Chapter 14

Outcomes of OSA and indications for different therapies

vy*,#, J-L. Pe pin*,#, R. Tamisier*,# and S. Launois-Rollinat*,# P. Le

Summary
Outcomes of obstructive sleep apnoea (OSA) have been extensively studied since the late 1990s. There have been a large number of controlled studies evaluating the effects of continuous positive airway pressure (CPAP) on sleepiness and daytime functioning, blood pressure, cardiovascular outcomes and metabolic parameters. These better-identified outcomes may help in determining to what extent CPAP is able to fully reverse the chronic consequences of OSA. Although there is clearly a significant impact of CPAP on excessive daytime sleepiness (EDS) and blood pressure, EDS may persist in a significant proportion of patients and blood pressure may fall only modestly under CPAP, i.e. 13 mmHg. Other treatments, such as pharmacological treatment, weight loss, positional treatment, oral appliances and upper airway surgery, should be considered, although the degree of evidence, apart from that for oral appliances and weight loss, is rather limited. From these data, the aim was to define strategies according to OSA severity. Finally, we suggest that comparison and combination of treatment modalities, e.g. CPAP for OSA alleviation and specific cardiovascular or metabolic treatments, may be critical as regards the chronic consequences of sleep apnoea. Keywords: Continuous positive airway pressure, obstructive sleep apnoea, oral appliances, pharmacological treatment, surgery, weight loss
*Sleep Disorders Centre, Rehabilitation and Physiology Dept, Grenoble University Hospital, Grenoble, and # Hypoxia PathoPhysiology Laboratory, Joseph Fourier University, National Institute for Health and Medical Research Unit 1042, Grenoble, France. vy, Exploration Correspondence: P. Le Fonctionnelle Cardio-Respiratoire, le Re e ducation et Physiologie, Po Centre Hospitalier Universitaire de Grenoble, BP 217 X, 38043 Grenoble, France, Email PLevy@chu-grenoble.fr

Eur Respir Mon 2010. 50, 225243. Printed in UK all rights reserved. Copyright ERS 2010. European Respiratory Monograph; ISSN: 1025-448x. DOI: 10.1183/1025448x.10025009

ince the late 1980s, obstructive sleep apnoea (OSA) has been identified as a common clinical condition. Epidemiological studies have confirmed a high prevalence of the disease in middleaged adults [1]. OSA is associated with significant neuropsychological impairment [26] and

225

VY ET AL. P. LE

marked cardiovascular and metabolic morbid conditions [711], leading to a significant increase in mortality [12, 13]. Since 1981, nasal continuous positive airway pressure (CPAP) has been the first-line therapy [14]. However, there are limitations to CPAP use owing to side-effects and intolerability in some patients [1517]. Thus, although there is no doubt that CPAP is virtually the only therapeutic possibility in severe OSA, alternatives are highly desirable in moderate OSA. Mild OSA, as well as upper airway (UA) resistance syndrome (UARS), an abnormal increase in UA resistance during sleep that results in daytime sleepiness [18], although still discussed as a specific entity, is also part of the spectrum of the disease where CPAP is not the only desirable treatment [19]. The treatment of OSA and other abnormal increases in UA resistance during sleep should achieve three goals: 1) alleviation of symptoms and improvement in quality of life [20]; 2) reduction in morbidity; and 3) a decrease in mortality. Consequently, the choice of a particular treatment for a given patient should induce the lowest possible level of side-effects while addressing these outcomes. Thus, for assessing different modes of treatment, it is obvious that the morbidity associated with different clinical situations should be clearly established. This is needed to define specific algorithms of management in each clinical situation.

Definitions
OSA has been redefined since the late 1990s [21]. In order to qualify as OSA, there should be excessive daytime sleepiness (EDS) that is not better explained by other factors or two or more minor symptoms (choking or gasping during sleep, recurrent awakenings from sleep, unrefreshing sleep, daytime fatigue and impaired concentration) plus overnight monitoring results demonstrating obstructed breathing during sleep of o5 events?h-1. These events may include any combination of obstructive apnoeas/hypopnoeas or respiratory-effort-related arousals (RERAs). A RERA has been defined as a sequence of breaths characterised by increasing respiratory effort leading to an arousal from sleep, but which does not meet the criteria for an apnoea or hypopnoea. There is a pattern of progressively more negative oesophageal pressure, terminated by a sudden change in pressure to a less negative level and an arousal lasting o10 s [21]. The use of a frequency of 5 events?h-1 as a minimal threshold value was based on epidemiological data suggesting that minimal health effects, such as hypertension, sleepiness and motor vehicle accidents, may be observed at an apnoea/hypopnoea index (AHI) threshold of 5 events?h-1 [22 25]. Additionally, data from intervention studies suggest that there is treatment-associated improvement in daytime function in mild-to-moderate sleep apnoea patients [2628]. Defining the severity of obstructive sleep apnoea/hypopnoea (OSAH) syndrome (OSAHS) is essential when establishing a strategy of treatment. It is usually suggested that the severity level should be based on two components: severity of daytime sleepiness, the rating of severity being based on the most severe component; and AHI based on overnight monitoring. Sleepiness should be defined as mild, moderate or severe. The severity of sleep-related obstructive breathing events has been rated as follows: mild: 515 events?h-1; moderate: 1530 events?h-1; and severe: .30 events?h-1. There are currently no adequate prospective studies that have validated severity criteria for sleepiness. The data justifying a severity index based on event frequency are derived from various studies evidencing an excess of morbidity at a given AHI [29]. It should be noted that sleepdisordered breathing (SDB) scoring definitions may significantly alter the outcomes [30], e.g. as regards hypopnoea or oxygen desaturation quantification. Thus the comparison between studies remains difficult since the AHI may vary significantly according to the scoring rules. It is obvious from the literature that the severity of oxygen desaturation is a major predictive factor for OSA morbidity, especially as regards cardiovascular consequences [9, 11, 31]. The most

226

OUTCOMES OF OSA AND TREATMENT

commonly used indices are the number of drops in arterial oxygen saturation (Sa,O2) (oxygen desaturation index), mean nocturnal Sa,O2, minimal nocturnal Sa,O2 and cumulative time spent below a given Sa,O2 e.g. 90% or 85%. PUNJABI et al. [30] have shown, in the Sleep Heart Health Study, that hypopnoeas associated with an oxyhaemoglobin desaturation of o4% are associated with prevalent cardiovascular disease independent of confounding covariates, which was not the case for hypopnoeas associated with less oxygen desaturation or arousals. This would suggest using oxygen desaturation as a criterion for establishing OSA severity. To our knowledge, however, there are limited data regarding other indices of oxygen desaturation, which makes it difficult to propose specific thresholds.

Severe OSA
Since 1981, CPAP has progressively become the reference treatment in OSAH [14]. Only very few alternatives should be discussed. UA surgery can be considered even in severe OSA, but in selected populations. Bariatric surgery is becoming more popular and also marks the progression of obesity worldwide. There is some improvement in OSA following bariatric surgery. There remain very limited data for consideration of stimulation of the hypoglossal nerve as an option. Lastly, oral appliances (OAs) are usually considered less effective than CPAP in severe OSA.

CPAP: compliance, duration of treatment and relevant outcome measures

As mentioned above, CPAP remains the first-line therapy in OSA. However, compliance is a key point. Several studies, coming mainly from the USA [3235], have demonstrated low compliance and irregular use of CPAP. However, many other studies have found a high rate of compliance (ranging 6580%) [3638] and acceptance (with ,15% of patients refusing this treatment after a single nights use in the laboratory) [36]. The differences observed in compliance may merely reflect the respective efficacy of technical and medical follow-up in the different countries. However, there are significant side-effects affecting a majority of patients using CPAP [15, 35]. The reason for high compliance despite side-effects (daily use of 56 h) [15] is obviously the clinical benefit obtained; only 1% of patients had no subjective benefit induced by their therapy [15]. Another major issue is the optimal duration of CPAP use. There are few data with which to establish a clear threshold. However, it seems that EDS and daytime functioning, including cognitive functioning improvements, are dependent upon CPAP duration [39]. In this particular study, thresholds above which further improvements were less likely relative to the nightly duration of CPAP were identified for the Epworth Sleepiness Scale (ESS) score (4 h), multiple sleep latency test (MSLT; 6 h) and Functional Outcomes of Sleep Questionnaire (7.5 h). A linear doseresponse relationship between increased use and achieving normal levels was shown for objective and subjective daytime sleepiness (fig. 1) [39]. Overall, this tends to demonstrate that the usual thresholds used in various countries, i.e. 3 or 4 h, are insufficient for suppressing OSA consequences. This also appears to be the case as regards blood pressure. It has been suggested from meta-analysis that the reduction in blood pressure obtained with CPAP is more or less related to increasing use [40]. Moreover, a recent study has demonstrated that CPAP treatment for 1 yr is associated with a small decrease in blood pressure in nonsleepy OSA patients. However, this effect was evidenced only in patients who used CPAP for .5.6 h?night-1 (table 1) [41]. Finally, an unanswered question is whether the chronic consequences of OSA can be managed by CPAP alone. This is an issue as regards patients with persistent EDS [42] despite adequate CPAP therapy. It should also be considered regarding hypertension, since antihypertensive drugs are far more effective than CPAP at controlling blood pressure [43], although there is a beneficial effect when combining both treatments (fig. 2) [43]. In addition, CPAP has been found to be effective at controlling blood pressure in specific populations, such as resistant hypertension [44]. Interestingly, in this latter study, a greater reduction in blood pressure was obtained when CPAP was used for .5.8 h?night-1. Another important question is whether CPAP is able to

227

VY ET AL. P. LE

70 Subjects with normal values % 60 50 40 30 20 10 0

2

>2_ <4

4_ <5 5_ <6 Nightly CPAP use h

6_ <7

improve OSA-associated metabolic changes [10]. This remains a conflicting issue. Several randomised controlled trials (RCTs) have shown no significant improvement in metabolic anomalies, including insulin sensitivity in obese OSA subjects, whether or not diabetic [45, 46], whereas others found the opposite [47]. EDS may play a role [48], but this is also much discussed [10].

UA surgery
Figure 1. Relationship between duration of continuous positive

Snoring and OSA are associated with recurrent sleep-induced narrowing or collapse of the pharyngeal airway at the level of the oropharynx and/or hypopharynx. The patency of this floppy segment is critically dependent upon UA anatomy and function. Anatomical factors that predispose to UA narrowing during sleep are craniofacial skeletal abnormalities, increased tongue size and/or redundant pharyngeal soft tissues. The more frequent modifications to cranial structure are nasal abnormalities, such as a deviated nasal septum, retroposition of the mandible associated with posterior displacement of the tongue and inferior position of the hyoid bone. The tongue and pharyngeal soft tissues (soft palate, tonsils, adenoids, etc.) are usually larger than in normal subjects, and these abnormalities are worsened by fat deposition and oedema induced by vibration injury and/or repeated UA collapse. Finally, UA size is also dependent upon lung volume, and, therefore, smaller lung volume may also contribute to reduce UA size in obese subjects. However, anatomical UA abnormalities explain the major part of variance in AHI only in young and lean subjects [49]. In obese and older patients, other factors, such as changes in UA collapsibility, ventilatory instability, fragmented sleep and abnormalities in UA muscle function, are predominant. Since anatomical UA abnormalities seem to play an important pathophysiological role in young and lean patients, these subjects probably represent the best candidates for surgical therapy. Uvulopalatopharyngoplasty (UPPP) is aimed at enlarging the oropharyngeal airway and reducing the collapsibility of this particular segment of the UA. Its rate of success is ,40% [50, 51]. Nonresponders usually exhibit a higher baseline AHI. Retropalatal collapse or narrowing is a factor of poor prognosis. Thus, when an imaging or endoscopic technique has undoubtedly shown
Table 1. Relationship between continuous positive airway pressure (CPAP) use and achieving a significant
reduction in blood pressure in nonsleepy obstructive sleep apnoea CPAP use h Systolic blood pressure Coeff f3.6 3.615.65 .5.65 0.071.692 -1.431.461 -3.731.372 95% CI -3.984.12 -4.932.06 -7.02 -0.45 p-value 0.9688 0.3273 0.0069 Diastolic blood pressure Coeff -1.381.060 -1.180.912 -3.510.857 95% CI -3.921.15 -3.371.00 -5.57 -1.46 p-value 0.1926 0.1964 0.0001

airway pressure (CPAP) use and achievement of normal levels of sleepiness and daily functioning (&: Epworth Sleepiness Scale; : Functional Outcomes of Sleep Questionnaire; m: multiple sleep latency test). Reproduced from [39] with permission from the publisher.

OUTCOMES OF OSA AND TREATMENT

Data are presented as mean SEM unless otherwise indicated. The coefficient (Coeff) is the result of mixedeffects linear models with data from all of the follow-up visits to evaluate the effect of the CPAP intervention. CI: confidence interval. Reproduced from [41] with permission from the publisher.

228

a) 160 150 SBP mmHg b) DBP mmHg 140 130 120 110 100 110 100 90 80 70 60 09:00

11:00

13:00

15:00

17:00

19:00

Figure 2. Additive effects of continuous positive airway pressure (..........) and an antihypertensive drug
(valsartan; ------) in obstructive sleep apnoea patients (: combination therapy). a) Systolic blood pressure (SBP), and b) diastolic blood pressure (DBP). Data are presented as meanSD. Reproduced from [43] with permission from the publisher.

awake retrolingual narrowing or, even more, retrolingual collapse during apnoeas, UPPP should be rejected. In summary, in OSA syndrome (OSAS) patients, surgery has not evidenced a significant impact upon short-term outcomes and long-term progression remains uncertain [52]. Thus UPPP indications, if any, should be restricted to patients with moderate disease and presupposed retropalatal narrowing. It should also be remembered that, by increasing mouth leaks, UPPP may compromise CPAP therapy and reduce the maximal level of pressure that can be tolerated [53]. Maxillofacial surgery is presumably the only surgical procedure that has achieved high success rates. Overall, maxillomandibular osteotomy is highly effective, with 7595% success [5457]. In a recent meta-analysis, this was confirmed, i.e. the mean success was 86% [56]. For the vast majority of the 627 OSA patients, however, the mean follow-up was ,6 months, and ranging 37.7 months [56]. Only 56 patients were included in long-term follow-up studies [55, 56]. At a mean follow-up of 43.729.5 months, 89% of patients were considered a surgical success, with a significant reduction in the AHI (66.226.0 versus 7.96.4 events?h-1; p,0.001) and no difference between the short- and long-term results [56]. Predictors of surgical success included younger age, lower pre-operative AHI and greater degree of maxillary advancement, and also lower pre-operative body mass index (BMI) (individual level data in multivariate analysis). The degree of mandibular advancement was not predictive of surgical success with univariate or multivariate analysis [56]. In addition, very recently, an elegant study compared surgery and CPAP in a randomised controlled fashion in 50 moderately obese severe OSA patients [58]. The authors did not evidence any difference in AHI or sleepiness improvement at 1 yr of follow-up [58]. It should also be remembered that this surgery is safe in expert hands, but not without side-effects, i.e. facial

229

VY ET AL. P. LE

21:00 23:00 Time h

01:00

03:00

05:00

07:00

09:00

paraesthesia that usually resolves but may persist in 15% of cases at 1 yr [56]. Overall, it represents a demanding procedure, requiring well-informed and well-motivated subjects.

Weight loss
Approximately 6070% of OSA patients are obese, i.e. exhibit a BMI of .28 kg?m-2 or a body weight in excess of the ideal weight by .20% [59]. The relationship between obesity and OSA remains unclear. However, it is one of the most commonly recognised risk factors [59]. Obesity appears to be largely determined by genetic factors that influence metabolic rate, fat storage and eating behaviour, and is associated with autonomic, endocrinological and hypothalamic functional abnormalities. This is particularly true as regards regional fat distribution, which may be of particular relevance to the pathogenesis of OSA, in which upper body and visceral fat may be greater risk factors than whole-body fat [10, 60]. Weight loss or gain has significant impacts on the severity of SDB [59, 61]. There is also a strong influence of weight reduction on snoring frequency and intensity. Both may result from the decrease of pharyngeal collapsibility obtained with weight loss. Weight loss is associated with not only a reduction in AHI and collapsibility but also almost complete elimination of apnoea when the critical pressure (Pcrit), reflecting collapsibility, is reduced below -4 cmH2O [62]. Can weight loss be achieved in obese OSA? Weight control is difficult to obtain and also to maintain. Recently, the effect of weight loss induced by a very-low-energy diet was evaluated in a randomised fashion [63]. In the intervention group, mean body weight was 20 kg lower than that of the control group, whereas its mean AHI was lower by 23 events?h-1. In the intervention group, five (17%) out of 30 were disease-free after the energy-restricted diet (AHI of ,5 events?h-1), with 15 (50%) out of 30 having mild disease (AHI of 514.9 events?h-1), whereas the AHI of all but one of the patients in the control group remained at o15 events?h-1. In a subgroup analysis of the intervention group, baseline AHI significantly modified the effectiveness of treatment, with a greater improvement in AHI in patients with severe OSA (AHI of .30 events?h-1) at baseline compared with those with moderate sleep apnoea (AHI of 1530 events?h-1) (AHI -38 versus -12 events?h-1; p,0.001), despite similar weight loss (19.2 versus 18.2 kg; p50.55). Thus it seems that severe OSA patients could be the best candidates for such caloric restriction [63]. There have been several controlled trials investigating bariatric surgery. There have been positive results in not only sleep apnoea syndrome but also its metabolic consequences and comorbid conditions [64]. However, despite the usual massive weight loss obtained with bariatric surgery, cure of sleep apnoea is not systematically obtained. From a recent meta-analysis, bariatric surgery reduced mean BMI by 17.9 kg?m-2 (95% confidence interval (CI) 16.519.3 kg?m-2), from 55.3 kg?m-2 (95% CI 53.557.1 kg?m-2) to 37.7 kg?m-2 (95% CI 36.638.9 kg?m-2) [65]. The baseline AHI of 55 events?h-1 (95% CI 49.060.3 events?h-1) was reduced by 38 events?h-1 (95% CI 31.944.4 events?h-1) to a final value of 16 events?h-1 (95% CI 12.619.0 events?h-1) (fig. 3). The authors noted that a significant proportion of OSA patients would have to continue CPAP despite this major improvement. In addition, it should be mentioned that OSA is one of the three conditions, along with deep vein thrombosis and impaired functional status, being associated with a risk of major adverse event during the peri and post-operative period of bariatric surgery [78]. This strongly suggests the need for diagnosis and treatment of OSA with CPAP for at least some time before and after such procedures.

OUTCOMES OF OSA AND TREATMENT

Can any other treatment be envisaged in severe OSA?

OAs are usually recommended rather in moderate sleep apnoea (see below). Pharmacological treatment in OSA, although still very limited or undergoing development (see below), may also apply to moderate OSA (see below). Electrical stimulation of muscles and nerves has been attempted in SDB. Several types of approach have been tested: surface electrodes, muscular

230

electrodes (on the surface of mus- a) CHARUZI [66] cles and intramuscularly), and SUGERMAN [67] nerve electrodes placed directly PILLAR [68] on the 12th nerve in order to 119.32 SCHEULLER [69] prevent UA collapse during sleep GUARDIANO [70] [79]. When electrodes were placed RASHEID [71] on the skin with the goal of VALENCIA-FLORES [72] stimulating the geniohyoid and DIXON [73] genioglossus muscles, the results KALRA [74] were disappointing. Although posiHAINES [75] tive results were initially reported FRITSCHER [76] with this procedure in OSAH, LETTIERI [77] further studies indicated that UA Overall dilators needed a high stimulus intensity, which consistently led to CHARUZI [66] sleep fragmentation, even when b) SUGERMAN [67] applied chronically [80]. Direct PILLAR [68] stimulation of the 12th nerve was then considered. With 12th nerve SCHEULLER [69] stimulation, coordination with the GUARDIANO [70] thoracic muscles is mandatory, and RASHEID [71] this problem has been handled by VALENCIA-FLORES [72] measurement of intrathoracic presDIXON [73] sure changes. From the preliminary KALRA [74] reports, it appears that several HAINES [75] technical points remain unresolved, FRITSCHER [76] and the rate of response is variable LETTIERI [77] when using unilateral stimulation Overall [79, 81]. Only a small group of 0 5 15 30 60 100 eight patients has been evaluated, in .h-1 AHI events the late 1990s in a multicentric study [82]. Although SDB correcFigure 3. Effects of bariatric surgery on apnoea/hypopnoea index tion was not optimal, stimulation (AHI) at a) baseline; and b) follow-up. Results of a meta-analysis. of the hypoglossal nerve resulted in Data are presented as AHI (& (size reflects weighting)) and 95% a significant decrease in Pcrit from confidence interval (horizontal bars). The centre of the diamond indicates the combined mean effect of the studies and its -1.321.97 to -5.303.30 cmH2O extremities the 95% confidence interval (?????: line of no effect). (p,0.05) without altering upstream Reproduced from [65] with permission from the publisher. resistance. There are currently ongoing studies evaluating the feasibility, safety and efficacy of this technique.

Study

Study

Moderate OSA and UARS

There are several epidemiological, pathophysiological and clinical questions that arise when defining, respectively, moderate sleep apnoea and UARS. UARS is a different clinical situation from simple snoring, where UA resistance may be slightly or moderately increased without sufficient respiratory efforts to produce micro-arousals and/or generate daytime somnolence. Whether this is a distinct entity from OSA remains controversial, and it is so far not acknowledged by international classifications [21, 83]. Defining moderate sleep apnoea is complex as the magnitude of overnight oxygen desaturation and the duration of the disease are difficult to assess, which affects the validity of intra-individual comparisons. Another factor is night-to-night variability, which is more pronounced in mild apnoeics, especially in the elderly. It also raises the question as to whether symptoms should be

231

VY ET AL. P. LE

moderate, including sleepiness, i.e. ESS score of 912. Defining outcomes in moderate sleep apnoea syndrome should be considered in two dimensions: 1) EDS and daytime functioning; and 2) cardiovascular outcomes. There is compelling evidence that mild-to-moderate sleep apnoea syndromes are associated with less EDS and daytime impairment. This is true despite the absence of a linear relationship between AHI and symptoms. Sleep fragmentation, AHI, respiratory efforts or oxygen desaturation indices usually each account for ,1015% of the variance of either subjective or objective EDS [24, 84 89]. However, all of these parameters are more or less linked to OSA severity in a similar manner, which makes it likely that there will be far fewer daytime symptoms in mild-to-moderate OSA. This is also true for cognitive deficits [2, 4, 90, 91]. Conversely, the outcome measures may differ from those in severe OSA. Specifically, attentional deficits may exist and significantly alter daytime functioning without perceived subjective sleepiness [6, 92]. This may be a relevant outcome when compromising OSA patients driving ability (fig. 4) [5]. Overall, cardiovascular consequences are also related to OSA severity, including AHI and oxygen desaturation severity indices. This is true in both general and clinical populations regarding hypertension [22, 9395], coronary heart disease [96], nocturnal arrhythmias [97] and stroke [98, 99]. This is also found as regards vascular subclinical markers, such as carotid intimamedia thickness and pulse wave velocity [100102]. However, cardiovascular changes are not restricted to severe OSA [9, 103, 104]. Thus, from a clinical point of view, in moderate OSA, elimination of apnoeas, hypopnoeas and RERAs should be obtained, together with suppression of snoring and EDS. However, additional outcomes could be suggested, such as attentional deficits and early cardiovascular changes. Regarding this latter point, it would seem appropriate to use subclinical cardiovascular markers since they have been demonstrated as predictive of future cardiovascular morbidity, i.e. myocardial infarction and stroke [105].

OUTCOMES OF OSA AND TREATMENT

CPAP treatment
CPAP in mild-to-moderate apnoeics raises two concerns. 1) Is CPAP compliance acceptable? 2) How does it compare to alternative treatments in terms of efficacy as regards symptoms and outcome measures as defined above? Long-term acceptance and mean rate of use were studied by 10 KRIEGER et al. [106] in non-apnoeic snorers and mild apnoeics (respira8 tory disturbance index (RDI) of 6 ,15 events?h-1). The acceptance was .60% at 3 yrs, with a mean 4 daily use of CPAP of -1 . However, 5.6 1.4 h ? day 2 although it resulted in significant 0 improvements compared to pla0 0.5 1.0 1.5 2.0 2.5 cebo, the compliance in mild Genuine RT s apnoeics was significantly lower in the study of ENGLEMAN and JOFFE Figure 4. Correlation between reaction time (RT) during driving [26], e.g. ,3 h. In further studies, simulation and during genuine driving. $: obstructive sleep apnoea compliance remained either close to syndrome (OSAS) patients (p50.05; r50.43); m: control subjects 5 h?night-1 [27, 107109] or less (p50.79; r50.06). Correlation for the whole group: p50.003; .......... r50.46. : regression line for OSAS patients; : [110, 111]. As a result, a recent regression line for control subjects. Reproduced from [5] with meta-analysis found a mean compermission from the publisher. pliance of 3.6 h [28], which is
12

232

Simulator RT s

clearly less than in more severe OSA subjects [38]. Is CPAP effective against symptoms in mild-to-moderate OSA? Meta-analyses indicated that CPAP significantly reduced subjective daytime sleepiness (ESS) by 1.2 points (95% CI 0.51.9 points; p50.001), improved objective daytime wakefulness (maintenance of wakefulness test (MWT)) by 2.1 min (95% CI 0.53.7 min; p50.011) and did not affect objective daytime sleepiness [28]. The two significant effects were small (effect size of ,0.30). The authors concluded that CPAP elicits small improvements in subjective sleepiness and objective wakefulness in people with mild-to-moderate OSAS, but that the effects on sleepiness are of limited clinical significance [28]. How does it compare to alternative treatments? Several comparisons have been made since 2000 in RCTs [107, 108, 111]. The evidence was recently reviewed [112], although not specifically in mildto-moderate OSA. However, the analysis was stratified by symptom and disease severity at baseline. CPAP significantly reduced ESS score compared to placebo (mean difference -2.7; 95% CI -3.45 -1.96). The benefit was greatest in patients whose symptoms were severe at baseline; severely symptomatic population: mean difference -5.0 (95% CI -6.5 -3.5); moderate: mean difference -2.3 (95% CI -3.0 -1.6); and mild: mean difference -1.1 (95% CI -1.8 -0.3). CPAP significantly improved the MWT score compared to control (mean difference 3.3 min; 95% CI 1.35.3 min) but not the MSLT score. There was no significant difference between CPAP and dental devices in the ESS, MWT or MSLT score, in a population with moderate symptoms. The authors concluded that CPAP is an effective treatment for OSAHS in moderate-to-severe symptomatic patients and that there may be benefits for mild symptoms. Dental devices may be a treatment option for mild-to-moderate symptoms.

Pharmacological treatment
A huge number of drugs have been tested in OSA with very little success, and the feasibility of an effective drug for preventing UA collapse is questioned [113, 114]. Drug research into OSA has been hampered by the lack of useful experimental systems and animal models for drug screening. In addition, the phenotypic characterisation of OSA seems to be incomplete, thus limiting the possibility of using stringent criteria for patient selection in drug studies. Finally, the criteria for defining the severity of OSA and disease impact seem to be insufficient for adequate definition of efficacy end-points in clinical trials [114]. When reviewing the data, most studies have been small and many trials have had methodological limitations [115]. Six drugs had some impact on OSA severity and two altered daytime symptoms. One study reported that AHI was lower following treatment with intranasal fluticasone compared with placebo (23.3 versus 30.3 events?h-1) in 24 participants with sleep apnoea and rhinitis [116]. Daytime alertness also improved. Physostigmine reduced the AHI to 41 events?h-1 compared to 54 events?h-1 on placebo [117], and, in a similar study, 15 mg mirtazapine produced a 50% improvement in AHI [118]. However, this was not confirmed by a more recent and larger RCT [119]. Paroxetine was also shown to reduce apnoeas by 35% exclusively during nonrapid eye movement sleep, and, amazingly, with no effects on hypopnoeas. In this study, there was no improvement in daytime symptoms [120]. Protriptyline is probably the drug that has been most commonly used for treating OSA. Several studies report protriptyline to be effective in 5070% of cases of OSA [121123], but its usefulness is limited by anticholinergic side-effects. To date, pharmacological treatment has demonstrated little effect on apnoeas and hypopnoeas. However, brainstem neurons represent a potentially important pharmacological target [113, 114, 124]. The ultimate goal of pharmacological approaches to snoring and OSA is the prevention of the sleep-related reduction in pharyngeal muscle activity and the subsequent alleviation of sleeprelated airway narrowing and closure. Although it is difficult to selectively target the proper neuronal structures, both increase in UA muscle activity and induced changes in sleep structure might be of interest. An appropriate drug for stimulation of the UA during sleep is still lacking, although several potential candidates have been tested in early phase-II studies since the late 1990s. As regards sleep structure, the arousal threshold could possibly be manipulated in order to
VY ET AL. P. LE

233

promote ventilatory stability. However, until now, this has not proven to be feasible and effective in reducing SDB. Further developments are expected in the field of combined treatments targeting OSA consequences or comorbid conditions, e.g. CPAP or OA plus pharmacotherapy, which applies to both severe and mild-to-moderate SDB. As already mentioned, it may be necessary to use antihypertensive drugs in combination with CPAP to control blood pressure [43]. In addition, residual EDS is relatively prevalent in OSA, despite adequate CPAP treatment [42], which may require use of wakefulness stimulants [125], after excluding any specific cause and improving CPAP duration, if feasible [39]. Finally, exercise and antioxidant and anti-inflammatory drugs are currently being evaluated in comparison or in addition to CPAP.

Weight loss
Bariatric surgery is not an option in mild-to-moderate OSA. Massive obesity is usually associated with severe OSA. OSA, when moderate, is not a major target for treatment with bariatric surgery. Thus, in mild-to-moderate OSA, weight loss has rather been performed using caloric restriction programmes and also, more recently, anorexigens or other drugs used in weight control. There are few RCTs comparing weight control to other modalities. In a relatively small group of moderate OSA (AHI 21 events?h-1), LAM et al. [126] compared CPAP, an OA and conservative measures, including sleep hygiene and a weight loss programme. The patients were randomised in parallel groups for 10 weeks. CPAP produced the best improvement in terms of physiological, symptomatic and quality-of-life measures, whereas the OA was slightly less effective. Weight loss, if achieved, resulted in an improvement in sleep parameters, but weight control alone was not uniformly effective.
OUTCOMES OF OSA AND TREATMENT

Recently, sibutramine was evaluated in terms of both weight changes and OSA control [127, 128], with positive results on both sides, as well as metabolic improvement [129]. However, sibutramine has been removed from the European market because data from the Sibutramine Cardiovascular Outcomes (SCOUT) trial [130] showed an increased risk of serious nonfatal cardiovascular events, such as stroke or heart attack, with sibutramine compared with placebo [131].

Sleep posture
It has long been recognised that snoring patients do so most loudly in the supine position. Similarly, it has been well proven that a large proportion of unselected patients with a diagnosis of OSAS demonstrate a different rate of apnoeic events in the lateral compared to the supine position [132]. Positional sleep apnoea syndrome has been defined as an AHI during the time in supine sleep that is two or more times that during sleep in the lateral position [133]. In a group of almost 600 patients, OKSENBERG et al. [134] found, in positional sleep apnoea, a slightly reduced BMI and age, better sleep efficiency, increased slow-wave sleep, less wake after sleep onset and microarousals, and reduced AHI and oxygen desaturations, as well as longer sleep latencies on the MSLT, compared to patients with nonpositional OSA. All of these characteristics correspond to moderate sleep apnoea syndrome. On logistic regression analysis, both RDI (upper limit 40 events?h-1) and BMI correlated negatively with the occurrence of positional sleep apnoea. In terms of prevalence, this was confirmed, since 49.5% of positional sleep apnoea was found in mild OSA (AHI of 515 events?h-1), 19.4% in moderate OSA (AHI of 1530 events?h-1) and only 6% in severe OSA (AHI of .30 events?h-1) [135]. Is positional treatment effective and feasible? It has been tested since the 1980s [136], compared with other treatment modalities [137, 138], further evaluated at 6 months [139] and, lastly, included in clinical practice guidelines [140, 141]. In patients trained to sleep on their side, with or without use of a sound alarm to prevent the supine position, ,50% are able to avoid the supine position on a long-term basis. There is, however, a lack of standardisation and innovation designed to provide patients with an adequate system for long-term positional treatment in OSA.

234

The positional therapy tennis ball technique, in which a tennis ball is placed into a pocket of a wide cloth band or belt attached around the abdomen such that the ball lies in the centre of the back, is the first technique to have been used. When the patients roll on to their back, they feel the pressure of the ball and instinctively roll back on to their side again. Several other methods have been used [133]. Some may use a T-shirt with a long vertical pocket holding three or four tennis balls along the back. This is, perhaps, less likely to slip out of place during sleep. Others have found that a large device consisting of a polyvinyl chloride pipe wrapped in foam (about the size of an American football) is more effective than the tennis ball [133]. A comparison between all of these devices regarding effectiveness, acceptance and compliance would be beneficial. When using the tennis ball technique, compliance appears to be ,40%, with 24% still able to avoid the supine sleep position following treatment cessation [139]. Regarding effectiveness, there has been a randomised crossover study comparing CPAP and positional treatment for 2 weeks in moderate positional OSA (AHI 178 events?h-1) [138]. There was a significant difference regarding AHI (mean difference of 6 events?h-1) and Sa,O2 (mean difference of 4% for nocturnal minimal Sa,O2) in favour of CPAP, but no difference regarding symptoms, sleep structure, objective vigilance, cognitive tests and quality of life [138]. In clinical guidelines, favouring factors for positional sleep apnoea are mentioned (i.e. low AHI, low-to-moderate BMI and younger subjects), and only two studies are considered sufficiently evidence-based [137, 138]. It is also emphasised that normalisation of the AHI should be checked owing to incomplete or variable responses to treatment [140].

Oral appliances
The term OAs defines devices inserted into the mouth in order to modify the position of the mandible, the tongue and other structures in the UA for the purpose of relieving snoring or sleep apnoea [142]. The goal of therapy with OAs is to modify the position of UA structures in order to enlarge the airway [143], to lower resistance and UA collapsibility [144]. The effects on UA muscle function may also be of importance due to the changes in the direction of muscle fibres. There is accumulated evidence that OAs are effective in mild OSA [145]. An OA improves subjective sleepiness and SDB compared with controls. CPAP appears to be more effective in improving SDB than OAs. However, the difference in symptomatic response between these two treatments is nonsignificant (table 2; fig. 5). Thus OAs may be recommended to patients with mild symptomatic OSA, and those who are unwilling or unable to tolerate CPAP therapy [145]. There are several possible primary contraindications to OAs, i.e. insufficient teeth to support the device, periodontal problems inducing tooth mobility and active temporomandibular joint (TMJ) disorder [147]. Primary contraindications were found in 34% of 100 consecutive patients, mainly
Table 2. Changes in sleepiness, vigilance, cognitive function and quality of life in obstructive sleep apnoea with continuous positive airway pressure (CPAP) and an oral appliance
Parameter# ESS score (Q) OSleR test Sleep latency s (q) Errors n (Q) Trail Making Test A (Q) Trail Making Test B (Q) Baseline 10.64.5 2094674 12.517.9 36.410.9 79.326.2 CPAP 8.23.9*** 2300391* 8.719.8* 30.18.9*** 68.522.2*** MAD 7.74.0*** 2312322* 4.37.5** 32.59.6* 73.433.0

Data are presented as mean SD. For each variable, p-values are adjusted for multiple comparisons using Bonferroni correction, i.e. p-values are multiplied by 3. MAD: mandibular advancement device; ESS: Epworth Sleepiness Scale; OSleR: Oxford Sleep Resistance. #: the arrows in parenthesis indicate the direction of improvement for each parameter. *: p,0.05; **: p,0.01; ***: p,0.001 versus baseline. Reproduced from [146] with permission from the publisher.

235

VY ET AL. P. LE

owing to dental problems. Moreover, another subgroup 35 (16%) of patients required close 30 supervision and follow-up to avoid 25 impairment of pre-existing TMJ * disorder and dental problems ** 20 [147]. Side-effects, tolerance and 15 * ** compliance have been studied ** 10 [148151]. Side-effects are com* 5 mon: mucosal dryness (86% of patients), tooth discomfort (59%), 0 hypersalivation (55%) [148] and Physical Social Pain Emotional Energy Sleep# also an increase in TMJ symptoms mobility isolation reaction# [150]. However, this does not seem Figure 5. Changes in quality of life in obstructive sleep apnoea to affect OA use [148, 150]. using the Nottingham Health Profile with continuous positive airway Compliance is declarative, which pressure (&) and an oral appliance (h). &: baseline. Data are makes it more difficult to compare presented as meanSEM. Lower scores indicate better functioning. with CPAP. However, during long*: p,0.05; **: p,0.01 versus baseline. #: significant treatment-byperiod effect. Reproduced from [146] with permission from the term use, .60% of patients declare publisher. using their device almost every night [150, 151]. In a recent RCT versus CPAP, OAs appeared to be an effective therapy in moderately sleepy and overweight OSA patients. Although less effective than CPAP, a successfully titrated OA was very effective at reducing AHI and was associated with a higher reported compliance, with .70% of patients preferring this treatment [146].
40
OUTCOMES OF OSA AND TREATMENT

Titration has been suggested for adjusting OAs [146, 152155]. Whether it improves OA efficacy and long-term compliance remains to be studied. However, 1-night titration of OAs seems to have a low negative predictive value for treatment success [146]. Comparison between devices is also an issue since there are currently a large number of different types of OA, including custom-made ones. Such comparisons exist but are difficult to convert into clinical practice recommendations [156, 157], apart from for thermoplastic devices, which can be neither recommended as a therapeutic option nor used as a screening tool to find good candidates for mandibular advancement therapy [157]. OAs have been evaluated with respect to cardiovascular outcomes. OAs significantly reduce blood pressure compared to control condition [158]. There is also an effect on oxidative stress and endothelial function (fig. 6) [159, 160]. In summary, OAs are indicated for use in patients with mild-to-moderate OSA, possibly in addition to behavioural measures, such as weight loss or positional treatment. Patients with moderate-to-severe OSA should have an initial trial of nasal CPAP as greater effectiveness has been shown with this intervention than with OAs. OAs are indicated for patients with moderate-tosevere OSA who are intolerant of or refuse treatment with nasal CPAP and are not candidates for UA surgery.

Treatment strategies
In cases of severe OSA, there is no doubt that CPAP remains the first-line treatment. Only maxillofacial surgery should be considered as a potential alternative, in a limited number of young, non-obese and well-motivated subjects. We would also suggest that specific maxillofacial anomalies should be present. Whether hypoglossal nerve stimulation may play a role remains doubtful at the present time. In the case of CPAP intolerance, if UA surgery is not possible, OAs should be evaluated as they can possibly be effective, even in some severe OSA.

236

Score

Moderate OSA remains difficult to define. We suspect that the RDI does not adequately reflect the severity of the disease. A combination of a low RDI, moderate daytime sleepiness or tiredness and the absence of obvious related cardiovascular morbidity may define moderate OSA. Thus the following strategy may be suggested. 1) A CPAP trial may be recommended, at least to establish whether or not CPAP, in normalising sleep and respiration, leads to the relief of the symptoms attributed to SDB. It should be remembered, however, that a significant placebo effect has been demonstrated when initiating CPAP treatment [161]. 2) OAs may, however, be indicated primarily in mild-to-moderate OSA, if feasible, particularly from a dental point of view. Either initially or in cases of primary or secondary failure of CPAP (patients refusing CPAP or becoming noncompliant), OAs should also be tried. 3) Surgical indications are limited regarding OSA.

a) 10 8 Peak G va,c MBC 6 4 2 0 b) 12.5 10.0 Peak G va,c MBC 7.5 5.0 2.5 0 Inclusion MAD Treatment CPAP

* *

Conclusions

Sleep apnoea syndrome outcomes have been extensively studied since the late 1990s as well-controlled studies have been published since 1999. Sleepiness, attentional deficits, blood pressure, and metabolic changes have been assessed in RCTs. Other ongoing studies are currently being performed in the USA, Spain [41, 162] and Australia and China [163]. This will provide additional information to the longitudinal cohort studies [7] and short-term intervention studies [161, 164]. Although there is growing evidence that CPAP is effective regarding sleepiness, daytime functioning and blood pressure, it is also obvious that most chronic consequences of OSA may not be fully reversed by CPAP alone. Residual sleepiness may persist despite CPAP treatment [39, 42], although longer CPAP use may be required. Blood pressure may not be fully controlled with CPAP [43]. Conversely, symptoms, i.e. sleepiness, do not necessarily need to be present in order to obtain a significant change in blood pressure with CPAP [41]. CPAP-induced metabolic changes are discussed much more, at least in obese subjects [10]. Combined therapy, associating CPAP and drugs targeting oxidative stress or inflammation, should be further validated. OAs have been extensively studied and used in clinical practice since the late 1990s. The effectiveness against symptoms in mild-to-moderate OSA seems comparable to that of CPAP [145, 146]. OA effects on cardiovascular and metabolic outcomes remain to be further studied. However, in mild OSA, OAs have become the first-line treatment, when feasible. Other treatments remain to be developed, e.g. drugs targeting UA muscle activity and hypoglossal nerve stimulation. In the context of

Figure 6. Changes with continuous positive airway pressure (CPAP) and an oral appliance (mandibular advancement device (MAD)) in peak cutaneous vascular conductance (Gva,c) following a) acetylcholine; and b) sodium nitroprusside iontophoresis. Boxes represent median and interquartile range; vertical bars represent 10th90th percentile; and points represent outliers. Changes with sodium nitroprusside were nonsignificant. MBC: multiple of baseline conductance (at inclusion). *: p,0.05 versus inclusion. Adapted from [159] with permission from the publisher.

237

VY ET AL. P. LE

epidemic obesity, weight loss, using either a very-low-energy diet or bariatric surgery, should be considered in obese subjects [63, 65].

Statement of Interest
pin is a member of the scientific council of Auxillia Medical (4,000J in 2010), on an J-L. Pe advisory board for Resmed (7,500J in 2010) and a consultant for Bioprojet (2,000J in 2010). veloppement to the 2010 7th Congress of the Mediterranean He was invited by Pneumologie De Union of Thoracic Diseases and by Resmed Foundation to the NIV experts meeting (2010 American Thoracic Society Congress), and was an invited speaker at the 2010 European vy has a consultancy from Resmed (12,000J/year) and is on an Respiratory Society congress. P. Le advisory board for Sanofi (7,000J/year). He was invited by Astra Zeneca to the 2010 Annual Congress of the American Thoracic Society and by Resmed to the 2010 World Congress of Cardiology, and was an invited speaker at the 2010 European Sleep Research Society and European Respiratory Society congresses.

References
1. 2. 3. 4. 5. Young T, Palta M, Dempsey J, et al. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993; 328: 12301235. Naegele B, Thouvard V, Pepin JL, et al. Deficits of cognitive executive functions in patients with sleep apnea syndrome. Sleep 1995; 18: 4352. Engleman H, Joffe D. Neuropsychological function in obstructive sleep apnoea. Sleep Med Rev 1999; 3: 5978. Naegele B, Launois SH, Mazza S, et al. Which memory processes are affected in patients with obstructive sleep apnea? An evaluation of 3 types of memory. Sleep 2006; 29: 533544. Mazza S, Pepin J-L, Naegele B, et al. Driving ability in sleep apnoea patients before and after CPAP treatment: evaluation on a road safety platform. Eur Respir J 2006; 28: 10201028. Mazza S, Pepin J-L, Naegele B, et al. Most obstructive sleep apnoea patients exhibit vigilance and attention deficits on an extended battery of tests. Eur Respir J 2005; 25: 7580. Marin JM, Carrizo SJ, Vicente E, et al. Long-term cardiovascular outcomes in men with obstructive sleep apnoeahypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005; 365: 10461053. Somers VK, White DP, Amin R, et al. Sleep apnea and cardiovascular disease: an American Heart Association/ American College Of Cardiology Foundation Scientific Statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council On Cardiovascular Nursing. Circulation 2008; 118: 10801111. Levy P, Pepin J-L, Arnaud C, et al. Obstructive sleep apnea and atherosclerosis. Prog Cardiovasc Dis 2009; 51: 400410. Levy P, Bonsignore MR, Eckel J. Sleep, sleep-disordered breathing and metabolic consequences. Eur Respir J 2009; 34: 243260. McNicholas WT, Bonsignore MR. Sleep apnoea as an independent risk factor for cardiovascular disease: current evidence, basic mechanisms and research priorities. Eur Respir J 2007; 29: 156178. Young T, Finn L, Peppard PE, et al. Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort. Sleep 2008; 31: 10711078. Punjabi NM, Caffo BS, Goodwin JL, et al. Sleep-disordered breathing and mortality: a prospective cohort study. PLoS Med 2009; 6: e1000132. Sullivan CE, Issa FG, Berthon-Jones M, et al. Reversal of obstructive sleep apnoea by continuous positive airway pressure applied through the nares. Lancet 1981; 1: 862865. Pepin J-L, Leger P, Veale D, et al. Side effects of nasal continuous positive airway pressure in sleep apnea syndrome. Study of 193 patients in two French sleep centers. Chest 1995; 107: 375381. Giles TL, Lasserson TJ, Smith BJ, et al. Continuous positive airways pressure for obstructive sleep apnoea in adults. Cochrane Database Syst Rev 2006; Issue, 3: CD001106. McDaid C, Griffin S, Weatherly H, et al. Continuous positive airway pressure devices for the treatment of obstructive sleep apnoeahypopnoea syndrome: a systematic review and economic analysis. Health Technol Assess 2009;13:iiiiv, xixiv, 1119: 143274. Guilleminault C, Stoohs R, Clerk A, et al. A cause of excessive daytime sleepiness. The upper airway resistance syndrome. Chest 1993; 104: 781787. Levy P, Pepin J-L, Mayer P, et al. Management of simple snoring, upper airway resistance syndrome, and moderate sleep apnea syndrome. Sleep 1996; 19: S101S110.

OUTCOMES OF OSA AND TREATMENT

6. 7.

8.

9. 10. 11. 12. 13. 14. 15. 16. 17.

18. 19.

238

20. Veale D, Poussin G, Benes F, et al. Identification of quality of life concerns of patients with obstructive sleep apnoea at the time of initiation of continuous positive airway pressure: a discourse analysis. Qual Life Res 2002; 11: 389399. 21. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force. Sleep 1999; 22: 667689. 22. Peppard PE, Young T, Palta M, et al. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000; 342: 13781384. 23. Kim HC, Young T, Matthews CG, et al. Sleep-disordered breathing and neuropsychological deficits. A population-based study. Am J Respir Crit Care Med 1997; 156: 18131819. 24. Gottlieb DJ, Whitney CW, Bonekat WH, et al. Relation of sleepiness to respiratory disturbance index: the Sleep Heart Health Study. Am J Respir Crit Care Med 1999; 159: 502507. 25. Kapur VK, Baldwin CM, Resnick HE, et al. Sleepiness in patients with moderate to severe sleep-disordered breathing. Sleep 2005; 28: 472477. 26. Engleman H, Kingshott R, Wraith P, et al. Randomized placebo-controlled crossover trial of continuous positive airway pressure for mild sleep apnea/hypopnea syndrome. Am J Respir Crit Care Med 1999; 159: 461467. 27. Monasterio C, Vidal S, Duran J, et al. Effectiveness of continuous positive airway pressure in mild sleep apnea hypopnea syndrome. Am J Respir Crit Care Med 2001; 164: 939943. 28. Marshall NS, Barnes M, Travier N, et al. Continuous positive airway pressure reduces daytime sleepiness in mild to moderate obstructive sleep apnoea: a meta-analysis. Thorax 2006; 61: 430434. 29. Punjabi NM. The epidemiology of adult obstructive sleep apnea. Proc Am Thorac Soc 2008; 5: 136143. 30. Punjabi NM, Newman AB, Young TB, et al. Sleep-disordered breathing and cardiovascular disease: an outcomebased definition of hypopneas. Am J Respir Crit Care Med 2008; 177: 11501155. 31. Levy P, Pepin J-L, Arnaud C, et al. Intermittent hypoxia and sleep-disordered breathing: current concepts and perspectives. Eur Respir J 2008; 32: 10821095. 32. Kribbs NB, Pack AI, Kline LR, et al. Objective measurement of patterns of nasal CPAP use by patients with obstructive sleep apnea. Am Rev Respir Dis 1993; 147: 887895. 33. Reeves-Hoche MK, Meck R, Zwillich CW. Nasal CPAP: an objective evaluation of patient compliance. Am J Respir Crit Care Med 1994; 149: 149154. 34. Engleman HM, Martin SE, Deary IJ, et al. Effect of continuous positive airway pressure treatment on daytime function in sleep apnoea/hypopnoea syndrome. Lancet 1994; 343: 572575. 35. Gay P, Weaver T, Loube D, et al. Evaluation of positive airway pressure treatment for sleep related breathing disorders in adults. Sleep 2006; 29: 381401. 36. Krieger J. Long-term compliance with nasal continuous positive airway pressure (CPAP) in obstructive sleep apnea patients and nonapneic snorers. Sleep 1992; 15: S42S46. 37. Fleury B, Rakotonanahary D, Hausser-Hauw C, et al. Objective patient compliance in long-term use of nCPAP. Eur Respir J 1996; 9: 23562359. 38. Pepin J-L, Krieger J, Rodenstein D, et al. Effective compliance during the first 3 months of continuous positive airway pressure. A European prospective study of 121 patients. Am J Respir Crit Care Med 1999; 160: 11241129. 39. Weaver TE, Maislin G, Dinges DF, et al. Relationship between hours of CPAP use and achieving normal levels of sleepiness and daily functioning. Sleep 2007; 30: 711719. 40. Haentjens P, Van Meerhaeghe A, Moscariello A, et al. The impact of continuous positive airway pressure on blood pressure in patients with obstructive sleep apnea syndrome: evidence from a meta-analysis of placebocontrolled randomized trials. Arch Intern Med 2007; 167: 757764. 41. Barbe F, Duran-Cantolla J, Capote F, et al. Long-term effect of continuous positive airway pressure in hypertensive patients with sleep apnea. Am J Respir Crit Care Med 2010; 181: 718726. 42. Pepin J-L, Viot-Blanc V, Escourrou P, et al. Prevalence of residual excessive sleepiness in CPAP-treated sleep apnoea patients: the French multicentre study. Eur Respir J 2009; 33: 10621067. 43. Pepin J-L, Tamisier R, Barone-Rochette G, et al. Comparison of continuous positive airway pressure and valsartan in hypertensive sleep apnea patients. Am J Respir Crit Care Med 2010; 182: 954960. 44. Lozano L, Tovar JL, Sampol G, et al. Continuous positive airway pressure treatment in sleep apnea patients with resistant hypertension: a randomized, controlled trial. J Hypertens 2010; 28: 21612168. 45. Coughlin SR, Mawdsley L, Mugarza JA, et al. Cardiovascular and metabolic effects of CPAP in obese males with OSA. Eur Respir J 2007; 29: 720727. 46. West SD, Nicoll DJ, Wallace TM, et al. The effect of CPAP on insulin resistance and HbA1c in men with obstructive sleep apnoea and type 2 diabetes. Thorax 2007; 62: 969974. 47. Lam JC, Lam B, Yao TJ, et al. A randomised controlled trial of nasal continuous positive airway pressure on insulin sensitivity in obstructive sleep apnoea. Eur Respir J 2010; 35: 138145. 48. Barcelo A, Barbe F, de la Pena M, et al. Insulin resistance and daytime sleepiness in patients with sleep apnoea. Thorax 2008; 63: 946950. 49. Mayer P, Pepin J-L, Bettega G, et al. Relationship between body mass index, age and upper airway measurements in snorers and sleep apnoea patients. Eur Respir J 1996; 9: 18011809.

239

VY ET AL. P. LE

50. Pepin J-L, Veale D, Mayer P, et al. Critical analysis of the results of surgery in the treatment of snoring, upper airway resistance syndrome (UARS), and obstructive sleep apnea (OSA). Sleep 1996; 19: S90S100. 51. Sher AE, Schechtman KB, Piccirillo JF. The efficacy of surgical modifications of the upper airway in adults with obstructive sleep apnea syndrome. Sleep 1996; 19: 156177. 52. Sundaram S, Bridgman SA, Lim J, et al. Surgery for obstructive sleep apnoea. Cochrane Database Syst Rev 2005; Issue, 4: CD001004. 53. Mortimore IL, Bradley PA, Murray JA, et al. Uvulopalatopharyngoplasty may compromise nasal CPAP therapy in sleep apnea syndrome. Am J Respir Crit Care Med 1996; 154: 17591762. 54. Riley RW, Powell NB, Guilleminault C. Obstructive sleep apnea syndrome: a review of 306 consecutively treated surgical patients. Otolaryngol Head Neck Surg 1993; 108: 117125. 55. Conradt R, Hochban W, Brandenburg U, et al. Long-term follow-up after surgical treatment of obstructive sleep apnoea by maxillomandibular advancement. Eur Respir J 1997; 10: 123128. 56. Holty JE, Guilleminault C. Maxillomandibular advancement for the treatment of obstructive sleep apnea: a systematic review and meta-analysis. Sleep Med Rev 2010; 14: 287297. 57. Bettega G, Pepin J-L, Veale D, et al. Obstructive sleep apnea syndrome. Fifty-one consecutive patients treated by maxillofacial surgery. Am J Respir Crit Care Med 2000; 162: 641649. 58. Vicini C, Dallan I, Campanini A, et al. Surgery versus ventilation in adult severe obstructive sleep apnea syndrome. Am J Otolaryngol 2010; 31: 1420. 59. Young T, Peppard PE, Taheri S. Excess weight and sleep-disordered breathing. J Appl Physiol 2005; 99: 15921599. 60. Fantuzzi G, Mazzone T. Adipose tissue and atherosclerosis: exploring the connection. Arterioscler Thromb Vasc Biol 2007; 27: 9961003. 61. Newman AB, Foster G, Givelber R, et al. Progression and regression of sleep-disordered breathing with changes in weight. The Sleep Heart Health Study. Arch Intern Med 2005; 165: 24082413. 62. Schwartz AR, Gold AR, Schubert N, et al. Effect of weight loss on upper airway collapsibility in obstructive sleep apnea. Am Rev Respir Dis 1991; 144: 494498. 63. Johansson K, Neovius M, Lagerros YT, et al. Effect of a very low energy diet on moderate and severe obstructive sleep apnoea in obese men: a randomised controlled trial. BMJ 2009; 339: b4609. 64. Grunstein RR, Stenlof K, Hedner JA, et al. Two year reduction in sleep apnea symptoms and associated diabetes incidence after weight loss in severe obesity. Sleep 2007; 30: 703710. 65. Greenburg DL, Lettieri CJ, Eliasson AH. Effects of surgical weight loss on measures of obstructive sleep apnea: a meta-analysis. Am J Med 2009; 122: 535542. 66. Charuzi I, Lavie P, Peiser J, et al. Bariatric surgery in morbidly obese sleep-apnea patients: short- and long-term follow-up. Am J Clin Nutr 1992; 55: 594S596S. 67. Sugerman HJ, Fairman RP, Sood RK, et al. Long-term effects of gastric surgery for treating respiratory insufficiency of obesity. Am J Clin Nutr 1992; 55: 597S601S. 68. Pillar G, Peled R, Lavie P. Recurrence of sleep apnea without concomitant weight increase 7.5 years after weight reduction surgery. Chest 1994; 106: 17021704. 69. Scheuller M, Weider D. Bariatric surgery for treatment of sleep apnea syndrome in 15 morbidly obese patients: long-term results. Otolaryngol Head Neck Surg 2001; 125: 299302. 70. Guardiano SA, Scott JA, Ware JC, et al. The long-term results of gastric bypass on indexes of sleep apnea. Chest 2003; 124: 16151619. 71. Rasheid S, Banasiak M, Gallagher SF, et al. Gastric bypass is an effective treatment for obstructive sleep apnea in patients with clinically significant obesity. Obes Surg 2003; 13: 5861. 72. Valencia-Flores M, Orea A, Herrera M, et al. Effect of bariatric surgery on obstructive sleep apnea and hypopnea syndrome, electrocardiogram, and pulmonary arterial pressure. Obes Surg 2004; 14: 755762. 73. Dixon JB, Schachter LM, OBrien PE. Sleep disturbance and obesity: changes following surgically induced weight loss. Arch Intern Med 2001; 161: 102106. 74. Kalra M, Inge T, Garcia V, et al. Obstructive sleep apnea in extremely overweight adolescents undergoing bariatric surgery. Obes Res 2005; 13: 11751179. 75. Haines KL, Nelson LG, Gonzalez R, et al. Objective evidence that bariatric surgery improves obesity-related obstructive sleep apnea. Surgery 2007; 141: 354358. 76. Fritscher LG, Canani S, Mottin CC, et al. Bariatric surgery in the treatment of obstructive sleep apnea in morbidly obese patients. Respiration 2007; 74: 647652. 77. Lettieri CJ, Eliasson AH, Greenburg DL. Persistence of obstructive sleep apnea after surgical weight loss. J Clin Sleep Med 2008; 4: 333338. 78. Flum DR, Belle SH, King WC, et al. Perioperative safety in the longitudinal assessment of bariatric surgery. N Engl J Med 2009; 361: 445454. 79. Kezirian EJ, Boudewyns A, Eisele DW, et al. Electrical stimulation of the hypoglossal nerve in the treatment of obstructive sleep apnea. Sleep Med Rev 2010; 14: 299305. 80. Guilleminault C, Powell N, Bowman B, et al. The effect of electrical stimulation on obstructive sleep apnea syndrome. Chest 1995; 107: 6773. 81. Eisele DW, Smith PL, Alam DS, et al. Direct hypoglossal nerve stimulation in obstructive sleep apnea. Arch Otolaryngol Head Neck Surg 1997; 123: 5761.

240

OUTCOMES OF OSA AND TREATMENT

82. Schwartz AR, Bennett ML, Smith PL, et al. Therapeutic electrical stimulation of the hypoglossal nerve in obstructive sleep apnea. Arch Otolaryngol Head Neck Surg 2001; 127: 12161223. 83. American Academy of Sleep Medicine, International Classification of Sleep Disorders. Diagnostic and Coding Manual. 2nd Edn. Westchester, American Academy of Sleep Medicine, 2005. 84. Chervin RD, Aldrich MS. Characteristics of apneas and hypopneas during sleep and relation to excessive daytime sleepiness. Sleep 1998; 21: 799806. 85. Kingshott RN, Engleman HM, Deary IJ, et al. Does arousal frequency predict daytime function? Eur Respir J 1998; 12: 12641270. 86. Bennett Lesley S, Barbour C, Langford B, et al. Health status in obstructive sleep apnea. Relationship with sleep fragmentation and daytine sleepiness, and effects of continuous positive airway pressure treatment. Am J Respir Crit Care Med 1999; 159: 18841890. 87. Punjabi NM, OHearn DJ, Neubauer DN, et al. Modeling hypersomnolence in sleep-disordered breathing. A novel approach using survival analysis. Am J Respir Crit Care Med 1999; 159: 17031709. 88. Adams N, Strauss M, Schluchter M, et al. Relation of measures of sleep-disordered breathing to neuropsychological functioning. Am J Respir Crit Care Med 2001; 163: 16261631. 89. Cheshire K, Engleman H, Deary I, et al. Factors impairing daytime performance in patients with sleep apnea/ hypopnea syndrome. Arch Intern Med 1992; 152: 538541. 90. Bedard MA, Montplaisir J, Richer F, et al. Obstructive sleep apnea syndrome: pathogenesis of neuropsychological deficits. J Clin Exp Neuropsychol 1991; 13: 950964. 91. Engleman HM, Kingshott RN, Martin SE, et al. Cognitive function in the sleep apnea/hypopnea syndrome (SAHS). Sleep 2000; 23: Suppl. 4, S102S108. 92. Mazza S, Pepin J-L, Deschaux C, et al. Analysis of error profiles occurring during the OSLER test. A sensitive mean of detecting fluctuations in vigilance in patients with obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2002; 166: 474478. 93. Hla KM, Young TB, Bidwell T, et al. Sleep apnea and hypertension. A population-based study. Ann Intern Med 1994; 120: 382388. 94. Young T, Peppard P, Palta M, et al. Population-based study of sleep-disordered breathing as a risk factor for hypertension. Arch Intern Med 1997; 157: 17461752. 95. Nieto FJ, Young TB, Lind BK, et al. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. JAMA 2000; 283: 18291836. 96. Peker Y, Kraiczi H, Hedner J, et al. An independent association between obstructive sleep apnoea and coronary artery disease. Eur Respir J 1999; 14: 179184. 97. Mehra R, Benjamin EJ, Shahar E, et al. Association of nocturnal arrhythmias with sleep-disordered breathing. The Sleep Heart Health Study. Am J Respir Crit Care Med 2006; 173: 910916. 98. Yaggi HK, Concato J, Kernan WN, et al. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med 2005; 353: 20342041. 99. Arzt M, Young T, Finn L, et al. Association of sleep-disordered breathing and the occurrence of stroke. Am J Respir Crit Care Med 2005; 172: 14471451. 100. Baguet JP, Hammer L, Levy P, et al. The severity of oxygen desaturation is predictive of carotid wall thickening and plaque occurrence. Chest 2005; 128: 34073412. 101. Drager LF, Bortolotto LA, Lorenzi MC, et al. Early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med 2005; 172: 613618. 102. Monneret D, Pepin J-L, Godin-Ribuot D, et al. Association of urinary 15-F2t-isoprostane level with oxygen desaturation and carotid intimamedia thickness in nonobese sleep apnea patients. Free Radic Biol Med 2010; 48: 619625. 103. Kohler M, Craig S, Nicoll D, et al. Endothelial function and arterial stiffness in minimally symptomatic obstructive sleep apnea. Am J Respir Crit Care Med 2008; 178: 984988. 104. Saletu M, Nosiska D, Kapfhammer G, et al. Structural and serum surrogate markers of cerebrovascular disease in obstructive sleep apnea (OSA): association of mild OSA with early atherosclerosis. J Neurol 2006; 253: 746752. 105. Lorenz MW, Markus HS, Bots ML, et al. Prediction of clinical cardiovascular events with carotid intimamedia thickness: a systematic review and meta-analysis. Circulation 2007; 115: 459467. 106. Krieger J, Kurtz D, Petiau C, et al. Long-term compliance with CPAP therapy in obstructive sleep apnea patients and in snorers. Sleep 1996; 19: S136S143. 107. Engleman HM, McDonald JP, Graham D, et al. Randomized crossover trial of two treatments for sleep apnea/ hypopnea syndrome: continuous positive airway pressure and mandibular repositioning splint. Am J Respir Crit Care Med 2002; 166: 855859. 108. Randerath WJ, Heise M, Hinz R, et al. An individually adjustable oral appliance versus continuous positive airway pressure in mild-to-moderate obstructive sleep apnea syndrome. Chest 2002; 122: 569575. 109. Marshall NS, Neill AM, Campbell AJ, et al. Randomised controlled crossover trial of humidified continuous positive airway pressure in mild obstructive sleep apnoea. Thorax 2005; 60: 427432. 110. Barnes M, Houston D, Worsnop C, et al. A randomized controlled trial of continuous positive airway pressure in mild obstructive sleep apnea. Am J Respir Crit Care Med 2002; 165: 773780. 111. Barnes M, McEvoy RD, Banks S, et al. Efficacy of positive airway pressure and oral appliance in mild to moderate obstructive sleep apnea. Am J Respir Crit Care Med 2004; 170: 656664.

241

VY ET AL. P. LE

112. McDaid C, Duree KH, Griffin SC, et al. A systematic review of continuous positive airway pressure for obstructive sleep apnoeahypopnoea syndrome. Sleep Med Rev 2009; 13: 427436. 113. Veasey SC. Will we ever have an effective pharmacotherapy for obstructive sleep apnea? Sleep 2005; 28: 1819. 114. Hedner J, Grote L, Zou D. Pharmacological treatment of sleep apnea: current situation and future strategies. Sleep Med Rev 2008; 12: 3347. 115. Smith I, Lasserson TJ, Wright J. Drug therapy for obstructive sleep apnoea in adults. Cochrane Database Syst Rev 2006; Issue, 2: CD003002. 116. Kiely JL, Nolan P, McNicholas WT. Intranasal corticosteroid therapy for obstructive sleep apnoea in patients with co-existing rhinitis. Thorax 2004; 59: 5055. 117. Hedner J, Kraiczi H, Peker Y, et al. Reduction of sleep-disordered breathing after physostigmine. Am J Respir Crit Care Med 2003; 168: 12461251. 118. Carley DW, Olopade C, Ruigt GS, et al. Efficacy of mirtazapine in obstructive sleep apnea syndrome. Sleep 2007; 30: 3541. 119. Marshall NS, Yee BJ, Desai AV, et al. Two randomized placebo-controlled trials to evaluate the efficacy and tolerability of mirtazapine for the treatment of obstructive sleep apnea. Sleep 2008; 31: 824831. 120. Kraiczi H, Hedner J, Dahlof P, et al. Effect of serotonin uptake inhibition on breathing during sleep and daytime symptoms in obstructive sleep apnea. Sleep 1999; 22: 6167. 121. Brownell LG, West P, Sweatman P, et al. Protriptyline in obstructive sleep apnea: a double-blind trial. N Engl J Med 1982; 307: 10371042. 122. Smith PL, Haponik EF, Allen RP, et al. The effects of protriptyline in sleep-disordered breathing. Am Rev Respir Dis 1983; 127: 813. 123. Whyte KF, Gould GA, Airlie MA, et al. Role of protriptyline and acetazolamide in the sleep apnea/hypopnea syndrome. Sleep 1988; 11: 463472. 124. Horner RL. Impact of brainstem sleep mechanisms on pharyngeal motor control. Respir Physiol 2000; 119: 113 121. 125. Santamaria J, Iranzo A, Ma Montserrat J, et al. Persistent sleepiness in CPAP treated obstructive sleep apnea patients: evaluation and treatment. Sleep Med Rev 2007; 11: 195207. 126. Lam B, Sam K, Mok WY, et al. Randomised study of three non-surgical treatments in mild moderate obstructive sleep apnoea. Thorax 2007; 62: 354359. 127. Yee BJ, Phillips CL, Banerjee D, et al. The effect of sibutramine-assisted weight loss in men with obstructive sleep apnoea. Int J Obes (Lond) 2007; 31: 161168. 128. Ferland A, Poirier P, Series F. Sibutramine versus continuous positive airway pressure in obese obstructive sleep apnoea patients. Eur Respir J 2009; 34: 694701. 129. Phillips CL, Yee BJ, Trenell MI, et al. Changes in regional adiposity and cardio-metabolic function following a weight loss program with sibutramine in obese men with obstructive sleep apnea. J Clin Sleep Med 2009; 5: 416 421. 130. Torp-Pedersen C, Caterson I, Coutinho W, et al. Cardiovascular responses to weight management and sibutramine in high-risk subjects: an analysis from the SCOUT trial. Eur Heart J 2007; 28: 29152923. 132. Cartwright RD. Effect of sleep position on sleep apnea severity. Sleep 1984; 7: 110114. 133. Oksenberg A, Silverberg DS. The effect of body posture on sleep-related breathing disorders: facts and therapeutic implications. Sleep Med Rev 1998; 2: 139162. 134. Oksenberg A, Silverberg DS, Arons E, et al. Positional versus nonpositional obstructive sleep apnea patients: anthropomorphic, nocturnal polysomnographic, and multiple sleep latency test data. Chest 1997; 112: 629639. 135. Mador MJ, Kufel TJ, Magalang UJ, et al. Prevalence of positional sleep apnea in patients undergoing polysomnography. Chest 2005; 128: 21302137. 136. Cartwright RD, Lloyd S, Lilie J, et al. Sleep position training as treatment for sleep apnea syndrome: a preliminary study. Sleep 1985; 8: 8794. 137. Cartwright R, Ristanovic R, Diaz F, et al. A comparative study of treatments for positional sleep apnea. Sleep 1991; 14: 546552. 138. Jokic R, Klimaszewski A, Crossley M, et al. positional treatment versus continuous positive airway pressure in patients with positional obstructive sleep apnea syndrome. Chest 1999; 115: 771781. 139. Oksenberg A, Silverberg D, Offenbach D, et al. Positional therapy for obstructive sleep apnea patients: a 6-month follow-up study. Laryngoscope 2006; 116: 19952000. 140. Morgenthaler TI, Kapen S, Lee-Chiong T, et al. Practice parameters for the medical therapy of obstructive sleep apnea. Sleep 2006; 29: 10311035. 141. Veasey SC, Guilleminault C, Strohl KP, et al. Medical therapy for obstructive sleep apnea: a review by the Medical Therapy for Obstructive Sleep Apnea Task Force of the Standards of Practice Committee of the American Academy of Sleep Medicine. Sleep 2006; 29: 10361044. 142. Lowe AA. Can we predict the success of dental appliance therapy for the treatment of obstructive sleep apnea based on anatomic considerations? Sleep 1993; 16: S93S95. 143. Ryan CF, Love LL, Peat D, et al. Mandibular advancement oral appliance therapy for obstructive sleep apnoea: effect on awake calibre of the velopharynx. Thorax 1999; 54: 972977.

242

OUTCOMES OF OSA AND TREATMENT

144. Ng AT, Gotsopoulos H, Qian J, et al. Effect of oral appliance therapy on upper airway collapsibility in obstructive sleep apnea. Am J Respir Crit Care Med 2003; 168: 238241. 145. Lim J, Lasserson TJ, Fleetham J, et al. Oral appliances for obstructive sleep apnoea. Cochrane Database Syst Rev 2006; Issue, 1: CD004435. 146. Gagnadoux F, Fleury B, Vielle B, et al. Titrated mandibular advancement versus positive airway pressure for sleep apnoea. Eur Respir J 2009; 34: 914920. 147. Petit FX, Pepin J-L, Bettega G, et al. Mandibular advancement devices: rate of contraindications in 100 consecutive obstructive sleep apnea patients. Am J Respir Crit Care Med 2002; 166: 274278. 148. Fritsch KM, Iseli A, Russi EW, et al. Side effects of mandibular advancement devices for sleep apnea treatment. Am J Respir Crit Care Med 2001; 164: 813818. 149. Rose EC, Staats R, Virchow C Jr, et al. Occlusal and skeletal effects of an oral appliance in the treatment of obstructive sleep apnea. Chest 2002; 122: 871877. 150. de Almeida FR, Lowe AA, Tsuiki S, et al. Long-term compliance and side effects of oral appliances used for the treatment of snoring and obstructive sleep apnea syndrome. J Clin Sleep Med 2005; 1: 143152. 151. Gindre L, Gagnadoux F, Meslier N, et al. Mandibular advancement for obstructive sleep apnea: dose effect on apnea, long-term use and tolerance. Respiration 2008; 76: 386392. 152. Petelle B, Vincent G, Gagnadoux F, et al. One-night mandibular advancement titration for obstructive sleep apnea syndrome: a pilot study. Am J Respir Crit Care Med 2002; 165: 11501153. 153. de Almeida FR, Bittencourt LR, de Almeida CI, et al. Effects of mandibular posture on obstructive sleep apnea severity and the temporomandibular joint in patients fitted with an oral appliance. Sleep 2002; 25: 507513. 154. Fleury B, Rakotonanahary D, Petelle B, et al. Mandibular advancement titration for obstructive sleep apnea: optimization of the procedure by combining clinical and oximetric parameters. Chest 2004; 125: 17611767. 155. Tsai WH, Vazquez JC, Oshima T, et al. Remotely controlled mandibular positioner predicts efficacy of oral appliances in sleep apnea. Am J Respir Crit Care Med 2004; 170: 366370. 156. Barthlen GM, Brown LK, Wiland MR, et al. Comparison of three oral appliances for treatment of severe obstructive sleep apnea syndrome. Sleep Med 2000; 1: 299305. 157. Vanderveken OM, Devolder A, Marklund M, et al. Comparison of a custom-made and a thermoplastic oral appliance for the treatment of mild sleep apnea. Am J Respir Crit Care Med 2008; 178: 197202. 158. Gotsopoulos H, Kelly JJ, Cistulli PA. Oral appliance therapy reduces blood pressure in obstructive sleep apnea: a randomized, controlled trial. Sleep 2004; 27: 934941. 159. Trzepizur W, Gagnadoux F, Abraham P, et al. Microvascular endothelial function in obstructive sleep apnea: impact of continuous positive airway pressure and mandibular advancement. Sleep Med 2009; 10: 746752. 160. Itzhaki S, Dorchin H, Clark G, et al. The effects of 1-year treatment with a Herbst mandibular advancement splint on obstructive sleep apnea, oxidative stress, and endothelial function. Chest 2007; 131: 740749. 161. Jenkinson C, Davies RJ, Mullins R, et al. Comparison of therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised prospective parallel trial. Lancet 1999; 353: 21002105. 162. Phillips B. Your tax dollars at work! or the APPLES trial bears fruit. J Clin Sleep Med 2008; 4: 419420. 163. Sleep Apnea Cardiovascular Endpoints Study. Sleep Apnea Cardiovascular Endpoints Study. www.savetrial.org Date last updated: 2010. Date last accessed: October 2010. 164. Pepperell JC, Ramdassingh-Dow S, Crosthwaite N, et al. Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised parallel trial. Lancet 2002; 359: 204210.

243

VY ET AL. P. LE