INTRODUCTION

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Nasal continuous positive airway pressure (CPAP) has been accepted worldwide as the treatment of choice for the sleep apnea/hypopnea syndrome (SAHS) (1). CPAP in this condition acts as a pneumatic valve stabilizing the upper airway and preventing its periodic collapse during sleep. This results in the disappearance of the respiratory events that occur in these patients during the night. Sleep fragmentation disappears and normal sleep architecture is restored, leading to clinical improvement of symptoms commonly attributed to SAHS. However, CPAP is only a symptomatic treatment, as it does not correct the underlying pathological condition. Although CPAP has regularly been used in the last decade, only a small number of studies have evaluated its effectiveness. These studies include placebo-controlled and noncontrolled trials (2). This fact, along with the policy costs of treating an increasing number of patients, has led to an ongoing controversy and recently, usefulness of CPAP has been questioned (6). The body of evidence that supports the use of this treatment in front of conservative measures (sleep hygiene and weight loss) should therefore be stronger than currently. An effective treatment for SAHS should have a dual purpose: to relieve clinical symptoms, thereby improving the quality of life, and to decrease associated morbidity and mortality. In dealing with this disorder, morbidity/mortality studies necessarily need a long-term follow-up. However, both quality of life and symptomatic improvement can be correctly assessed on the basis of short- and medium-term studies (7). Accordingly, we conducted a controlled trial to evaluate, in moderate to severe SAHS patients, the effect of conservative measures compared with conservative measures plus CPAP in improving SAHS-related clinical symptoms, daytime function, and self-perceived health status. Likewise, this design has the advantage of controlling for the exclusive effect of CPAP.

	METHODS

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Subjects and Design

We designed a controlled trial seeking differences in symptoms, health profile, and quality of life between patients treated with conservative measures and patients who received, in addition, treatment with CPAP. The study population initially included 114 consecutive patients with an established diagnosis of SAHS who required treatment with CPAP. The criteria for CPAP treatment were as follows: severe clinical symptoms (a minimum of symptoms such as a disabling active somnolence not attributable to other causes plus an impairment in daytime performance) along with an apnea/hypopnea index (AHI) > 15 or an AHI > 30 with mild to moderate clinical symptoms. During the assignment of treatment nine patients were not included because they had either severe or unstable cardiovascular disease or a hazardous job coincident with SAHS (drivers or those who handled dangerous machinery) (8). The final study population consisted of 105 patients. Taking into account the severity of the SAHS in our patients we decided to randomly allocate two patients in the CPAP group for every patient who received only conservative measures. Group 1 (37 patients) followed a program of conservative measures (sleep hygiene and a weight loss program). Group 2 (68 patients) received, in addition, treatment with CPAP. All patients received written information on recommendations and both groups had a close follow-up through appointments at 4, 8, and 12 wk in our outpatient clinic and, in addition, weekly telephone calls by a specialized nurse to encourage patients' compliance with treatment and to give friendly support. Before and 3 mo after each treatment, body weight was recorded and the patients completed five questionnaires under the supervision of a trained interviewer. These questionnaires focused on sleepiness, other symptoms related to sleep apnea, daytime function, health profile, and quality of life. The human ethics committee of our hospital approved the protocol and informed consent was obtained from all patients.

Diagnosis of SAHS

All patients underwent an overnight study by a validated procedure (9). Briefly, this was performed in all subjects using a Densa Pneumograph (Densa Ltd, Flint, UK) which measures oronasal flow by thermistor and thorax and abdominal motion. Arterial oxygen saturation (Sa_O2) was measured using a pulse oximeter (model 504; Critical Care Systems Inc., Waukesha, WI). A body position sensor differentiated between supine and side position. Apnea and hypopnea were defined according to commonly used clinical criteria of airflow cessation lasting 10 s or more for apneas and a 10-s period or more of discernible airflow reduction associated with a cyclical Sa_O2 dip (3%) for hypopneas. Manual scoring was done in all cases.

Group 1 (Conservative Treatment)

After diagnosis, the patients were informed about the nature of their disease and the need and importance to start a treatment. They were encouraged to: (1) complete enough hours of sleep every night; (2) sleep on their side; (3) avoid sedatives and alcohol consumption; and (4) lose weight by following a home diet prescribed by a dietician.

Group 2 (CPAP)

In addition to the conservative measures started by Group 1 these patients received CPAP treatment. CPAP titration was done with our standard validated procedure (10). Briefly, it was performed using the Rescare AutoSet System. The AutoSet system is a computer-based CPAP machine that performs an automatic pressure titration in response to snoring, inspiratory airflow contour morphology, or the presence of apneas or hypopneas. All patients in this group were instructed about the use of CPAP. They spent a full day in our sleep unit such that they could accommodate to the best-fitting mask and become familiar with the treatment with the help of a trained physiotherapist. After lunch, a short nap with CPAP was allowed to enhance patients' confidence with the device. Patients spent the rest of the afternoon practicing with the device with the staff available to resolve any question or problem. At night CPAP titration was done with the Rescare AutoSet system under the experienced surveillance of our ward nurses. The results were analyzed and the optimal CPAP pressure was selected.

Assessments (Questionnaires)

All patients in both groups were evaluated at inclusion and after 3 mo of treatment through different questionnaires. The questionnaires were answered under the supervision of a trained interviewer and focused on the following issues: sleepiness, other symptoms directly related to SAHS, daytime function, and finally, perceived health status and quality of life (questionnaires are fully detailed in the Appendix ).

Sleepiness. Two questionnaires were used: the classic Epworth sleepiness scale (ESS) (11, 12) and our own specific somnolence questionnaire being validated. The latter includes 10 items and subjects are asked to consider the possibilities they have of falling asleep in different situations: watching television, reading, against their will at any time, eating, driving when they stop at a traffic light, and other. The possible answers are scored as follows: never = 1, sometimes = 2, often = 3, always = 4. The final result is the total of the points scored in all items.

SAHS-related symptoms. We applied an in-house questionnaire that consists of 15 items that ask about snoring, breathing pauses, nocturia, dry mouth, morning headaches, and other common symptoms besides sleepiness reported by patients with SAHS. The results range from 15 (absence of symptoms) to 60 (maximally symptomatic patient).

Daytime function. Patients were also asked to complete an in-house questionnaire designed to explore the daytime function in SAHS. It comprises 19 items that inquire about the limitations and consequences of the disorder on everyday life. Examples of these items are: Do you have difficulty in concentrating because you are sleepy or tired? Do you have difficulty remembering things? Does it worry you to take someone in your car because you are afraid to fall asleep? Do you find it difficult to stay as active as you want in the afternoon because you fall asleep? Do you have sexual problems?

These items have four possible answers scored as follows: no, never = 1; rarely = 2; sometimes = 3; frequently = 4. The result is the addition of all the answers of the patient. Possible scores range from 19 (denoting absence of distress and functional consequences of SAHS) to 76 (maximal distress and impairment due to SAHS).

Nottingham health profile (NHP) questionnaire. This questionnaire is a generic instrument that measures perceived health status, focusing on social, psychological, or physical distress related to medical, social, or emotional problems and also the extent to which this distress disturbs the life of the subject (13, 14). The test contains 38 items that belong to six domains or subscales: energy, pain, sleep, emotional reactions, social isolation, and physical mobility. The patient is asked to give a "yes" or "no" answer to each item and the scores are calculated as follows: total number of affirmative answers to the items in one dimension divided by the total number of items in that dimension multiplied by 100. Possible scores therefore range from 0 (absence of distress in each dimension) to 100 (maximal distress).

Statistical Analysis

Data are expressed as mean ± SEM. An independent t test was applied at baseline between Group 1 and Group 2. The effect of conservative or conservative + CPAP treatment was assessed by a two-way analysis of variance (ANOVA). In addition, this analysis was completed by the assessment of the treatment response according to the calculated odds ratio (OR). For this purpose, according to the statistically significant results of the two-way ANOVA, we selected three clinically relevant outcome variables. The differences between baseline and follow-up in the three outcome variables were scored as +1, 1, or 0, according to an improvement, worsening, or no response, respectively. An improvement was considered when a positive punctuation > 0.5 standard deviation (SD) was obtained between baseline and follow-up assessments. A worsening was considered when a negative punctuation was > 0.5 SD. A nonsignificant change was considered when we obtained a punctuation between ± 0.5 SD in each of the outcome variables. We computed a global score based on the improvement of two of the three outcome variables without worsening of the remaining one, so that the final sum punctuation should be  2. Statistical significance was accepted at p < 0.05. All analyses were performed with the Statistical Package for Social Sciences (SPSS, rel. 6.1.3 for Windows; SPSS Inc., Chicago, IL).

	RESULTS

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Baseline data from the 105 SAHS patients who met the criteria for treatment with CPAP were: age: 53 ± 10 yr; body mass index (BMI) = 32 ± 6 kg/m²; AHI = 56 ± 20; and ESS = 12 ± 5. Mean baseline data from the two study groups did not show significant differences between age, gender, BMI, severity of SAHS, or sleepiness (Table 1), nor did statistical differences at baseline values in the scores of in-house sleep questionnaire, SAHS-related symptoms, daytime function, and in the NHP.

The overall weight loss in Group 1 was 3.1 kg whereas in Group 2 (CPAP) it was only 1.1 kg (p < 0.05). Within Group 1, managed only with conservative measures, 8.3% of the patients were able to lose 10% or more of their weight and 25% achieved a loss between 5 to 10% of their body weight. In Group 2, weight loss was 1.1 (p = nonsignificant [NS]) with 3% of the patients losing more than 10%, 10% lost between 5 and 10%, and 35% achieved a loss between 0 and 5%. The mean CPAP level prescribed was 9.1 ± 2 cm H₂O, and an adequate CPAP compliance (> 4.5 h/night) was achieved in 73% of the patients at 3 mo. The average nightly use was 5.2 ± 2 h.

Our main results are summarized in Table 2. We observed, after 3 mo, much greater improvement in the two sleepiness questionnaires in Group 2 receiving CPAP compared with Group 1 on conservative treatment alone (p < 0.001) (Figure 1). A similar significant improvement in the CPAP group was obtained in the questionnaires of SAHS-related symptoms (p < 0.001) and daytime function (< 0.005) (Figure 2). When the scores in the NHP test were analyzed, differences in the effect of treatment between groups were found in the domains of "energy" (p < 0.005) and "social isolation" (p = 0.03) (Figure 3). There was also a marginal trend to different effects of treatment in the dimensions of "physical mobility" (p = 0.09) and "emotional reactions" (p = 0.08). No differences between groups were shown in the effects of treatment in "pain" and "sleep" dimensions.

View larger version (14K): [in this window] [in a new window]   Figure 1.   Change after 3 mo of treatment in scores in the ESS (left) and in the in-house sleep questionnaire (right) in Group 1 (open bars) and Group 2 (shaded bars). Values are mean (± SEM).

View larger version (19K): [in this window] [in a new window]   Figure 2.   Change after 3 mo of treatment in scores in SAHS-related symptoms questionnaire (left) and in daytime function questionnaire (right) in Group 1 (open bars) and Group 2 (shaded bars). Values are mean (± SEM).

View larger version (20K): [in this window] [in a new window]   Figure 3.   Change after 3 mo of treatment in the six dimensions of the NHP in Group 1 (open bars) and Group 2 (shaded bars). Values are mean (± SEM).

For the OR calculation of the treatment response between both groups, the three domains selected were: ESS, SAHS- related symptoms, and the energy domain from the NHP questionnaire. In the conservative treatment group we observed an improvement in 35% of patients, whereas in the CPAP plus conservative treatment group an improvement was achieved in 78% of patients. The odds of experiencing a treatment response with CPAP plus conservative treatment compared with the conservative treatment alone was 6.52 (OR = 2.51 to 17.6, 95% confidence interval [95% CI]).

	DISCUSSION

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Our study was designed to obtain objective evidence of the effectiveness of CPAP therapy in SAHS patients. We have observed that the relief of sleepiness and other SAHS-related clinical symptoms and the improvement in health status after 3 mo was much greater in the group receiving conservative treatment plus CPAP than that with conservative measures alone. This difference in the impact of treatment between both groups was substantial and statistically significant. The improvement in the results in daytime function in the CPAP group is relevant as they indicate a superior well-being and comfort of patients under this treatment. A similar end-result can be derived from the results in the NHP questionnaire that showed marked differences between groups with greater improvement in domains of "social isolation" (mood) and "energy" (dynamism), and marginal in "emotional reactions" and "physical," in the group that received additionally CPAP. However, no differences were observed in "pain" and "sleep" scales. The lack of changes in the "pain" scale was logical because pain is not a symptom present in SAHS. As expected, the "sleep" scale did not change because this scale is designed to assess insomnia and not sleepiness. This finding also suggests a good tolerance to the CPAP treatment that does not seem to impair the quality of sleep. Thus, these results emphasize the importance of developing specific questionnaires for this disorder.

Benefits from CPAP treatment, including the improvement in SAHS-related symptoms, have been emphasized in previous studies. Douglas and coworkers in randomized placebo-controlled, crossover studies (2) provide considerable evidence of the effectiveness of CPAP in mild as well as in moderate to severe SAHS. However, a recently published meta-analysis (6) has questioned the effectiveness of CPAP treatment given the lack of conclusive evidence of benefits. Unfortunately, this particular analysis has moved public health authorities to question funding for SAHS management without a careful analysis of the clinical benefits. The sleep community has thus raised strongly conflicting points of view (15, 16). Whatever the case, the analysis has certainly driven attention to the need to ascertain objective clinical benefits of CPAP treatment. Accordingly, it is necessary to specifically compare CPAP effectiveness with the usual approach, namely conservative measures such as sleep hygiene and weight loss programs, which may appear to be a less expensive and less difficult alternative more appealing to those who handle health funds. To obtain further evidence of the effectiveness of CPAP in SAHS patients it is also necessary to test CPAP not only against a placebo, which has been demonstrated to have a considerable effect (2, 3), but alternatively with an approach that contemplates conservative measures in both groups under evaluation. The design has the advantage to control for the exclusive effect of the CPAP treatment. Furthermore, we should evaluate the outcome results in real conditions, i.e., without taking into account issues such as CPAP compliance or weight loss.

With this approach our study provides robust evidence of the effectiveness of CPAP treatment in the relief of SAHS- related clinical symptoms and improvement in measures of perceived health status. In addition, the questionnaires applied after a period of 3 mo proved to be appropriate to monitor the effects of CPAP on a short-term basis. Although the short period of study may raise some criticisms, the beneficial effects of CPAP treatment can likely be maintained over time compared with the disappointing outcome commonly observed with conservative measures.

Despite the current close follow-up, our results in weight loss in each arm of treatment were marginal (3.1 kg in Group 1 versus 1.1 kg in Group 2). It is possible that this minor difference could be attributed to the lower motivation to lose weight in patients who obtained improvement with CPAP. Nevertheless, these modest results are comparable to those recently reported (17). Overweight/obesity is a complex health problem that requires a multidisciplinary approach including behavioral therapy or gastric surgery in selected cases (18). In addition, it is also difficult to obtain objective evidence on the follow-up of sleep hygiene recommendations. However, CPAP treatment is not curative and, whenever prescribed, the same effort in encouraging compliance of CPAP must be made in the direction of an improvement in sleep hygiene and weight loss.

Recently, Redline and coworkers (19) have shown that patients with mild sleep-disordered breathing can improve their symptoms under CPAP therapy. We have made a similar analysis and selected three clinically relevant outcome variables (statistically significant in the two-way ANOVA), namely sleepiness (ESS), the SAHS-related symptoms questionnaire, and the energy domain from the NHP questionnaire. Our results in this group of severe SAHS patients have shown that the OR of experiencing a treatment response with CPAP plus conservative measures compared with the conservative measures alone is 6.52. The increased odds compared with the study of Redline and coworkers can probably be explained by the greater severity of the patients in our study.

We conclude that, despite the importance of general measures of sleep hygiene and weight loss, CPAP is currently the treatment of choice for moderate to severe SAHS. The study adequately supports the effectiveness of CPAP in symptomatic treatment for severe SAHS. Consequently, we believe that the indication of CPAP treatment in these patients is firmly established. Thus, our study confirms and extends previous findings on the effectiveness of CPAP and copes with some of the objections raised recently concerning this treatment. However, additional efforts must be made to further evaluate the effectiveness of the different approaches to treat this condition.