- Email: [email protected]
Prevalence of Sleep-Disordered Breathing and Continuous Positive Airway Pressure Compliance
Prevalence of Sleep-Disordered Breathing and Continuous Positive Airway Pressure Compliance* Results in Chinese Patients With First-Ever Ischemic Stroke David S.C. Hui, MBBS, FCCP; Dominic K.L. Choy, MBBS; Lawrence K.S. Wong, MD; Fanny W.S. Ko, MBChB; Thomas S.T. Li, MBChB; Jean Woo, MD; and Richard Kay, MD
Objective: To assess the prevalence of sleep-disordered breathing (SDB), continuous positive airway pressure (CPAP) acceptance, and CPAP compliance in patients who have experienced ischemic stroke. Design: A case-controlled study. Setting: A university hospital. Measurements and results: We recruited 23 women and 28 men, who were admitted to the hospital within 4 days of stroke onset, with a mean (ⴞ SD) age of 64.2 ⴞ 13.0 years and a body mass index (BMI) of 24.3 ⴞ 4.4 kg/m2 for this study. Twenty-seven patients (53%) and 9 patients (17.6%), respectively, reported a history of snoring and severe daytime sleepiness prior to experiencing a stroke, while the mean Epworth sleepiness scale score was 6.8 ⴞ 3.6. Polysomnography revealed 34 patients (67%) with an apnea-hypopnea index (AHI) of > 10 events per hour, 31 patients (61%) with an AHI of > 15 events per hour, and 25 patients (49%) with an AHI of > 20 events per hour. Significant obstructive SDB, defined as an AHI of > 20/h, was more prevalent in ischemic stroke patients than in control subjects (49% vs 24%, respectively; p ⴝ 0.04) and was associated with a higher BMI (p ⴝ 0.046). Among the 34 patients with an AHI of > 10/h, CPAP titration was tolerated by 16 patients, but only 4 patients who had typical sleep apnea features proceeded to home CPAP treatment with objective compliance over a period of 3 months of 2.5 ⴞ 0.6 h per night. A subgroup of 20 patients not receiving CPAP showed partial spontaneous improvement of SDB at 1 month (baseline AHI, 32.3 ⴞ 17.6 events per hour; AHI at 1 month, 23.0 ⴞ 18.8 events per hour; p ⴝ 0.01) with a trend toward improvement for the obstructive but no significant change for the central events, whereas no improvement in AHI was noted for the four patients receiving CPAP. Conclusion: There is a high prevalence of obstructive SDB in patients who have experienced acute ischemic stroke, which, in many cases, is different from classic obstructive sleep apnea syndrome, and this is reflected by the lack of significant sleepiness, poor CPAP acceptance, and partial spontaneous improvement at 1 month. (CHEST 2002; 122:852– 860) Key words: continuous positive airway pressure compliance; ischemic stroke; sleep-disordered breathing Abbreviations: AHI ⫽ apnea-hypopnea index; AI ⫽ apnea index; BI ⫽ Barthel index; BMI ⫽ body mass index; CBF ⫽ cerebral blood flow; CPAP ⫽ continuous positive airway pressure; ESS ⫽ Epworth sleepiness scale; HK ⫽ Hong Kong; NIH ⫽ National Institutes of Health; OSA ⫽ obstructive sleep apnea; OSAS ⫽ obstructive sleep apnea syndrome; SHQ ⫽ Sleep and Health Questionnaire; SDB ⫽ sleep-disordered breathing; Spo2 ⫽ pulse oximetric saturation
breathing (SDB), which is deS leep-disordered fined by an apnea-hypopnea index (AHI) of at least five events per hour of sleep, affects 24% of the middle-aged white men in Wisconsin1 and 14.4% of *From the Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong. This project was funded by Chinese University of Hong Kong direct grant No. 2084008. 852
the Chinese men in Hong Kong (HK).2 Obstructive sleep apnea syndrome (OSAS) is a common form of SDB that is characterized by repetitive episodes of Manuscript received August 23, 2001; revision accepted March 1, 2002. Correspondence to: David S.C. Hui, MBBS, FCCP, Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong; e-mail: [email protected] Clinical Investigations
partial or complete upper airway obstruction causing sleep fragmentation and symptoms.3 OSAS is equally common among the middle-aged white and HK Chinese populations with a minimum prevalence of 4%.1,2 Excessive daytime sleepiness is a major feature of OSAS, but there is increasing evidence linking SDB and cardiovascular complications. In a retrospective study by He et al,4 patients with an apnea index (AI) of ⬎ 20 events per hour had a higher morbidity and mortality related to vascular events than those with an AI of ⬍ 20 events per hour. Cross-sectional associations from the baseline examination of the Sleep Heart Health Study cohort have shown modest-to-moderate effects of SDB on various manifestations of cardiovascular diseases, and, relatively, SDB was more strongly associated with reported stroke and heart failure than with coronary artery disease.5 There is evidence that habitual snoring is a possible independent risk factor for hypertension6 and stroke,7–9 while other studies have implicated the obstructive type of SDB as a risk factor for stroke,10 –15 poor functional outcome,12 and poststroke mortality.8,12 Cerebrovascular disease has been a leading cause of morbidity and mortality in HK in recent years. Intracranial occlusive disease is the most commonly found vascular lesion among our acute stroke patients.16 There are currently no published data in HK concerning the relationship between SDB and stroke. Introduced by Sullivan et al17 2 decades ago, nasal continuous positive airway pressure (CPAP) has remained the “gold standard” treatment for patients with OSAS, with a high level of acceptance and compliance in our OSAS patients without stroke.18 Despite growing evidence of an unexpectedly high prevalence of SDB, which has been arbitrarily defined as an AHI of ⱖ 20 events per hour, of 28 to 68% and 22 to 80%, respectively, in the acute and rehabilitation phases among stroke victims,10 –15 none of these studies have addressed the more practical issue of CPAP acceptance and compliance among stroke victims who have confirmed SDB. In this study, we aimed to assess the following: (1) the prevalence of SDB in the acute phase; (2) whether there was any spontaneous improvement of SDB at 1 month; (3) factors that might predict the occurrence of a significant level of SDB; and (4) the acceptance and compliance of nasal CPAP treatment among our patients with significant SDB following a first-ever ischemic stroke. Materials and Methods We screened 80 consecutive patients for inclusion in this study who had been admitted with acute stroke to the Prince of Wales Hospital, an acute-care teaching hospital, over a period of 3 www.chestjournal.org
months. A control group of 25 volunteers, who were matched for age and body mass index (BMI), were recruited from the same hospital. Stroke Assessment Cerebral CT scanning was performed within the first 24 h of hospital admission to exclude hemorrhagic stroke. Cardiovascular risk factors were recorded, and these included a history of hypertension (defined as previously documented BP of ⬎140/90 mm Hg on at least two occasions or a requirement of antihypertensive medication before the ischemic stroke), diabetes mellitus (defined as a fasting plasma glucose level of ⬎ 7 mmol/L or the taking of antidiabetic medication before the stroke), hypercholesterolemia (defined as a fasting blood lowdensity lipoprotein cholesterol level of ⬎ 3.4 mmol/L or the taking of lipid-lowering medication before the stroke), smoking (defined by the number of pack-years smoked), and alcohol consumption (defined by the number of drinks ingested per week). Relevant medical history such as that for congestive heart failure, ischemic heart disease, and atrial fibrillation was documented. Patients were assessed within the first 2 days of hospitalization by one of the investigators. The site of ischemic stroke was determined clinically and from cerebral CT scans, and was classified according to the classification by Bamford et al.19 The severity of the neurologic deficits was assessed using the national Institutes of Health (NIH) stroke scale (scale, 0 to 42); in general, an NIH score of ⱖ 2 implies at least moderate severity.20 Functional ability was measured with the Barthel index (BI) [scale, 0 to 20], a widely used multifaceted scale that measures mobility and the activities of daily living. A BI of ⬍ 17 implies at least a moderate degree of functional impairment.21 Inclusion criteria included age of 30 to 80 years and the onset of first-ever ischemic stroke within 2 weeks. Exclusion criteria included hemorrhagic stroke, subjects who were in a stupor or coma, and those subjects with a deteriorating clinical state or any serious coexisting disease that would be likely to affect survival during the study period (eg, malignancy and unstable angina). Sleep Study Assessment Following a baseline stroke assessment, the Sleep and Health Questionnaire (SHQ)22 and the Epworth sleepiness scale (ESS)23 were administered to evaluate OSAS symptoms and subjective sleepiness, respectively, in the past month prior to the onset of ischemic stroke. The SHQ has been reported previously to be a valid means of characterizing symptom distribution in population surveys of OSAS.22 The questionnaire contains 16 questions grouped into five factors (ie, functional impact of sleepiness, self-reported breathing disturbances, roommate-observed breathing disturbances, driving impairment, and insomnia) and has been shown to be useful in predicting the occurrence of sleep apnea. The evaluation of responses to the questionnaire utilized either a 5-point frequency scale (never, rarely, sometimes, frequently, and almost always) or a 6-point Likert scale, which graded the severity of the symptoms. The responses were categorized as being mild, moderate, and severe for the purpose of data analysis. The ESS is a questionnaire assessing the likelihood of falling asleep in eight different situations in recent times.23 When accurate assessment could not be performed on the patient due to aphasia or cognitive impairment, information was obtained from the spouse or close relatives. Additional questions were included to document the use of alcohol and the subjects’ sleeping habits, including the subjects’ CHEST / 122 / 3 / SEPTEMBER, 2002
853
usual sleep schedule and, particularly, the sleep quality the night before beginning the sleep study. All patients were studied with overnight polysomnography (Alice 4; Healthdyne; Atlanta, GA) to assess objectively the degree of SDB. Polysomnography was performed within 3 days of the initial hospital admission between 10 pm and 7 am. Overnight polysomnography recorded EEG, electro-oculogram, submental electromyogram, bilateral anterior tibial electromyogram, ECG, chest and abdominal wall movement by inductance plethysmography and airflow by a nasal pressure transducer (PTAF 2; Pro-Tech; Woodinville, WA), which was backed up by oronasal airflow measured with a thermistor and finger pulse oximetry, as in our previous study.18 Sleep stages were scored according to the standard criteria of Rechtshaffen and Kales.24 Apnea was defined as the cessation of airflow for ⬎ 10 s, and hypopnea was defined as a reduction of airflow of ⱖ 50% for 10 s plus an oxygen desaturation of ⬎ 3% or an arousal. Predominantly obstructive SDB was diagnosed if the total AHI was ⱖ 10 events per hour and if at least 50% of events were obstructive and/or mixed, whereas central SDB was diagnosed when at least 50% of events were central. Significant SDB was arbitrarily defined as an AHI of ⱖ 20 events per hour of sleep as the prevalence of SDB increases with age,25 and older patients with ⬎ 20 obstructive respiratory events per hour of sleep have been reported to have shorter survival times than those with minimal SDB.26 Our study was approved by the Ethics Committee of the Chinese University of Hong Kong, and appropriate informed consent was obtained from the subjects. Following the polysomnography, each patient was interviewed by the respiratory physician on duty. Those with AHIs of ⱖ 10 events per hour were offered a trial of nasal CPAP treatment, as it is generally recommended that patients with documented vascular diseases (in this case, ischemic stroke) be treated at a lower threshold.27 Our nurse would select and fit a comfortable CPAP mask from a wide range of choices for the patient, who would then be given a short trial of CPAP therapy (AutoSet; Resmed; Sydney, Australia) for approximately 30 min for acclimatization in the afternoon. Attended CPAP titration was performed with the CPAP auto-titrating device (AutoSet) on the second night of the study in our hospital. Several studies28,29 have shown that automatic CPAP titration is as effective as manual titration in correcting the obstructive respiratory events, in arousal frequency, and in improving oxygenation. Throughout the night and the next morning, the nurses on duty would deal with any discomfort related to the CPAP treatment. The CPAP pressure for each patient was set at the minimum pressure needed to abolish snoring, obstructive respiratory events, and airflow limitation for 95% of the night, as determined by the overnight CPAP titration study. All the patients were prescribed the use of a CPAP device (Aria LX CPAP device; Respironics Inc; Murrysville, PA), which automatically turned on when the patients breathed into the mask and shut off when the mask was removed. The CPAP device (Aria LX) contains a microprocessor that records the time spent at effective pressure (measured by a mask pressure transducer recorder). We have adopted the following terminology as suggested by Grunstein and Sullivan30 describing patients interaction with CPAP: acceptance refers to the proportion of patients who meet selection criteria for CPAP treatment and actually proceed to have their pressure level determined; prescription refers to the proportion of patients who accept CPAP and commence home treatment; adherence refers to the proportion of patients who are prescribed CPAP and report that they are continuing to use CPAP; and usage refers to the proportion of patients with machines switched on for more than an arbitrary period of time. 854
For the purpose of this study, we measured objective compliance by the mean rate of CPAP use (hours per day), as reflected by the effective mask pressure time. In addition to repeating polysomnography for patients who were prescribed nasal CPAP treatment, other patients with baseline AHI values of ⱖ 10 events per hour who were not receiving CPAP treatment were invited to return for reassessment with the ESS and progress polysomnography at 1 month to look for any spontaneous improvement. For those patients who had commenced nasal CPAP treatment after the baseline polysomnography, objective CPAP compliance (ie, effective mask pressure) for ⬎ 3 months was assessed by examining the data downloaded from the software of the CPAP device. Statistical Analysis All data were presented as the mean ⫾ SD unless otherwise stated. Nominal data were analyzed with the 2 test. An unpaired t test was used for continuous data. For comparison between the patients and the control subjects, and between patients with an AHI of ⱖ 20 and those with AHI of ⬍ 20 events per hour, an unpaired t test was used for normally distributed variables and a Mann-Whitney U test was used for non-normally distributed variables. Statistical significance was set at p ⬍ 0.05. Data analysis was performed with a commercially available statistical analysis software package (SPSS, version 10.0 for Windows; SPSS Inc; Chicago, IL).
Results Of the 80 consecutive patients with acute stroke who we screened for this study, 16 patients (20%) were excluded because of radiographic evidence of hemorrhagic stroke. Of the remaining 64 patients, 51 patients met the inclusion criteria and consented to the study. There were 23 women and 28 men with a mean age of 64.2 ⫾ 13.0 years, a mean BMI of 24.3 ⫾ 4.4 kg/m2, a mean neck circumference of 38.1 ⫾ 3.4 cm, a mean systolic BP of 168 ⫾ 25 mm Hg, and a mean diastolic BP of 89 ⫾ 15 mm Hg. Forty-four percent of our subjects were smokers, while the frequency of associated medical diseases was as follows: hypertension, 55%; hypercholesterolemia, 62.7%; diabetes mellitus; 41%; ischemic heart disease, 8%; COPD, 6%; congestive heart failure, 2%; and atrial fibrillation, 2%. Stroke Assessment All of our patients were admitted to the hospital within 4 days of the onset of symptoms. The sites of ischemic stroke determined according to the Bamford classification19 were as follows: partial anterior circulation, 15 patients (29.4%); total anterior circulation, 5 patients (9.8%); lacunar, 26 patients (51%); and posterior circulation, 5 patients (9.8%). The mean BI was 14.3 ⫾ 4.5, and the mean NIH stroke score was 3.8 ⫾ 3.6. Sleep Assessment From the SHQ, 27 patients (53%) reported a history of snoring and 24 patients (47%) reported a Clinical Investigations
history of daytime sleepiness, while only 1 patient had history of witnessed apnea prior to experiencing the ischemic stroke (Table 1). The mean time between hospital admission and the sleep study was 2.7 ⫾ 2.0 days. From the polysomnography, the group AHI was 23 ⫾ 20 events per hour, the minimum pulse oximetric saturation (Spo2) during sleep was 84 ⫾ 9%, the total sleep time was 6.5 ⫾ 2.0 h, the arousal index was 24 ⫾ 13 arousals per hour, and the ESS was 6.8 ⫾ 3.6. The number of patients with an AHI of ⱖ 10 events per hour was 34 (67%), those with an AHI of ⱖ 15 events per hour was 31 (61%), the number with an AHI of ⱖ 20 events per hour was 25 (49%), and the number with an AHI of ⱖ 30 events per hour was 16 (31%). Of the 34 patients with a total AHI of ⱖ 10 events per hour, the mean AHI was 31.9 ⫾ 15.9 events per hour, the mean obstructive AHI was 27.4 ⫾ 15.1 events per hour, and the central AI was 3.7 ⫾ 6.3 events per hour, and, by definition, they all had the obstructive type of SDB. The characteristics of the control group (17 men and 8 women) were similar to the patients with ischemic stroke, but the frequency of significant obstructive SDB was lower in the control group (Table 2). Factors Associated With Significant SDB Factors that might predict significant SDB among the patients with ischemic stroke were assessed by comparing data between those with an AHI of ⱖ 20 events per hour vs those with an AHI of ⬍ 20 events per hour. A higher BMI was the only factor associated with those with significant SDB, who had a lower minimum Spo2 (Table 3). The site of the stroke (Bamford classification), the severity of the stroke (NIH scale), and functional status (BI) were found not to be associated with the severity of SDB.
Table 1—Distribution of Symptoms Related to SDB in the SHQ
Variables Impaired performance ability* Daytime sleepiness† Snoring frequency† Witnessed apnea† Nocturnal awakenings†
Never/Not Affected, Mild, Moderate, Severe, % (n ⫽ 51) % % % 60.8 53.0 47.1 98.1 66.7
23.5 21.6 17.6 2 21.6
11.8 7.8 5.9 0 5.9
3.9 17.6 17.6 0 5.9
*A 6-point Likert scale was used: 1 to 2 points, not affected; 3 to 4 points, mild; 5 points, moderate; 6 points, severe. †A 5-point frequency scale was used: never, not affected; rarely or less than once per week, mild; sometimes or 1 to 2 per week, mild; frequently or 3 to 4 per week, moderate; almost always or 5 to 7 per week, severe. www.chestjournal.org
Table 2—Ischemic Stroke Patients vs Control Subjects* Stroke Group (n ⫽ 51) Age, yr BMI, kg/m2 Neck circumference, cm ESS score AHI ⱖ 20 events/h
Control Group (n ⫽ 25) p Value
64 ⫾ 13 24.3 ⫾ 4.4 38.1 ⫾ 3.4 6.8 ⫾ 3.6 25 (49)
65 ⫾ 8 24.2 ⫾ 3.8 36.4 ⫾ 4.1 6.0 ⫾ 3.6 6 (24)
0.74 0.93 0.11 0.42 0.04
*Values given as mean ⫾ SD or No. (%), unless otherwise indicated.
CPAP Acceptance and Compliance All of the 34 patients with an AHI ⱖ 10 events per hour were given a 30-min trial of nasal CPAP (AutoSet) at 4 cm H2O for acclimatization in the afternoon. However, 14 patients refused to take part in the overnight CPAP titration study, and 4 patients could not tolerate the overnight study, while CPAP titration was successfully performed in 16 patients (47%) with a mean CPAP level of 10.8 ⫾ 1.4 cm H2O. Only 4 of the 16 patients proceeded to home CPAP treatment. The SHQ revealed that all four patients were snorers (mild, two patients; moderate, one patient; and severe, one patient) and that three patients had moderate-to-severe daytime sleepiness. The baseline sleep study of these four patients revealed mean a BMI of 30.8 ⫾ 4.7 kg/m2, a neck circumference of 43.0 ⫾ 1.3 cm, an AHI of 32 ⫾ 21 events per hour, a minimum Spo2 of 94 ⫾ 2%, an ESS of 10.3 ⫾ 2.6, and a CPAP level of 12.3 ⫾ 1.6 cm H2O. At 1 month, the mean AHI was 34 ⫾ 16 events per hour, also of a predominantly obstructive type (p ⫽ 0.47 compared to baseline AHI), while the mean ESS of the four patients was 9.3 ⫾ 7.4 at 1 month and 8.5 ⫾ 5.1 at 3 months. The objective CPAP compliance at ⬎ 3 months, as measured by the CPAP device monitor, was 2.5 ⫾ 0.6 h per night,
Table 3—Factors Associated With Significant SDB Postischemic Stroke* Factors
AHI ⱖ 20/h AHI ⬍ 20 events/h (n ⫽ 25) (n ⫽ 26) p Value
Age, yr 66.5 ⫾ 11.9 BMI, kg/m2 25.5 ⫾ 4.6 ESS score 7.3 ⫾ 3.7 SBP, mm Hg 168 ⫾ 25 DBP, mm Hg 89 ⫾ 13 NIH score 3.3 ⫾ 2.2 BI 15.2 ⫾ 4.3 Neck circumference, cm 37.7 ⫾ 3.4 Minimum Spo2, % 80.6 ⫾ 9.8
62.0 ⫾ 14.0 22.8 ⫾ 3.7 5.9 ⫾ 3.1 168 ⫾ 26 96 ⫾ 16 4.7 ⫾ 4.5 13.3 ⫾ 4.6 38.7 ⫾ 3.5 87.4 ⫾ 6.8
*Values given as mean ⫾ SD, unless SBP ⫽ systolic BP; DBP ⫽ diastolic BP.
otherwise
0.223 0.046 0.308 0.978 0.947 0.992 0.273 0.375 0.004 indicated.
CHEST / 122 / 3 / SEPTEMBER, 2002
855
and the percentage of nights with CPAP usage of ⱖ 4 h per night was 30 ⫾ 9%. Follow-up Sleep Study for Those Not Prescribed Nasal CPAP We had also invited patients with baseline AHI values of ⱖ 10 events per hour who had not been prescribed CPAP (n ⫽ 30) to return for repeat polysomnography at 1 month to look for any spontaneous improvement, but only 20 patients agreed to be readmitted to the hospital for this purpose. The mean age of the subgroup was 65.3 ⫾ 11.9 years, the mean BMI was 26.2 ⫾ 4.1 kg/m2, the mean neck circumference was 38.4 ⫾ 3.5 cm, and the mean ESS was 7.0 ⫾ 3.7. The severity of obstructive SDB improved over 1 month with fewer patients having significant SDB. There was a trend toward improvement for the obstructive respiratory events, but no significant change was noted for the central events at 1 month (Table 4). Outcome Of the 51 patients who had undergone the baseline polysomnography assessment following ischemic stroke, 1 patient died during hospital admission, 17 were discharged to home directly, while 33 were transferred to our rehabilitation hospital. Discussion This study has shown a high prevalence of significant obstructive SDB, arbitrarily defined as an AHI of ⱖ 20 events per hour of sleep, among our patients following a first-ever ischemic stroke in the acute phase compared to the control group (49% vs 24%, respectively; p ⫽ 0.04). The prevalence of snoring prior to stroke was 53%, while 55% of our patients experienced hypertension. Daytime sleepiness was reported by 47% of patients and was graded as severe in 17.6%. There were fewer patients with significant obstructive SDB in the rehabilitation
Table 4 —Subgroup of Patients (n ⴝ 20) with Followup Sleep Study at 1 Month vs Baseline* Variables
Baseline
1 Month
p Value
AHI OAHI CAI Minimum Spo2, % ESS score AHI ⱖ 20 events/h
32.3 ⫾ 17.6 27.3 ⫾ 16.4 5.0 ⫾ 7.6 80.4 ⫾ 8.7 7.0 ⫾ 3.7 16 (80)
23.0 ⫾ 18.8 20.5 ⫾ 16.9 2.5 ⫾ 5.7 83.3 ⫾ 9.0 7.3 ⫾ 5.5 9 (45)
0.01 0.07 0.22 0.20 0.78 0.02
*Values given as mean ⫾ SD or No. (%), unless otherwise indicated. OAHI ⫽ obstructive and mixed AHI; CAI ⫽ central apnea index. 856
phase at 1 month in the subgroup of 20 patients compared to baseline (45% vs 80%, respectively; p ⫽ 0.02). Despite lowering the treatment threshold to an AHI of ⱖ 10 events per hour, the acceptance rate for nasal CPAP was only 47%. The objective compliance for ⬎ 3 months was dismally low at 2.5 h per day for the four patients who were prescribed nasal CPAP treatment, with only 30% of nights with CPAP usage of ⱖ 4 h per night. Several clinical studies, which are briefly summarized in Table 5, have reported a high prevalence of obstructive SDB in stroke patients in the acute phase11–13,15 and in the rehabilitation phase.10,14,15 Some of these studies were limited by a relatively small sample size,10 –12 a lack of a control group,12,14,15 or mixing of a heterogeneous group of patients with transient ischemic attack, ischemic stroke, and hemorrhagic stroke.10,11,13–15 Nevertheless, in comparison with different populations of patients who had experienced postischemic stroke in whom SDB was defined as either an AHI of either ⱖ 10 or ⱖ 20 events per hour, our results are in agreement with other studies that there is an unexpectedly higher prevalence of obstructive SDB among the stroke victims than among the agematched control groups10,11,13 or with the results of other epidemiologic studies of the older age group.25,26 The BMI of our ischemic stroke patients with significant SDB was lower than the BMI of other Western populations. Nevertheless, a higher BMI was the only factor associated with significant SDB in our study, whereas, as also experienced by Parra et al,15 the stroke site, stroke severity, and functional status were not. Bassetti and Aldrich,13 however, have found a higher frequency of SDB in older patients with higher BMIs and more severe strokes. The partial spontaneous improvement of obstructive SDB at the follow-up polysomnography at 1 month among our subgroup of 20 ischemic stroke patients with a baseline AHI of ⱖ 10 events per hour suggests that preexisting SDB may have been worsened transiently by the acute cerebral ischemic event. In contrast, Parra et al15 have noted, in their 23 patients with transient ischemic attack and 59 patients with ischemic stroke, an improvement in central events at 3 months, while the obstructive component remained largely unchanged. There are several potential mechanisms linking SDB and stroke. Although epidemiologic studies can only establish an association rather than a causal role between SDB and hypertension, high levels of AHI31–33 and sleep time at ⬍ 90% oxygen saturation32,33 were associated with greater odds of hypertension in a dose-response fashion, independent of confounding factors such as age, sex, BMI, and other modifiable risk factors. Experimental studies by Clinical Investigations
Table 5—Prevalence of SDB Following Different Types of Cerebrovascular Accidents*
Study/Year/Age, yr Acute phase Dyken et al11/1996/64.7 Good et al12/1996/69 Bassetti and Aldrich13/ 1999/59 Parra et al15/2000/ 70 73 73 Hui et al/present study/64 Rehabilitation phase Mohsenin and Valor10/ 1995/56 Parra et al15‡/2000/ 72 72 72 Wessendorf et al14/2000/ 61 Present study§/2002/65
Type/Timing of Study Post-CVA
AHI, % ESS†
ⱖ 10/h
ⱖ 20/h
ⱖ 30/h
NA
71
46
38
NA 9⫾5
95 63
68 28
53 NA
Edentec/48–72 h
4.7 ⫾ 3.3
62
NA
26
I (112) H (10) I (51)
PSG/5 d
4.9 ⫾ 3.3 4.3 ⫾ 2.1 6.8 ⫾ 3.6
74 90 67
49
28 40 31
26.3
I (9) and H (1)
PSG/within 1 yr
NA
NA
80
NA
27.4
T (23)
Edentec/3 mo
4.5 ⫾ 2.8
30343
NA
13317
26.5 24.8 29.2 for AHI ⱖ 20 events/h 26.2
I (59) H (4) I (133) and H (14)
68364 75375 44
22
31319 75375 NA
100370
80345
40325
2
BMI, kg/m
CVA Type (No.)
27.8 (M) 32.9 (F) NA 29.2
I (20) and H (4)
PSG/15.7 d PSG/13 d PSG/9 d
27.3
I (19) T (32) and I (48) T (39)
26.2 26.7 24.3
I (20)
PSG/46 ⫾ 20 d
PSG/1 mo
7.7 for AHI ⱖ 20 events/h 7.0 ⫾ 3.7
*CVA ⫽ cerebrovascular accident; M ⫽ male; F ⫽ female; T ⫽ transient ischemic attack; I ⫽ ischemic; H ⫽ hemorrhagic; PSG ⫽ polysomnography; NA ⫽ not available; Edentec ⫽ a partial sleep study. †Values given as mean ⫾ SD. ‡In the study by Parra et al,15 a subgroup of 86 patients had polysomnography performed at baseline and repeated at 3 months. The categorized AHI results at baseline and at 3 months are shown. §In this study, a subgroup of 20 patients, with baseline AHI of ⱖ 10 events/h, had PSG repeated at 1 month, and the categorized AHI results at baseline and at 1 month are shown.
Fletcher et al34 and Brooks et al35 with rat and canine models, respectively, have shown that obstructive SDB can lead to the development of sustained hypertension. Peripheral resistance may increase as a result of recurrent arousals terminating the obstructive respiratory events and activating the sympathetic nervous system.36 In addition to hypertension, other potential mechanisms linking SDB and ischemic stroke include increased platelet activation, aggregation with possible effects of adrenergic stimulation on platelet function, and reduced fibrinolytic activity in patients with OSAS.37– 40 Interestingly ischemic stroke often occurs during sleep or the early morning hours,41,42 and platelets from healthy subjects have shown enhanced ability to aggregate between 6 am and 9 am.43 Changes in cerebral blood flow (CBF) have been reported during and after episodes of obstructive sleep apnea (OSA). In patients with OSAS, reduced regional CBF, especially in the brainstem and cerebellum during non-rapid eye movement sleep, has been noted during wakefulness compared to healthy subjects.44 A marked increase in intracranial pressure and a decrease in cerebral perfusion have been www.chestjournal.org
observed during OSAS.45 Fischer et al46 have detected, with transcranial Doppler ultrasonography, a 15% and 20% reduction, respectively, in the mean and systolic CBF velocities of the middle cerebral artery during sleep in patients with OSAS, while Netzer et al47 found a ⬎ 50% decrease in CBF in patients with OSAS compared to those with central apnea. A study48 using near-infrared spectroscopy has shown cerebral oxygen desaturation associated with cerebral hypoperfusion during episodes of OSA. An initial increase of 15% in CBF velocity immediately after termination of the OSA episode, followed by a 23% reduction with reference to baseline values, was observed by Balfors and Franklin,49 suggesting some impairment of vasodilator reserve. There are several favorable, hemodynamic effects of nasal CPAP on the cardiovascular system on patients with OSAS. The impairment in cerebral autoregulation can be corrected by nasal CPAP therapy.50 Sympathetic nerve activity in patients with OSAS can be reduced by CPAP treatment.51,52 Plasma levels of nitric oxide, a powerful vasodilator that is released from the endothelium, have been shown to be decreased in OSAS patients but can be promptly reversed by nasal CPAP treatment.53,54 CHEST / 122 / 3 / SEPTEMBER, 2002
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Effective treatment of OSAS with nasal CPAP can reduce platelet activation, aggregation,38 and morning fibrinogen levels in patients with OSAS without stroke.55 A recent randomized, oral placebo controlled study56 has shown that CPAP therapy over a period of 4 weeks can reduce BP in patients with OSAS, particularly in those who experience frequent episodes of nocturnal hypoxemia with 5-mm Hg drops in diastolic BP. The same degree of reduction in diastolic BP, achieved with antihypertensive medications, was associated with 42% and 31% decreases, respectively, in stroke over ⬎ 5 and 10 years.57,58 There is robust evidence showing significant improvement of symptoms, quality of life, and daytime function in patients treated with nasal CPAP.59 – 61 Our previous study18 on newly diagnosed OSAS patients who had not experienced strokes has shown full CPAP acceptance and a high objective compliance, and a high baseline AHI was the only significant independent predictor of better CPAP compliance. Others have found a positive correlation between the ESS scores,62,63 BMI,64 and CPAP compliance. The mean ESS scores among our 51 patients with ischemic stroke and those with significant SDB were 6.8 ⫾ 3.6 and 7.3 ⫾ 3.7, respectively, and there was no significant difference compared to the control group. Although the sample size was too small for meaningful statistical analysis, the four patients who were prescribed nasal CPAP had features of more classic OSAS with a higher mean baseline ESS score (10.3 ⫾ 2.6), BMI (30.8 ⫾ 4.7), and neck circumference (43.0 ⫾ 1.3 cm), and more prominent symptoms such as snoring and daytime sleepiness prior to stroke than those not accepting CPAP. These four patients most likely had OSAS before they experienced ischemic stroke, and this would also explain the lack of improvement in AHI in the follow-up polysomnography and their acceptance of nasal CPAP. The mean ESS scores in healthy subjects vs OSAS patients in a local study65 were found to be 7.5 ⫾ 3.0 and 13.2 ⫾ 4.7, respectively. The mean ESS scores reported by other studies of patients with stroke10 –15 were essentially within the normal range (Table 5). As our acute stroke patients presented mainly with motor deficits rather than daytime sleepiness, it was perhaps not surprising that CPAP acceptance and compliance were both low. Although the ESS score may not reflect objective measures of sleepiness,66 it has been reported to be more discriminating than the Maintenance of Wakefulness Test and the Multiple Sleep Latency Test67 as a test of daytime sleepiness. Another possible reason for poor CPAP acceptance might be related to partial spontaneous improvement of SDB, which we have observed in 858
our patients over a period of 4 weeks after the acute cerebral ischemic event. Nevertheless, a recent study68 conducted in the rehabilitation setting (mean ESS score, 7.2) has reported improvement in subjective well-being and a reduction in mean nocturnal BP following 10 days of CPAP treatment, while 70.5% of their subjects with ischemic or hemorrhagic stroke indicated, prior to hospital discharge, that they would adhere to CPAP treatment at home. Another study69 of a heterogeneous group of ischemic and hemorrhagic stroke patients with SDB has shown improvement of depressive symptoms with CPAP treatment in the rehabilitation phase, although only 50% of the subjects in that study were receiving CPAP therapy for ⬎ 4 h per night, with lower usage in those with delirium and severe cognitive impairment. There were several limitations with this study. We excluded patients who were medically unstable, delirious, comatose, or noncommunicative, and, therefore, our results might not reflect the prevalence of SDB in the severe end of the spectrum of ischemic stroke. To demonstrate whether SDB was an independent risk factor for stroke, a larger sample size with a control group, matched for age, sex, BMI, and other cardiovascular risk factors, would have been required. In summary, this study has shown a high prevalence of obstructive SDB in patients with ischemic stroke in the acute phase. A higher BMI is the only factor associated with significant SDB. In many cases, SDB in patients who have experienced acute stroke is different from classic OSAS, and this is reflected by the lack of significant sleepiness, poor CPAP acceptance, and partial spontaneous improvement at 1 month. Further studies are needed to assess which subset of stroke patients with SDB will benefit from CPAP, how to improve CPAP acceptance and compliance, and whether the early diagnosis and treatment of SDB will improve morbidity, mortality, and quality of life in such patients. ACKNOWLEDGMENTS: The authors thank Mr. W.C. Shum (Neurology RN) for collecting the stroke data and Sisters Mabel Tong, Fanny Chan, M.Y. Leung, and Ms. Erica Lee for their technical support with the sleep study and for providing CPAP education to our patients. We would also like to thank Drs. Timothy Kwok, K.H. Sze, and C.M. Lum for their input to our original research protocol, and Ms. Doris Chan and Dr. Anthony T. Chan for their statistical analysis for this project.
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3 McNamara SG, Grunstein RR, Sullivan CE. Obstructive sleep apnea. Thorax 1993; 48:754 –764 4 He J, Kryger MH, Zorick FJ, et al. Mortality and apnea index in obstructive sleep apnea. Chest 1988; 94:9 –14 5 Shahar E, Whitney C, Redline S, et al. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 2001; 163:19 –25 6 Hu F, Willett W, Colditz G, et al. Prospective study of snoring and risk of hypertension in women. Am J Epidemiol 1999; 150:806 – 816 7 Partinen M, Palomaki H. Snoring and cerebral infarction. Lancet 1985; 2:1325–1326 8 Spriggs D, French J, Murdy J, et al. Snoring increases the risk of stroke and adversely affects prognosis. Q J Med 1992; 83:555–562 9 Neau J, Meurice JC, Paquereau J, et al. Habitual snoring as a risk factor for brain infarction. Acta Neurol Scand 1995; 92:63– 68 10 Mohsenin V, Valor R. Sleep apnea in patients with hemispheric stroke. Arch Phys Med Rehabil 1995; 76:71–76 11 Dyken M, Somers V, Yamada T, et al. Investigating the relationship between stroke and obstructive sleep apnea. Stroke 1996; 27:401– 407 12 Good D, Henkle J, Gelber D, et al. Sleep disordered breathing and poor functional outcome after stroke. Stroke 1996; 27:252–259 13 Bassetti C, Aldrich M. Sleep apnea in acute cerebrovascular diseases: final report on 128 patients. Sleep 1999; 22:217–223 14 Wessendorf T, Teschler H, Wang YM, et al. Sleep-disordered breathing among patients with first-ever stroke. J Neurol 2000; 247:41– 47 15 Parra O, Arboix A, Bechich S, et al. Time course of sleeprelated breathing disorders in first-ever stroke or transient ischemic attack. Am J Respir Crit Care Med 2000; 161:375– 380 16 Wong KS, Huang YN, Gao S, et al. Intracranial stenosis in Chinese patients with acute stroke. Neurology 1998; 50:812– 813 17 Sullivan CE, Issa F, Berthon-Jones M, et al. Reversal of obstructive sleep apnea by continuous positive airway pressure applied through the nares. Lancet 1981; 1:862– 865 18 Hui DS, Choy DK, Li ST, et al. Determinants of CPAP compliance in a group of Chinese patients with obstructive sleep apnea. Chest 2001; 120:170 –176 19 Bamford J, Sandercock P, Dennis M, et al. Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet 1991; 337:1521–1526 20 Brott T, Adams HP, Olinger CP, et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke 1989; 20:864 – 870 21 Mahoney F, Barthel D. Functional evaluation: the Barthel index. Md Med J 1965; 14:61– 65 22 Kump K, Whalen C, Tishler P, et al. Assessment of the validity and utility of a sleep-symptom questionnaire. Am J Respir Crit Care Med 1994; 150:735–741 23 Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991; 14:540 –545 24 Rechtschaffen A, Kales A. A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. Los Angeles, CA: Brain Information Service, Brain Information Institute, University of California, 1968 25 Ancoli-Israel S, Kripke DF, Klauber MR, et al. Sleep disordered breathing in community-dwelling elderly. Sleep 1991; 14:486 – 495 www.chestjournal.org
26 Ancoli-Israel S, Kripke DF, Klauber MR, et al. Morbidity, mortality and sleep disordered breathing in community dwelling elderly. Sleep 1996; 19:277–282 27 Loube DI, Gay PC, Strohl KP, et al. Indications for positive airway pressure treatment for adult obstructive sleep apnea patients: a consensus statement. Chest 1999; 115:863– 866 28 Teschler H, Berthon-Jones M, Thompson AB, et al. Automated continuous positive airway pressure titration for obstructive sleep apnea syndrome. Am J Respir Crit Care Med 1996; 154:734 –740 29 Teschler H, Farhat AA, Exner V, et al. Autoset nasal CPAP titration: constancy of pressure, compliance and effectiveness at 8 month follow-up. Eur Respir J 1997; 10:2073–2078 30 Grunstein RR, Sullivan CE. Continuous positive airway pressure for sleep breathing disorders. In: Kryger MH, Roth T, Dement WC, eds. Principles and practice of sleep medicine. 3rd ed. Philadelphia, PA: WB Saunders, 2000; 894 –912 31 Lavie P, Herer P, Hoffstein V. Obstructive sleep apnoea as a risk factor for hypertension: population study. BMJ 2000; 320:479 – 482 32 Nieto FJ, Young TB, Lind BK, et al. Association of sleepdisordered breathing, sleep apnea and hypertension in a large community-based study. JAMA 2000; 283:1829 –1836 33 Peppard P, Young T, Palta M, et al. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000; 342:1378 –1384 34 Fletcher E, Lesske J, Qian W, et al. Repetitive episodic hypoxia causes diurnal elevation of blood pressure in rats. Hypertension 1992; 19:555–561 35 Brooks D, Horner L, Kozar C, et al. Obstructive sleep apnea as a cause of systemic hypertension: evidence from a canine model. J Clin Invest 1997; 99:106 –109 36 Leuenberger U, Jacob E, Sweer L, et al. Surges of muscle sympathetic nerve activity during obstructive apnoea are linked to hypoxaemia. J Appl Physiol 1995; 79:581–588 37 Rangemark C, Hedner J, Carlson J, et al. Platelet function and fibrinolytic activity in hypertensive and normotensive sleep apnea patients. Sleep 1995; 18:188 –194 38 Bokinsky G, Miller M, Ault K, et al. Spontaneous platelet activation and aggregation during obstructive sleep apnea and its response to therapy with nasal continuous positive airway pressure. Chest 1995; 108:625– 630 39 Eisensehr I, Ehrenberg BL, Noachtar S, et al. Platelet activation, epinephrine and blood pressure in obstructive sleep apnea syndrome. Neurology 1998; 51:188 –195 40 Wessendorf TE, Thilmann AF, Wang YM, et al. Fibrinogen levels and obstructive sleep apnea in ischemic stroke. Am J Respir Crit Care Med 2000; 162:2039 –2042 41 Marshall J. Diurnal variation in occurrence of strokes. Stroke 1977; 8:230 –231 42 Marler JR, Price TR, Clark GL, et al. Morning increase in onset of ischemic stroke. Stroke 1989; 20:473– 476 43 Tofler GH, Brezinski D, Schafer AI, et al. Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Engl J Med 1987; 316:1514 –1518 44 Meyer J, Sakai F, Yamaguchi F, et al. Regional changes in cerebral blood flow during standard behavioral activation in patients with disorders of speech and mentation compared to normal volunteers. Brain Lang 1980; 9:61–77 45 Jennum P, Borgesen S. Intracranial pressure and obstructive sleep apnea. Chest 1989; 95:279 –283 46 Fischer A, Chaudhary B, Taormina M, et al. Intracranial hemodynamics in sleep apnea. Chest 1992; 102:1402–1406 47 Netzer N, Werner P, Jochums I, et al. Blood flow of the middle cerebral artery with sleep-disordered breathing: correlation with obstructive hypopneas. Stroke 1998; 29:87–93 CHEST / 122 / 3 / SEPTEMBER, 2002
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48 Hayakawa T, Terashiwa M, Kayukawa Y, et al. Changes in cerebral oxygenation and hemodynamics during obstructive sleep apneas. Chest 1996; 109:916 –921 49 Balfors EM, Franklin KA. Impairment of cerebral perfusion during obstructive sleep apneas. Am J Respir Crit Care Med 1994; 150:1587–1591 50 Diomedi M, Placidi F, Cupini L, et al. Cerebral hemodynamic changes in sleep apnea syndrome and effect of continuous positive airway pressure treatment. Neurology 1998; 51:1051–1056 51 Somers VK, Dyken ME, Clary MP, et al. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 1995; 96:1897–1904 52 Narkiewicz K, Kato M, Phillips BG, et al. Nocturnal continuous positive airway pressure decreases daytime sympathetic traffic in obstructive sleep apnea. Circulation 1999; 100:2332–2335 53 Schulz R, Schmidt D, Blum A, et al. Decreased plasma levels of nitric oxide derivatives in obstructive sleep apnoea: response to CPAP therapy. Thorax 2000; 55:1046 –1051 54 Ip MS, Lam B, Chan LY, et al. Circulating nitric oxide is suppressed in obstructive sleep apnea and is reversed by nasal continuous positive airway pressure. Am J Respir Crit Care Med 2000; 162:2166 –2171 55 Chin K, Ohi M, Kita H, et al. Effects of nCPAP therapy on fibrinogen levels in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 1996; 153:1972–1976 56 Faccenda JF, Mackay TW, Boon NA, et al. Randomized placebo-controlled trial of continuous positive airway pressure on blood pressure in the sleep apnea-hypopnea syndrome. Am J Respir Crit Care Med 2001; 163:344 –348 57 Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke and coronary heart disease: 2. Short-term reductions in blood pressure: overview of randomised drug trial in their epidemiological context. Lancet 1990; 335:827– 838 58 MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary heart disease. Lancet 1990; 335:765–774 59 Engleman H, Martin S, Deary I, et al. Effect of continuous
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positive airway pressure treatment on daytime function in sleep apnea/hypopnea syndrome. Lancet 1994; 343:572–575 Engleman H, Kingshott R, Wraith P, et al. Randomized placebo-controlled crossover trial of continuous positive airway pressure for mild sleep apnea/hypopnea syndrome. Am J Respir Crit Care Med 1999; 159:461– 467 Jenkinson C, Davies R, Mullins R, et al. Comparison of therapeutic and sub-therapeutic nasal continuous positive airway pressure for obstructive sleep apnea: a randomized prospective parallel trial. Lancet 1999; 353:2100 –2105 Engleman H, Asgari-Jirhandeh N, McLeod A, et al. Selfreported use of CPAP and benefits of CPAP therapy. Chest 1996; 109:1470 –1476 McArdle N, Devereux G, Heidarnejad H, et al. Long-term use of CPAP therapy for sleep apnea/hypopnea syndrome. Am J Respir Crit Care Med 1999; 159:1108 –1114 Krieger J, Kurtz D, Petiau C, et al. Long-term compliance with CPAP therapy in obstructive sleep apnea patients and in snorers. Sleep 1996; 19:S136 –S143 Chung KF. Use of the Epworth Sleepiness Scale in Chinese patients with obstructive sleep apnea and normal hospital employees. J Psychosom Res 2000; 49:367–372 Chervin R, Aldrich MS. The Epworth sleepiness scale may not reflect objective measures of sleepiness or sleep apnea. Neurology 1999; 52:125–131 Johns MW. Sensitivity and specificity of the multiple sleep latency test (MSLT), the maintenance of wakefulness test and the Epworth sleepiness scale: failure of the MSLT as a gold standard. J Sleep Res 2000; 9:5–11 Wessendorf TE, Wang YM, Thilmann AF, et al. Treatment of obstructive sleep apnoea with nasal continuous positive airway pressure in stroke. Eur Respir J 2001; 18:623– 629 Sandberg O, Franklin K, Bucht G, et al. Nasal continuous positive airway pressure in stroke patients with sleep apnoea: a randomised treatment study. Eur Respir J 2001; 18:630 – 634
Clinical Investigations
Objective: To assess the prevalence of sleep-disordered breathing (SDB), continuous positive airway pressure (CPAP) acceptance, and CPAP compliance in patients who have experienced ischemic stroke. Design: A case-controlled study. Setting: A university hospital. Measurements and results: We recruited 23 women and 28 men, who were admitted to the hospital within 4 days of stroke onset, with a mean (ⴞ SD) age of 64.2 ⴞ 13.0 years and a body mass index (BMI) of 24.3 ⴞ 4.4 kg/m2 for this study. Twenty-seven patients (53%) and 9 patients (17.6%), respectively, reported a history of snoring and severe daytime sleepiness prior to experiencing a stroke, while the mean Epworth sleepiness scale score was 6.8 ⴞ 3.6. Polysomnography revealed 34 patients (67%) with an apnea-hypopnea index (AHI) of > 10 events per hour, 31 patients (61%) with an AHI of > 15 events per hour, and 25 patients (49%) with an AHI of > 20 events per hour. Significant obstructive SDB, defined as an AHI of > 20/h, was more prevalent in ischemic stroke patients than in control subjects (49% vs 24%, respectively; p ⴝ 0.04) and was associated with a higher BMI (p ⴝ 0.046). Among the 34 patients with an AHI of > 10/h, CPAP titration was tolerated by 16 patients, but only 4 patients who had typical sleep apnea features proceeded to home CPAP treatment with objective compliance over a period of 3 months of 2.5 ⴞ 0.6 h per night. A subgroup of 20 patients not receiving CPAP showed partial spontaneous improvement of SDB at 1 month (baseline AHI, 32.3 ⴞ 17.6 events per hour; AHI at 1 month, 23.0 ⴞ 18.8 events per hour; p ⴝ 0.01) with a trend toward improvement for the obstructive but no significant change for the central events, whereas no improvement in AHI was noted for the four patients receiving CPAP. Conclusion: There is a high prevalence of obstructive SDB in patients who have experienced acute ischemic stroke, which, in many cases, is different from classic obstructive sleep apnea syndrome, and this is reflected by the lack of significant sleepiness, poor CPAP acceptance, and partial spontaneous improvement at 1 month. (CHEST 2002; 122:852– 860) Key words: continuous positive airway pressure compliance; ischemic stroke; sleep-disordered breathing Abbreviations: AHI ⫽ apnea-hypopnea index; AI ⫽ apnea index; BI ⫽ Barthel index; BMI ⫽ body mass index; CBF ⫽ cerebral blood flow; CPAP ⫽ continuous positive airway pressure; ESS ⫽ Epworth sleepiness scale; HK ⫽ Hong Kong; NIH ⫽ National Institutes of Health; OSA ⫽ obstructive sleep apnea; OSAS ⫽ obstructive sleep apnea syndrome; SHQ ⫽ Sleep and Health Questionnaire; SDB ⫽ sleep-disordered breathing; Spo2 ⫽ pulse oximetric saturation
breathing (SDB), which is deS leep-disordered fined by an apnea-hypopnea index (AHI) of at least five events per hour of sleep, affects 24% of the middle-aged white men in Wisconsin1 and 14.4% of *From the Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong. This project was funded by Chinese University of Hong Kong direct grant No. 2084008. 852
the Chinese men in Hong Kong (HK).2 Obstructive sleep apnea syndrome (OSAS) is a common form of SDB that is characterized by repetitive episodes of Manuscript received August 23, 2001; revision accepted March 1, 2002. Correspondence to: David S.C. Hui, MBBS, FCCP, Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong; e-mail: [email protected] Clinical Investigations
partial or complete upper airway obstruction causing sleep fragmentation and symptoms.3 OSAS is equally common among the middle-aged white and HK Chinese populations with a minimum prevalence of 4%.1,2 Excessive daytime sleepiness is a major feature of OSAS, but there is increasing evidence linking SDB and cardiovascular complications. In a retrospective study by He et al,4 patients with an apnea index (AI) of ⬎ 20 events per hour had a higher morbidity and mortality related to vascular events than those with an AI of ⬍ 20 events per hour. Cross-sectional associations from the baseline examination of the Sleep Heart Health Study cohort have shown modest-to-moderate effects of SDB on various manifestations of cardiovascular diseases, and, relatively, SDB was more strongly associated with reported stroke and heart failure than with coronary artery disease.5 There is evidence that habitual snoring is a possible independent risk factor for hypertension6 and stroke,7–9 while other studies have implicated the obstructive type of SDB as a risk factor for stroke,10 –15 poor functional outcome,12 and poststroke mortality.8,12 Cerebrovascular disease has been a leading cause of morbidity and mortality in HK in recent years. Intracranial occlusive disease is the most commonly found vascular lesion among our acute stroke patients.16 There are currently no published data in HK concerning the relationship between SDB and stroke. Introduced by Sullivan et al17 2 decades ago, nasal continuous positive airway pressure (CPAP) has remained the “gold standard” treatment for patients with OSAS, with a high level of acceptance and compliance in our OSAS patients without stroke.18 Despite growing evidence of an unexpectedly high prevalence of SDB, which has been arbitrarily defined as an AHI of ⱖ 20 events per hour, of 28 to 68% and 22 to 80%, respectively, in the acute and rehabilitation phases among stroke victims,10 –15 none of these studies have addressed the more practical issue of CPAP acceptance and compliance among stroke victims who have confirmed SDB. In this study, we aimed to assess the following: (1) the prevalence of SDB in the acute phase; (2) whether there was any spontaneous improvement of SDB at 1 month; (3) factors that might predict the occurrence of a significant level of SDB; and (4) the acceptance and compliance of nasal CPAP treatment among our patients with significant SDB following a first-ever ischemic stroke. Materials and Methods We screened 80 consecutive patients for inclusion in this study who had been admitted with acute stroke to the Prince of Wales Hospital, an acute-care teaching hospital, over a period of 3 www.chestjournal.org
months. A control group of 25 volunteers, who were matched for age and body mass index (BMI), were recruited from the same hospital. Stroke Assessment Cerebral CT scanning was performed within the first 24 h of hospital admission to exclude hemorrhagic stroke. Cardiovascular risk factors were recorded, and these included a history of hypertension (defined as previously documented BP of ⬎140/90 mm Hg on at least two occasions or a requirement of antihypertensive medication before the ischemic stroke), diabetes mellitus (defined as a fasting plasma glucose level of ⬎ 7 mmol/L or the taking of antidiabetic medication before the stroke), hypercholesterolemia (defined as a fasting blood lowdensity lipoprotein cholesterol level of ⬎ 3.4 mmol/L or the taking of lipid-lowering medication before the stroke), smoking (defined by the number of pack-years smoked), and alcohol consumption (defined by the number of drinks ingested per week). Relevant medical history such as that for congestive heart failure, ischemic heart disease, and atrial fibrillation was documented. Patients were assessed within the first 2 days of hospitalization by one of the investigators. The site of ischemic stroke was determined clinically and from cerebral CT scans, and was classified according to the classification by Bamford et al.19 The severity of the neurologic deficits was assessed using the national Institutes of Health (NIH) stroke scale (scale, 0 to 42); in general, an NIH score of ⱖ 2 implies at least moderate severity.20 Functional ability was measured with the Barthel index (BI) [scale, 0 to 20], a widely used multifaceted scale that measures mobility and the activities of daily living. A BI of ⬍ 17 implies at least a moderate degree of functional impairment.21 Inclusion criteria included age of 30 to 80 years and the onset of first-ever ischemic stroke within 2 weeks. Exclusion criteria included hemorrhagic stroke, subjects who were in a stupor or coma, and those subjects with a deteriorating clinical state or any serious coexisting disease that would be likely to affect survival during the study period (eg, malignancy and unstable angina). Sleep Study Assessment Following a baseline stroke assessment, the Sleep and Health Questionnaire (SHQ)22 and the Epworth sleepiness scale (ESS)23 were administered to evaluate OSAS symptoms and subjective sleepiness, respectively, in the past month prior to the onset of ischemic stroke. The SHQ has been reported previously to be a valid means of characterizing symptom distribution in population surveys of OSAS.22 The questionnaire contains 16 questions grouped into five factors (ie, functional impact of sleepiness, self-reported breathing disturbances, roommate-observed breathing disturbances, driving impairment, and insomnia) and has been shown to be useful in predicting the occurrence of sleep apnea. The evaluation of responses to the questionnaire utilized either a 5-point frequency scale (never, rarely, sometimes, frequently, and almost always) or a 6-point Likert scale, which graded the severity of the symptoms. The responses were categorized as being mild, moderate, and severe for the purpose of data analysis. The ESS is a questionnaire assessing the likelihood of falling asleep in eight different situations in recent times.23 When accurate assessment could not be performed on the patient due to aphasia or cognitive impairment, information was obtained from the spouse or close relatives. Additional questions were included to document the use of alcohol and the subjects’ sleeping habits, including the subjects’ CHEST / 122 / 3 / SEPTEMBER, 2002
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usual sleep schedule and, particularly, the sleep quality the night before beginning the sleep study. All patients were studied with overnight polysomnography (Alice 4; Healthdyne; Atlanta, GA) to assess objectively the degree of SDB. Polysomnography was performed within 3 days of the initial hospital admission between 10 pm and 7 am. Overnight polysomnography recorded EEG, electro-oculogram, submental electromyogram, bilateral anterior tibial electromyogram, ECG, chest and abdominal wall movement by inductance plethysmography and airflow by a nasal pressure transducer (PTAF 2; Pro-Tech; Woodinville, WA), which was backed up by oronasal airflow measured with a thermistor and finger pulse oximetry, as in our previous study.18 Sleep stages were scored according to the standard criteria of Rechtshaffen and Kales.24 Apnea was defined as the cessation of airflow for ⬎ 10 s, and hypopnea was defined as a reduction of airflow of ⱖ 50% for 10 s plus an oxygen desaturation of ⬎ 3% or an arousal. Predominantly obstructive SDB was diagnosed if the total AHI was ⱖ 10 events per hour and if at least 50% of events were obstructive and/or mixed, whereas central SDB was diagnosed when at least 50% of events were central. Significant SDB was arbitrarily defined as an AHI of ⱖ 20 events per hour of sleep as the prevalence of SDB increases with age,25 and older patients with ⬎ 20 obstructive respiratory events per hour of sleep have been reported to have shorter survival times than those with minimal SDB.26 Our study was approved by the Ethics Committee of the Chinese University of Hong Kong, and appropriate informed consent was obtained from the subjects. Following the polysomnography, each patient was interviewed by the respiratory physician on duty. Those with AHIs of ⱖ 10 events per hour were offered a trial of nasal CPAP treatment, as it is generally recommended that patients with documented vascular diseases (in this case, ischemic stroke) be treated at a lower threshold.27 Our nurse would select and fit a comfortable CPAP mask from a wide range of choices for the patient, who would then be given a short trial of CPAP therapy (AutoSet; Resmed; Sydney, Australia) for approximately 30 min for acclimatization in the afternoon. Attended CPAP titration was performed with the CPAP auto-titrating device (AutoSet) on the second night of the study in our hospital. Several studies28,29 have shown that automatic CPAP titration is as effective as manual titration in correcting the obstructive respiratory events, in arousal frequency, and in improving oxygenation. Throughout the night and the next morning, the nurses on duty would deal with any discomfort related to the CPAP treatment. The CPAP pressure for each patient was set at the minimum pressure needed to abolish snoring, obstructive respiratory events, and airflow limitation for 95% of the night, as determined by the overnight CPAP titration study. All the patients were prescribed the use of a CPAP device (Aria LX CPAP device; Respironics Inc; Murrysville, PA), which automatically turned on when the patients breathed into the mask and shut off when the mask was removed. The CPAP device (Aria LX) contains a microprocessor that records the time spent at effective pressure (measured by a mask pressure transducer recorder). We have adopted the following terminology as suggested by Grunstein and Sullivan30 describing patients interaction with CPAP: acceptance refers to the proportion of patients who meet selection criteria for CPAP treatment and actually proceed to have their pressure level determined; prescription refers to the proportion of patients who accept CPAP and commence home treatment; adherence refers to the proportion of patients who are prescribed CPAP and report that they are continuing to use CPAP; and usage refers to the proportion of patients with machines switched on for more than an arbitrary period of time. 854
For the purpose of this study, we measured objective compliance by the mean rate of CPAP use (hours per day), as reflected by the effective mask pressure time. In addition to repeating polysomnography for patients who were prescribed nasal CPAP treatment, other patients with baseline AHI values of ⱖ 10 events per hour who were not receiving CPAP treatment were invited to return for reassessment with the ESS and progress polysomnography at 1 month to look for any spontaneous improvement. For those patients who had commenced nasal CPAP treatment after the baseline polysomnography, objective CPAP compliance (ie, effective mask pressure) for ⬎ 3 months was assessed by examining the data downloaded from the software of the CPAP device. Statistical Analysis All data were presented as the mean ⫾ SD unless otherwise stated. Nominal data were analyzed with the 2 test. An unpaired t test was used for continuous data. For comparison between the patients and the control subjects, and between patients with an AHI of ⱖ 20 and those with AHI of ⬍ 20 events per hour, an unpaired t test was used for normally distributed variables and a Mann-Whitney U test was used for non-normally distributed variables. Statistical significance was set at p ⬍ 0.05. Data analysis was performed with a commercially available statistical analysis software package (SPSS, version 10.0 for Windows; SPSS Inc; Chicago, IL).
Results Of the 80 consecutive patients with acute stroke who we screened for this study, 16 patients (20%) were excluded because of radiographic evidence of hemorrhagic stroke. Of the remaining 64 patients, 51 patients met the inclusion criteria and consented to the study. There were 23 women and 28 men with a mean age of 64.2 ⫾ 13.0 years, a mean BMI of 24.3 ⫾ 4.4 kg/m2, a mean neck circumference of 38.1 ⫾ 3.4 cm, a mean systolic BP of 168 ⫾ 25 mm Hg, and a mean diastolic BP of 89 ⫾ 15 mm Hg. Forty-four percent of our subjects were smokers, while the frequency of associated medical diseases was as follows: hypertension, 55%; hypercholesterolemia, 62.7%; diabetes mellitus; 41%; ischemic heart disease, 8%; COPD, 6%; congestive heart failure, 2%; and atrial fibrillation, 2%. Stroke Assessment All of our patients were admitted to the hospital within 4 days of the onset of symptoms. The sites of ischemic stroke determined according to the Bamford classification19 were as follows: partial anterior circulation, 15 patients (29.4%); total anterior circulation, 5 patients (9.8%); lacunar, 26 patients (51%); and posterior circulation, 5 patients (9.8%). The mean BI was 14.3 ⫾ 4.5, and the mean NIH stroke score was 3.8 ⫾ 3.6. Sleep Assessment From the SHQ, 27 patients (53%) reported a history of snoring and 24 patients (47%) reported a Clinical Investigations
history of daytime sleepiness, while only 1 patient had history of witnessed apnea prior to experiencing the ischemic stroke (Table 1). The mean time between hospital admission and the sleep study was 2.7 ⫾ 2.0 days. From the polysomnography, the group AHI was 23 ⫾ 20 events per hour, the minimum pulse oximetric saturation (Spo2) during sleep was 84 ⫾ 9%, the total sleep time was 6.5 ⫾ 2.0 h, the arousal index was 24 ⫾ 13 arousals per hour, and the ESS was 6.8 ⫾ 3.6. The number of patients with an AHI of ⱖ 10 events per hour was 34 (67%), those with an AHI of ⱖ 15 events per hour was 31 (61%), the number with an AHI of ⱖ 20 events per hour was 25 (49%), and the number with an AHI of ⱖ 30 events per hour was 16 (31%). Of the 34 patients with a total AHI of ⱖ 10 events per hour, the mean AHI was 31.9 ⫾ 15.9 events per hour, the mean obstructive AHI was 27.4 ⫾ 15.1 events per hour, and the central AI was 3.7 ⫾ 6.3 events per hour, and, by definition, they all had the obstructive type of SDB. The characteristics of the control group (17 men and 8 women) were similar to the patients with ischemic stroke, but the frequency of significant obstructive SDB was lower in the control group (Table 2). Factors Associated With Significant SDB Factors that might predict significant SDB among the patients with ischemic stroke were assessed by comparing data between those with an AHI of ⱖ 20 events per hour vs those with an AHI of ⬍ 20 events per hour. A higher BMI was the only factor associated with those with significant SDB, who had a lower minimum Spo2 (Table 3). The site of the stroke (Bamford classification), the severity of the stroke (NIH scale), and functional status (BI) were found not to be associated with the severity of SDB.
Table 1—Distribution of Symptoms Related to SDB in the SHQ
Variables Impaired performance ability* Daytime sleepiness† Snoring frequency† Witnessed apnea† Nocturnal awakenings†
Never/Not Affected, Mild, Moderate, Severe, % (n ⫽ 51) % % % 60.8 53.0 47.1 98.1 66.7
23.5 21.6 17.6 2 21.6
11.8 7.8 5.9 0 5.9
3.9 17.6 17.6 0 5.9
*A 6-point Likert scale was used: 1 to 2 points, not affected; 3 to 4 points, mild; 5 points, moderate; 6 points, severe. †A 5-point frequency scale was used: never, not affected; rarely or less than once per week, mild; sometimes or 1 to 2 per week, mild; frequently or 3 to 4 per week, moderate; almost always or 5 to 7 per week, severe. www.chestjournal.org
Table 2—Ischemic Stroke Patients vs Control Subjects* Stroke Group (n ⫽ 51) Age, yr BMI, kg/m2 Neck circumference, cm ESS score AHI ⱖ 20 events/h
Control Group (n ⫽ 25) p Value
64 ⫾ 13 24.3 ⫾ 4.4 38.1 ⫾ 3.4 6.8 ⫾ 3.6 25 (49)
65 ⫾ 8 24.2 ⫾ 3.8 36.4 ⫾ 4.1 6.0 ⫾ 3.6 6 (24)
0.74 0.93 0.11 0.42 0.04
*Values given as mean ⫾ SD or No. (%), unless otherwise indicated.
CPAP Acceptance and Compliance All of the 34 patients with an AHI ⱖ 10 events per hour were given a 30-min trial of nasal CPAP (AutoSet) at 4 cm H2O for acclimatization in the afternoon. However, 14 patients refused to take part in the overnight CPAP titration study, and 4 patients could not tolerate the overnight study, while CPAP titration was successfully performed in 16 patients (47%) with a mean CPAP level of 10.8 ⫾ 1.4 cm H2O. Only 4 of the 16 patients proceeded to home CPAP treatment. The SHQ revealed that all four patients were snorers (mild, two patients; moderate, one patient; and severe, one patient) and that three patients had moderate-to-severe daytime sleepiness. The baseline sleep study of these four patients revealed mean a BMI of 30.8 ⫾ 4.7 kg/m2, a neck circumference of 43.0 ⫾ 1.3 cm, an AHI of 32 ⫾ 21 events per hour, a minimum Spo2 of 94 ⫾ 2%, an ESS of 10.3 ⫾ 2.6, and a CPAP level of 12.3 ⫾ 1.6 cm H2O. At 1 month, the mean AHI was 34 ⫾ 16 events per hour, also of a predominantly obstructive type (p ⫽ 0.47 compared to baseline AHI), while the mean ESS of the four patients was 9.3 ⫾ 7.4 at 1 month and 8.5 ⫾ 5.1 at 3 months. The objective CPAP compliance at ⬎ 3 months, as measured by the CPAP device monitor, was 2.5 ⫾ 0.6 h per night,
Table 3—Factors Associated With Significant SDB Postischemic Stroke* Factors
AHI ⱖ 20/h AHI ⬍ 20 events/h (n ⫽ 25) (n ⫽ 26) p Value
Age, yr 66.5 ⫾ 11.9 BMI, kg/m2 25.5 ⫾ 4.6 ESS score 7.3 ⫾ 3.7 SBP, mm Hg 168 ⫾ 25 DBP, mm Hg 89 ⫾ 13 NIH score 3.3 ⫾ 2.2 BI 15.2 ⫾ 4.3 Neck circumference, cm 37.7 ⫾ 3.4 Minimum Spo2, % 80.6 ⫾ 9.8
62.0 ⫾ 14.0 22.8 ⫾ 3.7 5.9 ⫾ 3.1 168 ⫾ 26 96 ⫾ 16 4.7 ⫾ 4.5 13.3 ⫾ 4.6 38.7 ⫾ 3.5 87.4 ⫾ 6.8
*Values given as mean ⫾ SD, unless SBP ⫽ systolic BP; DBP ⫽ diastolic BP.
otherwise
0.223 0.046 0.308 0.978 0.947 0.992 0.273 0.375 0.004 indicated.
CHEST / 122 / 3 / SEPTEMBER, 2002
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and the percentage of nights with CPAP usage of ⱖ 4 h per night was 30 ⫾ 9%. Follow-up Sleep Study for Those Not Prescribed Nasal CPAP We had also invited patients with baseline AHI values of ⱖ 10 events per hour who had not been prescribed CPAP (n ⫽ 30) to return for repeat polysomnography at 1 month to look for any spontaneous improvement, but only 20 patients agreed to be readmitted to the hospital for this purpose. The mean age of the subgroup was 65.3 ⫾ 11.9 years, the mean BMI was 26.2 ⫾ 4.1 kg/m2, the mean neck circumference was 38.4 ⫾ 3.5 cm, and the mean ESS was 7.0 ⫾ 3.7. The severity of obstructive SDB improved over 1 month with fewer patients having significant SDB. There was a trend toward improvement for the obstructive respiratory events, but no significant change was noted for the central events at 1 month (Table 4). Outcome Of the 51 patients who had undergone the baseline polysomnography assessment following ischemic stroke, 1 patient died during hospital admission, 17 were discharged to home directly, while 33 were transferred to our rehabilitation hospital. Discussion This study has shown a high prevalence of significant obstructive SDB, arbitrarily defined as an AHI of ⱖ 20 events per hour of sleep, among our patients following a first-ever ischemic stroke in the acute phase compared to the control group (49% vs 24%, respectively; p ⫽ 0.04). The prevalence of snoring prior to stroke was 53%, while 55% of our patients experienced hypertension. Daytime sleepiness was reported by 47% of patients and was graded as severe in 17.6%. There were fewer patients with significant obstructive SDB in the rehabilitation
Table 4 —Subgroup of Patients (n ⴝ 20) with Followup Sleep Study at 1 Month vs Baseline* Variables
Baseline
1 Month
p Value
AHI OAHI CAI Minimum Spo2, % ESS score AHI ⱖ 20 events/h
32.3 ⫾ 17.6 27.3 ⫾ 16.4 5.0 ⫾ 7.6 80.4 ⫾ 8.7 7.0 ⫾ 3.7 16 (80)
23.0 ⫾ 18.8 20.5 ⫾ 16.9 2.5 ⫾ 5.7 83.3 ⫾ 9.0 7.3 ⫾ 5.5 9 (45)
0.01 0.07 0.22 0.20 0.78 0.02
*Values given as mean ⫾ SD or No. (%), unless otherwise indicated. OAHI ⫽ obstructive and mixed AHI; CAI ⫽ central apnea index. 856
phase at 1 month in the subgroup of 20 patients compared to baseline (45% vs 80%, respectively; p ⫽ 0.02). Despite lowering the treatment threshold to an AHI of ⱖ 10 events per hour, the acceptance rate for nasal CPAP was only 47%. The objective compliance for ⬎ 3 months was dismally low at 2.5 h per day for the four patients who were prescribed nasal CPAP treatment, with only 30% of nights with CPAP usage of ⱖ 4 h per night. Several clinical studies, which are briefly summarized in Table 5, have reported a high prevalence of obstructive SDB in stroke patients in the acute phase11–13,15 and in the rehabilitation phase.10,14,15 Some of these studies were limited by a relatively small sample size,10 –12 a lack of a control group,12,14,15 or mixing of a heterogeneous group of patients with transient ischemic attack, ischemic stroke, and hemorrhagic stroke.10,11,13–15 Nevertheless, in comparison with different populations of patients who had experienced postischemic stroke in whom SDB was defined as either an AHI of either ⱖ 10 or ⱖ 20 events per hour, our results are in agreement with other studies that there is an unexpectedly higher prevalence of obstructive SDB among the stroke victims than among the agematched control groups10,11,13 or with the results of other epidemiologic studies of the older age group.25,26 The BMI of our ischemic stroke patients with significant SDB was lower than the BMI of other Western populations. Nevertheless, a higher BMI was the only factor associated with significant SDB in our study, whereas, as also experienced by Parra et al,15 the stroke site, stroke severity, and functional status were not. Bassetti and Aldrich,13 however, have found a higher frequency of SDB in older patients with higher BMIs and more severe strokes. The partial spontaneous improvement of obstructive SDB at the follow-up polysomnography at 1 month among our subgroup of 20 ischemic stroke patients with a baseline AHI of ⱖ 10 events per hour suggests that preexisting SDB may have been worsened transiently by the acute cerebral ischemic event. In contrast, Parra et al15 have noted, in their 23 patients with transient ischemic attack and 59 patients with ischemic stroke, an improvement in central events at 3 months, while the obstructive component remained largely unchanged. There are several potential mechanisms linking SDB and stroke. Although epidemiologic studies can only establish an association rather than a causal role between SDB and hypertension, high levels of AHI31–33 and sleep time at ⬍ 90% oxygen saturation32,33 were associated with greater odds of hypertension in a dose-response fashion, independent of confounding factors such as age, sex, BMI, and other modifiable risk factors. Experimental studies by Clinical Investigations
Table 5—Prevalence of SDB Following Different Types of Cerebrovascular Accidents*
Study/Year/Age, yr Acute phase Dyken et al11/1996/64.7 Good et al12/1996/69 Bassetti and Aldrich13/ 1999/59 Parra et al15/2000/ 70 73 73 Hui et al/present study/64 Rehabilitation phase Mohsenin and Valor10/ 1995/56 Parra et al15‡/2000/ 72 72 72 Wessendorf et al14/2000/ 61 Present study§/2002/65
Type/Timing of Study Post-CVA
AHI, % ESS†
ⱖ 10/h
ⱖ 20/h
ⱖ 30/h
NA
71
46
38
NA 9⫾5
95 63
68 28
53 NA
Edentec/48–72 h
4.7 ⫾ 3.3
62
NA
26
I (112) H (10) I (51)
PSG/5 d
4.9 ⫾ 3.3 4.3 ⫾ 2.1 6.8 ⫾ 3.6
74 90 67
49
28 40 31
26.3
I (9) and H (1)
PSG/within 1 yr
NA
NA
80
NA
27.4
T (23)
Edentec/3 mo
4.5 ⫾ 2.8
30343
NA
13317
26.5 24.8 29.2 for AHI ⱖ 20 events/h 26.2
I (59) H (4) I (133) and H (14)
68364 75375 44
22
31319 75375 NA
100370
80345
40325
2
BMI, kg/m
CVA Type (No.)
27.8 (M) 32.9 (F) NA 29.2
I (20) and H (4)
PSG/15.7 d PSG/13 d PSG/9 d
27.3
I (19) T (32) and I (48) T (39)
26.2 26.7 24.3
I (20)
PSG/46 ⫾ 20 d
PSG/1 mo
7.7 for AHI ⱖ 20 events/h 7.0 ⫾ 3.7
*CVA ⫽ cerebrovascular accident; M ⫽ male; F ⫽ female; T ⫽ transient ischemic attack; I ⫽ ischemic; H ⫽ hemorrhagic; PSG ⫽ polysomnography; NA ⫽ not available; Edentec ⫽ a partial sleep study. †Values given as mean ⫾ SD. ‡In the study by Parra et al,15 a subgroup of 86 patients had polysomnography performed at baseline and repeated at 3 months. The categorized AHI results at baseline and at 3 months are shown. §In this study, a subgroup of 20 patients, with baseline AHI of ⱖ 10 events/h, had PSG repeated at 1 month, and the categorized AHI results at baseline and at 1 month are shown.
Fletcher et al34 and Brooks et al35 with rat and canine models, respectively, have shown that obstructive SDB can lead to the development of sustained hypertension. Peripheral resistance may increase as a result of recurrent arousals terminating the obstructive respiratory events and activating the sympathetic nervous system.36 In addition to hypertension, other potential mechanisms linking SDB and ischemic stroke include increased platelet activation, aggregation with possible effects of adrenergic stimulation on platelet function, and reduced fibrinolytic activity in patients with OSAS.37– 40 Interestingly ischemic stroke often occurs during sleep or the early morning hours,41,42 and platelets from healthy subjects have shown enhanced ability to aggregate between 6 am and 9 am.43 Changes in cerebral blood flow (CBF) have been reported during and after episodes of obstructive sleep apnea (OSA). In patients with OSAS, reduced regional CBF, especially in the brainstem and cerebellum during non-rapid eye movement sleep, has been noted during wakefulness compared to healthy subjects.44 A marked increase in intracranial pressure and a decrease in cerebral perfusion have been www.chestjournal.org
observed during OSAS.45 Fischer et al46 have detected, with transcranial Doppler ultrasonography, a 15% and 20% reduction, respectively, in the mean and systolic CBF velocities of the middle cerebral artery during sleep in patients with OSAS, while Netzer et al47 found a ⬎ 50% decrease in CBF in patients with OSAS compared to those with central apnea. A study48 using near-infrared spectroscopy has shown cerebral oxygen desaturation associated with cerebral hypoperfusion during episodes of OSA. An initial increase of 15% in CBF velocity immediately after termination of the OSA episode, followed by a 23% reduction with reference to baseline values, was observed by Balfors and Franklin,49 suggesting some impairment of vasodilator reserve. There are several favorable, hemodynamic effects of nasal CPAP on the cardiovascular system on patients with OSAS. The impairment in cerebral autoregulation can be corrected by nasal CPAP therapy.50 Sympathetic nerve activity in patients with OSAS can be reduced by CPAP treatment.51,52 Plasma levels of nitric oxide, a powerful vasodilator that is released from the endothelium, have been shown to be decreased in OSAS patients but can be promptly reversed by nasal CPAP treatment.53,54 CHEST / 122 / 3 / SEPTEMBER, 2002
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Effective treatment of OSAS with nasal CPAP can reduce platelet activation, aggregation,38 and morning fibrinogen levels in patients with OSAS without stroke.55 A recent randomized, oral placebo controlled study56 has shown that CPAP therapy over a period of 4 weeks can reduce BP in patients with OSAS, particularly in those who experience frequent episodes of nocturnal hypoxemia with 5-mm Hg drops in diastolic BP. The same degree of reduction in diastolic BP, achieved with antihypertensive medications, was associated with 42% and 31% decreases, respectively, in stroke over ⬎ 5 and 10 years.57,58 There is robust evidence showing significant improvement of symptoms, quality of life, and daytime function in patients treated with nasal CPAP.59 – 61 Our previous study18 on newly diagnosed OSAS patients who had not experienced strokes has shown full CPAP acceptance and a high objective compliance, and a high baseline AHI was the only significant independent predictor of better CPAP compliance. Others have found a positive correlation between the ESS scores,62,63 BMI,64 and CPAP compliance. The mean ESS scores among our 51 patients with ischemic stroke and those with significant SDB were 6.8 ⫾ 3.6 and 7.3 ⫾ 3.7, respectively, and there was no significant difference compared to the control group. Although the sample size was too small for meaningful statistical analysis, the four patients who were prescribed nasal CPAP had features of more classic OSAS with a higher mean baseline ESS score (10.3 ⫾ 2.6), BMI (30.8 ⫾ 4.7), and neck circumference (43.0 ⫾ 1.3 cm), and more prominent symptoms such as snoring and daytime sleepiness prior to stroke than those not accepting CPAP. These four patients most likely had OSAS before they experienced ischemic stroke, and this would also explain the lack of improvement in AHI in the follow-up polysomnography and their acceptance of nasal CPAP. The mean ESS scores in healthy subjects vs OSAS patients in a local study65 were found to be 7.5 ⫾ 3.0 and 13.2 ⫾ 4.7, respectively. The mean ESS scores reported by other studies of patients with stroke10 –15 were essentially within the normal range (Table 5). As our acute stroke patients presented mainly with motor deficits rather than daytime sleepiness, it was perhaps not surprising that CPAP acceptance and compliance were both low. Although the ESS score may not reflect objective measures of sleepiness,66 it has been reported to be more discriminating than the Maintenance of Wakefulness Test and the Multiple Sleep Latency Test67 as a test of daytime sleepiness. Another possible reason for poor CPAP acceptance might be related to partial spontaneous improvement of SDB, which we have observed in 858
our patients over a period of 4 weeks after the acute cerebral ischemic event. Nevertheless, a recent study68 conducted in the rehabilitation setting (mean ESS score, 7.2) has reported improvement in subjective well-being and a reduction in mean nocturnal BP following 10 days of CPAP treatment, while 70.5% of their subjects with ischemic or hemorrhagic stroke indicated, prior to hospital discharge, that they would adhere to CPAP treatment at home. Another study69 of a heterogeneous group of ischemic and hemorrhagic stroke patients with SDB has shown improvement of depressive symptoms with CPAP treatment in the rehabilitation phase, although only 50% of the subjects in that study were receiving CPAP therapy for ⬎ 4 h per night, with lower usage in those with delirium and severe cognitive impairment. There were several limitations with this study. We excluded patients who were medically unstable, delirious, comatose, or noncommunicative, and, therefore, our results might not reflect the prevalence of SDB in the severe end of the spectrum of ischemic stroke. To demonstrate whether SDB was an independent risk factor for stroke, a larger sample size with a control group, matched for age, sex, BMI, and other cardiovascular risk factors, would have been required. In summary, this study has shown a high prevalence of obstructive SDB in patients with ischemic stroke in the acute phase. A higher BMI is the only factor associated with significant SDB. In many cases, SDB in patients who have experienced acute stroke is different from classic OSAS, and this is reflected by the lack of significant sleepiness, poor CPAP acceptance, and partial spontaneous improvement at 1 month. Further studies are needed to assess which subset of stroke patients with SDB will benefit from CPAP, how to improve CPAP acceptance and compliance, and whether the early diagnosis and treatment of SDB will improve morbidity, mortality, and quality of life in such patients. ACKNOWLEDGMENTS: The authors thank Mr. W.C. Shum (Neurology RN) for collecting the stroke data and Sisters Mabel Tong, Fanny Chan, M.Y. Leung, and Ms. Erica Lee for their technical support with the sleep study and for providing CPAP education to our patients. We would also like to thank Drs. Timothy Kwok, K.H. Sze, and C.M. Lum for their input to our original research protocol, and Ms. Doris Chan and Dr. Anthony T. Chan for their statistical analysis for this project.
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