Published ahead of print on April 12, 2007, doi:10.1164/rccm.200606-795PP
© 2007 American Thoracic Society doi: 10.1164/rccm.200606-795PP
Diagnostic and Therapeutic Approach to Nonsleepy Apnea1 "Spanish Group of Sleep Disorders" Sleep Lab, Hospital Clinic Provincial–IDIBAPS, Barcelona, Spain; 2 Hospital Universitario La Paz, Madrid, Spain; and 3 Hospital University Arnau de Vilanova, IRB Lleida, Facultad de Medicina, Lleida, Spain Correspondence and requests for reprints should be addressed to Dr. J. M. Montserrat, M.D., Sleep Laboratory, Hospital Clinic Villarroel 170, 08036 Barcelona, Spain. E-mail: jmmontserrat{at}ub.edu ABSTRACT Epidemiological and observational studies suggest that sleep-disordered breathing is associated with the subsequent development of hypertension and ultimately with cardiovascular consequences. It may therefore be assumed that continuous positive airway pressure (CPAP) not only avoids sleep-related symptoms but could also mitigate cardiovascular consequences. Short-term studies have revealed a drop in blood pressure, especially in more severe, symptomatic cases of obstructive sleep apnea. Two recent studies have reported that nonsleepy obstructive sleep apnea is associated with an absence of reduced blood pressure after CPAP treatment. This suggests that this group of patients is less susceptible to the consequences of apneas, even those with mild–moderate hypertension or other cardiovascular disorders. However, in patients with severe cardiovascular disease or a higher number of obstructive events, CPAP treatment should be seriously considered.
Key Words: sleep-disordered breathing • symptoms • management and treatment • sleep apnea The indication of continuous positive airway pressure (CPAP) therapy for subjects with obstructive sleep apnea (OSA) is mainly based on the presence of related symptoms, of which sleepiness is the most common (1). This article addresses the issue faced by many physicians on whether to treat nonsleepy subjects with a high apnea–hypopnea index (AHI), especially where there is an association with cardiovascular disease. Given the high prevalence of OSA and cardiovascular disorders (2–6), this association could be coincidental, but it should be borne in mind that OSA could contribute to cardiovascular impairment, as has been suggested (7–9). Thus, CPAP treatment could be indicated when OSA is associated with cardiovascular disorders, regardless of the presence of related symptoms. Moreover, the association between OSA and traffic accidents or metabolic disorders could broaden the scope of the indication of CPAP treatment (10–14), because physicians could be tempted to opt for treatment with CPAP, despite the absence of OSA-related symptoms. This is of paramount importance in mild or in nonsymptomatic OSA, given its frequency (4–6). CONSEQUENCES OF NONSLEEPY APNEA The management of nonsleepy subjects (with an Epworth Sleepiness Scale [ESS] score of less than 10 and whose sleepiness does not disturb social or work activities) constitutes a major challenge because of the prevalence of individuals with this disorder, the absence of a clear definition of nonsleepy subjects, which is delicate and difficult, and the lack of large multicenter studies. Very few works have been performed on nonsleepy patients with OSA, as demonstrated by the dearth of abstracts at recent international meetings (15–17). One of the major difficulties of this disorder is how to determine the magnitude of the problem. How many patients can be included in the category of nonsleepy subjects? The definition of excessive daytime sleepiness (EDS) is a controversial issue that lies beyond the scope of this article. Both the objective (Multiple Sleep Latency Test) and the subjective (Epworth scale) tests used to evaluate EDS suffer from a number of limitations, such as low correlations and a large "grey area" where the classification of sleepy patients is not clear. Moreover, EDS is not a symptom exclusively related to sleep-disordered breathing. Although sleep deprivation is one of the major causes of EDS, other factors could be related to EDS. For instance, in a large cohort study, Bixler and colleagues demonstrated that EDS is more closely associated with depression and metabolic factors than with sleep-disordered breathing or sleep disruption (18). As stated above, epidemiological and observational studies suggest that OSA expressed as the AHI is associated with the subsequent development of hypertension (3–5) and with serious cardiovascular complications (2–4, 8, 9, 19). It has been suggested that OSA can induce some systemic biological reactions, such as systemic inflammation, oxidative stress, hypercoagulability, endothelial dysfunction, metabolic alteration, and sympathetic activity, which could result in the development of vascular diseases (7). Whether or not these affect cardiovascular mortality remains unclear. In an observational cohort study, Marin and coworkers (19) found that patients with untreated, severe OSA had a higher incidence of fatal and nonfatal cardiovascular events than untreated patients with mild–moderate disease, simple snorers, patients treated with CPAP, and healthy subjects. If it could be established that CPAP treatment improved the aforementioned disorders, and if this improvement resulted in a reduction of cardiovascular mortality, the clinical and economic repercussions could be far-reaching. However, although Marin and colleagues' study is especially significant, one should proceed with caution. The study is nonrandomized and the design induces bias. Other studies have demonstrated that adherent patients are different from nonadherent ones (20). EFFECTS OF CPAP For cardiovascular disorders and CPAP treatment, short-term randomized trials have shown that CPAP is beneficial for blood pressure (21–23), pulmonary hypertension (24), sympathetic traffic and biological reactions (25), cardiac function (26–27), strokes (28), and arrhythmias (29). However, other studies yield different results, especially with respect to improvement in hypertension (30–33), degree of the drop in blood pressure (21), and long-term effects (34). These findings give rise to a number of considerations that are summarized in Table 1. Despite the fact that most of the studies that demonstrate a decrease in blood pressure were undertaken on patients with typical OSA (with obesity, an AHI around 50, and an ESS score of around 14), these studies suffer from a number of limitations: the groups were heterogeneous in terms of sex, age, blood pressure at baseline, severity, and prevalence of novo or chronic hypertension. Furthermore, the number of patients was too small (21–23, 30, 31). The methodology varies from study to study. In the work of Pepperell and colleagues, the diagnosis was performed by oxymetry and patients with severe OSA represented 18% of their population (21). Another issue that demands urgent consideration is that of patients with refractory hypertension or those with severe heart failure. In this respect, Logan and coworkers and Martinez-Garcia and colleagues demonstrated a reduction in pressure under CPAP treatment (35, 36). However, there was no control group and the number of patients was small. In another study, by Campos-Rodriguez and associates, which was randomized, yielded contrasting results (30). Both of these studies were performed on a short-term basis. Kaneko and colleagues have raised a very important topic, the role of CPAP in the treatment of nonsleepy patients with heart failure (26). These authors demonstrated that treatment of OSA by CPAP in patients with heart failure lowered blood pressure and improved left ventricular ejection fraction. However, because the study was only 1 month long, it was not possible to determine whether these effects were long-lasting or whether they led to improvement in clinically important outcomes such as morbidity and mortality.
CPAP IN NONSLEEPY APNEA Regarding nonsleepy subjects, Barbé and colleagues conducted a multicenter placebo-controlled study, highlighting the presence or absence of sleepiness (37). Six Spanish teaching hospitals participated in this study. Fifty-five patients with nondaytime sleepiness (ESS < 10), an AHI greater than 30 events per hour, and no other major symptoms were studied. Quality of life, objective sleepiness (Multiple Sleep Latency Test score), cognitive function, and 24-hour arterial blood pressure monitoring did not vary from baseline to 6 weeks after the start of CPAP treatment. Another group, in Oxford, reported similar results in nonsleepy hypertensive patients (38). This group performed a randomized crossover study of 35 nonsleepy, mildly hypertensive patients with OSA treated with CPAP or with subtherapeutic CPAP for 1 month. At the end of the follow-up, there was no overall significant difference in the mean blood pressure between the two groups. Recently, Choi and coworkers presented similar results (17). These studies concur that CPAP treatment is not effective in decreasing blood pressure in nonsleepy patients. Nonsleepy patients, who account for a significant number of subjects with OSA, would not be treated with CPAP on the basis of OSA-related symptoms. However, given the issues discussed above and given the scarcity of works in this group of patients, there is a pressing need for data from short- and long-term studies similar to the one conducted by Colhoun and colleagues on atorvastatin in type 2 diabetes (39). The ongoing clinical trials "Spanish Cohort for the Study of the Effect of CPAP in Hypertension" (CEPECTA) (NCT00202527) and "Effect of Continuous Positive Airway Pressure on Hypertension and Cardiovascular Morbidity–Mortality in Patients with Sleep Apnea and No Daytime Sleepiness" (CERCAS) (NCT00127348) are attempts to address these concerns. Why is CPAP not effective in decreasing blood pressure in nonsleepy patients? To try to answer this question, we should consider some of the predispositions, confounders, and issues discussed above. The Oxford group suggests that these patients could constitute a population that is less susceptible to the cortical effects of apneas, leading to less fragmentation and its secondary symptoms (40). If a change occurred in the expression and in the consequences of cortical arousal, we could speculate about the role of genetics in the susceptibility of these subjects (41, 42). Therefore, some genes, including those that exert an influence over obesity and body fat distribution, craniofacial morphology, ventilatory control, and sleep–wake characteristics, could predispose some individuals to apneas. Other candidate genes could lead to the development of symptoms (20% of the population have more than 10 apneas/h but only 4–6% have symptoms). Furthermore, a number of environmental or behavioral factors (sedatives and alcohol) could aggravate the severity of the symptoms of OSA and could play a crucial part in individuals with a genetic predisposition. In addition, some confusion surrounds the data and their interpretation. One example of inconsistency is provided by the role of the sympathetic drive. One study shows that the effect of CPAP is evident only after extended therapy and that there is no change in blood pressure (43). Another study reveals changes in the sympathetic drive and blood pressure after 1 month (44). All of this suggests a large number of confounders (45). Hypertension is a disease with other potential etiologies or factors such as body fat distribution, age, sex, environment, and resistance to insulin. Insulin plays a role in the sympathetic nervous system and NO release. These activities could affect blood pressure and could therefore mask the role of obstructive events and CPAP treatment (46–48). Table 2 summarizes the present state of knowledge, as well as what needs to be known. More data are required on, among other areas, the effects of long-term improvement of CPAP, the function of CPAP in metabolic abnormalities, and the role of CPAP in the therapeutic arsenal for cardiovascular risk, especially in refractory hypertension or in severe cardiac failure. It would also helpful to be able to identify the group of patients who show the best response to treatment.
The evidence available to date is not sufficient to recommend CPAP in nonsleepy patients with OSA, even in those with hypertension. However, one should proceed with caution in serious cases, where CPAP could be considered, especially in patients with severe cardiovascular disease, such as refractory hypertension. There is a pressing need for more data on this issue, especially on a long-term basis. FOOTNOTES Supported in part by Ministerio de Ciencia y Tecnologia (SAF 200-0068), Sociedad Española de Patologia Respiratoria (SEPAR), and Fundación Catalana de Pneumonología (FUCAP). Originally Published in Press as DOI: 10.1164/rccm.200606-795PP on April 12, 2007
Conflict of Interest Statement: J.M.M. received Received in original form June 14, 2006; accepted in final form April 12, 2007 REFERENCES
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21,600 from Carburos Metalicos SA (Spain) for animal research on sleep apnea. The total amount received for the 2-year project is 
