ARTICLE IN PRESS

Stroke Volume Predicts Nocturnal Hypoxemia in the Acute Ischemic

Stroke after Intravenous Thrombolysis

Jaana K. Huhtakangas, MD,* Tarja Saaresranta, MD, PhD,†

Michaela K. Bode, MD, PhD,‡ Risto Bloigu, MSc,§ and
Juha Huhtakangas, MD, PhDk

The Goal: The aim of the study was to investigate whether stroke volume or the presence of
ischemic stroke lesion on follow-up computed tomography 1 day after admission had
association with sleep apnea among ischemic stroke patients undergoing thrombolysis.
Materials and Methods: We prospectively recruited 110 consecutive ischemic stroke
patients and performed computed tomography on admission and after 24 hours after
intravenous thrombolysis. Stroke volume was measured from post-thrombolysis computed
tomography scans. Unattended cardiorespiratory polygraphy with a 3-channel device was
performed during 48 hours after admission. Findings: Of 110 ischemic stroke patients
treated with thrombolysis 65.5% were men. Mean age was 65.8 years and body mass index
27.5 kg/m2. The mean Epworth sleepiness scale score was 4.7. Eight patients (12.7%) with
visible acute stroke after thrombolysis and none in the other group had hemorrhage as
complication (P ˂ .001). Sleep apnea, determined as a respiratory event index greater than
or equal to 5/hour, was diagnosed in 96.4% patients. Respiratory event index greater than
15/h was found in 72.8% of patients. Both mean baseline oxygen desaturation index (23.9
versus 16.5 , P = .028) and obstructive apneas/hour (6.2 versus 2.7, P = .007) were higher
in visible stroke group. Stroke volume (mean 15.9 mL) correlated with proportion of time
spent below saturation less than 90%, P = .025. Conclusions: Acute ischemic stroke patients
treated with thrombolysis with visible stroke were more likely to have nocturnal hypoxemia
than patients with not visible strokes. Stroke volume correlated with time spent below
saturation of 90 %.
Key Words: Thrombolysis—computed tomography—cardiorespiratory polygraphy— visible
stroke—sleep apnea.
© 2019 Published by Elsevier Inc.

Abbreviations: AHI, apnea hypopnea index; REI, respiratory event index; ODI, oxygen desaturation index; NIHSS, National Institutes of Health Stroke Scale;
BMI, body mass index; PAD, peripheral arterial disease; ESS, Epworth Sleepiness Scale; mRS, modified Rankin scale; HI, hemorrhagic infarction; PH,
parenchymal hematoma; AASM, American Academy of Sleep Medicine; ODI4, oxyhemoglobin decrease of greater than or equal to 4%; SD, standard deviation;
t-PA, intravenous recombinant tissue plasminogen activator
From the *Respiratory Medicine Unit, Institute of Clinical Medicine, Oulu University Hospital, MRC Oulu, Oulu, Finland; †Turku University Hospital,
Division of Medicine, Department of Pulmonary Diseases and Sleep Research Centre, Department of Pulmonary Diseases and Clinical Allergology, University
of Turku, Turku, Finland; ‡Oulu University Hospital, Department of Clinical Radiology, Oulu, Finland; §Medical Informatics and Statistics Research Group,
University of Oulu, Oulu, Finland; and ║Department of Neurology, Oulu University Hospital, Oulu, Finland.
Received April 13, 2019; revision received May 21, 2019; accepted June 5, 2019.
This study was supported by The Finnish Anti-Tuberculosis Association Foundation, V€aino€ and Laina Kivi Foundation, Tampere Tuberculosis Foundation,
The Research Foundation for Respiratory Diseases, Maire Taponen Foundation, and Jalmari and Rauha Ahokas Foundation. The ApneaLink Plus (Resmed,
Sydney, Australia) devices were provided by Resmed Finland.
We studied stroke volume and visible stroke association with sleep apnea among ischemic stroke patients with thrombolysis treatment in Oulu University
Hospital, Department of Neurology, Finland.
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2 J.K. HUHTAKANGAS ET AL.

Address correspondence to Jaana K. Huhtakangas, MD, Respiratory Medicine Unit, Institute of Clinical Medicine, Oulu University Hospital, Box 25,
Kajaanintie 50, Oulu 90029 OYS, Finland. E-mail: [email protected].
1052-3057/$ - see front matter
© 2019 Published by Elsevier Inc. https://doi.org/10.1016/j.jstrokecerebrovasdis.2019.06.017

Journal of Stroke and Cerebrovascular Diseases, Vol. &&, No. && (&&), 2019: &&&& 1
Introduction strokes into 2 size categories: patients with (n = 63) or without
(n = 47) visible acute ischemic stroke 24 hours after intravenous
Sleep apnea is characterized by repetitive episodes of upper thrombolysis. The thrombolysis was administered within
airway closing, decreases in oxygen saturation and increased
4.5 hours from the onset of symptoms for patients who were
sympathetic activation during sleep. In general population, it is
independent, had the National Institutes of Health Stroke Scale
present in 14% of middle-aged men and 5% of women,1 whereas
scores (NIHSS) over 2, and did not have any contraindications
among stroke patients the prevalence estimates of sleep apnea
for intravenous thrombolysis. The exclusion criteria for
range from 62.5% to 91.2%.2-4 Sleep apnea may increase the risk
thrombolytic therapy for stroke were defined according to the
of developing cardiovascular diseases5 through several
Finnish Current Care Guideline for Ischemic stroke.14 All study
pathways, such as intermittent hypoxia, sleep fragmentation,
patients participated voluntarily and gave their written informed
fl
chronic sympathetic activation, and systemic in ammation.6,7 consent. Our study protocol was approved by the ethics
The severity of sleep apnea is usually defined by the apnea committee of the Northern Ostrobothnia Hospital District (
approval number 21/2013).
hypopnea index (AHI) or respiratory event index (REI). Oxygen
desaturation index (ODI) reflects frequency of drops in oxygen The demographic data included age, sex, body mass index,
saturation and is a measure of intermittent hypoxia. The smoking habits, consumption of alcohol, snoring, hypertension,
recording time spent with oxygen saturation SaO2 less than 90% hypercholesterolemia, coronary artery disease, atrial fibrillation,
reflects the total time exposed to marked hypoxemia. After peripheral arterial disease, hemorrhage as complication, and
stroke 20% of patients develop oxygen desaturation within first deaths. Smoking habits were expressed as pack years and
few hours and nearly two-thirds are affected within the first 48 whether a patient was a current smoker or not. Daytime
hours.8 Stroke lesion can alter the central regulation of sleepiness was assessed by the Epworth Sleepiness Scale (scale
fi
respiration, leading to sleep apnea or producing weakness of 0-24).15 Stroke outcome was estimated by the modi ed Rankin
respiratory muscles.8 Sleep apnea patients with nocturnal scale (scale 0-5).16 The stroke severity was assessed by the
hypoxemia (oxygen saturation below 90%) are at risk of stroke, NIHSS (scale 0-35). 17 We classified patients into 2 groups
especially when desaturations exist more than 10% of nocturnal depending if they had or did not have a visible lesion in follow-
time.9 A systematic review reported obstructive sleep apnea up imaging.
after stroke to be a risk factor for both recurrent vascular event
The experienced neuroradiologist assessed all computed
and all-cause mortality.10 Among stroke patients, oxygen
tomography (CT) scans or magnetic resonance imaging (MRI)
desaturation,11 AHI,12 Scandinavian Stroke Scale,12 and stroke
available for the acute ischemic stroke lesions and stroke
size on admission13 have been reported to independently predict
volume measurements. Depending on the CTmachine,
impaired functional outcome among stroke patients.
sequential technique with 5 mm axial slices or helical
Our study had 3 aims. First, we investigated whether stroke acquisition providing volumetric data was used, the latter being
volume is associated with sleep apnea during the first 48 hours reformatted to 3-5 mm thick slices on axial plane. Area of each
in ischemic stroke patients, treated with thrombolysis. Second, infarction was determined by tracing their boundaries on each
we examined differences in nocturnal recording results of stroke slice on a clinical workstation. The obtained area was multiplied
patients with or without a visible lesion in follow-up imaging. with the slice thickness, and the volume of each slice was
Third, we also studied the association between the measures of summed. One patient had only MRI images available, and the
sleep disordered breathing and the presence of hemorrhage after volume was measured from diffusion weighted images in a
thrombolysis. As far the knowledge about the association similar manner. Multiple infarctions were combined as 1
between stroke size and sleep apnea related hypoxia is limited. volume. The hemorrhagic events were classified as hemorrhagic
infarction types 1 and 2 and parenchymal hematoma (PH) types
Materials and Methods fi
1 and 2 according to previous de nitions. 18
We recruited 204 consecutive ischemic stroke patients of the
age of 18 years or older, who were admitted to the Stroke Unit
at the Department of Neurology of the Oulu University Hospital
during April 2013 and January 2015. This study was performed
in Oulu, Finland. Of those we included all 110 stroke patients
receiving thrombolysis in this study. We classified ischemic
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STROKE VOLUME PREDICTS HYPOXEMIA IN STROKE 3

An unattended cardiorespiratory polygraphy with portable ttest. We used the 2-sample test of proportion to evaluate the
type 4 device19 (a 3-channel portable device, ApneaLink Plus, equality of proportions for both the modified Rankin scale
Resmed, Sydney, Australia) was performed on study patients. scores and sleep apnea severity. Group comparisons were
The nocturnal recordings were scored manually (American performed using the Mann-Whitney U test when the data were
Academy of Sleep Medicine, AASM criterion)20 by the same not normally distributed. Spearman correlation coefficient was
scorer without blinding. We used the threshold for arterial used to correlations between stroke volume and REI, ODI4, and
oxyhemoglobin decreases of greater than or equal to 4% per percent of time spent below saturation 90%. P values of less than
hour (ODI4). Nocturnal recording data with minimum 4 hours .05 were considered statistically significant. Statistical analyses
successful recording were accepted for analyses. The number of were computed using IBM SPSS (IBM Corp. Released 2013;
apneas and hypopneas per hour of nocturnal recording was IBM SPSS Statistics for Windows, Version 22.0, Armonk, NY:
expressed by REI. Hypopnea was defined as a greater than 30% IBM Corp.).
decrease of the baseline amplitude of breathing lasting greater
than or equal to 10 seconds that is associated with SaO2 drop of
greater than 3%. Sleep apnea was defined as an REI greater than Results
or equal to 5/h. Desaturation was described with measures of
In the entire cohort 65.5% were male, and the sex distribution
mean SaO2, lowest SaO2, and percentage of nocturnal recording
did not differ between the groups as shown in Table 1. There
time with SaO2 below 90%.
Table 1. Characteristics of patients at baseline, all data were recorded on admission
Patients with visible acute ischemic Patients without visible acute
stroke after thrombolysis ischemic stroke after
treatment n = 63 thrombolysis treatment n = Total n =
Characteristics of patients 47 110 P value
Men, n (%) 43 (68.3) 29 (61.7) 72 (65.5) .475
Mean age, years (SD) 64.7 (14.4) 67.4 (14.8) 65.8 (14.6) .345
Mean BMI, kg/m2 (SD) 27.4 (5.3) 27.5 (4.3) 27.5 (4.9) .937
Current smoking, n (%) 13 (20.6%) 7 (14.9%) 20 (18.2) .440
Mean pack years, years (SD) 9.5 (15.5) 7.6 (12.7) 8.7 (14.4) .392
Alcohol users, n (%) 11 (17.5) 8 (17.0) 19 (17.3) .952
Heavy alcohol users, 30 g/d, n (%) 1 (1.6) 2 (4.3) 3 (2.7) .575
Mean neck circumference, cm (SD) 43.0 (5.9) 41.1 (4.9) 42.2 (5.6) .084
Mean waist circumference, cm (SD) 103.4 (15.5) 103.2 (15.2) 103.3 (15.3) .942
Snoring, n (%) 46 (73.0%) 33 (70.2) 79 (71.8) .746
Mean ESS, score (SD) 4.5 (2.9) 5.0 (3.1) 4.7 (3.0) .455
Mean NIHSS (scale 0-30) (SD) 8.5 (5.5) 5.2 (3.5) 7.1 (5.0) <.001
Rankin scale (scale 0-5) n ( % )
Rankin scale 0 49 (44.5) 31 (28.2) 80 (72.7) .081
Rankin scale 1 8 (7.3) 7 (6.4) 15 (13.6) .085
Rankin scale 2 2 (1.8) 1 (.9) 3 (2.7) .693
Rankin scale 3 4 (3.6) 6 (5.5) 10 (9.1) .632
Rankin scale 4 0 (0) 2 (1.8) 2 (1.8) .285
Rankin scale 5 0 (0) 0 (0) 0 (0) 1.000
Hypertension n (%) 36 (57.1) 29 (61.7) 65 (59.1) .630
Hypercholesterolemia n (%) 25 (39.7) 21 (44.7) 46 (41.8) .599
Diabetes mellitus n (%) 13 (20.6) 8 (17.0) 21 (19.1) .633
Coronary artery disease n (%) 11 (17.5) 11 (23.4) 22 (20.0) .441
Atrial fibrillation n (%) 3 (4.8) 2 (4.3) 5 (4.5) 1.000
PAD n (%) 3 (4.8) 2 (4.3) 5 (4.5) 1.000
Hemorrhage as complication, n (%) 8 (12.7) 0 (.0) 8 (7.3) <.001
Death n % 3 (4.8) 1 (2.1) 4 (3.6) .634
BMI, body mass index; ESS, Epworth sleepiness scale; PAD, peripheral arterial disease.
Demographic and nocturnal recording data are reported as were no between-group differences in age, body mass index,
means and standard deviations (SD). The chisquare test or the smoking, pack years, alcohol users, neck- and waist
Fisher exact test was used to categorical variables, whereas circumference, snoring, Epworth Sleepiness Scale scores,
normally distributed variables were assessed by the Student’s Rankin scale scores, hypertension, hypercholesterolemia,
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4 J.K. HUHTAKANGAS ET AL.

Table 2. Unattended cardiorespiratory polygraphy results of patients with or without visible acute ischemic stroke after thrombolysis
treatment
Patients with visible Patients without
Outcome stroke n = 63 visible stroke = 47 Total n = 110 P value
Sleep apnea n (%) 59 (93.7) 47 (100.0) 106 (96.4) .134
Mean REI/h (SD) 35.8 (25.1) 30.9 (20.0) 33.7 (23.1) .257
Mean ODI4/h (SD) 23.9 (21.3) 16.5 (13.4) 20.7 (18.7) .028
Mean OAI/h (SD) 6.2 (9.3) 2.7 (3.0) 4.7 (7.5) .007
Mean CAI/h (SD) 4.9 (8.7) 2.5 (4.3) 3.9 (7.3) .053
Mean MAI/h (SD) .05 (.2) .06 (.4) .1 (.3) .799
Mean hypopneas/h (SD) 24.6 (19.3) 25.6 (18.5) 25.0 (18.9) .774
Mean average oxygen saturation (SD) 92.5 (2.0) 92.9 (2.3) 92.7 (2.1) .362
Mean lowest oxygen saturation (SD) 79.6 (8.7) 82.3 (6.9) 80.8 (8.0) .074
Saturation <90%, % (SD) 19.6 (22.2) 12.9 (21.6) 16.7 (22.1) .114
Sleep apnea severity
No sleep apnea n (%) 4 (3.6%) 0 (0) 4 (3.6) .189
Mild (REII 5-15/h) n (%) 12 (10.9) 14 (12.7) 26 (23.6) .771
Moderate (REI 15-30/h) n (%) 18 (16.4) 10 (9.1) 28 (25.5) .264
Severe (REI 30/h) n (%) 29 (26.4) 23 (20.9) 52 (47.3) .504

CAI, central apnea index; MAI, mixed apnea index; OAI, obstructive apnea index; ODI4, oxygen desaturation index 4%; REI, respiratory
diabetes, coronary artery disease, atrial fibrillation, peripheral region, and 21.7% in other region. The severity of sleep apnea
arterial disease and deaths. In the whole group, the mean volume in study patients, jointly with their stroke locations are
of stroke was 15.9 mL (median .6 mL, SD illustrated in Fig 2.
40.8). Patients with visible stroke had severer strokes measured Those 8 patients having hemorrhagic transformation all had
by NIHHS score. Hemorrhage as complication was detected sleep apnea. They had mean REI 43.5 (SD 19.8)/h, ODI4 29.1
only in the group with a CT lesion (8 /12.7%, P˂ .001). There (20.8)/h, obstructive apneas 6.6 (10.3)/h, central apneas 9.5
were 3 (4.8%) deceased patients in the visible stroke group and (11.6)/h, hypopneas 27.4 (15.7)/h, average oxygen saturation
1 (2.1%) in the other group. The mean time interval from 92.5 (1.9)%, lowest oxygen saturation 81.0 (2.4)%, and
baseline to death was 67.3 (SD 51.9) days. saturation below 90% 22.5 (24.4)% of time.
The results of unattended cardiorespiratory polygraphy of
patients with or without a CT lesion after thrombolysis are
Discussion
shown in Table 2. Sleep apnea (REI 5/h) was diagnosed in 106
(96.4%) patients. At least moderate (REI > 15/h) was found in Our main finding was that the ischemic stroke volume and
80 (72.8%) of patients. REI per hour, central apneas and nocturnal time spent below saturation 90% correlated positively.
hypopneas per hour, average saturation, lowest saturation, In the study of Iranzo et al21 the infarct volume did not differ
percentage of nocturnal recording time with SaO 2 below 90% between patients having AHI under or at least 10. Oxygen
and sleep apnea severity did not differ between the groups. The desaturation may impair brain damage because the oxygen
patients with visible stroke had higher ODI4/h (23.9 versus 16.5, delivery is reduced to penumbral brain tissue.8,22,23 Previous
P = .028) and more obstructive apneas/h (6.2 versus 2.7, P = studies have shown that nearly 20% of acute stroke patients
.007) as compared to the patients without visible stroke. develop intermittent hypoxia during first hours after stroke and
event index. almost twothirds within 48 hours.8,22,23 Kendzerska et al24
evaluated the association between obstructive sleep apnea
related variables and cardiovascular events and observed that
The infarct volume correlated positively with time spent SaO2
the sleep time with SaO2 below 90% was the strongest predictor
below 90% (P = .025; Fig 1). Stroke volume did not correlate
(hazard ratio 1.50) for cardiovascular events. Previous study has
with Rankin scale score, REI or ODI4. We could not analyze if
shown stroke patients with more severe strokes measured by
stroke size predicted sleep apnea, because 96.4% of patients had
NIHHS scale and increased age to be more likely to develop
sleep apnea (AHI 5/h), and the confidence interval was too
oxygen desaturation.22
wide. There was no correlation between volume (P = .904) or
visibility (P = .385) of stroke and diagnosis of sleep apnea with In our study, stroke patients with visible lesion on
cut-off REI greater than or equal to 15. The stroke was located neuroimaging after thrombolysis had higher ODI4 than those
in middle cerebral artery in 60.9% of cases, 17.3% in lacunar without visible lesion. In the study of Turkington et al25 the
median ODI4 was even higher (33) than in our study (20.7). In
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STROKE VOLUME PREDICTS HYPOXEMIA IN STROKE 5

an another study, the obstructive events associated with at least factors.31 Characteristics of patients were similar across the
4% drop in saturation and were independently associated with groups, with the exception of hemorrhage as complication. In
cardiovascular disease, suggesting that intermittent hypoxia is a previous reports, incidence of spontaneous hemorrhagic
matter of great importance.26 Untreated sleep apnea causes transformation (a spectrum of ischemia-related brain
hypoxia, sympathetic activation, systemic inflammation, hemorrhage) ranged from 13% to 43% in CT studies and
oxidative stress, and endothelial dysfunction which may start symptomatic hemorrhagic transformation from .6% to 20%.32,33
atherogenesis.27 In a study of 188 ischemic stroke patients, mean The incidence of hemorrhagic event of 12.7% in our cohort fits
oxygen saturation below 94% for 10 minutes on admission was to those previously reported ranges. Further, OSA severity
1 of the positive predictive factors for mortality.28 In this current among those having hemorrhage or not did not differ in our
study, stroke patients with visible stroke had fairly low mean study. A significant predictor of neurological worsening and
lowest saturation (79.6%). Turkington et al25 found that stroke higher mortality is only PH,34 which is defined as hemorrhagic
severity and the minimum saturation were independently transformation with dense blood clot(s) exceeding 30% of the
associated with disability after 6 months follow-up. infarct volume with significant space-occupying effect.18,35
Our patients with visible stroke had significantly more Three of our patients had PH 2 type hemorrhage. Ischemia in
obstructive apneas per hour than those without visible lesion. stroke patients is a result to inflammatory response,36 which
This is in line with previous studies,25,29 which also showed that broke normal cerebrovascular anatomy and physiology. When
obstructive apneas were the most common type of apneas ischemic area is reperfused the blood-brain-barrier is disrupted,
among stroke patients. Obstructive sleep apnea has been which causes impairment of autoregulation of brain vasculature
connected with an elevated risk of cardiovascular disease in and this can lead to blood extravasation and increased
numerous observational studies.5 , 30 However, it is still unclear fl
in ammation.37
if sleep apnea plays a significant role in the early phase of
development of vascular diseases.30 In the Multi-Ethnic Study Ifergane et al3 have reported that obstructive sleep apnea is
of Atherosclerosis with more than 6000 participants, obstructive associated with higher levels of inflammatory and coagulator
sleep apnea associated with subclinical coronary artery disease, biomarkers. Also the thrombolysis treatment of stroke with
independent of obesity and traditional cardiovascular risk intravenous recombinant tissue plasminogen activator may

Figure 1. Correlation between stroke volume and SaO2 percent below 90 %.

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6 J.K. HUHTAKANGAS ET AL.

Figure 2. Sleep apnea severity according to stroke location. Sleep apnea severity is divided to mild (REI 5-15/h), moderate (REI 15-30/h), and severe (REI 30 /
result to reperfusion injury and intracerebral hemorrhage.38 An Brain CT was available in 109 stroke patients. Only 1 patient
experimental piece of evidence proposes that tissue had only MRI images and the stroke volume was measured in a
plasminogen activator advances excitotoxic or ischemic similar manner from diffusion weighted images. The volume
neuronal death.39 measurements may not be accurate since they are influenced by
In our previous study, we found that NIHSS was associated several factors such as image quality, timing of imaging,
with sleep apnea severity in terms of REI and ODI.4 We could location and shape of the lesion, and the amount of edema thus
not show correlation between stroke volume and diagnosis of making the method prone to errors. Thus the exact stroke
sleep apnea and its severity. There was no correlation between volume was not possible to determine for all the patients. We
Rankin scale score, ODI4, REI, and ischemic stroke volume. measured infarct volume approximately 24 hours after
Only 8 patients had hemorrhagic event and the small number of thrombolysis. Therefore the influence of time to edema is
patients did not allow us to analyze correlation between supposed to be the same in all patients.
hemorrhage as complication and sleep apnea severity. We suggest considering to screen sleep apnea even during the
This is the first study evaluating the stroke size and sleep stroke unit care in case of thrombolysis therapy if a visible new
apnea among stroke patients who underwent thrombolysis. Our stroke CT lesion is present 24 hours after thrombolysis. The
study population was homogeneous since all ischemic stroke screening of sleep apnea among those suggested stroke patients
patients underwent thrombolysis. Our observational real-life leading to continuous positive airway pressure (CPAP)
prospective study with consecutive patients, wide age range and treatment may improve the outcome of their strokes and
high representation of females allows generalization of the decrease comorbidity, although further studies are warranted.
results at least in the Finnish population with acute ischemic
stroke and Conclusions
h) sleep apnea. In the current study, the stroke volume correlated with percent
of nocturnal time spent below saturation of 90 %. Time spent
thrombolytic treatment. However, prior studies have reported below saturation 90% seems to be more important factor than
that sleep apnea prevalence varies by race among middle-aged the conventional severity of sleep apnea defined by frequency of
adults,40 and therefore our results may not represent the situation apneic and hypopnoeic events.
in other countries.
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STROKE VOLUME PREDICTS HYPOXEMIA IN STROKE 7

Acknowledgments: We thank the staff of the Department of recombinant tissue plasminogen activator. The rt-PA acute
Neurology and the study participants for their collaboration. stroke study group. AJNR Am J Neuroradiol 1993;14:3-13.
19. Collop NA, Tracy SL, Kapur V, et al. Obstructive sleep apnea
devices for out-of-center (OOC) testing: technology
Conflict of Interest evaluation. J Clin Sleep Med 2011;7:531-548.
20. Berry RB, Budhiraja R, Gottlieb DJ, et al. Rules for scoring
The authors have no conflict of interest to disclose. respiratory events in sleep: update of the 2007 AASM manual
for the scoring of sleep and associated events. J Clin Sleep Med
2012;8:597-619.
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