MASA syndrome

Standard practice for continuous positive airway pressure (CPAP) treatment in sleep apnea and hypopnea syndrome (SAHS) requires pressure titration during attended laboratory polysomnography. However, polysomnographic titration is expensive and time-consuming. The aim of this study was to ascertain, in a large sample of CPAP-naive patients, whether CPAP titration performed by an unattended domiciliary autoadjusted CPAP device or with a predicted formula was as effective as CPAP titration performed by full polysomnography. The main outcomes were the apnea-hypopnea index and the subjective daytime sleepiness. We included 360 patients with SAHS requiring CPAP treatment. Patients were randomly allocated into three groups: standard, autoadjusted, and predicted formula titration with domiciliary adjustment. The follow-up period was 12 weeks. With CPAP treatment, the improvement in subjective sleepiness and apnea-hypopnea index was very similar in the three groups. There were no differences in the objective compliance of CPAP treatment and in the dropout rate of the three groups at the end of the follow-up. Autoadjusted titration at home and predicted formula titration with domiciliary adjustment can replace standard titration. These procedures could lead to considerable savings in cost and to significant reductions in the waiting list.

Keywords: autoCPAP titration; CPAP efficacy; CPAP titration; sleep apnea syndrome

The sleep npnea and hypopnea syndrome (SAHS) is a disorder affecting 2 to 4% of the adult population (1). Nasal continuous positive airway pressure (CPAP) is the most effective treatment in patients with SAHS symptoms (2-6).

Standard practice for CPAP treatment requires pressure titration during an attended laboratory polysomnography. The aim of this procedure is to identify an effective pressure to remove apneas, hypopneas, snoring, and arousals. However, polysomnographic titration is expensive and time-consuming. Autoadjusted titration with autoCPAP devices has been proposed (7) to overcome these disadvantages. These devices monitor one or more of the following parameters: snoring, flow, or impedance; these are monitored to detect respiratory events and adjust the CPAP pressure. They also calculate the optimal pressure automatically. To date, only autoCPAP titration by standard laboratory polysomnography has been recommended (8), given that very few studies (9-13) have been performed in unattended conditions, yielding contradictory results in CPAP-naive patients (11).

The prediction of CPAP pressure using a formula that includes the apnea-hypopnea index (AHI) and the anthropometric parameters has been proposed (14). This could also be used to simplify conventional CPAP titration (15, 16). A randomized crossover controlled study on 18 CPAP-naive patients demonstrated that the efficacy of a predicted formula titration with at-home self adjustment was similar to that of standard titration (17). In addition, a nonrandomized study (18) found a similar clinical improvement and CPAP adherence between predicted formula and standard titration groups. Therefore, if unattended autoadjusted or predicted formula CPAP titration is performed, considerable savings in cost and significant reductions in the waiting lists could be achieved worldwide.

The aim of this study was to ascertain, in a large sample of CPAP-naive patients, whether CPAP titration performed with an unattended domiciliary autoadjusted CPAP device or with a predicted formula was as effective as CPAP titration performed by full polysomnography. The main outcomes were the AHI and the subjective daytime sleepiness after fixed CPAP treatment. Thus, we ascertained whether these methods were alternatives to the conventional CPAP titration. Some of the results of this study have been reported in the form of an abstract (19).

METHODS

Study Design

This randomized controlled clinical trial included two test groups (autoadjusted and predicted formula titration) and one control group (standard titration). To determine differences in the main outcomes between groups, we used a power of 0.8 and an α error of 0.05. The study was open to the researchers and blinded to the technicians who set the questionnaires and analyzed the polysomnographies.

Patients

Patients requiring CPAP treatment-AHI ≥ 30 and relevant daytime subjective sleepiness (20) (Epworlh sleepiness scale ≥ 12)-aged between 18 and 70 years were consecutively recruited from 10 sleep centers in Spain. The exclusion criteria were as follows: psychophysical incapacity to perform questionnaires, patients with chronic disease (cancer, chronic pain, renal failure, moderate or severe chronic obstructive pulmonary disease, etc.), drug or alcohol addiction, Cheyne-Stokes syndrome, life-threatening SAHS, patients with previous uvulopalatopharyngoplasty (UPPP), absence of a partner at home, important chronic nasal obstruction, lack of skill in adjusting the nasal mask in a daytime CPAP trial (see STUDY PROTOCOL), and refusal to participate in the study. Three hundred sixty patients (120 patients per group) were finally included.

Study Protocol

Patients with suspicion of SAHS were referred for conventional polysomnography. The baseline and CPAP polysomnographic studies were analyzed manually, at each participating center, according to standard criteria (21, 22). The sample rate and the filtering of the signals were standardized across centers. The neurologic variables were respectively as follows: electroencephalogram (C3/A2 and C4/A1) 200 Hz and 35 to 0.5 Hz; electrooculogram 100 Hz and 35 Hz to 0.5 Hz; electromyogram 200 Hz and 70 to 15 Hz. Breathing variables were scored based on the flow tracing provided by a nasal cannula (sampling rate 40 Hz) in baseline polysomnographics and by a pneumotachograph (sampling rate 40 Hz) connected to the nasal mask in CPAP polysomnographic studies. Thoracoabdominal motion was measured by thoracic and abdominal bands. Oxygen saturation was recorded by a finger-pulse oximeter. An apnea was defined as an absence of airflow of ≥ 10 seconds and a hypopnea as any discernible airflow reduction for at least 10 seconds with a drop in oxygen saturation ≥ 3% or final arousal (20). After the baseline conventional polysomnography, a 20-minute daytime CPAP trial was performed only if the patient met the inclusion and exclusion criteria. The patients were also excluded when a significant nasal obstruction or a lack of skill in adjusting the nasal mask was detected during this CPAP trial. Once the patients were included, they were randomized into one of the three study groups (Figure 1).

Each center received written instructions from the coordinating center to carry out the study. This document standardized the questionnaires; the 20 minutes of CPAP trial; the information about the study and CPAP treatment for the patients; the three types of titration (standard, autoadjusted, and predicted formula); the list of the excluded and abandoned cases and secondary effects; the informed consent; and the visual analogical scale. The recommendations to perform the Epworth scale and the quality-of-life scales were also included in these guidelines while maintaining the specific recommendations of the authors. Patient inclusion was competitive at the centers. The inclusion period finished when the total number of patients included were 360. To avoid imbalance, each center could include up to 45 patients.

The data collection was performed in a home-designed electronic database available at each center. To minimize potential errors, the arithmetical calculation, prediction formula, and quality of life scales were automated. At the end of the study each center e-mailed the data (in Excel format) generated automatically by the software. All the data files were assembled together in one table to perform the final analysis at the coordinating center in Caceres.

Standard Titration

The patients included in this group underwent a second polysomnography for manual CPAP titration. The starting pressure was 4 cm H2O, and the pressure was increased by 1 cm H2O every 5 minutes until the apneas disappeared. Thereafter, the pressure was increased by 1 cm H2O every 10 minutes until the hypopneas, flow limitation, and snoring disappeared. This last pressure was considered to be the optimal pressure.

Autoadjusted Titration

The patients received information on the autoCPAP and slept at home with the device (Autoset-T; ResMed, Sydney, Australia) for one night. The pressure was set to start automatically, after 20 minutes for adaptation (from 4 cm H2O up to a maximum of 16 cm H2O). The same model of nasal mask (Mirage; ResMed) was used for all the patients. On the following morning the patient answered a simple questionnaire: (1) At what time did you fall asleep? (2) At what time did you wake up? The automatic pressure profile was reviewed in the sleep laboratory. The recording was considered to be acceptable if all the following criteria were met: (1) the total sleep time, subjectively appreciated by the patient, was at least 5 hours; (2) the recording period in the autoCPAP device was at least 6 hours; and (3) the mean leak was lower than 0.4 L/second in the statistics obtained from the autoCPAP machine or the leak was lower than 0.4 L/second for at least 5 hours in the visual estimation of the raw data. The recording was repeated for two additional nights whenever it was unacceptable. A titration failure was defined when none of the three recordings obtained were acceptable. The optimal pressure was determined visually on the raw data of the autoCPAP device ("view night profile") by analyzing the pressure that included 90% of the periods with a leak lower than 0.4 L/second (percentile 90) (23, 24).

Predicted Formula Titration

The optimal pressure was estimated by an equation already published (14): predicted pressure = (0.16 × BMI) + (0.13 × neck circumference) + (0.04 × AHI) - 5.12. If the pressure obtained was more than 9 cm H2O, then the patient started with 9 cm H2O at home. On Day 15 or Day 30 of follow-up, pressure could be increased by 1 or 2 cm H2O if the patient's partner affirmed that snoring or apnea was not completely eliminated. The optimal pressure was the pressure achieved after the third visit.

Follow-up and Outcomes

Once the optimal pressure was achieved, treatment was initiated with a fixed level of CPAP at home. Not all the centers had the same CPAP devices, but a manometer was used to check the pressure level in all the patients. The patients were evaluated on four occasions (Figure 1). The second and third visits were used to increase the CPAP pressure in the predicted formula group, and to try to alleviate the possible secondary effects in all the groups. After 12 weeks all patients underwent a new polysomnography with CPAP. The optimal pressure obtained in the initial titration was maintained throughout the night.

The main outcomes were the AHI and the Epworth sleepiness scale. The secondary outcomes were the different quality-of-life tests: FOSQ (Functional Outcomes of Sleep Questionnaire) (25), SF-36 (Medical Outcomes Study 36-Item Short-Form Health Survey) (26), EuroQol (27), and an analogical scale. The last one consisted of a 12-cm straight line on which the patient had to indicate his or her health status related specifically to SAHS. The limits of the line marked the worst and the best possible status. This test is similar to the EuroQol thermometer but related specifically to SAHS. Other secondary outcomes were the percentage of withdrawals, secondary effects, and CPAP compliance.

The study was approved by the ethics committees of the 10 centers. Informed consent was obtained from all the patients.

Interobserver Agreement on Autoadjusted Titration

Before the study, one researcher from each center underwent a short period of training based on five representative "Raw Data" graphics from the Autoset T. The training was performed to become acquainted with the visual analysis of the pressure. At the end of the investigation, we undertook another study to evaluate the interobserver agreement in the visual calculation of CPAP pressure (see the online supplement).

Statistical Analysis

We compared the characteristics of the three groups at baseline (before therapy) and CPAP pressure and use at the end of the study (after therapy) by one-way ANOVA for continuous variables. Where appropriate, differences between individual means were tested using the LSD (least significant difference) (SPSS 11.0; SPSS Inc., Chicago, IL). If the continuous variables were not normally distributed, a nonparametric test (Kruskal-Wallis and Dunn post hoc to identify differences between individual means) was used. For qualitative variables, χ^sup 2^ analysis or Fisher's exact test was employed. A p value of

RESULTS

One hundred six patients (23%) out of the 466 initially evaluated were excluded for the following reasons: chronic disease (40; 37.7%), severe nasal obstruction (13; 12.3%), refusal to participate in the study protocol (12; 11.3%), psychophysical incapacity to answer the questionnaires (10; 9.4%), absence of partner at home (10; 9.4%), alcohol addiction (9; 8.5%), previous UPPP (6; 5.7%), lack of skill in adjusting the nasal mask (5; 4.7%), and life-threatening SAHS (1; 0.9%).

The number of patients per center varied according to the competitive nature of the inclusion: four centers included 45 patients, one 39, one 37, two 33, one 31, and one included 7. No intercenter differences were found in the main and secondary outcomes. Out of 360 patients finally included, 45 (12.5%) abandoned the study (Table 1). No differences were found in the percentages of withdrawal between the standard (15.1%), the autoadjusted (10.9%), and predicted formula groups (11.3%). Likewise, there were no significant differences in the titration failures between the standard (2.4%) and the autoadjusted groups (4.2%).

The autoadjusted titration at home was achieved on the first attempt in 98 patients out of the 119 patients initially included. It was repeated once in 21 patients and twice in 11 patients. Titration failed in five patients. The reasons for these 32 repeated titrations were excessive leakage in 20 cases and a registration period under 6 hours or a sleep time under 5 hours (subjectively appreciated by the patient) in the remaining 12 cases.

In the predicted formula titration group, CPAP pressure was increased during the follow-up in 32 of 115 patients initially included. The total increase was 1 cm H2O in 16 patients, 2 cm H2O in 10, 3 cm H2O in 4, and 4 cm H2O in 2 patients.

The general characteristics of the population finally studied are shown in Table 2. No statistical differences were observed in the three study groups.

The Epworth Sleepiness Scale and the polysomnographic variables (AHI, arousal index, percentages of sleep periods, and oxygen saturation) showed a similar statistical improvement after CPAP treatment in all the groups (Table 3). The AHI under CPAP treatment was slightly higher in the predicted formula group.

The final CPAP pressure was lower (8.4 ± 1) in the predicted formula group than in the other two groups (standard [8.8 ± 1.9] and autoadjusted [9.1 ± 1.9]), although there were statistically significant differences only between autoadjusted and predicted formula groups. There were no statistical differences in the CPAP compliance between groups.

All the quality of life tests improved after treatment in all the groups (Table 4). In the autoadjusted group the degree of improvement in SF 36 physical and EuroQol was lower than that observed in the standard group. The quality of life scores at baseline were higher in the autoadjusted group than in the standard group (see DISCUSSION for details). In the predicted formula group the level of improvement in the quality of life tests was similar to that obtained in the standard group.

As regards the secondary effects (Table 5), there were no important differences between the standard and the other groups. Nevertheless, there was a tendency for the autoadjusted group to present more side effects.

DISCUSSION

This is the first randomized controlled study that determines whether autoadjusted CPAP titration at home or a predicted formula CPAP titration is an alternative to standard CPAP titration in a large sample of CPAP-naive patients. This study suggests that these alternative titration methods improve the clinical symptoms and the polysomnographic parameters while maintaining adherence, use of treatment, and frequency of secondary effects similar to those obtained with the standard method.

A number of studies have shown that some autoCPAP devices are effective in obtaining optimal CPAP pressure (28-30), but only a few of these studies have centered on the efficacy of autoCPAP titration in unattended conditions and CPAP-naive patients. As for the AHI, some clinical series have yielded acceptable results (9-11, 13). One randomized controlled study (12) showed that the improvement in sleepiness and the CPAP acceptance resembled that obtained by conventional titration despite the fact that no sleep studies were performed during the follow-up period to determine the AHI. Our study confirms the results of the clinical series (9, 10, 13) with the addition of an improvement in the polysomnographic variables.

Series (9) analyzed autoCPAP recordings, after 1 or 2 weeks of domiciliary CPAP use, to determine the optimal pressure. We obtained effective autoCPAP titration at home using only one night in 82% of the patients. Two additional nights were performed with the patients that failed during the first night. As a consequence, optimum CPAP pressure was obtained in 96% of all subjects in the autoadjusted group. This has important economic and practical implications given that the number of patients that can be titrated at home with one device is higher with our methodology.

One of the arguments against autoadjusted CPAP titration is that the oxygenation level is not measured (8). Our patients, in the autoadjusted titration group, suffered from significant oxygen desaturation in the baseline study. However, after CPAP treatment, the oxygenation parameters were similar to those of the standard titration group. Therefore, this finding challenges the need for measuring oxygen saturation during autoCPAP titration.

We used a specific autoCPAP device, the Autoset-T. This device monitors changes in airflow into the mask and monitors snoring. It responds to apneas, flow limitation, and snoring. Given that different autoCPAP devices monitor diverse parameters, the results of this study should not be extrapolated to other devices (31, 32).

To date, the main aim of the CPAP treatment has been to improve the clinical symptoms and to normalize the physiological variables in polysomnography. In our study, the improvement in symptoms such as sleepiness, arousal index, oxygen saturation, and the AHI was very similar in all the groups, although the predicted formula group had a higher number of residual apneas and hypopneas (Table 3). A number of well designed studies have shown that the AHI is an independent factor of cardiovascular risk (33-35) and traffic accidents (36-38), but long-term implications of residual apneas and hypopneas after CPAP treatment have not been established.

The optimal CPAP pressure in the predicted formula group has been calculated by a published equation (see METHODS). Whenever the pressure was more than 9 cm H2O, it was initially set at 9 and home adjustment was performed to achieve a better individual adaptation to high CPAP pressures. The mean pressure after domiciliary adjustment (8.4 ± 1.0) resembles the theoretical pressure calculated by the formula (8.4 ± 1.8), despite the initial reduction in the pressure (8.0 ± 0.9). Fitzpatrick and coworkers applied the same formula without an upper limit of pressure (17). Their mean initial CPAP pressure obtained was 8.5 ± 0.4, and the final pressure after home adjustment was 10.2 ± 2.0. This latter value is higher than our final CPAP pressure in the predicted formula group, probably because of differences in the methodology employed. Therefore, given our trend toward a higher residual AHI in the formula group, the possibility of refining our methodology could be considered, although a higher pressure could lead to more secondary effects and perhaps consequences in adherence and compliance of the treatment.

Most of the quality-of-life tests showed less improvement in the autoadjusted group than in the standard group (Table 4), probably because baseline quality-of-life tests were better in the autoadjusted group. Moreover, the less specific quality-of-life tests showed fewer improvements.

Out of the 466 patients initially included in the study, 45 dropped out during the study and 106 were excluded. The main reason for exclusion was the presence of disorders preventing the evaluation of the quality of life.

The study was open to the researchers and blinded to the technicians who set the questionnaires and analyzed the polysomnographies. This could have introduced a potential bias. However, a bias is highly unlikely given that the study was performed at 10 centers, and given that most of the questionnaires of the study were self-administered and that information to the patients about the CPAP treatment was standardized.

In conclusion, the results of this study suggest that CPAP titration can be performed with a home-autoadjusted CPAP device or with a predicted formula with domiciliary adjustment. Full polysomnography is not the only method that can adequately adjust the CPAP pressure (Figure 2). These procedures could lead to considerable savings in cost and to significant reductions in the waiting lists.

Conflict of Interest Statement: J.F.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.J. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; F.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; C.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; L.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; F.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.M.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Acknowledgment: The authors are indebted to Dr. D. O. Rodenstein and GlaxoSmithKline for their technical help and to Veronica Rodrír the translation and preparation of the manuscript.

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Juan F. Masa, Antonio Jiménez, Joaquin Durán, Francisco Capote, Carmen Monasterio, Mercedes Mayos, Joaquin Terán, Lourdes Hernández, Ferrán Barbé, Andrés Maimó, Manuela Rubio, and José M. Montserrat

San Pedro de Alcántara Hospital, Cáceres; Hospital de Valdecilla, Santander; Txagorritxu Hospital, Vitoria; Virgen del Rocío Hospital, Sevilla; Hospital de Bellvitge, Sant Pau Hospital, and Clinic Hospital, Barcelona; General Yagüe Hospital, Burgos; Son Dureta Hospital, and Joan March Hospital, Palma de Mallorca, Spain

(Received in original form December 3 1, 2003; accepted in final form July 27, 2004)

Supported by ISCIII-RTIC-03-11, JUNTAEX-IPR00A064, and SEPAR.

The authors are members of the Spanish Group of Breathing Sleep Disorders.

The authors acknowledge the cooperation of the following group: Alejandro Pedro-Mingo, GlaxoSmithKline, Madrid, Spain; Agustín Sojo, San Pedro de Alcántara Hospital, Cáceres, Spain; Rosario Carpizo and Marta Cabello, Hospital de Valdecilla, Santander, Spain; Ramón Rubio and Germán de la Torre, Txagorritxu Hospital, Vitoria, Spain; Carmen Carmona and Georgina Botebol, Virgen del Rocío Hospital, Sevilla, Spain; María Somoza and Marina Lumbierres, Hospital de Bellvitge, Barcelona, Spain; Fátima Morante and Joaquin Sanchis, Sant Pau Hospital, Barcelona, Spain; Mónica Gonzalez and M, L. Alonso Alvarez, General Yagüe Hospital, Burgos, Spain; and Lola R. Mayoralas and Margalida Bosch, Son Dureta Hospital, Palma de Mallorca, Spain.

Correspondence and requests for reprints should be addressed to Juan F. Masa, M.D., C/ Rafael Alberti 12, 10005 Caceres, Spain. E-mail: fmasa@separ.es

This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Am J Respir Crit Care Med Vol 170. pp 1218-1224, 2004

Originally Published in Press as DOI: 10.1164/rccm.200312-1787OC on July 28, 2004

Internet address: www.atsjournals.org

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