiable (hypertension, smoking, low cholesterol Hypertension continues to be implicated as the
levels, diabetes, increased alcohol consumption, and most important risk factor for ICH as more studies

Intracerebral Hemorrhage, ed. J. R. Carhuapoma, S. A. Mayer, and D. F. Hanley. Published by Cambridge University Press. 17
# J. R. Carhuapoma, S. A. Mayer, and D. F. Hanley 2010.
 Section 2: Etiology of non-traumatic ICH

are conducted. In a recent Korean study the risk of by the elevated values of blood pressure in
ICH was 4.9 for stage one hypertension (blood pres- hypertension is weakened by the hyaline material.
sure 140–159/90–99 mmHg), 11.6 for stage two hyper- The presence of hyaline material in the cerebral vas-
tension (blood pressure 160–179/100–109 mmHg), cular wall has been correlated with a minimal resist-
and 28.8 for stage three hypertension (blood ance of the surrounding cerebral parenchyma. It also
pressure > 180/> 109 mmHg), as compared with nor- has been suggested as an explanation as to why the
motensive (blood pressure < 140/< 90 mmHg) sub- cerebral parenchyma is the only tissue in which blood
jects [28]. In one study, the odds ratio for ICH was pressure variations can lead to vascular rupture and
3.5 with untreated hypertension but only 1.4 for cerebral hemorrhage [32,33].
treated hypertension, which suggests that treatment
of hypertension can prevent ICH [29]. More direct Association of brain microbleeds,
evidence comes from a study of 4736 patients
> 60 years of age with isolated systolic hypertension, hypertension, and intracerebral hemorrhage
wherein treatment resulted in an adjusted relative risk Magnetic resonance imaging gradient echo T2
of 0.46 for ICH, and the benefit was observed within sequences display brain microbleeds as small, homoge-
one year [30]. Systolic blood pressure > 160 mmHg, neous, round foci of low signal intensity. A systematic
also contributes to increased incidence of ICH in review of published literature regarding brain micro-
patients who are on oral anticoagulation [31]. bleeds revealed the prevalence of brain microbleeds
was 5% (95% confidence interval 4–6) in healthy
Pathology of hypertension and intracerebral adults, 34% (95% confidence interval 31–36) in people
with ischemic stroke, and 60% (95% confidence inter-
hemorrhage val 57–64) in people with non-traumatic ICH [34].
Hypertension contributes to decreasing the elasticity By pooling data that could be extracted from similar
of arteries, thereby increasing the likelihood of rup- studies, it appears that brain microbleeds are associ-
ture in response to acute elevations in intravascular ated with hypertension (odds ratio 3.9, 95% confi-
pressure [32]. Hypertensive patients suspected of dence interval 2.4–6.4) and diabetes mellitus (odds
primary intraparenchymal hematoma died and were ratio 2.2, 95% confidence interval 1.2–4.2) in other-
subsequently autopsied in order to assess the alter- wise healthy adults, and they are associated with
ations of extraparenchymal and intraparenchymal hypertension (odds ratio 2.3, 95% confidence interval
vascular structures. The spectrum of the lesions 1.7–3.0) in adults with cerebrovascular diseases [34].
due to arterial hypertension, at the level of the intra- They are also associated with hypertension, left ven-
parenchymal blood vessels, included all steps of vas- tricular hypertrophy, advanced small-vessel disease
cular wall degeneration, from hypertrophy of smooth and amyloid angiopathy [35]. Cerebral microbleeds
muscle layer to complete hyalinization of arterial have a topographic distribution similar to that of
wall, but with a focal irregular distribution, not ICH, suggesting that they are regionally associated
related with the proximity of hemorrhagic focus [17,36]. Hemorrhages that involve the putamen,
[32]. The capillary walls showed focal or circumferen- globus pallidum, thalamus, internal capsule, periven-
tial thickening due to the densification of the type IV tricular white matter, pons, and cerebellum are often
collagen material from the basement membrane attributed to hypertensive small-vessel disease, par-
structure which is attributed to high arterial blood ticularly in a patient with known hypertension [37].
pressure. The CD34 immunostaining showed that Further strengthening the association between brain
endothelial cells kept their structural integrity [32]. microbleeds and hypertension is a study of hemodi-
Over the course of many years, persistent hyper- alysis patients that did not show an association
tension leads to cerebral vascular wall damage that between hemodialysis and brain microbleeds, instead
can be seen with the hyalinization of excessive fibrillar the authors concluded that the presence of other
material from arteriolar wall or from basement mem- factors, such as hypertension, strongly contributed
branes, otherwise termed sclerosis (arteriolar and [38]. Microbleeds most commonly appear in patients
even capillary) with hyalinosis. Hypertensive vasculo- with a history of chronic hypertension [39–42]. Many
18 pathy inhibits the contractile capability of arterioles. patients with chronic renal failure have a long history
The vascular wall resistance to the stress determined of chronic hypertension.
 Chapter 2: Acute hypertensive response in ICH

Acute hypertensive response American Heart Association/American Stroke

Acute systolic blood pressure and mean Association guidelines for management
arterial pressure elevation of acute hypertensive response
Initially, after an acute ICH the blood pressure With regards to treating hypertension in patients with
reaches a maximum and over the course of the next ICH hemorrhage the American Heart Association/
24 hours declines spontaneously [43,44]. Elevated American Stroke Association distinguishes between
early-mortality rates have been clearly demonstrated those patients with and those without elevated intracra-
in ICH patients who present with high arterial nial pressure in their blood pressure management guide-
pressures [45–55]. Stroke patients are frequently lines. The current American Heart Association/
chronically hypertensive, and their brain hydraulic American Stroke Association guidelines (see Table 2.1)
autoregulatory curve is shifted to the right [56]. A recommends considering aggressive reduction when sys-
mean arterial pressure of approximately 50–150 mmHg tolic blood pressure exceeds 200 mmHg or mean arterial
helps maintain a constant cerebral blood flow in non- pressure exceeds 150 mmHg. In this case, measurements
stroke patients [57]. Higher mean arterial pressure should be repeated every 5 minutes. In patients in whom
levels are better tolerated by hypertensive stroke systolic blood pressure exceeds 180 mmHg or mean
patients. Stroke patients with a history of hyperten- arterial pressure exceeds 130 mmHg, and without evi-
sion are at risk of critical hypoperfusion for mean dence or suspicion of elevated intracranial pressure, a
arterial pressure levels usually well tolerated by nor- modest reduction of blood pressure should be con-
motensive individuals [58]. Mean arterial hyperten- sidered, targeting blood pressure at 160/90 mmHg or a
sion should gradually be reduced below 120 mmHg mean arterial pressure of 110 mmHg. In this case, meas-
in persons with a history of chronic hypertension, urements should be repeated every 15 minutes. The
but a reduction of > 20% should be avoided and blood pressure target of 160/90 mmHg is supported by
mean arterial pressure should not be reduced to < 84 a prospective observational study that showed a trend
mmHg [59,60]. toward improved outcome in ICH patients in whom

Table 2.1. Recommended American Heart Association/American Stroke Association guidelines for treating elevated blood pressure
in spontaneous intracerebral hemorrhage

SBP MAP Suspicion CPP Blood pressure Comment

and/or checks/clinical
evidence of re-examination
elevated ICP
1 > 200 mmHg > 150 mmHg Every 5 min Consider aggressive BP
or if reduction with continuous IV
infusion
2 > 180 mmHg > 130 mmHg Yes > 60–80 Consider monitoring ICP and
or if mmHg reducing BP using intermittent
or continuous IV medications
to keep CPP > 60–80 mmHg
3 > 180 mmHg > 130 mmHg No Every 15 min Consider a modest reduction
or if of BP (e.g., MAP of 110 mmHg
or target BP of 160/90 mmHg)
using intermittent or
continuous IV medications
to control BP
Notes: BP ¼ blood pressure, CPP ¼ cerebral perfusion pressure, ICP ¼ intracranial pressure, IV ¼ intravenous, SBP ¼ systolic blood pressure,
MAP ¼ mean arterial pressure.
Source: Adapted from [62]. 19
 Section 2: Etiology of non-traumatic ICH

Table 2.2. European Stroke Initiative recommendations for treating elevated blood pressure in spontaneous intracerebral
hemorrhage [39]

BP lowering is not routinely recommended. Treatment of elevated BP in patients with acute ICH is recommended if BP is
elevated above the following levels and confirmed by repeated measurements.
a. 170/100 mmHg (or a MAP of 125 mmHg) is the recommended target BP in patients with a known history of
hypertension or have clinical/ECG changes indicative of chronic hypertension who have a SBP > 180 mmHg and/or
DBP > 105 mmHg, if treated.
b. 150/90 mmHg (or a MAP of 110 mmHg) is the recommended target BP in patients without a known history of
hypertension who have a SBP > 160 mmHg and/or DBP > 95 mmHg, if treated.
c. Avoid reducing the MAP by more than 20%.
d. For patients who are being monitored for elevated ICP the BP limits and targets should be adapted to higher values to
guarantee a CPP > 70 mmHg.
Intravenous labetalol or urapidil, intravenous sodium nitroprusside or nitroglycerin and captopril (per os) are the
recommended drugs for BP treatment. Oral nifedipine and any drastic blood pressure decreases should be avoided.
Notes: BP ¼ blood pressure, CPP ¼ cerebral perfusion pressure, DBP ¼ diastolic blood pressure, ECG ¼ electrocardiogram, ICH ¼ intracerebral
hemorrhage, ICP ¼ intracranial pressure, MAP ¼ mean arterial pressure, SBP ¼ systolic blood pressure.
Source: Adapted from [56].

systolic blood pressure was lowered within six hours of hypertension (see Table 2.2). An upper limit of systolic
hemorrhage onset; a reduction of systolic blood pressure blood pressure of 180 mmHg and a diastolic blood pres-
to a target of less than 160/90 mmHg was associated with sure of 105 mmHg is recommended for patients with
neurological deterioration in 7% of patients and with known prior hypertension or signs of chronic hyperten-
hemorrhagic expansion in 9% [61]. The previous recom- sion (left ventricular hypertrophy on electrocardiogram
mendation was to maintain a systolic blood pressure less and changes in the retina). If treatment is necessary, the
than or equal to 180 mmHg and/or a mean arterial target blood pressure should be 170/100 mmHg (or a
pressure of less than 130 mmHg. mean arterial pressure of 125 mmHg). In patients with-
In patients in whom systolic blood pressure out known hypertension, the upper recommended
exceeds 180 mmHg or mean arterial pressure exceeds limits are 160 mmHg for systolic blood pressure and
130 mmHg, and there is evidence or suspicion of 95 mmHg for diastolic blood pressure. If treatment is
elevated intracranial pressure, monitoring of intra- necessary, the target blood pressure should be 150/
cranial pressure and cerebral perfusion pressure 90 mmHg (or a mean arterial pressure of 110 mmHg)
(cerebral perfusion pressure ¼ mean arterial pressure – [1,56]. In any case, mean arterial pressure should not be
intracranial pressure) is recommended and blood lowered by more than 20% of the baseline value. In
pressure lowering should be adapted to maintain cere- critically ill patients, blood pressure should preferably
bral perfusion pressure greater than 60–80 mmHg. In be measured continuously, or every 15 minutes if this is
any case, mean arterial pressure should not be lowered not possible. European Stroke Initiative guidelines also
by more than 20% of the baseline value. In critically recommend adapting arterial blood pressure thresholds in
ill patients, blood pressure should preferably be meas- patients with increased intracranial pressure to maintain a
ured continuously, or every 15 minutes if this is not cerebral perfusion pressure of 70 mmHg or greater [1,39].
possible [62]. A cerebral perfusion pressure greater than
60 mmHg is supported by studies done with traumatic
brain hemorrhage and spontaneous ICH [63–66]. Pathophysiological consequences
of treating acute hypertensive response
European Stroke Initiative guidelines for Hematoma growth and acute hypertensive
management of acute hypertensive response response
20 The European Stroke Initiative recommendation of Blood pressure monitoring and treatment is a critical
blood pressure management is based on a history of issue in the treatment of acute ICH because studies
 Chapter 2: Acute hypertensive response in ICH

Hibernation Reperfusion Normalization Fig. 2.1 Stages of cerebral blood flow

Stage (0–2 days) Stage (2–14 days) Stage (> 14 days) changes associated with ICH. Upper row:
light checker pattern demonstrates
reduced rCBF (hypoperfusion); dark
checker pattern demonstrates increased
rCBF (hyperperfusion); lower row: light gray
represents regions of hypometabolism.
rCBF

rCBF, regional cerebral blood flow [60].

Metabolism

have shown that reducing the blood pressure in acute was not associated with growth of the ICH in the
ICH may prevent or slow the growth of the hema- Recombinant Activated Factor VII ICH trial and
toma as well as decrease the risk of rebleeding. This in the largest prospective study of intracerebral
is especially true for hemorrhage resulting from a growth [72–74]. Isolated systolic blood pressure,
ruptured aneurysm or arteriovenous malformation, less than or equal to 210 mmHg, was not clearly
in which the risk of continued bleeding or rebleeding related to hemorrhagic expansion or neurological
is presumed to be highest. Multivariate analyses indi- worsening [67].
cate a strong correlation between elevated systolic
blood pressure and subsequent hematoma expansion
[67,68]. Retrospective analyses indicate that acute Hypoperfusion in perihematomal area
blood pressure reduction has been associated with a There still remains an ongoing debate of whether to
decrease in hematoma expansion [69,70]. Several aggressively lower blood pressure in the setting of the
retrospective studies show that elevated systolic blood acute phase of the ICH. An uncertainty exists of
pressure greater than 160 mmHg on admission has whether there is a perihematomal area of critical
been associated with growth of the hematoma, but hypoperfusion that may experience further perile-
this has not been demonstrated in prospective studies sional ischemia as a result of the lowering of the blood
of ICH growth [68,71–73]. pressure (Fig. 2.1) [75,76]. Decreased cerebral perfu-
Hemorrhagic enlargement occurs more frequently sion pressure secondary to the reduced blood pressure
in patients with elevated systolic blood pressure, but it could compromise adequate cerebral blood flow
is not known whether this is an effect of increased due to increased intracranial pressure [61]. While
growth of ICH with associated increases in intra- some neuroimaging studies using single-photon
cerebral pressure or whether increased blood pressure emission computerized tomography, functional MRI
is a contributing cause to the growth of ICH [70]. The or perfusion computerized tomography suggest that
risk of hemorrhagic expansion with mild blood pres- there may be an area of critical hypoperfusion sur-
sure elevation may be lower and must be balanced rounding the hematoma [77–79], most other studies
with the theoretical risks of inducing cerebral ischemia using positron emission tomography, MRI perfusion
in the edematous region that surrounds the hemor- imaging or perfusion computerized tomography
rhage in primary ICH, in which a specific large-vessel found reduced cerebral blood flow, but far above 21
vasculopathy is not apparent. Baseline blood pressure ischemic levels, consistent with oligemia [76,80–84].
 Section 2: Etiology of non-traumatic ICH

Contradictive results regarding perilesional hypo- Table 2.3. Possible intravenous medications for control of
hypertension in patients with intracerebral hemorrhage
perfusion, hematoma growth, and clinical outcome
are observed in clinical studies of blood pressure Drug Intravenous Continuous
lowering in ICH [50,61,70–74,85,86]. bolus dose infusion rate
Hydralazine 5–20 mg IVP 1.5–5 µg/(kg min)
every 30 min
Decrease in perihematomal edema
Enalapril 1.25–5 mg IVP NA
by reducing blood pressure every 6 h*
The reduction in the volume of the perihematomal
Esmolol 250 µg/kg IVP 25–300 µg/(kg min)
edema, which has a direct correlation to hematoma loading dose
volume, may be associated with the decrease in blood
pressure [87,88]. Studies in acute ICH patients using Nicardipine NA 5–15 mg/h
MRI studies provide evidence that edema in acute Nipride NA 0.1–10 µg/(kg min)
ICH is plasma derived and oligemia is not an etio- Nitroglycerin NA 20–400 µg/min
logical factor [81,82]. A combination of clot retrac-
tion, reflecting successful hemostasis and the oncotic Labetalol 5–20 mg every 2 mg/min
force supplied by thrombin and other proteins 15 min (maximum
300 mg/d)
may lead to fluid formation within the perihemato-
mal region. Edema formation may decrease with the Urapidil 12.5–25 mg 5–40 mg/h
reduction of the blood pressure and subsequently the bolus
capillary hydrostatic pressures as a result of altered Notes: d ¼ day, h ¼ hour, IVP ¼ intravenous push, NA ¼ not
Starling forces around the hematoma [89]. applicable, min ¼ minutes.
*The enalapril first test dose should be 0.625 mg, because of the risk
of precipitous blood pressure lowering.
Pharmacological treatment of acute Source: From [56,62].

hypertensive response
Drugs recommended for use in lowering blood pres-
character [93]. Other dihydropyridine calcium chan-
sure in acute stroke include labetalol, hydralazine,
nel blockers do not share this property [94–96].
nicardipine, and nitroprusside [90,91]. As of yet there
Nicardipine is photoresistant, water-soluble, and can
is no single agent that is recommended to help reduce
be administered intravenously, unlike other dihydro-
blood pressure. Due to the high rates of dysphagia
pyridines. Intravenous nicardipine has a rapid onset
and impaired consciousness, in acute ICH, intraven-
of action (1–2 minutes) with an elimination half-life
ous therapy is the route of choice for treatment [89].
of 4010 minutes and the major effects last from
The advantage of intravenous drugs is that they also
10 to 15 minutes. It is also rapidly distributed, extensively
have a faster onset of action and the dose can be
metabolized in the liver, and rapidly eliminated [97].
titrated to achieve a desired blood pressure target
Several studies have been conducted supporting
(Table 2.3).
the use of nicardipine in the reduction of blood pres-
sure in the acute ICH patient. Powers et al. evaluated
Nicardipine the effect of intravenous nicardipine in seven subjects
Nicardipine, a dihydropyridine-derivative antagonist with ICH (6–22 hours after symptom onset) [85].
of the L-type calcium channel, has an onset of action Using a positron emission tomography scan with
within minutes. Nicardipine demonstrates greater O15-water as the radioactive tracer, regional cerebral
selectivity for binding of calcium channels in vascular blood flow was measured. After baseline measure-
smooth muscle cells than in the cardiac myocytes ments of regional cerebral blood flow using the
[92]. This relative tissue selectivity is important in positron emission tomographic scan were made,
the drug’s utility for the treatment of hypertension. nicardipine was administered as an initial bolus of
In animal studies of cerebral ischemia and myocardial 2–8 mg followed by a continuous infusion of 2 to
22 infarction, nicardipine demonstrated a possible 15 mg/h titrated to reduce mean arterial pressure
membrane-stabilizing action, linked to its lipophilic by 15%. There was no significant difference in the
 Chapter 2: Acute hypertensive response in ICH

perihematoma regional cerebral blood flow before evaluating the effectiveness of intravenous labetalol in
and after treatment using nicardipine. When used achieving a blood pressure of less than 160/90 mmHg
to acutely reduce mean blood pressure below within 24 hours of symptom onset [61]. Boluses of
130 mmHg, nicardipine has also been shown to be 10–80 mg of intravenous labetalol were administered
safe and effective in acute ICH patients [98]. Qureshi provided the heart rate remained greater than 60
et al. used nicardipine to achieve the target blood beats per minute. The drug was well tolerated, but
pressure in 25 of 29 (86%) patients in a single-center only 10 patients achieved the target blood pressure
prospective study supplemented by retrospective with labetalol alone and the other 17 required addi-
chart review. Prolonged hypotension was observed tional agents (intravenous hydralazine and/or nitro-
in one patient and tachycardia in another. Two prusside) [61]. Intravenous labetalol treatment has
patients required additional antihypertensive agents. the benefit of minimal side effects with a rapid onset
Nicardipine was also used in a separate single-center of action and the disadvantage of sustained hypoten-
protocol study for acute blood pressure reduction in sive effect with prolonged usage.
ICH patients (n ¼ 188) presenting within 24 hours of
symptom onset [99]. All patients were also treated
with an antifibrinolytic therapy (tranexamic acid 2 g Direct acting vasodilators: hydralazine,
intravenously over 10 minutes). Nicardipine was
administered as a 2–4 mg bolus followed by a continu- nitroprusside, and glyceryl trinitrate
ous intravenous infusion as needed to keep systolic Hydralazine, a peripheral vasodilator, acts by relaxing
blood pressure less than 150 mmHg. No adverse events vascular smooth muscle cells leading to the reduction
associated with nicardipine were reported. Hematoma of arterial blood pressure. There is a latency of less
growth occurred in 4.3% of patients, which is than or equal to 15 minutes following an intravenous
lower than the rate observed in other observational dose, but thereafter hydralazine reduces blood pres-
studies [89]. sure for less than or equal to 12 hours [100]. Head-
ache, hypotension, and palpitations are the common
side effects associated with hydralazine. Hydralazine
Labetalol has been used in conjunction with labetalol to lower
Labetalol is an a- and b-adrenergic antagonist metab- systolic blood pressure to less than 160 mmHg [61].
olized by the liver that is commonly used in stroke Low rates of neurological deterioration were associ-
centers throughout the world. Labetalol can be ated with hydralazine usage and it was well tolerated
administered either as intermittent boluses or as a by the study participants.
continuous infusion. Given intravenously, its hypo- Sodium nitroprusside reduces arterial blood
tensive action begins within 2 minutes, peaks at pressure because it reduces both preload and after-
5–15 minutes and lasts 2–4 hours [100]. Both European load. It acts within seconds and lasts for 1–2 minutes
and North American guidelines recommend intra- with pretreatment blood pressure levels being
venous labetalol as a first-line agent in ICH patients reached within 1–10 minutes after the infusion is
requiring acute antihypertensive therapy [56,101]. stopped [100].
Intravenous boluses of labetalol (10–80 mg bolus A prospective feasibility assessment of blood
every 10 minutes, up to 300 mg) can be used to treat pressure reduction in acute ICH has also used sodium
hypertension in the emergency department. nitroprusside. Infusions of 0.2–5 mg/(kg min) were
Studies, using intravenous boluses of labetalol, well tolerated in the ten patients treated with nitro-
have been conducted in patients with ICH and sub- prusside [61]. Nitroprusside is also a spontaneous
arachnoid hemorrhage in hopes of determining the nitric oxide donor. Nitric oxide is a potent vasodilator
characteristics of blood pressure reduction and its and inhibitor of circulating platelets. The spontan-
tolerability. Bolus doses (10–25 mg) of intravenous eous donation of nitric oxide theoretically makes
labetalol reduced systolic blood pressure by 6–19% nitroprusside a non-optimal agent for use in ICH
and diastolic blood pressure by 3–26% with no patients, although its effect on platelet function in
adverse hemodynamic consequences [102]. The time these patients has not been assessed. One study in
to maximum reduction of blood pressure in the study ischemic stroke, however, showed impaired platelet 23
was 5–35 minutes. There was also a prospective study aggregation with nitroprusside [103].
 Section 2: Etiology of non-traumatic ICH

Outpatient management of chronic diastolic and consequently the stroke risk was signifi-
cantly lower when compared to the double placebo
hypertension following intracerebral cohort. A reduction of 5 mmHg systolic and 3 mmHg
hemorrhage diastolic blood pressure was observed in the group
Recurrent bleeding rates after hypertensive ICH are as that received perindopril alone, but the stroke risk
high as 5.4% [104,105]. The European Stroke Initia- was not discernibly different from that among partici-
tive and American Heart Association/American pants who received single placebo. In comparison
Stroke Association guidelines emphasize the control with double placebo, combination therapy was asso-
of hypertension as the most important modifiable risk ciated with a lower risk of each of the main stroke
factor for spontaneous ICH in the acute setting. In the subtypes: fatal or disabling stroke (60/1770 versus
non-acute, outpatient setting, treating hypertension is 110/1774; relative risk reduction 46% [95% confi-
the most important step to reduce the risk of ICH and dence interval 27–61]), ischemic stroke (126 versus
probably recurrent ICH as well [62]. Modification of 191; relative risk reduction 36% [95% confidence
the other risk factors, as discussed above, will also interval 19–49]), and cerebral hemorrhage (12 versus
contribute to the prevention of ICH. An outpatient 49; relative risk reduction 76% [95% confidence
regimen of antihypertensive medication begins after interval 55–87]), over the course of four years [107].
the patient is clinically stable, able to swallow medica-
tion or take oral medications through a gastrointest- Ongoing clinical trials
inal tube, and near discharge from the acute care Until ongoing clinical trials of blood pressure inter-
hospital. A recent systematic review of blood pressure vention for ICH are completed, physicians must
reduction in the prevention of stroke recurrences, manage blood pressure on the basis of the present
including ICHs, revealed a positive association between incomplete evidence, Class IIb, Level of Evidence C.
the magnitude of blood pressure reduction and the risk Blood pressure management represents one of the
of vascular events [106]. These results suggest that major controversies in acute ICH treatment. As of
continued outpatient blood pressure monitoring and 2007, there are five ongoing trials attempting to evalu-
treatment does play a significant role in decreasing ICH ate the relationship between blood pressure and
recurrence while at the same time suggests there is a ICH: Antihypertensive Treatment in Acute Cerebral
need for further studies to determine which if any Hemorrhage (ATACH), Intensive Blood Pressure
antihypertensive is superior in its treatment effects [29]. Reduction in Acute Cerebral Hemorrhage Trial
There was no strong evidence until recently that (INTERACT), IntraCerebral Hemorrhage Acutely
reducing blood pressure after ICH reduces the rate of Decreasing Arterial Pressure Trial (ICH-ADAPT),
recurrent ICH. The PROGRESS (Perindopril Protec- IntraCerebral Hemorrhage Acutely Decreasing Arterial
tion Against Recurrent Stroke) study has also shown Pressure Extended Trial (ICH-ADAPT-E) and the
benefits of antihypertensive treatment for high risk, Nicardipine for the Treatment of Hypertension in
non-hypertensive individuals as well as for those with Patients with Ischemic Stroke, Intracerebral Hemor-
hypertension, with combination, perindopril (angio- rhage or Subarachnoid Hemorrhage (CARING) trial.
tensin converting enzyme inhibitor) and indapamide
(diuretic) treatment. PROGRESS, a double-blind
randomized trial, comparing perindopril (4 mg daily),
Antihypertensive Treatment in Acute
with or without indapamide (2–2.5 mg daily), versus Cerebral Hemorrhage (ATACH)
placebo for the prevention of recurrent stroke in The Antihypertensive Treatment in Acute Cerebral
individuals with a history of non-disabling cerebro- Hemorrhage (ATACH) trial is a prospective, open-
vascular disease, irrespective of blood pressure showed label phase I safety and tolerability study started in
that reducing the blood pressure in this patient popu- 2005 that plans to study 60 patients. The specific goals
lation also reduced the risk of recurrent strokes [107]. are to: (1) determine the tolerability of the treatment as
Antihypertensive treatment was initialized at least two assessed by achieving and maintaining three different
weeks after stroke. In the participants being treated systolic blood pressure goals with intravenous nicardi-
with perindopril plus indapamide blood pressure was pine (5–15 mg/h intravenous infusion) for 18–24 hours
24 reduced by a mean of 12 mmHg systolic and 5 mmHg postictus in subjects with ICH who present within
 Chapter 2: Acute hypertensive response in ICH

6 hours of symptom onset; (2) define the safety, Hemorrhage Acutely Decreasing Arterial Pressure
assessed by the rate of neurological deterioration Extended Trial (ICH-ADAPT-E), initiated in 2007, are
during treatment and serious adverse events, of three both multicenter, randomized, open-label, blinded-
escalating systolic blood pressure treatment goals using endpoint trials that are designed to demonstrate
intravenous nicardipine infusion: 170–200 mmHg, whether blood pressure reduction following ICH stroke
140–170 mmHg and 110–140 mmHg; and (3) obtain is safe and does not result in cerebral ischemia. Intracer-
preliminary estimates of the treatment effect using the ebral Hemorrhage Acutely Decreasing Arterial Pressure
rate of hematoma expansion (within 24 hours) and Trial allows for treatment within six hours of the ICH
modified Rankin scale (mRS) and Barthel index at whereas the ICH-ADAPT-E allows treatment within
3 months following symptom onset [108,109]. 24 hours of ICH. Both the ICH-ADAPT and the ICH-
ADAPT-E plan on studying 82 patients. The trials
randomize patients who have acute ICH, confirmed
Intensive Blood Pressure Reduction in Acute by CT scan. All primary ICH patients, irrespective of
Cerebral Hemorrhage Trial (INTERACT) location (lobar/subcortical or brainstem), as well as
Started in 2005, the Intensive Blood Pressure Reduction anticoagulant-related hemorrhages will be eligible.
in Acute Cerebral Hemorrhage Trial (INTERACT) is Patients must also have two systolic blood pressure
a phase III, randomized, open-label, international, measurements greater than or equal to 150 mmHg
safety/efficacy study. The pilot trial, aiming to study recorded greater than two minutes apart. Those in
400 patients, is being done to plan for a major trial the treatment group will receive a 10 mg intravenous
that will determine whether lowering high blood pres- bolus of labetalol, administered over one minute, along
sure levels after the start of a stroke caused by ICH with a protocol designed to achieve and maintain
will reduce the chances of a person dying or surviving systolic blood pressure less than or equal to 150 mmHg
with a long-term disability. The inclusion criteria for within one hour of treatment. Patients randomized
this trial include: (1) patients with acute stroke due to the control group will be managed according to
to spontaneous ICH confirmed by clinical history current American Stroke Association guidelines.
and CT scan; (2) at least two systolic blood pressure One hour after initial treatment (two hours after
measurements of greater than or equal to 150 mmHg randomization), all patients will undergo a standard
and less than or equal to 200 mmHg, recorded two or non-contrast CT brain scan. Perfusion CT images will
more minutes apart; (3) able to commence randomly be acquired with the administration of intravenous
assigned blood pressure lowering regimen within six iodinated contrast (40 ml) given over 10 seconds with
hours of stroke onset; (4) able to be actively treated computed tomography images acquired every 0.5
and admitted to a monitored facility, e.g. intensive seconds for 50 seconds. All patients will have a second
care unit/acute stroke unit. Patients randomized to non-contrast CT brain scan at 24 hours, in order to
intensive blood pressure lowering are started on assess for additional hematoma expansion and peri-
locally available, intravenous treatment and changed hematomal edema volume. Acute parenteral therapy
when feasible to oral agents. The specific treatments that will be administered only if systolic blood pressure is
can be used are: labetalol hydrochloride, metoprolol greater than or equal to 180 mmHg. After 24 hours,
tartrate, hydralazine hydrochloride, glycerol trinitrate, the stroke team physician will manage blood pressure
phentolamine mesylate, nicardipine, Urapidil, esmolol, in the manner they feel is appropriate. Physicians will
clonidine, enalaprilat and nitroprusside. The primary be encouraged to start oral antihypertensive therapy,
end point is mortality and dependency according to an administered via nasogastric feeding tube if necessary,
mRS score of 3–5 at three months [62,110,111]. after the initial 24 hours. The primary end point is
perihematomal regional cerebral blood flow, as meas-
ured with a CT perfusion scan two hours after anti-
Intracerebral Hemorrhage Acutely Decreasing hypertensive therapy is initiated [1,112,113].
Arterial Pressure Trial (ICH-ADAPT)
and ICH-ADAPT-E CARING trial
Intracerebral Hemorrhage Acutely Decreasing Arterial The CARING trial, Nicardipine for the Treatment 25
Pressure Trial (ICH-ADAPT) and the Intracerebral of Hypertension in Patients with Ischemic Stroke,
 Section 2: Etiology of non-traumatic ICH

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Other documents randomly have
different content
 Here we come picking up silver and gold,
Silver and gold, silver and gold,
Here we come picking up silver and gold,
All on Tom Tiddler’s ground.

For a little while caution was shown on both sides, while Jim darted to
left and right, trying to catch the cautious figures that did not venture far
out. Then Edith started to run in earnest, and Jim flew after her. She ran up
the bank trying to dodge him, and just as she felt him touch her she felt a
sudden warm, choking sensation in her throat that made her cough.
“Hurrah!” screamed Jim. “I touched you, Aunt Edith!”
“Yes, Jim, I’m caught,” she said.
Then she put up her handkerchief to her mouth, and looked at it as she
withdrew it again. There was a little stain on it, very bright red.
 CHAPTER XIV

T HERE was a big-ribbed looking-glass outside the window of the

doctor’s consulting-room, that tilted in the warm, reddish sunlight of the
September morning, while through the open sash there stole in the
aromatic smell of fresh-laid asphalt. There was not much traffic going on,
only occasionally the clip-clop of a horse’s hoofs sounded staccato on the
wooden pavement of Harley Street, and Edith could hear without effort all
that Sir Thomas was saying.
He hardly led up to it, for she had come there that morning simply to
know what the result of his examination had been, and he merely asked her
a question or two as to her health since the birth of the baby. And then,
without preparing her, for he knew that there is no breaking such news, he
told her quite quietly, in a word or two.
Edith had been sitting opposite the window, looking at him with her
pleasant, direct gaze, as if giving her very courteous attention to a story that
did not particularly entertain her, but in which she was bound, for
politeness’ sake, to appear interested. But when he finished she smiled at
him as if his tale had had some slightly humorous conclusion. She did not
feel in the least stunned, nor had she any consciousness of having received
a shock. Only for a moment the little trivial circumstances of the hour and
the place grew more vivid; she noticed that the clock on the chimney-piece
had stopped, odd in the consulting-room of a great doctor; that Sir Thomas
had a scar running across the back of his left hand; that one of her own
gloves had fallen on to the floor. Then this attention to trivialities subsided
again, and she felt perfectly normal, perfectly herself.
“Thank you for telling me so kindly and considerately,” she said. “You
see how successful you have been, how little it has upset me? It is then—it
is very serious.”
“Yes.”
Again she smiled at him.
“I quite understand,” she said.
Sir Thomas got up and held out his hand to her.
 “Ah, my dear lady,” he said, “you are a brave woman. Meet your—your
illness with the same bravery day by day. Those are the patients, people like
you, who get well, and get well quickly.”
“What are my chances?” she asked briskly.
“They are excellent. Thanks to that little hæmorrhage you had last week,
and thanks to your common sense in consulting me about it without losing
time, we have detected the disease in an early stage. All depends now—
humanly speaking—on yourself, on your obedience to what we tell you to
do, and the scrupulous rigour with which you carry out your treatment.”
That allusion to treatment, to obedience to orders, brought Edith closer,
more immediately in contact, as it were, with the news.
“You have no doubt whatever that I have consumption?” she asked
quickly.
“I am afraid none. Of course the hæmorrhage, as I told you before, might
have come from the throat, but the examination I have made since I saw
you last proves the presence of what you call the little insects.”
“And what am I to do?” she asked.
“Go out to Davos as soon as ever you can. I would have you leave by
this afternoon’s train, if it was possible. And there you will live out of doors
day and night as far as possible. Until you check the disease it gains on you.
As I told you, you have an excellent chance, and you mustn’t imperil it by
delay.”
Edith considered this for a moment.
“I will be at Davos in a fortnight from to-day,” she said. “That is
reasonable, is it not?”
“Yes, if you will be an outdoor invalid in the interval,” he said.
Edith was silent, wondering at herself for the perfect calmness which she
felt. At first she thought that the suddenness of the news might have partly
stunned her, but the minutes were passing, and still she had no
consciousness of having received a shock. She understood, too, the gravity
of the sentence which had been pronounced; it was not that her mind
refused to grasp it. Now she almost laughed.
“I feel I ought to apologise for being so unagitated,” she said, “but I
don’t feel the least inclined to be agitated. Perhaps I have been fearing this
all these last days, and anyhow the fear is removed, now I know. Now about
my plans; I will tell you.”
Edith hesitated again. She had known Sir Thomas from her childhood;
he had done all that was possible for her late husband; he had brought her
child into the world. She determined to ask him several things which
concerned her, so it seemed, more intimately than her illness.
“Can you give me a quarter of an hour now?” she asked. “There are
several questions I want to put to you. How dazzling this reflected sun is.
Ah, I can sit out of the glare there!”
She moved her place so that she sat with her back to the light and
covered her eyes with her hands.
“First, then, about my plans,” she said. “I will be at Davos in a fortnight,
but I won’t promise to be an invalid in the interval. I mean to go with my
husband to Munich for ten days and hear Wagner opera. We had planned it
all, you see, and we shall start in two days. From there I will go to Davos.”
“Ah, I protest against that!” said Sir Thomas. “It means fatigue,
excitement, bad air, the three things you must avoid. I will speak to Mr.
Grainger myself.”
“No, indeed, you must not,” said she. “It must be I who tell him. Now, I
don’t mean to tell him until after we have seen the opera together. Oh, Sir
Thomas, I can’t. I simply can’t start my invalid life without one more treat,
as the children say, without one more week of Indian summer. After that, I
promise to tell him, and I promise to be the most willing and obedient of
patients. It does mean such a lot to me! I can’t tell you how much. I shall
fret and worry over not having gone there with him if I don’t go. But I
intend to. So please tell me how to minimise any harm it may do me.”
There was no doubt she was in earnest over this; that week at Munich
with Hugh, even now within half an hour of the news she had heard,
seemed to her to matter more than anything else. A far less acute man than
Sir Thomas could have seen that.
“Of course, if you intend to fret over not having gone—” he began.
“I don’t intend to; I shan’t be able to avoid it, and, indeed, I will be so
good afterwards and so determined to get well. But just a little more
happiness first!”
 Yes; the thought of missing Munich clearly touched her more intimately
than the knowledge that this deadly disease had built nests in her. It was the
child’s cry for “five minutes more” before bedtime, five minutes of
romance, of play. Munich and its music, much as she loved it, was, in itself,
nothing to her; what she could not bear to miss was this extra week of
holiday, this one more week of Hugh’s unsuspecting, joyful companionship.
However well he bore this news when he knew, he would still be bearing it.
Until she was well again, if she was going to get well, his sky would always
be overcast; he would be anxious, solicitous, with fear always in the back of
his mind, however well he hid it, and she felt she must be partner for just a
little while more of his riotous boyish happiness, which was so “Hugh” to
her. Some part of this, no doubt, Sir Thomas guessed; he knew at any rate
that she had set her mind on another week of life. He knew, too, from his
previous knowledge of her, that she was one of those whose body is in fine
obedience to their will, and whose will is set on health and the joy of living.
“But will you be sensible during that week at Munich?” he asked. “Will
you rest when you are tired, and stop at home and not go to the opera if you
feel it is too much for you?”
Edith took her hands away from her eyes with a superb wide gesture.
Her need was imperative; she did not care what price was paid for it.
“No, I won’t promise to be in the least sensible during that week,” she
said. “I might just as well not go to Munich at all, as be sensible. I mean to
have a splendid time just for one week more, to watch Hugh’s complete
happiness just for that week, and know that it is mine. And if I die a month
sooner in consequence, I will say ‘Thank God for Munich,’ with my latest
breath. After that week I will tell Hugh everything; I will be very good, very
obedient, and, oh, how cheerful! But I will have this week as we planned
it.”
At heart Sir Thomas exulted in the obstinacy of his patient. He loved
those who loved the joys of living, and made light of their infirmities even
at the risk of increasing them. But he felt professionally bound to apply the
brake here.
“But, my dear lady, how can you have a splendid time—which with all
my heart I desire for you—if you are feeling very tired and languid? You
can’t—your body must react on your mind. Also you will risk having
another hæmorrhage; you will risk, for the sake of a week, doing yourself a
damage that it may take six months to repair.”
Edith leaned forward in her chair, brilliant, radiant, her brave soul
shining like a beacon in her tired eyes.
“You know all about me,” she said; “I have suffered a good deal of
mental pain in my life, and I think that that has taught me to despise
physical discomfort. Anyhow, I do. I don’t care how tired I get for just this
week, and I defy all the little insects in the world to make me enjoy myself
less. So that is settled. And now I have one or two more questions, and then,
if you please, we will call my sister in, and tell her.”
She leaned back again, and again covered her eyes with her hands. She
was getting into more intimate lands now, and was silent a moment.
“Will this age me much?” she asked, “I mean, if I get well, shall I be an
old woman? I am, as you know, much older than my husband, and if this
will further increase the difference in our ages it might be better——”
Sir Thomas cut this short with some decision.
“It will do nothing of the kind,” he said. “If you do as you are told, the
very cure itself, which heals your disease, will rest you in other ways. When
you are well again, you will be better in general health and younger than
you are now. At least, I have often seen that happen. Only you must fight
the little insects to the death. And you have a good chance of doing so.”
Again the hands came away from her eyes, and the shadow of the fear
that had been there before was past away.
“Thank you, my dear friend,” she said. “Now, is Davos a dreadful place?
Can a man be there much without being bored to death? And what is the
shortest time in which you think I could get well?”
“I have known cures of cases far worse than yours being complete in a
year, as far as the actual presence of disease goes. But that means a year of
complete invalid life, passed at Davos, or perhaps at some higher place just
for the summer months, without ever coming down into lower air.”
“You mean I mustn’t come to England for a year?” asked Edith.
“Not if you want to give yourself the best chance. Davos is delightful in
the winter for any man who cares about outdoor sports, but I should say
very dull when the ice goes.”
 “And what is the risk of infection to others? Would it be better, I mean,
for my husband, when he is at Davos to live in a hotel. I suppose I shall take
a house, shall I not?”
“The risk would be unappreciable.”
“Or for my sister, or her children, or my baby?”
“There would be no risk if you are sensible about it. You would not, of
course, well, kiss anybody. And there are other precautions as well, which
of course you will observe.”
Edith nodded at him.
“Yes, I will be very sensible,” she said. “And now please call Peggy in,
and I will tell her.”
“I will just examine your heart first,” he said. “It will not take more than
a minute or two. I remember there was a little weakness.”
He was satisfied, however, with this.
“No, that is sound enough,” he said. “It is a little weak in its action, but
there is nothing wrong. But, my dear lady, you have to concentrate all your
forces to fight this new enemy. You must, you absolutely must avoid fatigue
and worry.”
But she cut him short.
“Ah then, I must certainly go to Munich,” she said. “It will save me no
end of worry. Now let us have Peggy in; I want to tell her at once.”
Peggy was but next door, and the summoning of her in took no longer
than the opening of it. At present all she knew was that Edith wanted to get
a clean bill of health before starting for Munich. She had confessed to
fatigue, but had breathed to her sister no suspicion of her fear, and their
coming up to town together was a plan that had been formed several weeks
before. And though the length of time that she had been kept in the waiting-
room, while Edith saw Sir Thomas alone, had a little disquieted her, yet the
serenity of Edith’s face when she was admitted to his consulting-room,
immensely reassured her. Then Sir Thomas closed the door behind her, and
she sat down opposite her sister. Edith spoke:
“Dear Peggy,” she said, “I suppose I ought to break it to you, but it’s so
ridiculous to break things. I’ve got consumption. Isn’t it dreadful?”
Peggy looked at her blankly, and then this most unorthodox patient
leaned back in her chair and burst into shouts of laughter. She simply could
not help it, the blankness of Peggy’s face was so excruciatingly funny. Then
the infection of the laughter caught her sister also, and they just sat and
laughed. Once Peggy tried to compose her face, and said, “Oh, Edith!” in a
trembling voice, but that set Edith off again till the tears streamed.
“Oh, I’m better!” she said at length. “But how funny it was. I should
never be good at breaking things to people, should I, Sir Thomas? O Peggy,
what a pity Hugh wasn’t here, too! He loves laughing. Yes, and we’re going
to Munich just as we planned, and after that I go to Davos for a whole year.
Then, if I am good, perhaps I shall be quite well again, and younger and
better than I am now. That will be an advantage.”
“Oh, my darling,” said Peggy. “I am so—so—there are no words.”
“No, it was much better to laugh. Fancy there being a humorous side to
consumption. What a good thing! And since Sir Thomas has allowed me to
go to Munich, I shall not tell Hughie till afterward. And from there I go
straight to Davos, and behave too beautifully. That is a fair statement of our
interview, is it not, Sir Thomas? Now, Peggy, we must go home to lunch. I
am so hungry.”
But the doctor could not quite let this pass.
“I’ve been doing my utmost to persuade Mrs. Grainger not to go to
Munich,” he said. “Will she listen to you?”
“Not for a single instant,” said Edith.
“My dear lady, be serious for a moment.”
Edith rose.
“Oh, don’t make me laugh again,” she said. “Good-bye, Sir Thomas, you
are the kindest man in the world. Please come and see me to-morrow, and
tell me whom I shall be under, and all about it. I must have a house there. I
hate hotels. Perhaps we had better go to a hotel first, until we can get
something to suit us. And you and the children, Peggy, are coming out to
stay with me, but I mustn’t kiss you. Sir Thomas, since I am to be idle by
your orders, you will probably receive some time next year a small book
with the compliments of the author, called ‘Our Life in High Altitudes.’ ”
They got into the brougham that was waiting and drove off. Then in spite
of orders Peggy turned to her sister and kissed her.
“You blessed darling,” she said. “But, oh, Edith, don’t be so splendid
about it, or you will break my heart.”
 Edith still had that radiant look with which she had heard her sentence.
“Splendid?” she said. “I’m not splendid. I am behaving exactly as I feel
inclined. Is it odd, do you think? I don’t. Besides, what would be the use of
curling up and snivelling? I’m not made like that.”
“No, you dear,” said Peggy, half-sobbing, “that’s just it. That’s just the
splendidness that makes me cry.”
Edith took her sister’s hand.
“Ah, don’t Peggy!” she said. “Don’t let us give way for a single second
if we can help. Don’t let us ever think about giving way, or else that will
become natural. I won’t. I won’t! I will not!” she said with great emphasis.
There was silence a moment, then Edith spoke again.
“Now I shall sit out on my balcony all afternoon,” she said, “and hold
this all in front of me, till I am quite certain that I fully realise it. And then,
Peggy, this evening I will talk it over with you just once, and from then
until—until the time that I am well again, we will never allude to it any
more.”
“Yes, dear,” said she.
Then Edith’s face broadened into a great smile again.
“And, oh, what a beautiful laugh we had,” she said. “I can truly say in
the future, if I am very much amused about something, ‘I haven’t laughed
so much since they told me I had consumption.’ ”
“Don’t, don’t!” said Peggy.
Peggy, even in September, was full of business. There was a factory to
be visited, a school of work to be inspected, and a “home” where surprise-
descents were distinctly good for the matron, who was not wholly
satisfactory, and it was not till after six that she got back to Rye House. But
busy though she had been, it had required all her force and determination to
get through her errands, for her mind kept flying back like a released spring
to Edith, whom she had left sitting out in the warm autumn sunshine, facing
what she had been told, adjusting, as she would have to do, her mind and
her whole self to new conditions. When Peggy got back, they were to have
their talk, just the one talk.
The hours had passed quickly for Edith, and if anyone had watched her,
not knowing what occupied her mind so intensely, he would have said that
here was a woman with a true gift of lotus-eating, so quietly she sat, so
content to do nothing whatever. Once or twice only in those hours did
anything of a disquieting nature seem to cross her mind, and even then a
couple of sharp-drawn breaths, or a sudden look as of pain or fright in her
eyes, soon past, was all the surface sign of it. And at the end, when she
heard Peggy’s motor draw up at the door, it was with the same patient and
smiling content, which for the most of the afternoon had lain like sunlight
on her face, that she went downstairs.
The two had tea together in Peggy’s sitting-room, and then Edith took
her favourite chair and spoke. Again there was no transition possible from
the topics of the day which had occupied them at tea, and she began without
preamble.
“Yes, dear, I have thought it all out,” she said, “and I know at this
moment just how I feel about it, and what I hope I shall continue to feel.
Peggy, it is so simple; big things always are, I think. Isn’t that a blessing?
Now I shall begin at the beginning, not like Hugh’s stories, which begin in
the middle, and go on till I get to the end, and then I shall stop. I don’t want
you to say anything at all. It’s my innings.”
“Peggy, I don’t want to die, and I don’t intend to die if I can help. I want
and mean to get well, and I shall do all I can to get well. But when one is
told that one has consumption, one has to realise that it may mean that one
is not going to get well. So about dying. You must take care of Hugh, won’t
you? And you must make him marry again. I tell you that because—oh, my
dear, the flesh is so strong—though I mean to tell him that myself if I find I
am getting worse instead of better, I can’t be certain that I shall be able to.
All that is at all decent in me will urge me to tell him, but there is a lot in
me that isn’t, and I find, and shall find, it difficult to think of him as another
woman’s husband. And perhaps my tongue will quite refuse to ask him to
promise that he will marry again. So I ask you to tell him in case I don’t.
“That is the most important thing if I die. And, oh, Peggy, if I am to die,
pray that it may come quick, and pray that I shall not be afraid. I hope I
shall not, but one can’t tell. And pray that my darling will be with me when
it comes, that his face will be the last I see here. Just as I know—oh, how I
know it—that when he joins me, mine will be the first that he sees on the
other side.
“Then this afternoon I wondered also how matters could be arranged,
what about Dennis? And as I couldn’t possibly know, it was no use thinking
about that.”
“Peggy, next to Hugh and baby, you are the person I am most sorry to
leave. Don’t miss me too much although I should be frantic if I thought you
wouldn’t. And remember that if I die, I now, in my sober senses, bless and
praise God for the exquisite happiness I have had. I should have loved to
have had other children, to have seen them grow up; I can’t help being
sorry, if that is not to be. That is why I don’t want to die. But, oh, what a
splendid time I have had. I thank God for it. Remember that.”
Edith had been speaking again with her hands over her eyes just as she
had spoken to the doctor this morning, but here she took them away, and
grasped one of her sister’s hands in both hers.
“And one thing more about dying, and I have done,” she said. “You
mustn’t let it hurt you to hear me talk of it, Peggy. It is just this. You know
how you dissuaded me from marrying Hugh, saying the years which made
me old would leave him young. Well, perhaps you were right, and perhaps
this is the solution of it. If so, I am quite content. I would infinitely rather
die than have that wintry tragedy. I just want to assure you of that, and that
is all about dying.”
Edith sat silent a moment, and Peggy could not speak, for it was all she
could do not to break into open weeping. Had Edith been less gallant, less
courageous of soul, she could have consoled and strengthened her. But she
stood in no need of that; and the tears that stood in Peggy’s eyes were more
of love and admiration than of pity.
Then Edith rose.
“Now all that is gone,” she said. “We put it all behind us; it is not to be. I
am going to live, and, oh, my dear, do you know what that old angel, Sir
Thomas, told me? He said that if I got well as I intend to do—I should be
younger and better than I am now. There is the other solution. I would
dearly like to renew my youth a little, to have the health and vigour of the
past year over again for a few years more. That is worth living for. Some
day I shall write a list of things worth living for. There are heaps of them.
Sunshine and snow, and Hugh, and music and you, and ‘Gambits’ and baby.
Those are only the first few that occur to me, but there are about twenty
million others and I am going to live for them all. They are ‘Things in
General,’ in fact, which we spoke of the other day, and are all delightful. As
you said, one has to make them part of you. And I am going to do exactly
what I am told, and leave nothing undone that can help to make me well,
and do nothing that can stand in the way of that. Ah, I forgot Munich! But
please don’t argue about Munich. I intend to go there. Also, Peggy, I am
going to tell Hugh a lie about it. I shall tell him that Sir Thomas said it
couldn’t possibly hurt me, in fact, that he recommended me to go.
Otherwise, you see, Hugh will think it very wrong of me not to have told
him first, so that he might refuse to go. I daresay it is wrong, and it is also
selfish, because I am doing it simply for my pleasure. But I don’t care. I
will start being good next Tuesday week, and not before. Oh, and one more
arrangement! I wish you would take care of baby and his nurse until we get
settled at Davos.”
“Why, of course!” said Peggy.
“That is dear of you. And you must come out with the children and be
with us a great deal, both for Hugh’s sake and mine. Oh, Peggy, Hugh
mustn’t get bored, and I don’t see how to help it. He mustn’t stop with me
out there after the ice goes. I can’t cut into his life like that. Ah! well—one
needn’t think about that yet. And, my dear, if ever you see me faltering and
being cowardly or despondent or ungrateful, try not to notice it. It won’t be
me: it will be these nasty little insects. I shall be doing my best! I promise
you that. And that is all, I think.”
Again she held out her hands for Peggy, but that would not do for Peggy.
“Ah! you mustn’t kiss me,” cried Edith. “I promised not to kiss
anybody.”
But Peggy clung to her.
“Thank God for people like you!” she said.

Hugh was to arrive (and did so) next day, for he and his wife were
starting from town the morning after for Munich, and he arrived rather in
the manner of a loquacious whirlwind in the middle of lunch. He greeted
neither Peggy nor Edith, but waved a telegraphic form at them.
“I’ve got to say ‘Yes’ or ‘No’ at once!” he cried. “It was handed to me at
the station at Mannington, but I couldn’t reply before I saw you, Edith, as
Munich is your treat. Burgmann is ill, and they ask if I will sing ‘Tristan’ on
Monday week in his place. Yes, at Munich, of course, I said so. Heavens!
Do you grasp the inwardness of this sacred fact? An Englishman asked to
sing ‘Tristan’ in Germany, to the high ge-born Tedeschi! Lord, what fun! I
shall go mad, as Mr. Tree said. But how frightfully chic it would be to say
‘No.’ Yes, chicken, please.”
He sat down and turned to Edith.
“It’s our last evening there,” he said, “and it’s the last performance of the
cycle. Which shall we do? Shall we sing, or shall we see? I want you to
settle.”
Edith took the prepaid form which Hugh had been waving about with the
other.
“I don’t settle,” she said; “it settles itself. Of course you sing. Please
have this sent at once, will you, Peggy?”
“Oh! but that’s rather sudden,” said Hugh. “You don’t consider me. I
shall have no more fun now until it’s over. No cigarettes, no anything but
scales. It may be awfully nice for you—I say, that sounds so gloriously
conceited, but I won’t alter it—but it will absolutely spoil Munich for me.”
“Oh! Hughie, it crowns it for both of us,” said she.
“I travelled up with Mrs. Owen,” said Hugh, eating very rapidly, “and I
think she’s going to the dogs, and if so, it’s your influence Edith. She
smoked a cigarette in the train. I don’t think your influence is a very good
one. You domineer, too: you domineer most frightfully. That sending of the
telegram was mere brute force.”
“But you told me to settle. I did so. Why, Hugh, it is the most gorgeous
thing that ever happened. It’s the best birthday present I ever received.”
Hugh dropped his knife and fork with a crash, and jumped up.
“Why, I remembered this morning,” he said, “and that silly telegram
drove it out of my head again. Edith, my darling, many, many happy returns
——”
He bent over her to kiss her, and, forgetful for the moment, she raised
her face to his. Then, and it was like a stab to her, she remembered. Hugh’s
face was close to hers, his lips all but touched her.
“Ah! no,” she cried quickly; “you mustn’t kiss me. I’ve—I’ve got a cold,
and if I gave it you, you might not be able to sing. Thank you, dear, a
thousand times, for your good wishes.”
Hugh looked at her for a moment in mild astonishment.
“As if I cared,” he said.
 “Ah, but I do,” said Edith. “You catch cold so easily, too.”
Hugh went back to his seat.
“I don’t like your having colds,” he said, “independently of the fact that I
mayn’t kiss you on your birthday. You had one in August; now you’ve got
another. I’ve a good mind—” And then he stopped.
“Hugh, it’s very rude to begin sentences and not finish them,” said
Peggy.
“Yes, isn’t it? By the way, all my music is down at Mannington. I must
go and get a copy of ‘Tristan’ this afternoon, as I shall have to begin
learning it up again at once. What are my ladies going to do?”
Peggy, it appeared, was at leisure, and offered to drive him where he
wanted in the motor; Edith had “things,” so she comprehensively expressed
it, and was at nobody’s disposal till tea. This, as a matter of fact, suited
Hugh’s “good mind” very well, and soon after lunch he set out with Peggy.
But no sooner were they alone than he announced a strangely disconcerting
manœuvre.
“Yes, let’s go and get ‘Tristan’ first,” he said, “and then I want you to
drop me at Sir Thomas Ransom’s. Edith’s got no business to have colds. I
shall get him to come and see her. I’ve several times thought she wasn’t
very well, but she always said she was. Do you think she’s well, Peggy?”
This was awkward, but after an extremely rapid consideration, Peggy
concluded that she had a prior engagement of secrecy to Edith, which
entailed what is elegantly called “diplomacy,” in dealing with Hugh.
“No, since you ask me, I don’t,” she began.
“Then, why didn’t you tell me?”
After all diplomatic truth would serve her purpose. And she proceeded to
use extremely misleading accuracy.
“Because Edith knows it herself,” she said; “and as a matter of fact, went
to see Sir Thomas yesterday, so there is no need for you to go. In any case,
Hugh, you can’t spring a doctor on a grown-up person, as if she was a child.
But I know she saw Sir Thomas yesterday. In fact”—Peggy paused a
moment, wondering how far astray truth-telling would lead her—“in fact, I
went with her.”
“And what did he say?” asked Hugh, with inconvenient abruptness.
Peggy looked firmly out of the window.
 “Oh! what doctors always say; avoid over-excitement and curried
prawns, and hot rooms and fatigue.”
“Then, did he know she was going to Munich?”
“Yes; oh, yes—I am certain of that! He—he encouraged her to go.”
Peggy was beginning to feel slightly feverish with the strain of this, and
there was a heartache in every word. But she had promised secrecy, and
secrecy implied that she would do her best that Hugh should suspect
nothing. But it was rather hard work, for Hugh showed no sign of being
tired of questioning her. Diplomatic truth, too, having served its turn, was
discarded, and diplomatic inexactitude had become necessary.
“She needed encouragement, then,” said Hugh. “She felt not quite up to
it.”
“Not at all. She wanted to go very much, and he encouraged her, as I
said.”
The motor stopped at this moment by the music shop where Hugh was to
buy “Tristan,” and he got out.
“I shan’t be a minute,” he said. “Will you wait for me and drive me to
Harley Street?”
For a moment after Hugh had left her Peggy seriously considered the
propriety of telling the worse lie, breaking the previous engagement. She
knew quite well that what she and Sir Thomas had been unable to do Hugh
could do with the utmost ease. In a moment Edith would consent to go to
Davos at once if Hugh wished it, but Hugh, in order to wish it, had to know
what Peggy knew and was bound not to tell him. Yet her mind hesitated
between the two courses, and for the first minute of waiting she had no idea
whether she would break faith to Edith or really lie—properly lie to Hugh.
She had seen that he was already more than half way toward suspicion.
Either she had to quiet that by really magnificent lying, or by lying, quite as
magnificent, break faith with her sister, and tell him all. Then, too, he was
determined to see Sir Thomas. Perhaps Sir Thomas might not see his way to
lying, if Hugh asked, as he probably would, more of these direct questions.
And if Sir Thomas was to tell him, it was clearly much better that she
should do so first. If anybody was to tell the truth, she had much better be
the first to tell it.
And then the determining factor came into her mind, and that was the
freedom and individuality of all persons. When vital matters, matters of life
and death and love, came on to the stage, the ordering of the stage, the
ordering of the crowd, the lights, the whole arrangement, must be made to
fit the chief actor. Edith on this half-tragic, half-triumphant stage that was
set for her had chosen the manner of the enactment. Peggy was but a figure
in the crowd; Edith ordered her to stand thus, and to do thus, and to say
thus. It was Edith’s show. She had ordered Hugh also into his place, that
place where her heart was. And her lover, her beloved, had to obey no less
than Peggy. This week of Munich was ordained. Edith knew the risks she
ran, and she chose to run them, and, after all, it was her business. It might
be expensive, but it was fine. It was young, too—gloriously, unwisely
young—so young that it made Peggy feel dreadfully old. There was no
calculation about it, no counting of cost. Edith was willing to risk anything
to have the week she wanted, the week of the boisterous, unsuspecting
Hugh. Oh! that passionate enjoyment of the pleasure of somebody else! The
seven veils of the sanctuary lift there. It was the abandonment of love; and
whether the tragedy to be paid for was long weeks of lingering illness, or
any other supreme torture, the price was cheap. Peggy divined that; Edith
knew it. And mentally Peggy abased herself when the light of that vision
shone upon her, as it did while she waited in Berners Street for Hugh.
He did not keep her waiting long, and Peggy at once began to weave the
web of the deceit that was forced on her. Few people had had less practice
in that difficult art than she, and as she conducted this piece of diplomacy,
she felt that she really must have a great natural gift that way. At the same
time she remembered having been diplomatic to Hugh over the question of
their going to Mannington in the summer, and her diplomacy had been
blessed with singular success. Now she had two objects in view, one that
Hugh should not go to Sir Thomas, the other that the vague uneasiness that
was certainly rising, mist-like, from his mind should be dispelled. Edith
should have the sunny week that her soul desired, and for that an unanxious,
unsuspecting Hugh was necessary. She should have him, if Peggy could
procure him.
“Such a wise idea of yours to go and see Sir Thomas!” she said, with
extraordinary craft, “because he will certainly laugh at you, and that
perhaps will set your mind at ease. And it’s most important that it should be
at rest. Really it matters more than anything else.”
“Why? How is that?” asked Hugh.
 “Oh! dear me, how stupid men are! Can’t you see that Edith is looking
forward to Munich with the keenest, most vivid anticipations? Well, at the
risk of making you more conceited than you are already, I will tell you why.
It’s because she is going to be alone with you and your enjoyment. There is
nothing in the world she loves as much as seeing you have a good time.
And it will spoil it all for her if you are uneasy and causelessly anxious.
That’s why I urge you to see Sir Thomas.”
This had a very distinct effect on Hugh.
“My seeing Sir Thomas is nothing,” he said. “But I felt as if you were
keeping something back. Can’t you tell me what he said?”
“I can’t go into medical details,” said Peggy; “but I can tell you this, that
when Edith called me in after she had consulted him and told me what he
had said we both simply sat and roared with laughter. And I rather think he
joined.”
Hugh gave a great sigh of relief, and Peggy ejaculated “God forgive
me!” below her breath.
“Oh, why didn’t you tell me that?” he said.
“Because I thought it so much better that you should see Sir Thomas,”
said Peggy quite glibly.
Hugh turned on her.
“You have the making of a diplomatist,” he said. “What’s the use of my
seeing Sir Thomas now you have told me that? And Edith really looks
forward to Munich, and it will spoil it if I’m not in tearing spirits? Lord! I
won’t spoil it. Where shall we go instead?”
“The Zoo,” said Peggy without hesitation.
Hugh called the changed direction out of the window to the chauffeur,
and sat silent awhile.
“After all, it was absurd of me to think there could be anything wrong,”
he said, “or of course she would have told me.”
Peggy sighed, an elaborate, effective sigh.
“I was wondering when that would occur to you,” she observed.
Hugh let this pass.
“So I’ve just got to—to shout and sing?” he asked.
 “Yes, if you want Edith to have a good time. I can tell you, too, that I
have never seen her look forward with such pleasure to anything as this
Munich trip. It’s taken her fancy.”
“I’m her man, then,” said Hugh.

Peggy thought it incumbent on her to tell Edith what had occurred,

feeling that she might view this deliberate deception in a different light to
the mere concealment which was all that she had contemplated. But Edith
poured scorn on her scruples.
“Peggy, you are a true friend!” she said, “and how easily you seem to
have—well, told the truth. It’s quite Bismarckian. Have you been practising
lately?”
Peggy was slowly pulling off her gloves.
“No, I don’t think I have,” she said. “Oh! I was diplomatic with Hugh
once in the summer, I remember, and I rather enjoyed it. But, oh! Edith, it
gave me the heartache this afternoon. And what will Hugh think of me
when he knows?”
“He will think that you have been a true friend to me,” said her sister.
“He will love you for it when—when he understands. Ah! but we are on
forbidden ground again.”
Edith paused.
“I remember once talking to you about Hugh’s first appearance in town,”
she said. “I told you then that if he failed, which was impossible, I should
not be sorry, because I would have to comfort him again, and make him
happy. Well, that is closer to me now. When I tell him what Sir Thomas told
me yesterday he will want that comfort. But now he will really want it, for I
am more to him than his art.”
Edith gently smoothed the sofa cushion beside her.
“I am—I really am!” she said.
. . . . . . . .
The dressing-gong sounded sonorously and its echoes died into silence.
“You will see,” said Edith.
 CHAPTER XV

E DITH finished writing the words “gigantic success,” and then laid down
her pen, having filled the very small space allotted to correspondence on
a picture postcard that bore on its back a highly-coloured view of the
opera-house in Munich, and on the space allotted to the address the name of
Peggy. Then she tore it up. She wanted to say more than that to Peggy, and
though she was tired, she felt she must write her a letter which should give
her in less meagre quantity (and in quality things more private than could be
sent face upward through Europe) some little impression of the week that
had elapsed since she left England. And in order to do that she found that
she must arrange and sound her thoughts and her memory, for she had lived
simply from the minute to the minute, enjoying each to the uttermost, yet
somehow not grudging their passage, for each was sufficient in itself.
Her windows were wide open, but the sun had slanted westward, so that
the balcony outside was in shade, though ever so little way beyond the
white glare fell on the road with its avenue of dusty trees. Though
September was near to its end, and during the first three days of their stay
here there had been cold and frosty nights, it seemed as if the sun had
repented of his winter-heralding withdrawal, and had come back to give
them a few hours more of summer days. And at this moment it struck Edith,
yet with no touch of sadness, how like to this beneficent return of June-like
heat was her own case. In London, ten days ago, the forerunning foot of
winter had struck her, yet now in her life, no less than in the ordering of the
season of the year, summer with shout and banners renewed for a moment
its miracle. Outside it was hot and windless and dry, and as she moved to
her window she drew in a long breath of the eternal, unfading air. There
even the sensitive leaves of the white poplars were still; there was but little
traffic in the street, the awnings below her room and above her balcony
neither stirred nor flapped in the blazing tranquillity. Calm, omnipotent
summer reigned. And to-night Hugh was to sing in “Tristan.”
It was not in Munich, so she felt, it was not on the Cornish coast, it was
not by the banks of the Scheldt or the Pegnitz, nor even in the giant-built
towers of Walhalla, that she had lived during this week that would come to
a close to-night. She and Hugh had lived far away from any human place,
yet in a place that, lovers and music-lovers, each had felt to be his own, and
more familiar and dear than any other home. Heart and treasure lay there,
and even Walhalla was leagues, immeasurable leagues, below it. Trouble
and anxiety and fear were strangers to it, or at the most (and that only for
one of them) lay as some thunderstorm in an Alpine valley lies far below
the feet and the eyes of those who have climbed above it into the clear,
passionate altitudes that are domed in sky and floored by ice. All week long
they had mounted, mounted through the fine austere air; and life, all they
knew of life, had been put in a crucible and distilled for their drinking. All
that was to be, whatever that was, had for these days been expunged from
memory and from anticipation; it had been all to sit on this rose-coloured
peak, hand-entwined, without seeing the troubled cloud below, without
hearing the thunder and the voices that cried out of it. She had determined
not to think of the descent, not to conjecture about the dangers and misty
passages of the journey till the time for descent had come. It would come
to-night, but before it came there would come the divinest hour of all, the
rosiest flames of sunset, when she would sit in the hushed house and hear....
The week had been her treat to Hugh, and the compact had been that he
should ask no questions. Possibly it was child-like, possibly it was a
barbaric notion of hospitality; but it had given her enormous pleasure to
throw money about for him, to take the most expensive suite of rooms, to
have masses of fresh flowers in day after day, to have a really smart
carriage always waiting, to have meals in a private dining-room. Somehow,
on the material plane, infinitesimal though it all was, she wanted to express
that which so filled and flooded her; she would have liked to furnish this
room afresh, to have railings of gold for the balconies and frescoes for the
walls, and then at the end of the week to burn and destroy it all. She had, in
fact, gone as far as was consistent with sanity, but not being insane had not
gone farther.
Tired! Oh! how tired she had been again and again, and how indomitably
she had spurned fatigue! The glory, the jest of it, too! Again and again Hugh
had said that he really must, if she didn’t mind, lie down and rest, if he was
to keep awake during the opera. She had beaten him at his own game, at
youth, and time and again he had confessed as much. He had even confided
to her his projected errand to Sir Thomas on their last day in London, in
order to satisfy himself that she was “up to Munich.” Now it was he who
had wondered if he was. But all the time she had clung to her supposed
cold; she had insisted that she had a really bad one, and that she would not
permit Hugh the least risk of catching it. And at such moments a cloud
came over her sun, there was an echo of heart-breaking things from the
valley below, and hunger on these heights.
Yes; fear had been there; she knew that her ears had heard that echo and
her heart had felt that hunger, though for a stray moment or two only. As
quick as hands could move her fingers had stopped her ears, and nimbly
had put before her heart the feast that was spread for it now. And it was only
of the perfection of the present hour that she wrote to Peggy; no hint of the
coming winter was there, though measured by the actual lapse of minutes it
was but an hour or two before summer would cease. But before summer
ceased she would see Tristan once more, her Tristan.
By the time her letter to Peggy was finished it was time for her to dress
for the opera. Hugh had already gone down to the house, and she had a little
soup and a cutlet only, for, as usual, they were going to have supper
together after the opera. To-night, however, since Hugh was going to sing,
he had eaten nothing for some hours before, and their supper was to be of
substantial nature. She had planned it all; she had ordered the dishes that
she liked as well as he. They were going to have some cold soup, a dish of
blue trout, a partridge, and a savoury. All this was bathed in the setting rays
of this last day of summer sun; it would illumine, too, their coffee, and the
cigarette which Hugh would smoke with it. And during that cigarette, so she
determined, summer was to cease. It was then she would tell him.

For a moment, as she dressed for the opera, she wondered how he would
take it. It was worse for him than her; her whole attitude toward life and her
instinct told her that with the same certainty with which she knew that it
was easier, vastly easier for her to know that she had consumption than it
would have been to learn that Hugh had. That was what love meant; just
that one simple fact that to the woman who loves, her husband is more truly
herself than she. That was no news to her; she had known it ever since she
had known Hugh. And it could not have been true of her if it had not been
true of him also. Oh, poor Hugh, poor Hugh!
Then with complete erasure she banished the thoughts of what that hour
round about midnight this evening would bring. She was still in love with
life, with the huge exultant happiness that is the birthright of clean and
normal souls who love another. Such happiness, the highest and the best of
all earthly bliss, is no niggardly distillation of human life; to produce it a
hundred or a myriad souls have not to be boiled down in torment of fire or
refined through starvation of joy so that, basil-like, it may put forth its
flowers from roots that have been enriched with the life-blood and tears of
the many, nor is it rare or recondite and only to be perceived by the Æolian
harps of the world. Instead it is a common, common bliss; none seek it or
strain after it, but there are but few who do not find it. Her sweet simple
soul loved Hugh; Hugh, as simple as herself, loved her. And if shadows of
the dark valley were near, that would be the all-sufficing lamp which would
dissipate them.
Then crowning this crown, which was hers, was a further gem-like
circlet. To him the supreme gift of song had been given, to her the
supremacy of appreciation.... And it was time to go downstairs and drive to
the opera to hear “Tristan.”
. . . . . . . .
It had been arranged that, since the opera-house was so close to their
hotel, she should not wait for Hugh when it was over, but come straight
home, and she waited there some time before he joined her in an exultation
of happiness. The ceasing of summer, which was now so close in the
measure of minutes, not hours any longer, was banished from her
consciousness. Hugh and Tristan, inextricably intermingled, usurped it all.
She tried to reconstruct the events of the evening, and found them misty.
She only knew that the audience, German, instinctively opposed to an
English artist, but critical, lancet-like, and, after all, when their emotions
were roused, fair, had lost their heads. Fat London had been moved over
Hugh’s Lohengrin; but Germany, not fat, like London, in matters of
perception and appreciation, had been much more than moved.
What had happened exactly?... The end of the first act? Yes, Hugh had
been nervous, quite obviously nervous, and had not done himself justice,
nor had he done justice to the glorious rôle for which he was cast. And
then? Edith had sent round a note to him, saying:
“My darling, I am playing Isolde, and I don’t find you. Isolde, Isolde.”
And a note had come back to her.
“I’m so nervous I can’t do anything. But I’ll try, Isolde.”
 It appeared that he had tried. As the curtain went down on the second act
the theatre rose as if the Emperor had entered. But it was Hugh.
It was Hugh in the third act. Hugh! And critical Germany during the
third act committed a unique fault of taste. It had been foreshadowed in a
way, because once and again as Tristan yearned for the coming of the ship a
sort of under-breathed groan had gone through the packed house. Then,
when Tristan had sung his last note, the interruption occurred. The play was
stopped; the orchestra, inaudible beneath the shouts, were stopped also, and
a huge roar of applause went up, damning the artistic reputation of Munich
for years to come. “Tristan! Tristan!” was the cry. But to Edith the cry was
“Hugh!”
Ah! but how proud she was of him then, not for that which he had done,
but for that which he did not do. He had fallen, loose jointed, and lay with
face toward the house, and not a quiver of eyelash, not a movement of the
nightingale throat, not a curl of his mouth answered the thunder of the
applause. Edith had not, even when that thunder rose to its highest, been
afraid that he would respond, but it was glorious to her to see how still he
lay. An almost irresistible appeal had come from the thousand throats, but
the artist since it was personal, since it was to his voice and his personality
to which it was made, was utterly unconscious of it. Tristan, who he was,
lay dead. Soon after Isolde sang the Liebestod.
“The death song,” thought Edith. “What if I sing another? Oh, Hugh,
Hugh!”
It was then that Hugh came in, as she sat in the window, while the table
laid for their supper stood ready. Munich had gone mad about him, and
from where she sat in the window she had heard the distant roar that had
greeted him as he came out of the theatre, which had grown gradually
louder and louder till now the square outside was packed with the music-
mad. She had guessed at once what that distant roar meant, and her guess
had grown into certainty as it grew louder and nearer. And Hugh came in.
“Ah! your note to me,” he said—“it was that. Oh! isn’t it fun? I told you
it would be! And they took the horses out and dragged me, the darlings!”
The agitated proprietor tapped and entered, and a short conference
ensued. The upshot was that if the high-born would of his graciousness
show himself or sing on the balcony, all would be well, otherwise the
inhabitants of the hotel might have a night that began very late. If the high-
born gave permission, the proprietor would announce the fact.
“But I’m so hungry!” said Hugh.
The proprietor had been present at the opera.
“I beseech you!” he said.
“Yes, Hugh,” said Edith.
“Then you will come with me?” asked Hugh.
Ah! but how the summer sun blazed then. She but nodded to him, and
with a reverence of extraordinary amplitude to them both, the proprietor
shouted a few guttural words from the balcony. Then he bowed and came
back into the room.
Hugh took Edith’s arm.
“Together,” he said; and together they went out on to the balcony. The
night was windless, and the flame of the gas-lamps burned without
wavering. The whole square was packed with faces, and full of a low
hubbub of talk. But when the two appeared the hubbub ceased and silence
like an incoming tide spread everywhere. Then Hugh turned quickly to the
proprietor.
“Hi! did you say I was going to sing?” he asked.
“I said it was possible. A thousand pardons,” said this perfidious man,
manœuvring into a better place.
Hugh drew a long breath, and with his arm in Edith’s stepped on to the
edge of the balcony. Then he turned side-face to the crowd, unlinked his
arm from hers, and took both her hands in his. He did not look out over the
crowd; he looked at her. And he sang:
“Du meine Seele, du mein Herz.”
At the end there was dead silence, for he unloosed one of his hands and
held it to the crowd.
“Good-night, friends,” he said in good, firm German; “and we are all
going to sleep. Hush! Thank you.”
Then he took Edith’s arm again, and they went back to the waiting
supper. The window, through which they had entered again, he had left
wide open, but the only sound that came in was the movement of feet
dispersing.
 “And that was the best of all, Hughie!” said she.

Edith could not quite rise to the superficial heights of gaiety during their
supper, but it was even more impossible for her to rise—or sink—to any
tragic level. Some equable level was there; she neither feared what she had
to tell, nor did she rise to it by any exaltation of spirit that commanded her
to think that nothing mattered, when happiness shone like this. Life and
death and sickness and health in her mind took their natural level; all of
them were to her the commonplace of souls that lived; to every soul these
things happened; they were all on the same plane, because they were so big.

Just as she had anticipated, Hugh took a cigarette with his coffee, and
she watched the burning ash get nearer to his fingers. When it got quite
close she would speak. At present it was half an inch off. So she still talked
of that of which they had talked.
“But why Tristan did not come to life when the Liebestod was sung over
him,” she said, “is what I cannot imagine. Surely it was enough to make the
dead live.”
“Sing it over me, then,” said Hugh, “when you watch by my corpse. I
will come to life, I promise you, which is more than I did to-night. What
Vandals, to interrupt like that!”
“Yes, Vandals,” said she; “but I didn’t feel surprised.”
“O, that’s all rot,” said Hugh. “But how I loved the interruption, and how
I longed to open one eyelid. But I didn’t.”
“No, you didn’t.”
Hugh leaned forward over the table, his eyes and his hands toward his
wife.
“My life!” he said. “How stupid that sort of phrase used to sound until
one knew that it was true. My life! Yes, I look at you, my life; that has
become literally true. Oh, true in big ways and small ways alike.”
The cigarette was getting shorter, and Hugh took a long inhalation of it,
and flipped off a piece of charred paper.
“Yes, big ways and small ways,” he repeated. “Big ways, because you
gave me myself, which is you, and small ways because I sang to-night, both
in the silly opera-house and on that silly balcony, because I was you. Don’t
you understand? Sometimes I think you don’t and it is so odd that you
shouldn’t.”
Still Edith was silent, for she would have to speak very soon now, and
without a pause Hugh went on—
“Considering that it is you who made me begin to understand,” he said,
“it is odd that you shouldn’t know what you have done. I don’t know who
and what you are, or who or what I am, but I do know that we are It. It, life,
call it what you please. And how is your cold?” he asked suddenly, placing
his cigarette-end in his coffeecup.
The burning ash hissed in protest, and was still. Then Edith answered
him.
“It isn’t any better, Hughie,” she said. “It won’t be better for a long time.
Are you comfortable there? If not, let us move, because I have to talk to
you.”
Once before she remembered having said to Peggy that she almost
wanted Hugh to be unhappy so that she might comfort him, for she knew, or
thought she knew, that she could always do that. But she had to make him
unhappy first—strike this dreadful blow. Already, so to speak, he had seen
her arm raised against him in the few words she had just spoken: he knew
that some blow impended, and though his face was still eager and vivid, the
expression on it seemed suddenly fixed. He waited—tense, rigid, while his
hand that had just dropped the cigarette-end into his cup turned over at the
wrist, like a dead hand, and dropped on to the table-cloth. Then he spoke
below his breath.
“Quick—tell me quickly,” he said; “I can bear anything except waiting.”
She took the hand that lay on the table-cloth in both of hers, but it still
lay, as if dead, not responding to her pressure.
“I have got consumption,” she said.
Hugh drew back his head a moment, blinking and wincing as if from a
physical blow, and summer stopped.
Neither moved, neither spoke. Edith, having struck the inevitable blow,
laid down the weapon, and her soul stood waiting, so to speak, listening
eagerly for Hugh to call to her in his pain, so that she might go to him and
comfort him and bind up the wound she had made. There was nothing
nearer to her heart than that, nothing that she so desired, and nothing of all
that had been could be so exquisite. Summer might have stopped, but on
this winter’s day there was splendour of sun and snow. She had not foreseen
that.
But just yet Hugh could not call to her, he could not even need her yet,
for he was dizzy and reeling with the blow. He had no power to move: the
very fact that a moment before all the depths of his nature—all the strength
of his love for her—had been so dominant, so triumphant, made this
paralysis the more complete. And in this stunning of his true and essential
self, the surface perception, the mere habitual work of eyes and ears and
touch seemed suddenly quickened, just as Edith’s had been when Sir
Thomas told her this same thing. A little odour as of caramel came from the
cup where he had dropped his cigarette-end, from the sugar no doubt, which
had been burned before the sweet dregs quenched the red-hot ash: as his
hand turned over on to the table-cloth he had knocked the spoon out of the
saucer, and the clink of it as it fell sounded in his ears more clearly than
even those four words which Edith had spoken. The lace curtains by the
window out of which so short a time ago he and Edith had stepped on to the
balcony just stirred in a little breeze that had arisen during the last half-
hour; on the mantelpiece a striking clock jarred to show the hour was
approaching. And the touch of Edith’s hands on his meant no more to him
than would the touch of any other hand have meant. Hands touched him,
anybody’s hands. Eyes looked at him, too, from that beloved face opposite,
but they were anybody’s eyes, it was anybody’s face.
Then the sensitiveness of surface-perception grew a little deadened as
the paralysis of the internal perception began, very slowly, starting from the
surface and working gradually inward, to pass off.
“And we were so happy!” he said.
So he was beginning to need her.
“Yes, thank God, my darling,” said she. “Let us often think how happy
we have been.”
He could not receive, assimilate more than that at once. It was for the
moment no use, so she felt, to speak hopefully, determinedly of the future,
of her unquenchable resolve to get well. He would be ready for that soon,
but not quite yet, poor darling. So she waited.
“When did you know?” asked he quietly.
 “Just before we left London. I could not do without this beautiful week
we have just had, Hughie. So I did not tell you till it was over.”
“Then—then your having a cold meant that?” he asked.
“Yes.”
Hugh pushed back his chair with sudden vehemence, got up, and
roughly, strongly, so that she was both hurt and startled, flung his arms
round her, pinioning hers, and kissed her. He devoured her face with kisses,
eyes and mouth, forehead and hair and neck were sealed with the redness
and fervour of his lips. It was vain for her to struggle with this almost
savage outburst of love; it was in vain for her to remonstrate, for he stopped
her breath with his. Yet she tried; but, oh, how sweet it was to find her
struggle, her remonstrance, useless. How during this last ten days she had
missed and yearned for the caress of his eager breath, the roughness and
smoothness of his face, his eyes burning close to hers as they burned now.
And for him that physical contact which the tumult of his love demanded
shook off the paralysis and the stunning. It was as if a man struck by
apoplexy had had his blood let, as in the primitive surgery of old days. It
was this strong flow of it that restored him to himself.
“Oh, my soul, my soul,” he whispered, “to think that you have borne it
alone. Thank God, that is over. But you cut me to the heart in not telling me.
I didn’t deserve that from you.”
His lip quivered, his eyes were brimming with tears that soon ran over,
and it was she who kissed them away. Just for that moment she could not
help it. “Be sensible, not kiss anybody”—the words of the doctor sounded
like gibberish. Hugh was crying, the doctor did not allow for that
contingency. Nothing in the world mattered at this moment but that she
should comfort him. He had never cried before, as far as she knew, and the
sobs came from so deep within him.
“Oh, if it was selfish, forgive me,” she said; “but it was not thus that I
meant it. I did want one week more so much, my darling, one week to
crown all the others.”
She had told Peggy that she meant quite distinctly to lie to Hugh, to tell
him that Sir Thomas had recommended her to go to Munich. But quite
suddenly she found she could not lie to him. No question arose in her mind
as to the morality of telling the truth or the immorality of falsehood. It was
not a moral choice that was now flashed before her, it was a mere question
of what was possible and what was not.
“It has crowned the others,” she said, “and I am exultant that we have
got it. Oh, Hughie, we have captured this week, snatched it from all the
foolish physicians who forbade it. Yes, dear, my selfishness went as far as
that. He told me not to come. So I came, and I am more glad than I can say.
He told me also to be sensible, not to kiss anybody. I have disobeyed him
there too. So forgive me for both.”
Hugh had drawn his chair close to hers.
“Oh, forgive, forgive,” he said. “What word is that between us?”
“No; it is a foolish word from me to you,” she said; “but understand
then. Can’t you understand? Just now you wondered at me for not
understanding what you said I had done. I wonder at you now for not
understanding what joy your joy has been to me. Why, it is mine, and more
mine because it is yours. Hughie, though I asked you just now to forgive, I
tell you that I am delighted with what I have done. It is like—a dog that has
stolen a bone, and looks deprecating. All the time he licks his lips. He has
had it; it tasted so good, and though he may be beaten subsequently, his
mouth still waters at the remembrance. Mine does. There would have been a
shadow over this week if you had known.”
“There would never have been this week at all,” he broke in.
“Oh, don’t be too sure—I am very obstinate when I want a thing.”
Yes; she was comforting him already, and though he did not know it, she
did. He thought that she spoke but of the past, she knew that she was
already bracing him for the future. And his smile assured her. And gently,
cunningly, she continued to build out of the past.
“Oh, Hughie,” she said, “it was the funniest scene—dear old Sir Thomas
told me, and then we called Peggy in, and I said, ‘Oh, Peggy, I’ve got
consumption.’ And then I burst out laughing, and Peggy laughed too. We sat
and roared.”
Hugh frowned at this.
“Peggy knew?” he asked. “She lied to me, then; that is what it comes to.
She told me that she laughed when you told her what Sir Thomas said was
the matter with you, so that I might think it was nothing.”
 “Yes, dear,” said Edith, “she had already promised not to interfere. If she
had—well, not equivocated to you, she would have lied to me. It was very
awkward for her, but she did her best. It was a conspiracy——”
“Directed against me.”
“Yes, darling; directed against you. I have already asked your
forgiveness, you know.”
Hugh looked round the room with mute, appealing eyes.
“Is it real?” he asked. “Is this horror real?”
Edith said nothing. He was not facing it yet with his best self; Hugh had
better than that to give. She knew it would come, for it was there. And the
infinite pity of love waited for it. When it came it would prove to have been
worth waiting for. Soon he would speak words which came from her own
heart. He would say what she felt, and more, what she sought to feel. There
was more in Hugh than was, so to speak, accessible, unlocked in her own
soul. The love-key would open it. All the wordless sensations, impressions,
strivings, of this week when she had been alone with her secret knowledge
were in him. The winter sun of the comfort she could bring to him would be
blinded by a brighter light. It was he who was going to unveil it. Often and
often, so she almost hoped, in the weeks and months that lay before them,
she would have to light his candle of patience and hope. But all the time his
sun would light her path.
But at this moment poor Hugh wanted his candle.
“What did he—what did Sir Thomas tell you?” he asked brokenly.
“That I had an excellent chance. That I was the sort of person who got
well. That I was going to get well. That when I got well, I should be
younger and better than now. I liked that, Hugh. We shall be more of an age,
so they say.”
“Oh, that silly joke,” said he.
“Yes, it will be knocked on the head, and I shall put cold-cream on your
venerable nose and give you your gruel, and then go downstairs again to
play with the children, when I have tucked you up in bed and shut the
window for fear you should catch cold. It will be fun.”
“Don’t, don’t,” said Hugh.
But she was comforting him.
 “That will not be in the immediate future, dear,” she said; “and I want to
tell now about the immediate future. Now, don’t gasp. To-morrow I must go
to Davos. I have looked out the train already; we go—because you are
coming too—we go to a place called Landquart, and up from there. I
promised Sir Thomas to do that, Hugh. I have to stop there till I am well; it
comes to that, practically.”
Then suddenly Edith found she wanted comfort herself, comfort on the
lower level, so to speak, not from the high level.
“Ah, that is dreadful,” she cried; “it may be a year, it may be more,
before I see our dear home again, and the down all gray and green above it,
and the garden and the water-meadows, and—and Mrs. Owen,” she added,
comforting herself by that eternal comforter of humour. But she slipped out
of its hands again.
“Oh, Hughie,” she said, giving way to the pathos of little things, which
are so big, “I love our home so; it was all so dear and pleasant and cheery.
And you sang your exercises in our room, and I added up books in another,
and the gales bugled outside. Or it was summer, and the miracle of
motherhood came to me. And afterward you and Daisy and Jim, all you
children, dressed up, and—and we played Tom Tiddler’s Ground, and Jim
caught me, and there was blood on my handkerchief. That is all over.”
Though here it was the lower level of comfort that she required, it was
something of the high level that met her. Swift as a spurred horse, Hugh
answered to this.
“Over? What are you thinking of?” he said. “Nothing is over. Why, it is
just because we have lived those divine days that they are not over. They
are here; we have them now. They make us. We won’t look back; there is no
need, for all that you say is past is present, bone of our bone, and the flesh
on it. You know that. ‘Days that are no more,’ as that silly poem says. There
are no days that are no more, except the days we don’t remember. All we
remember and rejoice in are the days that have been and are, the days that
live, and the things that live, the things that get entwined with love, so that
the down above Chalkpits and the river and the water-meadows are all here,
here with you and me. How can you be so foolish as to think otherwise?”
It was Edith again who was silent. As the angel moved the waters of
Bethesda, so some angel, she knew, had moved Hugh’s soul, and the love-
key was already turning in the wards of her own locked chambers. Already,
in his last words, the door was ajar, a chink of light shone out. Sorrow,
compassion, had enlightened him; it was his very weakness that gave him
strength.
He sat upright, facing her, and though his mouth still quivered and his
eyes were wet, those signs came from another source.
“But you don’t think otherwise!” he said. “It is the past that makes the
future for us. It was we who made us love the dear home, and it is we who
will make us love Davos, and, if need be, Landquart, just as devotedly. We
make the place we live in.”
The door swung wide now.
“And whatever comes, God bless it,” said Hugh. “Oh, soul talks to soul,
does it not, now? If I get run over by a train it is all right. If you don’t get
better, if you die, it is all right. It must be, because we are lovers, you and I.
There is nothing more than that in the world. Why should there be? What
could there be? Supposing the world was all a hideous joke, and we little
people were just puppets on a stage that meant nothing, what then? We still,
you and I now, feel as if it was real. We can’t ask more than that, for there is
nothing more to ask. It is real to us. We snap our fingers at cancer,
consumption, fever, all that people make statistics about. Who cares? Those
things are the unreal things.”
Hugh’s voice dropped suddenly; till now it had been almost song. But
now it became husky and dim.
“But the down above the house is real,” he said, “since it was there that
you told me of Andrew Robb. And the garden seat is real, because you sat
there and cried. And, to be egotistic, the nursery at Cookham is real,
because—well, because Daisy wouldn’t go to sleep. Moth and rust cannot
corrupt those things. Thieves cannot steal anything that is worth stealing,
whatever form the thieves take. They may take many forms, illness, disease.
Oh, Edith!”
The inevitable restriction bound the human soul. Reach out as we may
toward the infinite, toward what we know is true and real, and indeed
concerns us, yet the fact that we are men and women living on this earth
and bound bodily by the finite laws of time and space, imposes a similar
limitation on the spirit, else it would burst its bonds. And such is the
inevitable irony of things, this reaction, this tweak at the rope which binds
us to earth, brings about a fall more peremptory and convincing in
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