INTRODUCTION

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Patients with the sleep apnea/hypopnea syndrome (SAHS) suffer from daytime dysfunction, in particular excessive daytime sleepiness (1, 2), cognitive decrements (3, 4), and increased psychopathology (5, 6). Consequences of daytime dysfunction in SAHS include an increased risk of vehicle accidents (7), impaired work performance (8), and disharmony in personal relationships (9). Continuous positive airway pressure (CPAP) therapy is the current treatment of choice for SAHS, and improves daytime function (10, 11). However, several recent studies have shown no clear relationship between disease severity as assessed by the apnea/hypopnea frequency and response to CPAP (10, 12). Daytime deficits similar to those found in SAHS can be produced in normal subjects by inducing recurrent brief arousals from sleep (13, 14). We thus hypothesized that such brief microarousals from sleep produce the daytime dysfunction in SAHS patients. Previous studies seeking correlations between baseline function and arousal frequency (1, 5, 15) have mainly failed to show close relationships, but are unavoidably affected by interindividual differences in premorbid function. We have thus sought to avoid interindividual differences by using each patient as his or her own control to investigate whether the magnitude of improvement of daytime function with CPAP therapy is related to the baseline microarousal frequency. The second aim of this study was to determine which therapeutic benefits obtained by using CPAP are correlated with objective CPAP use.

	METHODS

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Patients

We performed a prospective study on consecutive patients with SAHS who had > 15 apneas plus hypopneas/hour slept (apnea + hypopnea index [AHI]) on polysomnography, in addition to either excessive daytime sleepiness (Epworth score  8) or two other major symptoms of SAHS (2). This study was not performed as a placebo-controlled study as we wished to examine the magnitude of changes found in individual patients in real clinical practice. The limitations of this approach are detailed in the DISCUSSION section. Patients with coexisting sleep disorders, chronic obstructive pulmonary disease, asthma, neurological disorders, or those who lived further than 50 miles from the sleep center were excluded. Sixty-seven consecutive patients agreed to participate in the study. Five patients failed to return for repeat daytime testing and so were excluded from the analysis, as improvements in daytime function could not be determined in these patients. Drop out reasons were patient death (n = 1, from carcinoma diagnosed after recruitment), spouse death (n = 1), work commitments (n = 2), and quitting CPAP after 1 mo into follow-up period (n = 1).

Protocol

Diagnostic polysomnography. At baseline patients underwent a single night of full diagnostic polysomnography (PSG) according to our standard techniques (16, 17) with monitoring of the electroencephalogram (EEG), electro-oculogram (EOG), and electromyogram (EMG), oronasal airflow, thoracic and abdominal respiratory effort, oximetry, and body position. All signals were recorded onto a computerized system (Compumedics S, Victoria, Australia) using a 16-channel polygraph configuration.

CPAP titration. Before commencing CPAP therapy, all patients returned to the sleep center overnight for a CPAP titration study to achieve the optimal fixed pressure to minimize respiratory events and microarousals from sleep for that individual. In the first 47 patients, specialist nursing staff conducted a manual CPAP titration. Patients were wired up for full polysomnography and then CPAP was manually titrated to the correct therapeutic pressure to abolish all visible nocturnal SAHS events. In the latter 15 patients, the optimal CPAP pressure was determined by an automated titration device (AutoSet; ResMed, Abingdon, UK) and the CPAP unit set at the 90th centile of the overnight pressure.

Treatment follow-up. In the morning after the CPAP titration, all patients were issued with CPAP machines for home use. All CPAP machines ("Smart Start" or "Elite" machines, ResMed UK, Abingdon, UK) contained pressure sensors to measure the time spent at the prescribed pressure (the effective pressure). Mean effective CPAP use was calculated over the 6-mo follow-up period, to give a mean CPAP usage for the given time period. All patients were followed up with a phone call from a CPAP nurse at 2 and 21 d, and seen in the outpatient sleep clinic at 1, 3, and 6 mo after commencing CPAP. At clinic visits, CPAP compliance data from Elite machines were downloaded onto a personal computer. CPAP machine and mask problems or other adverse effects were discussed and rectified wherever possible by the nursing and medical sleep staff.

Outcome measures. All patients underwent a battery of daytime tests at baseline and at the end of the 6 mo of CPAP therapy to measure a wide range of functions affected by SAHS (5, 10). The 6-mo time point was chosen to provide a measure of outcomes after medium to long-term use of CPAP. Daytime function was not assessed at the other time points to minimize the effects of learning with repeated testing (10) and to limit the number of days the patients had to give up for testing. Daytime sleepiness was measured objectively using the maintenance of wakefulness test (MWT) (18) and subjectively by the Epworth (19) and Stanford (20) sleepiness scales. SAHS symptoms were rated using an in-house symptom questionnaire (11), mood by the Hospital Anxiety and Depression Scale (21), and quality of life by the Short Form (SF-36) (22) and the Nottingham Health Profile Part 2 (23) scales. A battery of cognitive function tests was administered in the afternoon of the daytime session, consisting of block design, digit symbol, paced auditory serial addition task, trail making A and B, simple unprepared reaction time, and Steer Clear (10, 14). These performance tests respectively measured the cognitive processes of visuospatial ability, coding speed, attention, visuomotor speed, mental flexibility, reaction time, and vigilance. Patients were instructed to withdraw from caffeine on the evening prior to the daytime testing, and throughout the test day decaffeinated drinks were provided.

In addition to the daytime function outcomes, the effective CPAP use was downloaded at the clinic visits at 1, 3, and 6 mo.

Data Analyses

Sleep stages were manually scored using standard Rechtschaffen and Kales (24) scoring guidelines. An apnea was defined as a complete cessation of airflow for a minimum of 10 s, and a hypopnea as a 50% or greater reduction in thoracoabdominal movement for a minimum of 10 s (16). The total number of respiratory events was divided by total sleep time (TST) to give an AHI. Microarousals were scored using the Cheshire definition (5, 25) of a return to theta or alpha on the EEG for at least 1.5 s, with a concurrent rise in EMG tone, however brief. Oxygen desaturations of  2%, 3%, and 4% from the running baseline were calculated from the overnight study using an automatic desaturation detection algorithm (Compumedics S, Victoria, Australia) and divided by TST to give desaturation indices. For the manual CPAP titrations, only the time spent at the final CPAP pressure was scored, for all of the above measures.

Statistical Analyses

Differences between outcome variables measured at baseline and on CPAP were both normally and non-normally distributed and so for consistency, the nonparametric Wilcoxon rank sum test for paired differences was used throughout. All changes in daytime function were presented as  outcome values [(Baseline outcome measure)  (on-CPAP outcome measure)]. Relationships between baseline nocturnal variables and  daytime function measures, and between CPAP use and  daytime function measures were evaluated by Spearman rank correlations. Correlations were partial, controlling for age, as age affects daytime function (26). All tests were two-tailed and a probability value of less than 0.05 was accepted as statistically significant. All data were analyzed using SPSS for Windows (27).

	RESULTS

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Patients

In the 62 patients (60 male, 2 female) who completed the 6 mo CPAP follow-up period by returning for the repeat daytime tests (Table 1) the mean ± SD effective objective CPAP use averaged over the 6 mo was 4.8 ± 2.4 h per night (range = 0 to 8.8 h/night). There was no significant variation in CPAP usage with time (mean use 0 to 1 mo 5.1 ± 2.2 h; 1 to 3 mo 4.8 ± 2.5 h; 3 to 6 mo 4.7 ± 2.5 h; p > 0.60). The microarousal frequency, apnea and hypopnea frequency, hypoxemia indices, and the percentage of wakefulness all significantly decreased (all p < 0.00001; Table 2), and the minimum oxygen saturation, percentage slow wave sleep, and rapid eye movement (REM) sleep all significantly increased after CPAP therapy (all p < 0.0006; Table 2). Significant improvements in daytime function measures were found after 6 mo of CPAP therapy. Both the subjective and objective measures of daytime sleepiness significantly improved with CPAP therapy (all p < 0.003; Table 3), as did measures of quality of life, mood, and self-reported SAHS symptoms (all p < 0.03; Table 3). Cognitive performance tests measuring coding speed, reaction time, and attention all improved with CPAP therapy (all p < 0.05; Table 3).

Baseline SAHS Predictors of Changes in Daytime Function

Sleep fragmentation. Baseline microarousal frequency was only significantly correlated with one outcome measure,  reaction time gaps (when reaction time response > 1 s;  = 0.30, p = 0.02). Baseline microarousal frequency was not significantly correlated with changes in sleepiness (Table 4; Figure 1A) or any other measure of daytime function.

View larger version (14K): [in this window] [in a new window]   View larger version (13K): [in this window] [in a new window]   Figure 1.   Relationships between changes in MWT with CPAP (MWT at baseline  MWT on CPAP, min) and (A) arousal frequency, (B) apnea + hypopnea frequency, (C ) minimum oxygen saturation.

Breathing pattern. The baseline AHI only significantly correlated with one outcome measure, trail making A completion time ( = 0.26, p = 0.045; Table 4; Figure 1B).

Oxygenation. Measures of baseline hypoxemia were significantly correlated with changes in objective sleepiness, as measured by the MWT (Figure 1C). Patients with more severe hypoxemia demonstrated the greatest improvements in MWT (represented by a negative change in MWT in Figure 1C). Baseline hypoxemia, however, did not significantly correlate with changes in Epworth score (Table 4). Measures of hypoxemia also significantly correlated with changes in quality of life and SAHS symptom ratings (Table 4). Changes in reaction time, attention, and visuomotor speed also significantly related to baseline hypoxemia (Table 4).

Relationships between CPAP Use and Changes in Daytime Function

Significant relationships were found between CPAP use and changes in self-ratings of daytime function (Table 5; Figures 2A and 2B), subjective sleepiness, SAHS symptoms, and quality of life (  0.25, p < 0.05). Other daytime function measures of objective sleepiness and changes in cognitive performance did not significantly relate to CPAP use (all   0.24, p > 0.07).

View larger version (11K): [in this window] [in a new window]   Figure 2.   Significant relationships between mean compliance and (A) changes in Epworth score with CPAP (Epworth at baseline  Epworth on CPAP), (B) changes in SAHS symptom score with CPAP (symptom score at baseline  symptom score on CPAP).

	DISCUSSION

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This study shows that in patients with SAHS, the magnitude of improvement in daytime function after CPAP therapy is not closely related to pretreatment microarousal frequency or apnea/hypopnea frequency. There were statistically significant relationships between measures of baseline overnight oxygenation and improvements in daytime function, but in no case did this explain more than 22% of the observed variance in response.

The current study showed significant improvements in both the nocturnal SAHS features, and daytime function measures of objective and subjective sleepiness, quality of life, mood, and cognitive performance after 6 mo of CPAP therapy. However, this was not a controlled study, thus as with previous uncontrolled studies (28) such improvements cannot firmly be attributed to the direct therapeutic effect of CPAP, as neither learning nor placebo effects could be excluded as contributors toward the improvements. Engleman and coworkers (10, 11) controlled for placebo and learning effects and found treatment-related benefits for many of the areas of daytime function, which improved in the current study.

This study did not confirm the hypothesis that brief arousals from sleep predict improvement in daytime function with CPAP. In fact microarousals only predicted an improvement in one daytime measure, reaction time, and AHI only significantly correlated with trail making A completion time. These findings are in agreement with previous studies on sleep apneics, which found a lack of strong relationships between AHI and improvements in daytime sleepiness with CPAP (10, 12). Conversely, Bennett and coworkers (31) found baseline measures of sleep fragmentation, and the apnea and hypopnea frequency, to significantly predict improvements in daytime sleepiness. In that study, measures of body movement and computerized EEG together explained 51% of the response in objective sleepiness to CPAP therapy. It should be noted that the population studied by Bennett and coworkers (31) was on average much milder than in the current study, with the inclusion of many subjects with normal AHIs (median AHI 16, 90th central range 2 to 67, in comparison to a median AHI of 54, 90th central range 20 to 126, in the current study). This population difference may explain the stronger relationships found by Bennett (31). Another possible explanation of the difference would be if the inclusion of more normal subjects in Bennett's study (31) provided a greater spread of variables, thus improving the statistical likelihood of significant correlations. However, we do not think this is a likely explanation as the distribution of both baseline variables [e.g., AHI 90th central range: current study 106/h; Bennett's study (31) 65/h] and outcome variables [e.g., median Epworth score: current study 13, range 4 to 24, Bennett's study (31) 14, range 5 to 21; median MWT: current study 33, range 3 to 40 min; Bennett's study (31) 30, range 5 to 40 min]. We believe further studies are required to clarify the difference between the two investigations.

In the current study measures of overnight oxygenation significantly predicted a diverse range of improvements in daytime function. The strongest correlations were seen between either minimum overnight oxygen levels or the frequency of 4% desaturations, and improvements in daytime function. Thus our results suggest that patients with severe repetitive oxygen desaturations recorded at diagnostic polysomnography are more likely to have greater improvements in daytime sleepiness, quality of life, reaction time, and self-reported SAHS symptoms with CPAP therapy. The current study used a diverse range of daytime function tests to estimate impairments that may influence many daily functions, such as driving ability, work ability, social interactions, and self-esteem. Despite this, baseline predictors of improvements in daytime function with CPAP were few.

Mean CPAP use significantly related to improvements in subjective sleepiness, SAHS symptoms, vitality, and general well-being, but not with objective sleepiness, mood, or measures of cognitive performance. Although in this study these relationships could incorporate placebo as well as real treatment effects, we have previously found in placebo-controlled trials (10, 11) that there are relationships between these subjective outcome measures and objective CPAP use. These results could suggest that patients who notice changes in their own symptoms of sleepiness and quality of life are more likely to consistently use their CPAP machines, as a direct personal benefit is obtained, or alternatively that increased use drives greater improvement. There is some evidence that the latter is true, at least in part, from a controlled study showing that greater nursing support of patients on CPAP results in both greater CPAP use and improved outcomes (32), but the former is almost certainly factor too.

We failed to prove our original hypothesis that the magnitude of improvement with CPAP was related to the frequency of arousals resulting from the SAHS at baseline. There are several possible explanations for this. First, the accuracy of scoring arousals has been questioned (33). Variability in scoring would result in weakening of any actual relationships. However, our own data have shown good reproducibility of arousal scoring in our laboratory (25) and thus we do not believe this is a major factor. Nevertheless, visual arousal scoring is not as robust and reproducible as the readily computerized measures, such as oxygen saturation or movement, that may contribute to the finding of significant correlations between improvements and oxygenation measures in this and Bennett's study (31), and the computerized measures of sleep fragmentation in Bennett's study (31). Second, night-to-night variation in sleep variables may result in the data from a single night's study being a relatively poor predictor of response. Third, many of the tests of daytime function are influenced by volition and motivation, which may add further noise to the prediction of improvement. Indeed further investigation of the effects of psychological profile on the improvements with treatment is needed. Fourth, the magnitude of improvement in function may relate to premorbid function level, which cannot be determined. Fifth, the study deliberately did not differentiate placebo effects from real treatment effects and thus the signals analyzed as changes will have included both. Sixth, differing CPAP usage may affect the relationship between baseline measures and changes with treatment, and there is not a good correlation between baseline measures and CPAP use (34). Lastly, the neurophysiologically determined arousals may not be what is influencing daytime function. Arousals that are not visible on the EEG produce daytime function deficits (35), and other more sensitive indices of arousal require further investigation (31). Alternatively, it may be indirect consequences of the arousalssuch as sleep stabilitynot the arousals themselves that result in the impairments of daytime function, but this was not evident in an earlier study (15).

This study suggests that improvements in daytime function with CPAP therapy are largely independent of baseline polysomnographic severity.