Common complaints in obstructive sleep apnea (OSA) include

Scientific investigations Fatigue, Tiredness, and Lack of Energy Improve with Treatment for OSA Wattanachai Chotinaiwattarakul, M.D. 1 ; Louise M. O Brien, Ph.D. 1,2 ; Ludi Fan, M.S. 3 ; Ronald D. Chervin, M.D., M.S. 1 1 Sleep Disorders Center and Department of Neurology, and 2 Department of Oral and Maxillofacial Surgery, University of Michigan, Ann Arbor, MI; 3 Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI Objectives: Many patients with obstructive sleep apnea complain of fatigue, tiredness, or lack of energy in addition to sleepiness, or instead of sleepiness. We explored whether self-defined fatigue, tiredness, and lack of energy improve, like sleepiness, after treatment with positive airway pressure (PAP). Methods: We conducted a prospective survey of adults referred to a University-based sleep disorders center and confirmed to have obstructive sleep apnea on polysomnography. Surveys were mailed to 1539 patients 6 months to 3 years after they were prescribed PAP for home use. Results: Participants (n = 313) included 183 who reported using PAP 5 hours per night, 96 who were considered inadequately treated because they had no active treatment or used PAP < 5 hours per night, and 34 treated by surgery or other means and therefore excluded from subsequent analysis. At follow-up in comparison to baseline, subjects adherent to PAP reported less fatigue, tiredness, lack of energy, and sleepiness (p < 0.05 for each). Improvement of each symptom except for lack of energy was significantly better (p < 0.05) among PAP-adherent subjects than among inadequately treated subjects. Conclusions: Patients complaints of fatigue, tiredness, and lack of energy, like sleepiness, can improve substantially with good adherence to PAP for obstructive sleep apnea. Therefore, patients who prefer a range of common, related terms other than sleepiness to describe their problem may benefit from investigation and treatment for any underlying sleep-disordered breathing. Keywords: Fatigue; tiredness; lack of energy; sleepiness; sleep apnea, obstructive; questionnaire; polysomnography; CPAP Citation: Chotinaiwattarakul W; O Brien LM; Fan L; Chervin RD. Fatigue, tiredness, and lack of energy improve with treatment for osa. J Clin Sleep Med 2009;5(3):240-245. Common complaints in obstructive sleep apnea (OSA) include excessive daytime sleepiness, loud snoring, gasping or choking at night, and witnessed apneas. 1 These symptoms can vary between individuals, but sleepiness perhaps in part because of related motor vehicle crashes, 2 psychological morbidity, and impaired quality of life 3,4 is one of the most well-studied complaints from OSA patients. 1,5,6 Sleepiness can be assessed by both subjective 7 and objective methods. 8,9 By either type of measure, sleepiness generally responds well to OSA treatment, usually by positive airway pressure (PAP). 10,11 However, treatment effectiveness can be limited by variable adherence to prescribed therapy. On average, PAP use tends to fall between 3.0 and 5.0 hours per night. 12-16 Despite the importance placed on sleepiness, many OSA patients do not necessarily find the term relevant to them, and many prefer other words to describe what affects them most prominently. An evaluation of 190 consecutive sleep clinic patients with polysomnographically-confirmed OSA showed that chief complaints can be expressed as fatigue, tiredness, or lack Submitted for publication October, 2008 Submitted in final revised form January, 2009 Accepted for publication February, 2009 Address correspondence to: Ronald D. Chervin. M.D., M.S., Michael S. Aldrich Sleep Disorders Laboratory, C734 Med Inn, SPC 5845, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5845; Tel: (734) 647-9064; Fax: (734) 647-9065; E-mail: chervin@umich.edu Journal of Clinical Sleep Medicine, Vol.5, No. 3, 2009 222 of energy rather than sleepiness itself. 17 Women, in particular, reported higher levels of fatigue, tiredness, and lack of energy than did men. Surprisingly, the total percentage of patients who preferred these other terms to sleepiness was about 78%. The term most often chosen was lack of energy (selected by about 40% of patients), whereas sleepiness was endorsed as paramount by only 22%. Fatigue, tiredness, and lack of energy, however, can be caused by many different disorders, and before OSA is added to that list, evidence that these complaints resolve with effective OSA treatment, as readily as sleepiness does, would be most useful. Quality of life instruments are often sensitive to sleep disorders and their treatment, probably in part because they include sleepiness-related constructs, such as the energy/vitality subscale of the SF-36. 18,19 However, use of these instruments has not produced data on specific words preferred by patients to describe their complaints, or direct comparison of those words to sleepiness, which is often the main focus of inquiry during an interview intended to screen for sleep apnea. No published study has yet investigated the extent to which common complaints other than sleepiness in particular, fatigue, tiredness, and lack of energy also improve when OSA is controlled by PAP. The main goal of the current research, therefore, was to examine this practical clinical question. We also assessed whether patients with good PAP adherence experience more improvement in each symptom than do those with poor adherence, and whether women report more improvement than do men.

Fatigue in OSA Subjects MATERIALS AND METHODS With institutional review board approval, we used a sleep laboratory clinical database to identify all subjects who met the following criteria: (1) diagnosis of OSA, based on referral for suspected OSA and confirmation of 5 or more apneas or hypopneas per hour of sleep on a diagnostic, laboratory-based polysomnogram; (2) age 18 years; and (3) relevant items of a Sleepiness Impact Profile 17 completed between July 1, 2004 and March 31, 2007 as part of routine laboratory procedure at the time of baseline polysomnography. Subjects were excluded if they had narcolepsy or another diagnosed sleep disorder likely to contribute to persistent sleepiness, fatigue, tiredness, or lack of energy after treatment for OSA. Subjects were not excluded on the basis of the many other medical and psychiatric illnesses that could potentially affect these symptoms. Exclusion for the large number of conditions relevant to the four complaints would have narrowed the sample size unreasonably and limited generalizability of the findings. Procedures and Measures In January and February 2008, the investigators mailed to each eligible subject a short letter to introduce this study, several specific question-items from the Sleepiness Impact Profile, an Epworth Sleepiness Scale, several additional questions, a written informed consent, and a postage-paid return envelope. Initially, potential subjects who had not responded after 4-6 weeks were approached by phone. However, the additional responses received after phoning 512 subjects (43% of the originally targeted sample) amounted only to 15 (3% of the 512), and therefore the practice was discontinued. The Sleepiness Impact Profile 17 is a 2-part questionnaire developed by the investigators in 1996 and now used routinely for clinical purposes. The first part asks about effects of specified symptoms on daily life. Answers are provided on Likert scales. The second part contains 5 questions designed to identify, for each subject, the complaint that he or she views as most troublesome. For the present protocol, a subset of Sleepiness Impact Profile question-items were re-administered to previously studied sleep laboratory patients. Several additional questions asked about age, gender, ethnicity, race, occupation, PAP adherence, any other treatment for obstructive sleep apnea, and current medication for excessive daytime sleepiness. The Epworth Sleepiness Scale assesses subjective sleep propensity by asking the subject to rate his or her chance of dozing in 8 different sedentary situations. 7 Likert scale ratings for each of the 8 items are scored on a scale of 0-3. Summed scores range from 0-24, and scores 10 suggest excessive daytime sleepiness. Adequate PAP adherence was defined as greater than 5.0 hours of self-reported PAP use per night on average. This approximates another commonly used threshold (> 4 h per night for 70% of nights 20 ), was anticipated based on our past research 12 to capture about two-thirds of the subjects as targeted in our power analyses, and in fact proved to do so with reasonable accuracy. Statistical Analysis All data were entered by an investigator into a computer database and re-entered for verification. Statistical evaluations were carried out using SPSS version 14.0 for Windows (SPSS Inc, Chicago, IL) or SAS version 9.1 (SAS Institute, NC). The main outcomes were improvements at follow-up in sleepiness, fatigue, tiredness, and lack of energy. Subjects who reported that these symptoms occurred often or almost always were considered symptomatic, and remaining subjects were considered not symptomatic. We used the nonparametric McNemar s test to assess changes in symptomatic status after PAP treatment, for those subjects who reported each symptom initially (Aim 1). We used a χ 2 test to compare the proportions of PAP-adherent vs. inadequately treated patients who became newly not symptomatic for sleepiness, tiredness, fatigue, and lack of energy (Aim 2). We conducted similar analyses, in an exploratory manner, for men and women separately. Samples sizes were planned as follows. For McNemar s test in Aim 1, 200 patients would provide 91% power to detect a pre- vs. post-treatment change in symptom frequency of 0.10 if the proportion of discordant pairs is 0.20 and a 2-sided significance level is 0.05. In Aim 2, for a χ 2 test with a 0.05 2-sided level of significance, 200 PAP-adherent subjects with 100 inadequately treated subjects and would provide 85% power to detect a difference between groups even if as few as 15% of adherent subjects improved while as many as 5% of inadequately treated subjects did so. We therefore aimed to study 200 PAPadherent subjects and 100 inadequately treated subjects. Subjects RESULTS A total of 2,444 patients who completed the baseline Sleepiness Impact Questionnaire were identified from the database, and questionnaires were sent to 1,539 who met the additional inclusion criteria. Of these, 363 (23.6%) responded, 313 participated, 48 declined to participate, and 2 returned the questionnaires but did not identity themselves (Figure 1). The mean age of the 1539 eligible subjects was 53.6 ± 13.0 years, and 833 (54.1%) were men. Similarly, among the 313 participants, the mean age was 54.7 ± 12.5 years (p = 0.1 in comparison to non-participating eligible subjects), and 178 (56.9%) were men (p = 0.88). All 313 participants provided unambiguous answers to question-items 1, 2, 3, and 4, and more than 90% did so for questions 5, 6, and 7 (Table 1). A total of 248 patients (79.2%) reported regular PAP use, but 24 of these also reported other combined treatments for OSA (Figure 1). Among 65 patients who were not on PAP, 55 had no current treatment. Among 224 patients treated with PAP only, 183 reported good adherence. Therefore, a total of 96 patients were classified as having inadequate treatment: 41 because they were nonadherent and 55 because they had no active treatment. Characteristics of the 183 PAP-adherent and 96 inadequately treated patients are shown in Table 2. Data from these 279 patients were used for subsequent analyses. Patients adherent to PAP, in comparison to inadequately treated patients, showed a high- Journal of Clinical Sleep Medicine, Vol.5, No. 3, 2009 223

W Chotinaiwattarakul, LM O Brien, L Fan et al Table 1 Question-Items Selected from the Sleepiness Impact Questionnaire for Use in this Follow-Up Study Item no. Question-items Response rate (%) among n = 313 1 Sleepiness is a problem for me. 100 2 Fatigue is a problem for me. 100 3 Tiredness is a problem for me. 100 4 Lack of Energy is a problem for me. 100 5 Which most affects your ability to accomplish what you want? 94 6 Which is the worst problem for you? 93 7 If you could be cured completely of only one of these problems, which would you choose? 94 For items 1-4, responses were provided on a 5-point Likert scale: (1) never, (2) seldom, (3) occasionally, (4) often, (5) almost always. For the last 3 items, one of 4 responses could be chosen: (1) sleepiness, (2) fatigue, (3) lack of energy, (4) tiredness. All 4 symptoms were self-defined, as no definition was provided. 1539 patients were mailed questionnaires and invited to participate 363 patients responded 313 subjects agreed to participate 248 subjects reported regular PAP use 65 subjects did not use PAP 183 subjects reported good PAP adherence 2,445 patients were identified from sleep center database 9 used oral appliances 1 had uvulopalatopharyngoplasty 1 had bimaxillary advancement 13 used modafinil 41 subjects reported < 5.0 h of PAP use per night on average (a) 55 subjects reported no active treatment (b) N = 96 PAP-non-adherent subjects (a + b) Figure 1 Identification of the 279 OSA patients (183 adherent to PAP and 96 inadequately treated) whose data formed the basis for the reported analyses. er mean apnea/hypopnea index at baseline but no significant difference in Epworth Sleepiness Scale scores. At follow-up, Epworth scores were lower in PAP-adherent patients than in inadequately treated patients (p = 0.04). Frequency of Each Complaint Before and After PAP 4 used oral appliances 4 had uvulopalatopharyngoplasty 1 had bimaxillary advancement 1 used modafinil At baseline, similar proportions of patients with good PAP adherence and inadequate treatment reported each complaint sleepiness, fatigue, tiredness, and lack of energy as their most important symptom. However, at follow-up, each symptom was significantly less common among PAP-adherent subjects than among inadequately treated subjects (Table 2). Repetition of these analyses using different thresholds to define inadequate CPAP adherence (< 4 h or 5.5 h per night) instead of 5 h per night did not change the above findings to an appreciable extent. The one possible exception was for lack of energy at follow-up, which no longer differed significantly between PAP-adherent and inadequately treated patients (p = 0.18) when poor adherence was defined as < 4 h per night. After PAP treatment, lack of energy retained its position as the most important symptom, relative to sleepiness, tiredness, and fatigue, for the 183 PAP-adherent patients we studied. The percentage of these patients who said that lack of energy most affected their ability to accomplish what they wanted showed no change (from 46% to 46%, p = 1.00). The percentage who said that lack of energy was their worst problem also showed little change (from 40% to 36%, p = 0.42), as did the percentage who said that lack of energy was the problem they most desired to be cured (from 41% to 45%, p = 0.40). Transitions from Symptomatic to Non-Symptomatic Status Among patients with good PAP adherence, we found at follow-up that the tendency for each complaint sleepiness, fatigue, tiredness, and lack of energy to have improved from symptomatic (occurring often or almost always) to nonsymptomatic easily reached significance (Table 3). Furthermore, the likelihood of such improvement among those who initially were symptomatic was generally higher among PAPadherent subjects than among those who were inadequately treated (Table 4). The one exception was for lack of energy. This finding that improvement in sleepiness, fatigue, and tiredness, but not lack of energy depended at least in part on PAP adherence was also confirmed in more complex general linear models in which the change in Likert-scale complaint rating was regressed on hours of reported PAP use per night, age, and gender (data not shown). Gender Among participants who were adherent to PAP, women in comparison to men showed only non-significant increases in frequencies of sleepiness, fatigue, or tiredness, both before and again after treatment (Table 5). However, women more frequently reported lack of energy, to a statistically significant extent, both before and after treatment. With adherent use of PAP, transitions from symptomatic to not symptomatic for each of the 4 complaints, within each gender separately, still proved more likely than the reverse transitions (McNemar tests, each p 0.05, except for fatigue in men, where p = 0.053). Journal of Clinical Sleep Medicine, Vol.5, No. 3, 2009 224

Table 2 Subject Characteristics Fatigue in OSA Variables PAP Adherent Inadequately p Value** Patients Treated Patients (n = 183) (n = 96) Age (years) 54.4 ± 11.7 54.3 ± 13.9 0.98 Number of men 105 (57.4%) 54 (56.3%) 0.96 Apnea/hypopnea index (events/h) at diagnosis 42.9 ± 37.1 29.5 ± 28.2 0.001 Epworth Sleepiness Scale score at baseline 10.2 ± 4.9 9.9 ± 5.3 0.69 Epworth Sleepiness Scale score at follow-up 8.2 ± 4.5 9.6 ± 5.9 0.04 Baseline Symptoms* Sleepiness 72 (39.3%) 35 (36.5%) 0.73 Fatigue 80 (43.7%) 47 (49.0%) 0.48 Tiredness 96 (52.5%) 52 (54.2%) 0.89 Lack of energy 100 (54.6%) 57 (59.4%) 0.53 Follow-Up Symptoms* Sleepiness 43 (23.5%) 39 (40.6%) 0.004 Fatigue 54 (29.5%) 46 (47.9%) 0.004 Tiredness 60 (32.8%) 46 (47.9%) 0.002 Lack of energy 67 (36.6%) 47 (49.0%) 0.046 *Number of subjects who reported each symptom to occur almost always or often. **Independent sample t-tests or χ 2 tests, as appropriate. Data shown as mean ± SD or n (%). Table 3 Resolution of Symptomatic Status in Subjects with Good PAP adherence Conditions (n = 183) Symptom Symptom Asymptomatic New emergence p Value Complaints resolved persisted at baseline and of symptom (McNemar test * ) follow-up Sleepiness 48 (26%) 24 (13%) 92 (50%) 19 (10%) 0.001 Fatigue 45 (25%) 35 (19%) 84 (46%) 19 (10%) 0.002 Tiredness 56 (31%) 40 (22%) 67 (37%) 20 (11%) < 0.001 Lack of Energy 47 (26%) 53 (29%) 69 (38%) 14 (8%) < 0.001 * Compares crossovers, i.e., patients whose symptom resolved to those who newly developed the symptom. Data shown as no. (row %). Discussion This prospective follow-up survey of nearly 300 adult OSA patients demonstrates for the first time, to our knowledge, that self-defined complaints of fatigue, tiredness, and lack of energy have the potential for robust improvement, just as sleepiness does, after adequate PAP treatment. Although this was not a randomized clinical trial, further evidence for a biological effect of PAP on the subjective complaints was provided by comparison of PAP-adherent subjects to a natural control group, namely those who reported little or no use of PAP. These comparisons showed that improvements at follow-up in fatigue, tiredness, and sleepiness, if not lack of energy, were substantially more common among PAP-adherent patients than among those who were inadequately treated. Improvements occurred in both men and women, despite observations in our previous work, 17 current data, and other studies that men sometimes endorse these symptoms to a lesser extent than women do. Our findings are compatible with previous reports that PAP adherence is associated with improvements in OSA symptoms, daytime sleepiness, cognitive impairment, blood pressure, and quality of life. 21-25 Our new results, focused on patient complaints, have important implications for clinical practice, where patient descriptions of fatigue, tiredness, and lack of energy may lead to investigations and differential diagnoses that do not address sleep disorders. Whether greater PAP adherence in this study actually caused greater improvements in fatigue, tiredness, and sleepiness remains uncertain. Conversely, greater responses to treatment could have encouraged greater PAP adherence. Patients perceptions of symptomatic benefit following PAP therapy, and their sense that this treatment has health value have been shown to be associated with better adherence. 26,27 However, if adherence improved symptoms or symptom response encouraged adherence, either mechanism reinforces our original hypotheses that fatigue and tiredness, in addition to sleepiness, are important symptoms of OSA. Why lack of energy differed from other symptoms in relation to PAP adherence is not clear. This symptom is often the most concerning to patients with OSA, both before 17 and in current data after treatment with PAP. Lack of energy could potentially reflect changes in depressed mood, known to be common in OSA. 28 Mood may improve after OSA treatment by either active intervention or placebo. 29 Possible interpretations are that OSA does not cause lack of energy and depressed mood, or that a causal effect exists but is not reversible (beyond placebo effect) by PAP. One strength of the current study, as well as a limitation, is that symptoms were not defined for patients, who were required to use their own definitions for sleepiness, fatigue, tiredness, and lack of energy. This study design feature makes results generalizable to clinical practice, when patients present emphasiz- Journal of Clinical Sleep Medicine, Vol.5, No. 3, 2009 225

W Chotinaiwattarakul, LM O Brien, L Fan et al Table 4 Reported Symptom Improvement (Change from Symptomatic to Not Symptomatic) Among Pap-Adherent and Inadequately Treated Subjects Complaints No. of patients Proportion of patients (%) with symptom improvement p Value with complaint PAP-adherent Inadequately treated (χ 2 test) at baseline Sleepiness 107 48/72 (66.7%) 11/35 (31.4%) 0.001 Fatigue 127 45/80 (56.3%) 16/47 (34.0%) 0.03 Tiredness 148 56/96 (58.3%) 19/52 (36.5%) 0.02 Lack of Energy 157 47/100 (47.0%) 21/57 (36.8%) 0.29 Table 5 Data for PAP-Adherent Men Vs. Women Variables Men Women p Value** (n = 105) (n = 78) Age (years) 53.3 ± 12.1 55.4 ± 12.4 0.25 Apnea/hypopnea index (events/h) at diagnosis 52.9 ± 39.6 29.4 ± 28.6 < 0.001 Epworth Sleepiness Scale score at baseline 10.4 ± 4.9 9.9 ± 5.0 0.45 Epworth Sleepiness Scale score at follow-up 8.6 ± 4.9 7.6 ± 4.0 0.12 Baseline Symptoms* Sleepiness 38 (36.2%) 34 (43.6%) 0.39 Fatigue 43 (41.0%) 37 (47.4%) 0.47 Tiredness 49 (46.7%) 47 (60.3%) 0.10 Lack of energy 49 (46.7%) 51 (65.4%) 0.02 Follow-Up Symptoms* Sleepiness 24 (22.9%) 19 (24.4%) 0.95 Fatigue 30 (28.6%) 24 (30.8%) 0.87 Tiredness 32 (30.5%) 28 (35.9%) 0.54 Lack of energy 30 (28.6%) 37 (47.4%) 0.01 *Number of subjects who reported each symptom to occur almost always or often. **Independent sample t-tests or χ 2 tests, as appropriate. Data shown as mean ± SD or n (%). ing any one of these symptoms. The limitation is that medical constructs for sleepiness, fatigue, tiredness, or lack of energy to the extent that they have been defined may differ from what we studied. Although fatigue, tiredness, and lack of energy by any definition remain scarcely explored in OSA patients, one previous preliminary report did describe use of the Fatigue Severity Scale 30 and the Epworth Sleepiness Scale to assess 164 OSA patients before and after treatment with PAP. 31 That study, like ours, found that subjective fatigue and sleepiness both improved after 1 to 20 months of PAP. Fatigue improved significantly even among patients without evidence of baseline sleepiness, and among those with only mild OSA. As we anticipated when we planned our study, about onethird of our patients proved on follow-up to be inadequately treated for OSA. Our sleep disorders center, accredited for more than 2 decades, attempts to implement routine follow-up appointments for all patients not under the care of other faculty comfortable with management of OSA. Our findings suggest that interventions as simple as periodic surveillance by mail could uncover significant numbers of patients who remain inadequately treated. Although the minimally sufficient nightly use of PAP remains uncertain, PAP adherence demonstrates a doseresponse relationship to several different clinical outcomes. 23-25 A limitation of the present study is that our Likert-scale measures of sleepiness, fatigue, tiredness, and lack of energy have not been formally validated. However, this study of how patients use these terms was not intended to examine medically defined constructs, and our question-items with identical structures for each term were ideal for valid comparisons. Use of instruments such as the Fatigue Severity Scale would not have allowed this, and in any case, no validated gold standards exist for tiredness and lack of energy. Duration of PAP use per night in this study was assessed by subjective measurement, which is known to underestimate objective adherence. 13,14 However, any discrepancies with objective data would most likely have created conservative errors, rather than augmenting robust differences we observed between PAP-adherent and inadequately treated subjects. Only a minority of eligible patients (20%) participated in this follow-up survey, and a more inclusive sample might have shown different results. However, changes within subjects or between groups should be less sensitive than frequency data to selection bias. In addition, data on age and gender, at least, of eligible nonparticipants and participants did not show significant differences. In conclusion, PAP treatment is associated with reduced fatigue, tiredness, and lack of energy, as both male and female patients perceive them, to an extent that appears no less robust than perceived improvements in sleepiness. These findings and the underlying concept that OSA may produce fatigue, tiredness, and lack of energy more often than sleepiness have important implications for both research and clinical settings. Restorative properties of normal sleep may well include key elements that extend beyond subjective sleepiness or alertness. Studies that seek to establish the prevalence of sleep apnea in part by asking about sleepiness 32 may produce inaccurate results if they do not ask also about related concepts such as fatigue, tiredness, and lack of energy. In clinical settings, clinicians must be aware that chief complaints of fatigue, tiredness, or lack of energy rather Journal of Clinical Sleep Medicine, Vol.5, No. 3, 2009 226

Fatigue in OSA than sleepiness do not rule out the possibility of OSA as a treatable underlying cause. Acknowledgments The authors are grateful to Siriraj Hospital, Thailand for support of Dr. Chotinaiwattarakul s work on this project; to the subjects who volunteered to participate; to Kenneth Guire and Kathleen Welch for statistical assistance in planning this study; and to Jocelynn Owusu for her help in the execution of this study. Work performed at: University of Michigan, Ann Arbor, MI Support: NIH (HL080941); Siriraj Hospital, Bangkok, Thailand; University of Michigan Department of Neurology; and University of Michigan Department of Oral and Maxillofacial Surgery Disclosure Statement This was not an industry supported study. Dr. Chervin is on the advisory board of Pavad Medical and has been paid honoraria by Respironics. Respironics helped to fund an endowed chair at the University of Michigan held by Dr. Chervin at the time of this study. 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