Obstructive sleep apnea is frequent in patients with hypertensive intracerebral hemorrhage and is related to perihematoma edema.

Abstract

Obstructive sleep apnea (OSA) is related to increased systemic inflammation and arterial hypertension. We hypothesize that OSA is frequent in patients with acute hypertensive intracerebral hemorrhage (ICH) and is related to the perihematoma edema.
Thirty-two non-comatose patients with a hypertensive ICH underwent polysomnography in the acute phase. Perihematoma edema volume was measured on CT scans at admission, after 24 h (early control) and after 4-5 days (late control). The Spearman coefficient (r(s)) was used for correlations.
OSA occurred in 19 (59.4%) patients. The apnea-hypopnea index was correlated with relative edema at admission CT (r(s) = 0.40; p = 0.031), early CT (r(s) = 0.46; p = 0.011) and at late CT (r(s) = 0.59; p = 0.006).
OSA is highly frequent during the acute phase of hypertensive ICH and is related to perihematoma edema.

Full text

Page 1

Fax +41 61 306 12 34
E-Mail karger@karger.ch
www.karger.com
Original Paper
Cerebrovasc Dis 2010;29:36–42
DOI: 10.1159/000255972
Obstructive Sleep Apnea Is Frequent in Patients
with Hypertensive Intracerebral Hemorrhage and
Is Related to Perihematoma Edema
Octavio M. Pontes-Neto a Regina M.F. Fernandes a Heidi H. Sander a
Larissa A.T. da Silva a Débora C. Mariano
Draulio B. de Araujo a Antonio C. dos Santos c João P. Leite a
a Fernando Nobre
b Gustavo Simão c
a Department of Neuroscience and Behavior, b Cardiology Division and c Radiology Division of the Department of
Internal Medicine, Ribeirão Preto School of Medicine, University of São Paulo, São Paulo , Brazil

Background
Sleep breathing disorders are highly prevalent in pa-
tients with established cardiovascular and cerebrovascu-
lar diseases [1] . Among the sleep breathing disorders, ob-
structive sleep apnea (OSA) has been proposed as an in-
dependent risk factor for the development of essential
hypertension [2] . OSA has also been found in up to 77%
of patients with an acute ischemic stroke, and has been
related to early neurological deterioration and to in-
creased long-term mortality in this population [3–5] .
Possible mechanisms include increased cardiovascular
variability, activation of the coagulation cascade, in-
creased oxidative stress and systemic inflammation
[6–8] .
Intracerebral hemorrhage (ICH) is the most deadly
subtype of stroke, as approximately 65% of its victims
are dead after 1 year [9] . Hematoma expansion and the
development of perihematoma edema are 2 of the major
factors that may contribute to the high morbidity and
mortality of ICH [10–12] . Animal studies demonstrate
that brain edema peaks around the fourth day after
ICH [13] . In humans, the edema volume could exceed
that of the original hematoma, and lead to elevated in-
Key Words
Intracerebral hemorrhage ? Perihematoma edema ?
Sleep apnea
Abstract
Background: Obstructive sleep apnea (OSA) is related to in-
creased systemic inflammation and arterial hypertension.
We hypothesize that OSA is frequent in patients with acute
hypertensive intracerebral hemorrhage (ICH) and is related
to the perihematoma edema. Methods: Thirty-two non-co-
matose patients with a hypertensive ICH underwent poly-
somnography in the acute phase. Perihematoma edema vol-
ume was measured on CT scans at admission, after 24 h (ear-
ly control) and after 4–5 days (late control). The Spearman
coefficient (r s ) was used for correlations. Results: OSA oc-
curred in 19 (59.4%) patients. The apnea-hypopnea index
was correlated with relative edema at admission CT (r s = 0.40;
p = 0.031), early CT (r s = 0.46; p = 0.011) and at late CT (r s =
0.59; p = 0.006). Conclusions: OSA is highly frequent during
the acute phase of hypertensive ICH and is related to perihe-
matoma edema.
Copyright © 2009 S. Karger AG, Basel
Received: June 22, 2009
Accepted: August 12, 2009
Published online: November 5, 2009
Dr. Octávio Marques Pontes-Neto, MD, PhD
Departamento de Neurociências e Ciências do Comportamento, Divisão de
Neurologia, Faculdade de Medicina de Ribeirão Preto , Universidade de São Paulo
Av. dos Bandeirantes 3900, Monte Alegre, Ribeirão Preto, SP 14049-900 (Brazil)
Tel. +55 16 3602 2556, Fax +55 16 3914 3044, E-Mail octaviopontes @ rnp.fmrp.usp.br
© 2009 S. Karger AG, Basel
1015–9770/10/0291–0036$26.00/0
Accessible online at:
www.karger.com/ced

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OSA and Perihematoma Edema
Cerebrovasc Dis 2010;29:36–42
37
tracranial pressure or shift in the midline structures
with subsequent neurological deterioration or death
[11, 12] .
The frequency and the clinical impact of OSA in acute
phase of ICH are still unknown. We hypothesize that
OSA is frequent in patients with ICH, and may be related
to increased development of perihematoma edema.
Subjects and Methods
We prospectively assessed 132 consecutive patients between
with a first-ever ICH admitted to the Emergency Department of
our University Hospital from January 2006 to January 2008. All
patients had a baseline computerized axial tomography (CT) scan
on admission. According to the exclusion criteria, 66 patients
with stupor or coma that demanded orotracheal intubation in the
first 24 h of stroke onset for airway protection were excluded from
the study. Additionally, 34 patients were also excluded from the
study because they were admitted 1 48 h after stroke onset, were
! 18 or 1 80 years old, had baseline oxyhemoglobin saturation
! 92% or had secondary causes of ICH (anticoagulant use, under-
lying aneurysm or vascular malformation, tumor, head trauma,
or hemorrhagic transformation of ischemic infarcts). Finally, 32
patients with a primary ICH were included in this analysis. They
underwent a full polysomnography (PSG) in the first night after
admission and had 2 follow-up CT scans 24 h after admission and
at day 4/5. This study was approved by the ethics committee at our
institution, and written informed consent was obtained from
each patient or their relatives.
Data Collection
We collected demographic, clinical, laboratory, polysomno-
graphic and radiological data. On admission, information about
the patients was collected from themselves or their relatives us-
ing a comprehensive questionnaire that included demographi-
cal data, the frequency of risk factors for stroke, sleep habits,
sleep disturbances that were noticed before the stroke (snoring,
daytime sleepiness, non-restorative sleep) and hemorrhage on-
set-to-imaging time. Additionally, patients were assessed with
physical and neurologic examinations that included axillary
temperature, mean arterial blood pressure (MAP; calculated as
1/3 systolic + 2/3 diastolic blood pressure), pulse oximetry,
Glasgow coma scale and National Institute of Health Stroke
Scale (NIHSS) scores (on admission and daily until discharge)
[14] . Early neurologic deterioration was defined as an increase
of 4 points in the NIHSS in the first 48 h [15] . Body mass index
and cervical perimeter were measured during admission. Labo-
ratory data collected on admission included electrocardiogram,
chest radiography, and standard blood tests (serum glucose and
complete blood counts – hemoglobin, hematocrit and white cell
count) at presentation. We also registered the hospital morbid-
ity and mortality. The NIHSS and the modified Rankin Scale
(mRS) scores were collected on follow-up visits in the outpatient
clinic at approximately 6 months after discharge to assess mor-
tality and the degree of neurological and functional recovery
after ICH [14] .
Polysomnographic Assessment
PSG was performed at the hospital ward from 11:
00 PM to
7:
II TM ; Mundelein, Ill., USA), without interfering with convention-
al care of the patient. System variables included 6 EEG channels
(F3-A1, F4-A2, C3-A1, C4-A2, O1-A1, O2-A2), electro-oculo-
gram, chin and left and right anterior tibial surface electromyo-
gram, electrocardiogram, nasal and oral airflow, thoracic and ab-
dominal movements, and oxyhemoglobin saturation. Sleep stages
were scored according to standard criteria [16] . Apnea was de-
fined as the absence of airflow for at least 10 s. In obstructive ap-
nea, respiratory effort was maintained, whereas in central apnea,
breathing movements were absent. Mixed apnea was defined as a
combination of central and obstructive apnea. Hypopnea was de-
fined as a thoracoabdominal amplitude decrease 1 50% for at least
10 s with either an arousal or an oxygen desaturation 1 3%.
Cheyne-Stokes respiration was defined as a periodic crescendo
and decrescendo breathing pattern with central apnea or hypop-
nea. The apnea-hypopnea index (AHI) was defined as the average
number of apnea and hypopnea episodes per hour of sleep, and
sleep apnea was defined by an AHI 6 10 and further classified as
obstructive or central according to type of event that predomi-
nates [3, 5] .
00 AM, by using a full digital PSG system (BioLogic Sleepscan
Radiological Measurements
We measured the hematoma and edema volumes on admis-
sion and follow-up CT scans, done after 24 h and between 4 and
5 days after admission. A single evaluator (O.M.P.N), experienced
in the interpretation of CT and blinded to patients’ clinical and
polysomnographic data, analyzed all CT scans to conduct volu-
metric measurements of ICH and edema lesion volumes. All im-
ages were processed offline using ImageJ 1.38 (NIH, public do-
main). The ICH and edema volumes were calculated using a semi-
automated process. The examiner manually drew regions of
interest (ROI) by tracing the perimeter of appropriate high- and
low-attenuation zones in each slice throughout the lesion ( fig. 1 ).
Automated threshold values, based on Hounsfield unit measure-
ments, were then applied to differentiate hematoma from skull
and brain parenchyma from perihematoma edema. Using the
threshold values to differentiate hematoma from edema, contigu-
ous voxels were automatically summed to yield a hematoma vol-
ume and absolute edema volume (the volume of the hematoma
and surrounding edema). Relative edema was then calculated di-
viding the absolute edema by hematoma volume. In order to fa-
cilitate data calculation, relative edema volume was also multi-
plied by 100 to express perihematoma edema volume as a percent-
age of the associated hematoma volume.
The blinded observer drew the ROI on an initial subset of 10
patients twice, at an interval of 2 weeks apart. The test/retest
agreement was r = 0.98 for edema and hematoma volume mea-
surements. Another investigator (G.S.) independently drew the
ROI on the same subset of 10 patients. The interobserver agree-
ment was r = 0.90 for edema and hematoma volume measure-
ments. Because the intra- and interobserver reliability was ex-
tremely high, only 1 measurement by 1 observer (O.M.P.N.) was
used for the remainder of the ROIs.
Statistical Analysis
In univariate analyses, Fisher’s exact test was used for categor-
ical data and Wilcoxon rank-sum test for quantitative data. For-

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Pontes-Neto et al.
Cerebrovasc Dis 2010;29:36–42
38
ward stepwise logistic regression analyses were used to identify
the independent predictors of AHI 6 10 and AHI 6 30. The inde-
pendent contribution of variables with a p value ! 0.05 on uni-
variate analyses was assessed. Results are expressed as mean 8
SD, median 8 interquartile range (IQ), adjusted odds ratios, and
corresponding 95% CI. The Spearman correlation coefficient (r s )
was used to determine the presence or absence of a correlation
between quantitative variables, including AHI and relative edema
volume on admission, after 24 h and on days 4–5. Statistical sig-
nificance was corrected for multiple comparisons by Bonferroni
correction (p ! 0.01). We used the following limits for the inter-
pretation of the correlation coefficient value: weak (r s between 0.2
and 0.5); moderate (r s between 0.5 and 0.8); strong (r s between 0.8
and 1); perfect (r s = 1) [17] . All statistical analyses were done with
the SPSS package (version 15.0 for Windows; Chicago, Ill., USA).
Results
A total of 132 patients were admitted to our Emergen-
cy Department with ICH during the study period. One
hundred subjects were excluded from the present analy-
sis: 66 were comatose and underwent subsequent orotra-
cheal intubation in the first 24 h, 12 had a secondary
cause of ICH, 7 had stroke onset more than 48 h before
admission, 7 had previous ischemic stroke, 3 had a previ-
ous ICH, for 3 patients it was impossible to obtain in-
formed consent, and 2 underwent urgent surgery in the
first 24 h. Data from the remaining 32 subjects were in-
cluded in this analysis.
There were 23 men and 9 women with a mean age of
57 8 11.8 years. The mean MAP on admission was 144.3
8 28.4 mm Hg. The mean BMI was 26.5 8 4.9, the mean
cervical perimeter was 39.92 8 3.28 cm. The most fre-
quent ICH risk factors reported were: arterial hyperten-
sion in 32 (100%), chronic alcohol abuse in 21 (65.6%),
smoking in 18 (56.3%), obesity in 12 (37.5%), sedentary
lifestyle in 10 (31.3%), diabetes in 9 (28.1%), and aspirin
use in 7 (21.9%). History of habitual snoring was retrieved
from 14 (43.8%) patients, history of witnessed respiratory
pauses during sleep reported by bed partner in 4 (12.5%),
and excessive daytime sleepiness in 3 (9.4%) patients. No
patient received medications, such as hypnotics, that
could have induced OSA or worsened the AHI.
The mean time between the onset of symptoms and
admission was 13.0 8 12 h. At presentation, the most
frequent neurological signs were hemiparesis, present in
31 (96.8%) patients, dysarthria in 26 (81.3%), and aphasia
in 20 (62.5%). Stroke was noticed on wakening in 8 pa-
tients (25%) and occurred during wakefulness in 24
(75%). At admission, the median NIHSS score was 15 (IQ:
10–20) and median GCS score was 14 (IQ: 12–15). The
mean serum glucose was 128 8 48.1 mg/dl, mean white
blood cell count was 10,340 8 3,972 cells/ ? l, and mean
platelet count was 233,000 8 71,219 platelets/ ? l. None of
the patients studied showed signs of dehydration, and
blood tests on admission showed no evidence of renal
dysfunction or significant electrolyte disturbances. No
patient received mannitol or other osmotic treatment for
ICH.
Thirty patients (93.8%) had deep ICH and 2 (6.2%) had
lobar ICH. The mean onset-to-imaging time was 14.6 8
11.8 h for the admission CT scan, 41.3 8 20.6 h for the
24 h follow-up CT scan, and 111.5 8 39.7 h for the late
follow-up scan. Table 1 lists the means 8 SD of hema-
toma and perihematoma edema volumes at admission,
ab
Fig. 1. Depiction of the measurements of
hematoma and perihematoma edema.
ROIs drawn around the perimeters of the
perihematoma edema ( a ) and hematoma
( b ) in all CT slices. Volumes from all slices
were summed: V 1 (Veh) = edema + hema-
toma; V 2 (Vh) = hematoma; absolute ede-
ma = Vh – Veh; relative edema = absolute
edema/Vh (relative edema volume was
also multiplied by 100 to express perihe-
matoma edema volume as a percentage of
the associated hematoma volume).
Color version available online

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OSA and Perihematoma Edema
Cerebrovasc Dis 2010;29:36–42
39
after 24 h and 4–5 days later. As shown, whereas the he-
matoma size increased by approximately 33% from base-
line to day 4 to 5, the relative edema volume doubled dur-
ing this time period. There was no significant correlation
between the percent change in hematoma volumes and
percent change in the corresponding relative perihema-
toma edema volume (r s = 0.27; p = 0.30).
The median duration of hospitalization was 12 days
(range: 2–42; mean 8 SD: 16 8 10.9). Eleven (34.4%) had
early neurological deterioration. Seven (21.9%) patients
died during hospitalization. The mortality rate was 18.5%
in 30 days, 21.8% in 90 days, and 31.3% in 180 days. The
median NIHSS score was 12.5 (IR:4–31) at 3 months. Six
(18.8%) patients had mRS ^ 2 at 3 months.
The mean latency between stroke onset and PSG was
20.2 8 12.5 h ( table 2 ). The mean AHI was 24.27 8 24.0
(range 0–92). Twenty patients (62.5%) had an AHI 6 10.
Of these, 9 had an AHI 6 30. Among the 20 patients
with AHI 6 10, apneas were predominantly obstructive
in 19 (95%) subjects, and central in only 1 (5%). Cheyne-
Stokes respiration was detected in 3 (9.4%) patients, in
whom clinical examination and history did not disclose
signs or symptoms suggestive of heart failure. At echo-
cardiography, all of them had concentric ventricular hy-
pertrophy, but the ejection fraction was within normal
values.
Compared to the patients with AHI ! 10, patients with
AHI 6 10 had no differences in age, BMI, previous his-
tory of witnessed apneas or hypersomnia, risk factors for
stroke, systolic and diastolic blood pressure, hematocrit,
temperature on admission, fasting serum glucose, ICH
location and volume, neurologic impairment, or func-
tional outcome during the 6 months of follow-up. Never-
theless, in patients with AHI 6 10, a positive history of
loud frequent snoring was far more frequent (60 vs. 16.7%,
p = 0.02) than in patients with AHI ! 10. That was the
only significant difference between patients with AHI
! 10 and AHI 6 10. In patients with AHI 6 30, a positive
history of loud frequent snoring was also more frequent
(66.7 vs. 16.7%, p = 0.03) when compared to patients with
AHI ! 10. Additionally, patients with AHI 6 30 had more
relative perihematoma edema (56.24 8 26.6 vs. 37.8 8
19.60; p = 0.029) than patients with AHI ! 10. We found
no correlation between AHI 6 10, AHI 6 30, and out-
come.
Table 3 shows the correlation coefficients of clinical
and polysomnographic variables (including serum AHI
on admission) with relative edema volume. After adjust-
ing for multiple comparisons, there was a significant pos-
itive correlation between AHI and relative perihematoma
edema volume that was weak at baseline (r s = 0.40; p =
0.030), at 24 h (r s = 0.46; p = 0.011) and increased to mod-
erate at day 4–5 (r s = 0.59; p = 0.006). The total white
blood cell count on admission was the only other clinical
or laboratorial variable that had a positive correlation
with relative edema volume at day 4–5 (r s = 0.57; p =
0.008).
Discussion
Using a full PSG system, we evaluated 32 consecutive
non-comatose patients with an acute hypertensive ICH
and found a high percentage (59.4%) of OSA. To our
knowledge, this is the first study that focused on the fre-
quency and severity of OSA in patients with acute hyper-
tensive ICH using a full PSG (the gold standard diagnos-
Table 1. A summary of hematoma and edema (absolute and rela-
tive) mean volumes at admission, after 24 h and 4–5 days after-
wards
BaselineAfter 24 h Day 4–5
Hematoma, cm3
Absolute edema, cm3
Relative edema, %
26.5822.4
9.789.1
46.7823.9
29.4825.1
13.9812
57.6835.3
35.4830.3
20.0819.3
79.5845.3
Table 2. PSG findings
Total time recorded, min
Total sleep time, min
Sleep efficiency, %
Sleep stages, %
Stage N1
Stage N2
Stage N3
Stage R
AHI, n
AHI ≥5
AHI ≥10
Obstructive apneas
Central apneas
AHI ≥20
AHI ≥30
Cheyne-Stokes respiration
CT90 during PSG, %
339.7870.8
222.4891
65825.8
96.8850.6
83.5856.1
18.21823.54
24.0824.5
24.27824.0
25 (78.1)
20 (62.5)
19 (95)
1 (5)
16 (50)
9 (28.1)
3 (9.4)
5.9814.5
CT90 = Percentage of time with hemoglobin saturation
<90%.

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Pontes-Neto et al.
Cerebrovasc Dis 2010;29:36–42
40
tic method). Moreover, we found a consistent relationship
between the severity of OSA in the acute phase of ICH
and the development of perihematoma edema, measured
on serial CT scans done at admission, after 24 h and
days 4–5.
At least 3 previous studies that searched for sleep
breathing disorders in the acute phase of stroke have in-
cluded ICH patients among their series [18–20] . In 2 of
those studies, data from the few ICH patients included
were analyzed together with ischemic stroke patients [18,
19] . In the third study, no distinction was possible be-
tween obstructive and central events because the authors
only used pulse oximetry to screen for sleep apneas [20] .
All of those studies have found high percentage (64–90%)
of oxygen desaturations in the acute phase of ICH, which
is in accordance with our results. We found a higher fre-
quency (43.8%) of previous snoring in our study popula-
tion of hypertensive ICH patients and history of snoring
was associated with OSA at PSG, which may suggest that
OSA was present before the ICH. Whether OSA indepen-
dently contributed to the development of ICH is specula-
tive, and should be addressed by future prospective stud-
ies that follow hypertensive patients with and without
OSA.
Several mechanisms contribute to the development of
brain edema after ICH. There is an early phase during the
first few hours after the ictus involving hydrostatic pres-
sure during hematoma formation and clot retraction, a
second phase during the first 24 h resulting from throm-
bin production and activation of the coagulation cascade,
and a delayed phase involving hemolysis of red blood
cells and hemoglobin-mediated toxicity [21, 22] . The
amount of perihematoma edema has also been related to
several factors such as the serum ferritin level and in-
creased activity of matrix metalloproteinase-9, an en-
zyme that is important for the remodeling of the blood
brain barrier and appears to play a key role in the gen-
eration of perihematoma edema [23–26] .
Patients with OSA experience repetitive episodes of
hypoxia/reoxygenation during transient cessation of
breathing that promote systemic oxidative stress, activa-
tion of the coagulation cascade, inflammation, and im-
paired repair capacity of the vascular endothelium [6] .
Therefore, OSA may contribute in several pathways to the
development of perihematoma edema. Most interesting-
ly, OSA has also been recently related to increased activ-
ity of matrix metalloproteinase-9 [27] . These findings
give biological plausibility for the association between
OSA and perihematoma edema, but the role of matrix
metalloproteinase-9 on this association needs to be ad-
dressed by additional studies in the future.
There are some limitations to our study, mainly re-
lated to a relatively small sample size. As expected, sev-
eral ICH patients that were initially screened for this
study were comatose and required early orotracheal intu-
bation for airway protection. As orotracheal intubation
and positive ventilation prevent OSA in the acute phase,
screening with PSG is neither applicable nor necessary
for those patients; therefore, they were excluded from the
study. Exclusion of comatose patients has also been fre-
quent in ICH trials because a severe pre-hospital neuro-
logic deterioration might prevent the required prognosis
for some therapeutic interventions [28, 29] . Although this
might limit the direct extrapolation of our conclusions to
the whole population of ICH patients, there are no clear
reasons to believe that the correlation between AHI and
edema would behave differently in patients with more se-
vere ICH. Most notably, our findings apply to the impor-
Table 3. Correlation coefficients of admission clinical, laboratory and polysomnographic data with the relative edema volume at base-
line, after 24 h and on day 4–5
Admission
CT scan
p value 24 h CT scanp value Day 4 to 5
CT scan
p value
Onset-to-image time
White cell count
Mean arterial pressure
Baseline serum glucose
AHI
0.27
0.29
–0.23
0.17
0.40
0.14
0.13
0.90
0.35
0.03*
0.24
0.30
–0.11
0.04
0.46
0.19
0.12
0.56
0.80
0.01*, a
–0.04
0.57
–0.27
0.16
0.59
0.84
0.008*, a
0.23
0.48
0.006*, a
* p = 0.05.
a Statistically significant correlation (p < 0.01) corrected for multiple comparisons.

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OSA and Perihematoma Edema
Cerebrovasc Dis 2010;29:36–42
41
tant subgroup of ICH patients with higher Glasgow coma
scale scores at admission, i.e. those with a greater risk of
inhospital neurologic deterioration [29] . These are also
the patients most likely to benefit from potential treat-
ment modalities intended to prevent deterioration, such
as haemostatic treatment, early surgical intervention or
non-invasive positive ventilation. Hence, our results are
important at least for hypothesis generating at this
point.
We found no association among AHI and outcome.
Nevertheless, this study was not planned to detect a sig-
nificant difference regarding mortality at this moment.
Indeed, it is still controversial whether or not perihema-
toma edema formation contributes to ICH-induced neu-
rological deficits [12, 21] . Subsequent studies might help
to clarify the clinical impact of OSA in the evolution of
ICH patients.
In conclusion, we found that OSA is highly frequent
in non-comatose patients during the acute phase of hy-
pertensive ICH, and its severity correlates to the devel-
opment of perihematoma edema. Given the biological
plausibility of this association, additional studies are
necessary to confirm a causal relationship between sleep
apnea and perihematoma edema, the clinical impact
of OSA in the evolution of patients with acute ICH, and
whether there is any prospect for non-invasive pres-
sure ventilation to decrease edema in selected patients
with ICH.

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