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Correlates of daytime sleepiness in patients with asthma
Sleep Medicine 7 (2006) 607–613 www.elsevier.com/locate/sleep
Original article
Correlates of daytime sleepiness in patients with asthma Mihaela Teodorescu a,*, Flavia B. Consens a, William F. Bria b, Michael J. Coffey b, Marc S. McMorris c, Kevin J. Weatherwax a, Ann Durance c, John Palmisano a, Carolyn M. Senger a, Ronald D. Chervin a b
a Sleep Disorders Center and Department of Neurology, University of Michigan Health System, Ann Arbor, MI USA Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA c Division of Allergy and Clinical Immunology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
Received 20 October 2005; received in revised form 1 February 2006; accepted 2 February 2006 Available online 3 July 2006
Abstract Background and purpose: Patients with asthma often complain of daytime sleepiness, which is usually attributed to a direct effect of asthma on nocturnal sleep quality. We investigated this and other potential explanations for daytime sleepiness among asthmatics. Patients and methods: One hundred fifteen adult asthmatics were assessed for perceived daytime sleepiness (one question item), subjective sleepiness (Epworth Sleepiness Scale score, ESS), obstructive sleep apnea risk (Sleep Apnea scale score within Sleep Disorders Questionnaire, SA-SDQ), asthma severity step, relevant comorbid conditions, and current asthma medications. Results: Among all subjects, 55% perceived excessive daytime sleepiness and 47% had ESS > 10. Most subjects reported snoring (n = 99, or 86%) and many snored habitually (n = 44, 38%). The ESS correlated with SA-SDQ (P < 0.0001), male gender (P = 0.01), and asthma severity step (P = 0.04). In a multiple regression model, the ESS was independently associated with SASDQ (P = 0.0003) and male gender (P = 0.02), but not with asthma severity step (P = 0.51). There were no correlations between ESS and age, body mass index (BMI), forced expiratory volume in one second as percent of predicted value (FEV1%), comorbidities, or medication used to treat asthma. Conclusions: Sleepiness is common in asthmatics and may reflect occult obstructive sleep apnea more often than effects of asthma itself, other comorbid conditions, or asthma medications. 2006 Elsevier B.V. All rights reserved. Keywords: Asthma; Sleepiness; Sleep apnea, Obstructive; Epworth Sleepiness Scale; Sleep Disorders Questionnaire
1. Introduction Daytime sleepiness is a particularly frequent complaint in patients with asthma [1,2]. Daytime sleepiness has a negative impact on quality of life, work performance, and risk for motor vehicle crashes or work-related acci-
* Corresponding author. Address: Michael S. Aldrich Sleep Disorders Laboratory, University of Michigan Health System, 8D 8702 University Hospital, Box 0117, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0117, USA. Tel.: + 1 734 647 9064; fax: + 1 734 647 9065. E-mail address: [email protected] (M. Teodorescu).
1389-9457/$ - see front matter 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2006.02.001
dents [3]. In general, daytime sleepiness is often the result of poor sleep quality, and asthmatics do commonly complain about difficulty with initiation [1,4] and maintenance of sleep, especially in the early morning [1,5]. Such sleep disturbances become more frequent with increased nocturnal asthma symptoms [1]. Nocturnal wakefulness correlates with daytime airways obstruction, as measured by forced expiratory volume in one second as percent of predicted value (FEV1%) [1]. Sleep studies in asthmatics have provided some objective evidence of poor sleep quality as evidenced by a reduced sleep time, delayed latency to sleep, frequent awakenings after sleep onset, early morning arousals and reduced slow wave sleep
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[4,6]. Therefore, daytime sleepiness in asthma is often thought to be the consequence of a direct effect of nocturnal asthma on sleep quality. Both increased subjective sleepiness and poor sleep quality scores were documented recently in a large population of asthmatics [7], but two therapeutic strategies for asthma failed to improve subjective sleepiness and sleep quality scores [8]. These results suggest that other possible reasons for daytime sleepiness in asthmatics also should be considered. Excessive daytime sleepiness (EDS) is one of the most common presenting symptoms of obstructive sleep apnea (OSA), in itself a common and frequently unrecognized condition [9,10]. Snoring is frequent in both OSA patients and asthmatics [2,11,12]. Recently, in a sample of 22 difficult-to-control asthmatics, daytime sleepiness was reported by 20 (90.9%) of the subjects and OSA was demonstrated by polysomnography in 21 (95.5%) of them [13]. Furthermore, asthma frequently coexists with allergic rhinitis and chronic sinusitis [14], gastroesophageal reflux disease (GERD) [15], obesity [16], and psychopathology such as anxiety, depression and panic disorders [17,18], all of which are known to be associated with daytime sleepiness [3,5,19,20]. The medications commonly used to treat asthma tend to have stimulating, anxiety-provoking or mood-depressing properties [5,21,22] that could interfere with sleep quality and exacerbate daytime sleepiness. Previous studies of sleepiness in asthma have been limited by reliance on patient-reported asthma diagnosis or have not included information on comorbid conditions and medications that could influence sleepiness. We therefore studied a sample of medically well-characterized asthmatics with validated survey measures to examine possible reasons for EDS. In particular, we hypothesized that unrecognized OSA is an important contributor to EDS in asthmatics. 2. Methods 2.1. Subjects This study was approved by the Institutional Review Board and conducted between May 2004 and February 2005. Clinic rosters were used to identify patients returning for routine asthma follow-up visits at the University of Michigan Pulmonary Clinics and Briarwood AsthmaAirways Center. Patients completed the screening questionnaires if they were 18–75 years old, able to provide informed consent, and willing and able to complete the survey. Patients at the clinics for urgent asthma-related visits and women who were pregnant were not surveyed. 2.2. Survey content The survey was comprised of three parts. The first questionnaire asked about perceived sleepiness (‘Do
you feel that you are excessively sleepy?’) and then presented the Epworth Sleepiness Scale (ESS) [23], a frequently used eight-item self-administered subjective sleepiness measure. The subject rates, on a scale of 0– 3, the likelihood that he or she would doze off or fall asleep during eight different situations commonly encountered in daily life. Scores are tallied across the eight items with an ESS score greater than 10 being considered indicative of subjective sleepiness [23]. This scale has previously demonstrated a high level of internal consistency among its eight items, high test-retest reliability, and the ability to distinguish between patients with excessive daytime sleepiness from normal subjects [24,25]. The second questionnaire was the Sleep Apnea scale of the Sleep Disorder Questionnaire (SA-SDQ) [26]. The 12-item SA-SDQ has been validated in a large sample of patients as a risk assessment instrument for OSA [26]. This scale consists of eight symptom-items that ask about snoring, witnessed apneas, worsening of snoring while sleeping supine or after drinking alcohol, history of hypertension, and other OSA symptoms. Responses are provided on a five-point Likert scale from ‘never’ to ‘always’. Four additional items, rated on a scale of 1–5, elicit data on age, weight, body mass index (BMI) and smoking status. Subjects who endorsed snoring as occurring with any frequency were categorized as ‘snorers’, and those who snored ‘usually’ or ‘always’ as habitual snorers. A report of observed episodes of ‘stopping breathing in sleep’ occurring with any frequency was considered indicative of witnessed apnea. The total SA-SDQ scores range from 12 to 60. Scores 36 for men and 32 for women have been proposed as screening cut-off values above which sleep apnea becomes clinically probable, though lower scores have been suggested in specific patient populations [27]. One of the advantages of the SA-SDQ for the purposes of this study is that it does not include questions about daytime sleepiness. As daytime sleepiness in asthmatics may have a multitude of causes, a sleepiness item included in this screening tool would not provide an accurate assessment of sleepiness related strictly to OSA in asthmatics. The third instrument was an asthma questionnaire which included items about frequency of daytime and nighttime asthma symptoms (designed following current National Asthma Education and Prevention Program Guidelines-NAEPP-Classification of Asthma Severity) [28]. When available, peak flow diaries were obtained either from the patients or from their medical charts. 2.3. Medical records review Medical records were subsequently reviewed to ascertain the specialist-made diagnosis of asthma, exclude subjects with any additional lung diseases, and obtain the other information necessary to accu-
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rately assess the asthma severity step. Data included FEV1% values from spirometry performed at the current visit or most recently, as requested by the evaluating physicians, and peak flow diaries when available. The asthma step was assigned according to NAEPP guidelines, in order of increasing severity: step 1 (mild-intermittent asthma), patients with daytime symptoms 2 days/week, nighttime symptoms 2 nights/month, FEV1 80% and peak expiratory flow rates (PEFR) variability < 20%; step 2 (mild-persistent asthma), patients with daytime symptoms 3–6 days/week, nighttime symptoms 3–4 nights/month, FEV1 80% and PEFR variability 20–30%; step 3 (moderate-persistent asthma), patients with daily asthma symptoms, nocturnal symptoms 5/month FEV1 between > 60 and < 80% or PEFR variability > 30%; step 4 (severe-persistent asthma), patients with continuous daytime symptoms, frequent nighttime symptoms, FEV1 60% or PEFR variability > 30%. The PEFR variability was calculated by dividing the difference between the highest and the lowest daily PEF value by the daily mean PEF [5] and multiplying the result by 100. The asthma step was determined by the most severe qualifying feature among those listed [28]. Medical records also were searched for established diagnoses of sleep-disordered breathing (SDB) and use of its treatment, and relevant comorbid conditions including rhinitis, chronic sinusitis, nasal polyps, GERD, and psychiatric conditions (e.g. depression, anxiety, and panic disorders). Medical records also listed current medications used to treat asthma that could have an influence on sleepiness. These included inhaled and oral corticosteroids, long-acting bronchodilators, theophylline, and anticholinergic medications. 2.4. Data analysis Statistical analysis was carried out using the SAS statistical software package (Version 8.01, SAS Institute Inc., Cary, NC). Chi-square tests were used to determine gender differences in current smoking status, asthma severity step, comorbid conditions, medication use, and OSA symptoms. T-tests were used to assess for any gender differences in continuous demographic variables (age, natural logarithm-transformed BMI), pulmonary function tests values, ESS and SA-SDQ scores. Spearman correlation coefficients were calculated to test for associations between ESS scores and potential causes of sleepiness, and for confounding variables. Multivariable linear regression models of ESS as the outcome were used to test for independent associations with variables that demonstrated statistically significant correlations in the univariable analyses. Models were additionally tested after adjustment for BMI. The significance level was set at P < 0.05.
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3. Results 3.1. Subjects’ characteristics Among 156 consecutive asthmatics who were approached between May 2004 and February 2005, 150 completed the informed consent and survey. Additional lung diseases (such as chronic obstructive pulmonary disease, bronchiectasis, sarcoidosis, interstitial lung disease, and hypersensitivity pneumonitis) were present in 15 subjects, who were excluded from the present analysis. Forty (30%) of the remaining subjects had a prior diagnosis of SDB, and half of them were being treated at the time of survey and therefore were excluded from further analysis. Table 1 lists the characteristics of the remaining 115 subjects, including demographics (age, gender, BMI and current smoking), asthma severity measures (asthma step, FEV1%), and other physiologic parameters, relevant comorbidities, and medications. The distribution of BMI values was skewed to the right by a few high BMI observations. The BMI ranged from 20.5 to 58.6, with a median of 29.6. The first and third BMI quartiles were capped at 25.5 and 35.1, respectively. Morning and evening peak flow rates,
Table 1 Demographics, medical history, and medication use for all subjects (n = 115) Characteristic
Mean±SD, or number (%) of subjects
Age (years) Gender (Female) BMI (kg·m 2) Current smokebrs Asthma severity step 1 Asthma severity step 2 Asthma severity step 3 Asthma severity step 4 FEV1% FVC % FEV1/FVC FEF25–75% History of rhinitis History of chronic sinusitis History of nasal polyps History of GERD History of psychopathology Using inhaled corticosteroid Using oral corticosteroid Using inhaled long-acting bronchodilator Using antileukotriene agents Using theophylline Using inhaled anticholinergic
47±13 79 (69) 31±7 5 (4) 28 (24) 18 (16) 31 (27) 38 (33) 87±22 91±20 72±13 61±29 87 (76) 24 (21) 13 (11) 70 (61) 39 (34) 101 (88) 18 (16) 78 (68) 55 (49) 5 (4) 15 (13)
Definition of abbreviations: SD, standard deviation; BMI, body mass index; FEV1%, forced expiratory volume in one second; FVC%, forced vital capacity; FEF25–75%, forced expiratory flow between 25 and 75% of vital capacity (all these physiologic variables are expressed as percentages of the predicted values); GERD, gastroesophageal reflux disease.
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M. Teodorescu et al. / Sleep Medicine 7 (2006) 607–613 Table 2 Multiple linear regression model of Epworth Sleepiness Scale scores on Sleep Apnea scores (from the Sleep Disorders Questionnaire [26]), male gender and asthma severity step (overall R2 = 0.183)
100%
n=99
90% 80% 70% 60%
n=63
50%
Variable
Beta
Standard Error
Partial R2 *
P-value
SA-SDQ scores Male gender Asthma severity step
0.23 2.47 0.29
0.06 1.02 0.43
0.111 0.050 0.004
0.0003 0.02 0.51
n=44
40%
n=36
30% 20% 10% 0%
Perceived Excessive Daytime Sleepiness
Snoring with Any Frequency
Habitual Snoring
Witnessed Apneas
Definition of abbreviations: * Partial R2, squared partial correlation type II; SA-SDQ, Sleep Apnea scale of the Sleep Disorder Questionnaire [26].
Fig. 1. Obstructive sleep apnea symptoms among 115 asthmatics.
recorded at least 3 days/week during the prior 2 weeks were available for 41 subjects, 19 in asthma severity step 4 (PEFR variability mean±SD: 8.65±5%), 10 in step 3 (6.1±5.7%), 7 in step 2 (4.7±3.4%) and 5 in step 1 (2.3±0.25%). The PEFR variability did not determine the asthma severity step for any of these subjects. No significant gender differences were found for any of the variables presented in Table 1 (all P > 0.10).
Regression of ESS simultaneously on SA-SDQ scores, male gender, and asthma severity step showed that the first two explanatory variables, but not asthma severity step, retained independent associations with subjective sleepiness scores (Table 2). Additional adjustment for BMI had no effect on these results (P = 0.0003 for SA-SDQ, P = 0.04 for male gender, P = 0.48 for asthma severity step, and P = 0.22 for BMI).
3.2. Daytime sleepiness, ESS scores, and other OSA symptoms
4. Discussion
Perceived EDS and other OSA symptoms are shown in Fig. 1. The mean ESS score was 10±6 and ESS scores > 10 were found in 54 subjects (47%). The mean ESS score of those subjects with perceived EDS was 12±6, whereas the mean ESS score of those who denied this complaint was 8±5 (P = 0.0005). The SA-SDQ scores that suggested probable OSA [26] were found in 39 (49%) of the women and 12 (33%) of the men (v2 = 2.58, P = 0.11). Perceived sleepiness, other OSA symptoms shown in Fig. 1, and the mean SA-SDQ score (31±8) each showed no significant differences between men and women (all P 0.10). 3.3. Correlates of ESS scores The ESS scores correlated with SA-SDQ scores (q = 0.359, P < 0.0001), male gender (q = 0.231, P = 0.01), and asthma severity step (q = 0.187, P = 0.04). The ESS scores were higher in men than in women (12±5 vs. 9±6, P = 0.02). Higher ESS scores were associated with habitual snoring (12±6 vs. 9±5, P = 0.001), as was perceived EDS (v2 = 11.76, P = 0.0006). In contrast, no significant correlations emerged between ESS and age, BMI, smoking status, FEV1%, forced expiratory flow between 25 and 75% of vital capacity (FEF25–75%), history of rhinitis, chronic sinusitis, nasal polyps, GERD, coexistent psychopathology, or medications used to treat asthma (including inhaled or oral corticosteroids, inhaled long-acting bronchodilators, theophylline, or inhaled anticholinergics) (all P > 0.10).
This study of patients with asthma confirms previous findings in smaller samples that daytime sleepiness is a common problem. More importantly, the new data suggest for the first time that the severity of sleepiness is independently associated with underlying OSA symptoms rather than asthma severity, other comorbidities, or medications used to treat asthma. Our sample of asthmatics, well-characterized by clinical evaluation and objective measures, included all but a small proportion of subjects who declined to enroll in the study. The high participation rate (96%) may suggest that asthmatic patients are concerned about their sleep. This specialty clinic-based sample was composed predominantly of women, reflecting the known female-gender predominance of asthma prevalence and its morbidity within the general population [29]. The median BMI in our sample reached the borderline between overweight and obesity, consistent with previous reports of excess weight among asthmatics [16]. The distribution of asthma severity somewhat skewed towards more severe cases (27 and 33% of the subjects were in step 3 and 4, respectively) probably reflects the tertiary care setting. The frequency of asthma comorbidities evaluated is similar to that reported previously [14,15,17,18]. Consistent with current asthma treatment guidelines [30], a large proportion of our subjects were using inhaled corticosteroids and long-acting bronchodilators, as opposed to oral steroids, theophylline, and anticholinergics. Thus, our survey results should be reasonably representative of asthmatic outpatients in a fairly stable condition who are followed routinely at many specialty clinics.
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The frequency of perceived EDS in our sample (55%) exceeded that found in the general population in industrialized countries, which ranged from 9 to 15% when a similar inquiry was used [31–33]. The frequency in our study closely resembles the 44% previously reported in another sample of asthmatics [1]. In addition, the 47% of subjects with an abnormal ESS ( > 10) in this sample surpasses the 7–25% reported in the general population [33,34], but resembles a frequency of 39% previously reported in asthmatics [7]. The self-reported frequencies of snoring (86%) and habitual snoring (38%) in our sample are higher than those reported in general populations (55% [35] and 7–21%, respectively [36,37]) when similar defining criteria were used. The frequency of witnessed apneas (31%) reported in our sample is also higher than the 5–7% found in general populations [12,35]. Among all our tested variables that could influence sleep quality and sleepiness in asthmatics, a validated risk assessment scale for OSA demonstrated the strongest independent association with subjective sleepiness scores. In addition, a high rate (30%) of previously diagnosed sleep-disordered breathing was apparent in our initial sample of 135. The reasons for such a high frequency of OSA symptoms in this population of asthmatics are not certain, and our cross-sectional study is not designed to prove cause and effect. Several plausible hypotheses have been proposed to explain the association of asthma and OSA [13,38–40]. Some of these include anatomic or functional abnormalities of the upper airway related to obesity, nasal disease or GERD-induced upper airway inflammation, asthma or medication-induced sleep fragmentation, chronic systemic steroid therapy, and the adverse impact on upper airway patency of lung volume reduction during sleep in asthmatics. However, such mechanisms remain largely unstudied. Our study, like others [33,41], found that asthmatic men were sleepier than asthmatic women, but reasons remain unclear. ‘Sleepiness’ has different meanings for different people, and complaints such as feeling ‘unrested during the day’[33] or ‘fatigued, tired, or lacking energy during the day’[42] may be more important than sleepiness to women with OSA. Inclusion of such terms in our study might have revealed even greater levels of OSA-related morbidity. All patients with difficult-tocontrol asthma in a previous study reported morning fatigue [13]. The ESS sometimes correlates with the respiratory disturbance index [25,43], and male asthmatics may prove to have more severe OSA than females asthmatics, as in general population [43]. The lack of independent associations between subjective sleepiness scores and asthma severity, rhinitis, chronic sinus disease, nasal polyps, GERD, psychopathology, and medications used for asthma does not eliminate the possibility that in an individual asthmatic these factors could still contribute to the complaint of daytime
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sleepiness. Our sample, recruited at a tertiary care center, included a wide range of asthma severity and a larger proportion of step 3 and step 4 asthmatics than that found in the general asthma population [44]. Therefore, any impact of asthma-associated nocturnal sleep disruption on sleepiness should have been readily apparent. However, one limitation is that this study could not include objective quantification of disease control for these comorbid conditions. Nevertheless, these conditions were recognized by experienced physicians in proportions similar to those reported elsewhere. Once these known aggravators of asthma were diagnosed, they were most likely addressed in many cases, perhaps with a reduction in their contribution to sleepiness. The lack of an association between ESS and BMI suggests that factors other than BMI may explain the observation of an independent association of ESS with OSA risk, and that obesity may not be the only powerful risk factor for OSA in asthmatics. Indeed, Yigla et al. [13] in difficult-to-control asthmatics, after a long period (8.9±3.3 years) of corticosteroid treatment, found no association between BMI or neck circumference (or substantial increases in BMI with time) and the respiratory disturbance index. Further studies of risk factors for OSA in asthmatics will be needed. A second limitation of this investigation is that comparison subjects without asthma were not studied. Frequencies of OSA symptoms must therefore be compared with prior reports from general populations, and only a limited number of studies have used similar screening tools and definitions. However, prior large epidemiological studies [2,12] and a study that used a control group [1] have found rates of sleepiness in asthmatics to be similar to ours. Furthermore, sufficient variability in explanatory and outcome measures existed within our sample of asthmatics to demonstrate targeted associations, which retain no less validity because control subjects were not surveyed. Finally, our investigation included objective assessments of asthma severity, but not polysomnography to confirm the diagnosis of OSA. However, the SA-SDQ has been validated in a large sample of patients and demonstrated to have good sensitivity and specificity for OSA [26]. The SA-SDQ has been used previously in specific disease populations and has been found to be a strong predictor of OSA [45,46]. Use of well-validated questionnaires to identify OSA risk, if not the condition itself, is a well-established approach to investigate new hypotheses when the expense of full prospective polysomnography on a large scale cannot yet be justified. In conclusion, this study is the first to the authors’ knowledge to test whether high frequencies of sleepiness among asthmatics might be explained by an excess frequency of underlying OSA. The independent correlation between subjective sleepiness and OSA symptoms suggests that untreated OSA among outpatients with asth-
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ma may make substantial contributions to complaints of EDS. Prospective studies that demonstrate improved sleepiness in asthmatics after treatment of comorbid OSA would further support these initial cross-sectional observations. Acknowledgements The authors thank Jack D. Kalbfleisch, PhD and Yining Ye, MS for their expert statistical support, and Radu C. Nistor and Jesica M. Pedroza for assistance with administration of screening questionnaires and entry of data. The authors thank the physicians at the University of Michigan Pulmonary Clinics and Briarwood Asthma-Airways Center for their help in identification of subjects for this study. This work was supported by University of Michigan General Clinical Research Center (MO1 RR00042) and University of Michigan Department of Neurology Training Grant (T32 NS07222). Conflict of interest disclosures The following authors: M Teodorescu, WF Bria, MJ Coffey, MS McMorris, KJ Weatherwax, J Palmisano, CM Senger and RD Chervin have nothing to disclose. Dr FB Consens and A Durance RN have received speaker’s honoraria (each under $10,000 in the last year) from GlaxoSmithKline, and from Novartis Pharma and Genentech, respectively.
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Original article
Correlates of daytime sleepiness in patients with asthma Mihaela Teodorescu a,*, Flavia B. Consens a, William F. Bria b, Michael J. Coffey b, Marc S. McMorris c, Kevin J. Weatherwax a, Ann Durance c, John Palmisano a, Carolyn M. Senger a, Ronald D. Chervin a b
a Sleep Disorders Center and Department of Neurology, University of Michigan Health System, Ann Arbor, MI USA Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA c Division of Allergy and Clinical Immunology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
Received 20 October 2005; received in revised form 1 February 2006; accepted 2 February 2006 Available online 3 July 2006
Abstract Background and purpose: Patients with asthma often complain of daytime sleepiness, which is usually attributed to a direct effect of asthma on nocturnal sleep quality. We investigated this and other potential explanations for daytime sleepiness among asthmatics. Patients and methods: One hundred fifteen adult asthmatics were assessed for perceived daytime sleepiness (one question item), subjective sleepiness (Epworth Sleepiness Scale score, ESS), obstructive sleep apnea risk (Sleep Apnea scale score within Sleep Disorders Questionnaire, SA-SDQ), asthma severity step, relevant comorbid conditions, and current asthma medications. Results: Among all subjects, 55% perceived excessive daytime sleepiness and 47% had ESS > 10. Most subjects reported snoring (n = 99, or 86%) and many snored habitually (n = 44, 38%). The ESS correlated with SA-SDQ (P < 0.0001), male gender (P = 0.01), and asthma severity step (P = 0.04). In a multiple regression model, the ESS was independently associated with SASDQ (P = 0.0003) and male gender (P = 0.02), but not with asthma severity step (P = 0.51). There were no correlations between ESS and age, body mass index (BMI), forced expiratory volume in one second as percent of predicted value (FEV1%), comorbidities, or medication used to treat asthma. Conclusions: Sleepiness is common in asthmatics and may reflect occult obstructive sleep apnea more often than effects of asthma itself, other comorbid conditions, or asthma medications. 2006 Elsevier B.V. All rights reserved. Keywords: Asthma; Sleepiness; Sleep apnea, Obstructive; Epworth Sleepiness Scale; Sleep Disorders Questionnaire
1. Introduction Daytime sleepiness is a particularly frequent complaint in patients with asthma [1,2]. Daytime sleepiness has a negative impact on quality of life, work performance, and risk for motor vehicle crashes or work-related acci-
* Corresponding author. Address: Michael S. Aldrich Sleep Disorders Laboratory, University of Michigan Health System, 8D 8702 University Hospital, Box 0117, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0117, USA. Tel.: + 1 734 647 9064; fax: + 1 734 647 9065. E-mail address: [email protected] (M. Teodorescu).
1389-9457/$ - see front matter 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2006.02.001
dents [3]. In general, daytime sleepiness is often the result of poor sleep quality, and asthmatics do commonly complain about difficulty with initiation [1,4] and maintenance of sleep, especially in the early morning [1,5]. Such sleep disturbances become more frequent with increased nocturnal asthma symptoms [1]. Nocturnal wakefulness correlates with daytime airways obstruction, as measured by forced expiratory volume in one second as percent of predicted value (FEV1%) [1]. Sleep studies in asthmatics have provided some objective evidence of poor sleep quality as evidenced by a reduced sleep time, delayed latency to sleep, frequent awakenings after sleep onset, early morning arousals and reduced slow wave sleep
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[4,6]. Therefore, daytime sleepiness in asthma is often thought to be the consequence of a direct effect of nocturnal asthma on sleep quality. Both increased subjective sleepiness and poor sleep quality scores were documented recently in a large population of asthmatics [7], but two therapeutic strategies for asthma failed to improve subjective sleepiness and sleep quality scores [8]. These results suggest that other possible reasons for daytime sleepiness in asthmatics also should be considered. Excessive daytime sleepiness (EDS) is one of the most common presenting symptoms of obstructive sleep apnea (OSA), in itself a common and frequently unrecognized condition [9,10]. Snoring is frequent in both OSA patients and asthmatics [2,11,12]. Recently, in a sample of 22 difficult-to-control asthmatics, daytime sleepiness was reported by 20 (90.9%) of the subjects and OSA was demonstrated by polysomnography in 21 (95.5%) of them [13]. Furthermore, asthma frequently coexists with allergic rhinitis and chronic sinusitis [14], gastroesophageal reflux disease (GERD) [15], obesity [16], and psychopathology such as anxiety, depression and panic disorders [17,18], all of which are known to be associated with daytime sleepiness [3,5,19,20]. The medications commonly used to treat asthma tend to have stimulating, anxiety-provoking or mood-depressing properties [5,21,22] that could interfere with sleep quality and exacerbate daytime sleepiness. Previous studies of sleepiness in asthma have been limited by reliance on patient-reported asthma diagnosis or have not included information on comorbid conditions and medications that could influence sleepiness. We therefore studied a sample of medically well-characterized asthmatics with validated survey measures to examine possible reasons for EDS. In particular, we hypothesized that unrecognized OSA is an important contributor to EDS in asthmatics. 2. Methods 2.1. Subjects This study was approved by the Institutional Review Board and conducted between May 2004 and February 2005. Clinic rosters were used to identify patients returning for routine asthma follow-up visits at the University of Michigan Pulmonary Clinics and Briarwood AsthmaAirways Center. Patients completed the screening questionnaires if they were 18–75 years old, able to provide informed consent, and willing and able to complete the survey. Patients at the clinics for urgent asthma-related visits and women who were pregnant were not surveyed. 2.2. Survey content The survey was comprised of three parts. The first questionnaire asked about perceived sleepiness (‘Do
you feel that you are excessively sleepy?’) and then presented the Epworth Sleepiness Scale (ESS) [23], a frequently used eight-item self-administered subjective sleepiness measure. The subject rates, on a scale of 0– 3, the likelihood that he or she would doze off or fall asleep during eight different situations commonly encountered in daily life. Scores are tallied across the eight items with an ESS score greater than 10 being considered indicative of subjective sleepiness [23]. This scale has previously demonstrated a high level of internal consistency among its eight items, high test-retest reliability, and the ability to distinguish between patients with excessive daytime sleepiness from normal subjects [24,25]. The second questionnaire was the Sleep Apnea scale of the Sleep Disorder Questionnaire (SA-SDQ) [26]. The 12-item SA-SDQ has been validated in a large sample of patients as a risk assessment instrument for OSA [26]. This scale consists of eight symptom-items that ask about snoring, witnessed apneas, worsening of snoring while sleeping supine or after drinking alcohol, history of hypertension, and other OSA symptoms. Responses are provided on a five-point Likert scale from ‘never’ to ‘always’. Four additional items, rated on a scale of 1–5, elicit data on age, weight, body mass index (BMI) and smoking status. Subjects who endorsed snoring as occurring with any frequency were categorized as ‘snorers’, and those who snored ‘usually’ or ‘always’ as habitual snorers. A report of observed episodes of ‘stopping breathing in sleep’ occurring with any frequency was considered indicative of witnessed apnea. The total SA-SDQ scores range from 12 to 60. Scores 36 for men and 32 for women have been proposed as screening cut-off values above which sleep apnea becomes clinically probable, though lower scores have been suggested in specific patient populations [27]. One of the advantages of the SA-SDQ for the purposes of this study is that it does not include questions about daytime sleepiness. As daytime sleepiness in asthmatics may have a multitude of causes, a sleepiness item included in this screening tool would not provide an accurate assessment of sleepiness related strictly to OSA in asthmatics. The third instrument was an asthma questionnaire which included items about frequency of daytime and nighttime asthma symptoms (designed following current National Asthma Education and Prevention Program Guidelines-NAEPP-Classification of Asthma Severity) [28]. When available, peak flow diaries were obtained either from the patients or from their medical charts. 2.3. Medical records review Medical records were subsequently reviewed to ascertain the specialist-made diagnosis of asthma, exclude subjects with any additional lung diseases, and obtain the other information necessary to accu-
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rately assess the asthma severity step. Data included FEV1% values from spirometry performed at the current visit or most recently, as requested by the evaluating physicians, and peak flow diaries when available. The asthma step was assigned according to NAEPP guidelines, in order of increasing severity: step 1 (mild-intermittent asthma), patients with daytime symptoms 2 days/week, nighttime symptoms 2 nights/month, FEV1 80% and peak expiratory flow rates (PEFR) variability < 20%; step 2 (mild-persistent asthma), patients with daytime symptoms 3–6 days/week, nighttime symptoms 3–4 nights/month, FEV1 80% and PEFR variability 20–30%; step 3 (moderate-persistent asthma), patients with daily asthma symptoms, nocturnal symptoms 5/month FEV1 between > 60 and < 80% or PEFR variability > 30%; step 4 (severe-persistent asthma), patients with continuous daytime symptoms, frequent nighttime symptoms, FEV1 60% or PEFR variability > 30%. The PEFR variability was calculated by dividing the difference between the highest and the lowest daily PEF value by the daily mean PEF [5] and multiplying the result by 100. The asthma step was determined by the most severe qualifying feature among those listed [28]. Medical records also were searched for established diagnoses of sleep-disordered breathing (SDB) and use of its treatment, and relevant comorbid conditions including rhinitis, chronic sinusitis, nasal polyps, GERD, and psychiatric conditions (e.g. depression, anxiety, and panic disorders). Medical records also listed current medications used to treat asthma that could have an influence on sleepiness. These included inhaled and oral corticosteroids, long-acting bronchodilators, theophylline, and anticholinergic medications. 2.4. Data analysis Statistical analysis was carried out using the SAS statistical software package (Version 8.01, SAS Institute Inc., Cary, NC). Chi-square tests were used to determine gender differences in current smoking status, asthma severity step, comorbid conditions, medication use, and OSA symptoms. T-tests were used to assess for any gender differences in continuous demographic variables (age, natural logarithm-transformed BMI), pulmonary function tests values, ESS and SA-SDQ scores. Spearman correlation coefficients were calculated to test for associations between ESS scores and potential causes of sleepiness, and for confounding variables. Multivariable linear regression models of ESS as the outcome were used to test for independent associations with variables that demonstrated statistically significant correlations in the univariable analyses. Models were additionally tested after adjustment for BMI. The significance level was set at P < 0.05.
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3. Results 3.1. Subjects’ characteristics Among 156 consecutive asthmatics who were approached between May 2004 and February 2005, 150 completed the informed consent and survey. Additional lung diseases (such as chronic obstructive pulmonary disease, bronchiectasis, sarcoidosis, interstitial lung disease, and hypersensitivity pneumonitis) were present in 15 subjects, who were excluded from the present analysis. Forty (30%) of the remaining subjects had a prior diagnosis of SDB, and half of them were being treated at the time of survey and therefore were excluded from further analysis. Table 1 lists the characteristics of the remaining 115 subjects, including demographics (age, gender, BMI and current smoking), asthma severity measures (asthma step, FEV1%), and other physiologic parameters, relevant comorbidities, and medications. The distribution of BMI values was skewed to the right by a few high BMI observations. The BMI ranged from 20.5 to 58.6, with a median of 29.6. The first and third BMI quartiles were capped at 25.5 and 35.1, respectively. Morning and evening peak flow rates,
Table 1 Demographics, medical history, and medication use for all subjects (n = 115) Characteristic
Mean±SD, or number (%) of subjects
Age (years) Gender (Female) BMI (kg·m 2) Current smokebrs Asthma severity step 1 Asthma severity step 2 Asthma severity step 3 Asthma severity step 4 FEV1% FVC % FEV1/FVC FEF25–75% History of rhinitis History of chronic sinusitis History of nasal polyps History of GERD History of psychopathology Using inhaled corticosteroid Using oral corticosteroid Using inhaled long-acting bronchodilator Using antileukotriene agents Using theophylline Using inhaled anticholinergic
47±13 79 (69) 31±7 5 (4) 28 (24) 18 (16) 31 (27) 38 (33) 87±22 91±20 72±13 61±29 87 (76) 24 (21) 13 (11) 70 (61) 39 (34) 101 (88) 18 (16) 78 (68) 55 (49) 5 (4) 15 (13)
Definition of abbreviations: SD, standard deviation; BMI, body mass index; FEV1%, forced expiratory volume in one second; FVC%, forced vital capacity; FEF25–75%, forced expiratory flow between 25 and 75% of vital capacity (all these physiologic variables are expressed as percentages of the predicted values); GERD, gastroesophageal reflux disease.
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M. Teodorescu et al. / Sleep Medicine 7 (2006) 607–613 Table 2 Multiple linear regression model of Epworth Sleepiness Scale scores on Sleep Apnea scores (from the Sleep Disorders Questionnaire [26]), male gender and asthma severity step (overall R2 = 0.183)
100%
n=99
90% 80% 70% 60%
n=63
50%
Variable
Beta
Standard Error
Partial R2 *
P-value
SA-SDQ scores Male gender Asthma severity step
0.23 2.47 0.29
0.06 1.02 0.43
0.111 0.050 0.004
0.0003 0.02 0.51
n=44
40%
n=36
30% 20% 10% 0%
Perceived Excessive Daytime Sleepiness
Snoring with Any Frequency
Habitual Snoring
Witnessed Apneas
Definition of abbreviations: * Partial R2, squared partial correlation type II; SA-SDQ, Sleep Apnea scale of the Sleep Disorder Questionnaire [26].
Fig. 1. Obstructive sleep apnea symptoms among 115 asthmatics.
recorded at least 3 days/week during the prior 2 weeks were available for 41 subjects, 19 in asthma severity step 4 (PEFR variability mean±SD: 8.65±5%), 10 in step 3 (6.1±5.7%), 7 in step 2 (4.7±3.4%) and 5 in step 1 (2.3±0.25%). The PEFR variability did not determine the asthma severity step for any of these subjects. No significant gender differences were found for any of the variables presented in Table 1 (all P > 0.10).
Regression of ESS simultaneously on SA-SDQ scores, male gender, and asthma severity step showed that the first two explanatory variables, but not asthma severity step, retained independent associations with subjective sleepiness scores (Table 2). Additional adjustment for BMI had no effect on these results (P = 0.0003 for SA-SDQ, P = 0.04 for male gender, P = 0.48 for asthma severity step, and P = 0.22 for BMI).
3.2. Daytime sleepiness, ESS scores, and other OSA symptoms
4. Discussion
Perceived EDS and other OSA symptoms are shown in Fig. 1. The mean ESS score was 10±6 and ESS scores > 10 were found in 54 subjects (47%). The mean ESS score of those subjects with perceived EDS was 12±6, whereas the mean ESS score of those who denied this complaint was 8±5 (P = 0.0005). The SA-SDQ scores that suggested probable OSA [26] were found in 39 (49%) of the women and 12 (33%) of the men (v2 = 2.58, P = 0.11). Perceived sleepiness, other OSA symptoms shown in Fig. 1, and the mean SA-SDQ score (31±8) each showed no significant differences between men and women (all P 0.10). 3.3. Correlates of ESS scores The ESS scores correlated with SA-SDQ scores (q = 0.359, P < 0.0001), male gender (q = 0.231, P = 0.01), and asthma severity step (q = 0.187, P = 0.04). The ESS scores were higher in men than in women (12±5 vs. 9±6, P = 0.02). Higher ESS scores were associated with habitual snoring (12±6 vs. 9±5, P = 0.001), as was perceived EDS (v2 = 11.76, P = 0.0006). In contrast, no significant correlations emerged between ESS and age, BMI, smoking status, FEV1%, forced expiratory flow between 25 and 75% of vital capacity (FEF25–75%), history of rhinitis, chronic sinusitis, nasal polyps, GERD, coexistent psychopathology, or medications used to treat asthma (including inhaled or oral corticosteroids, inhaled long-acting bronchodilators, theophylline, or inhaled anticholinergics) (all P > 0.10).
This study of patients with asthma confirms previous findings in smaller samples that daytime sleepiness is a common problem. More importantly, the new data suggest for the first time that the severity of sleepiness is independently associated with underlying OSA symptoms rather than asthma severity, other comorbidities, or medications used to treat asthma. Our sample of asthmatics, well-characterized by clinical evaluation and objective measures, included all but a small proportion of subjects who declined to enroll in the study. The high participation rate (96%) may suggest that asthmatic patients are concerned about their sleep. This specialty clinic-based sample was composed predominantly of women, reflecting the known female-gender predominance of asthma prevalence and its morbidity within the general population [29]. The median BMI in our sample reached the borderline between overweight and obesity, consistent with previous reports of excess weight among asthmatics [16]. The distribution of asthma severity somewhat skewed towards more severe cases (27 and 33% of the subjects were in step 3 and 4, respectively) probably reflects the tertiary care setting. The frequency of asthma comorbidities evaluated is similar to that reported previously [14,15,17,18]. Consistent with current asthma treatment guidelines [30], a large proportion of our subjects were using inhaled corticosteroids and long-acting bronchodilators, as opposed to oral steroids, theophylline, and anticholinergics. Thus, our survey results should be reasonably representative of asthmatic outpatients in a fairly stable condition who are followed routinely at many specialty clinics.
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The frequency of perceived EDS in our sample (55%) exceeded that found in the general population in industrialized countries, which ranged from 9 to 15% when a similar inquiry was used [31–33]. The frequency in our study closely resembles the 44% previously reported in another sample of asthmatics [1]. In addition, the 47% of subjects with an abnormal ESS ( > 10) in this sample surpasses the 7–25% reported in the general population [33,34], but resembles a frequency of 39% previously reported in asthmatics [7]. The self-reported frequencies of snoring (86%) and habitual snoring (38%) in our sample are higher than those reported in general populations (55% [35] and 7–21%, respectively [36,37]) when similar defining criteria were used. The frequency of witnessed apneas (31%) reported in our sample is also higher than the 5–7% found in general populations [12,35]. Among all our tested variables that could influence sleep quality and sleepiness in asthmatics, a validated risk assessment scale for OSA demonstrated the strongest independent association with subjective sleepiness scores. In addition, a high rate (30%) of previously diagnosed sleep-disordered breathing was apparent in our initial sample of 135. The reasons for such a high frequency of OSA symptoms in this population of asthmatics are not certain, and our cross-sectional study is not designed to prove cause and effect. Several plausible hypotheses have been proposed to explain the association of asthma and OSA [13,38–40]. Some of these include anatomic or functional abnormalities of the upper airway related to obesity, nasal disease or GERD-induced upper airway inflammation, asthma or medication-induced sleep fragmentation, chronic systemic steroid therapy, and the adverse impact on upper airway patency of lung volume reduction during sleep in asthmatics. However, such mechanisms remain largely unstudied. Our study, like others [33,41], found that asthmatic men were sleepier than asthmatic women, but reasons remain unclear. ‘Sleepiness’ has different meanings for different people, and complaints such as feeling ‘unrested during the day’[33] or ‘fatigued, tired, or lacking energy during the day’[42] may be more important than sleepiness to women with OSA. Inclusion of such terms in our study might have revealed even greater levels of OSA-related morbidity. All patients with difficult-tocontrol asthma in a previous study reported morning fatigue [13]. The ESS sometimes correlates with the respiratory disturbance index [25,43], and male asthmatics may prove to have more severe OSA than females asthmatics, as in general population [43]. The lack of independent associations between subjective sleepiness scores and asthma severity, rhinitis, chronic sinus disease, nasal polyps, GERD, psychopathology, and medications used for asthma does not eliminate the possibility that in an individual asthmatic these factors could still contribute to the complaint of daytime
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sleepiness. Our sample, recruited at a tertiary care center, included a wide range of asthma severity and a larger proportion of step 3 and step 4 asthmatics than that found in the general asthma population [44]. Therefore, any impact of asthma-associated nocturnal sleep disruption on sleepiness should have been readily apparent. However, one limitation is that this study could not include objective quantification of disease control for these comorbid conditions. Nevertheless, these conditions were recognized by experienced physicians in proportions similar to those reported elsewhere. Once these known aggravators of asthma were diagnosed, they were most likely addressed in many cases, perhaps with a reduction in their contribution to sleepiness. The lack of an association between ESS and BMI suggests that factors other than BMI may explain the observation of an independent association of ESS with OSA risk, and that obesity may not be the only powerful risk factor for OSA in asthmatics. Indeed, Yigla et al. [13] in difficult-to-control asthmatics, after a long period (8.9±3.3 years) of corticosteroid treatment, found no association between BMI or neck circumference (or substantial increases in BMI with time) and the respiratory disturbance index. Further studies of risk factors for OSA in asthmatics will be needed. A second limitation of this investigation is that comparison subjects without asthma were not studied. Frequencies of OSA symptoms must therefore be compared with prior reports from general populations, and only a limited number of studies have used similar screening tools and definitions. However, prior large epidemiological studies [2,12] and a study that used a control group [1] have found rates of sleepiness in asthmatics to be similar to ours. Furthermore, sufficient variability in explanatory and outcome measures existed within our sample of asthmatics to demonstrate targeted associations, which retain no less validity because control subjects were not surveyed. Finally, our investigation included objective assessments of asthma severity, but not polysomnography to confirm the diagnosis of OSA. However, the SA-SDQ has been validated in a large sample of patients and demonstrated to have good sensitivity and specificity for OSA [26]. The SA-SDQ has been used previously in specific disease populations and has been found to be a strong predictor of OSA [45,46]. Use of well-validated questionnaires to identify OSA risk, if not the condition itself, is a well-established approach to investigate new hypotheses when the expense of full prospective polysomnography on a large scale cannot yet be justified. In conclusion, this study is the first to the authors’ knowledge to test whether high frequencies of sleepiness among asthmatics might be explained by an excess frequency of underlying OSA. The independent correlation between subjective sleepiness and OSA symptoms suggests that untreated OSA among outpatients with asth-
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ma may make substantial contributions to complaints of EDS. Prospective studies that demonstrate improved sleepiness in asthmatics after treatment of comorbid OSA would further support these initial cross-sectional observations. Acknowledgements The authors thank Jack D. Kalbfleisch, PhD and Yining Ye, MS for their expert statistical support, and Radu C. Nistor and Jesica M. Pedroza for assistance with administration of screening questionnaires and entry of data. The authors thank the physicians at the University of Michigan Pulmonary Clinics and Briarwood Asthma-Airways Center for their help in identification of subjects for this study. This work was supported by University of Michigan General Clinical Research Center (MO1 RR00042) and University of Michigan Department of Neurology Training Grant (T32 NS07222). Conflict of interest disclosures The following authors: M Teodorescu, WF Bria, MJ Coffey, MS McMorris, KJ Weatherwax, J Palmisano, CM Senger and RD Chervin have nothing to disclose. Dr FB Consens and A Durance RN have received speaker’s honoraria (each under $10,000 in the last year) from GlaxoSmithKline, and from Novartis Pharma and Genentech, respectively.
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