Abstract
Objective:
Efficient diagnosis and treatment of obstructive sleep apnea (OSA) can be difficult because of time delays imposed by clinic visits and serial overnight polysomnography. In some cases, it may be desirable to initiate treatment for suspected OSA prior to polysomnography. Our objective was to compare the improvement of daytime sleepiness and sleep-related quality of life of patients with high clinical likelihood of having OSA who were randomly assigned to receive empiric auto-titrating continuous positive airway pressure (CPAP) while awaiting polysomnogram versus current usual care.
Methods:
Serial patients referred for overnight polysomnography who had high clinical likelihood of having OSA were randomly assigned to usual care or immediate initiation of auto-titrating CPAP. Epworth Sleepiness Scale (ESS) scores and the Functional Outcomes of Sleep Questionnaire (FOSQ) scores were obtained at baseline, 1 month after randomization, and again after initiation of fixed CPAP in control subjects and after the sleep study in auto-CPAP patients.
Results:
One hundred nine patients were randomized. Baseline demographics, daytime sleepiness, and sleep-related quality of life scores were similar between groups. One-month ESS and FOSQ scores were improved in the group empirically treated with auto-titrating CPAP. ESS scores improved in the first month by a mean of −3.2 (confidence interval −1.6 to −4.8, p < 0.001) and FOSQ scores improved by a mean of 1.5, (confidence interval 0.5 to 2.7, p = 0.02), whereas scores in the usual-care group did not change (p = NS). Following therapy directed by overnight polysomnography in the control group, there were no differences in ESS or FOSQ between the groups. No adverse events were observed.
Conclusion:
Empiric auto-CPAP resulted in symptomatic improvement of daytime sleepiness and sleep-related quality of life in a cohort of patients awaiting polysomnography who had a high pretest probability of having OSA. Additional studies are needed to evaluate the applicability of empiric treatment to other populations.
Citation:
Drummond F; Doelken P; Ahmed QA; Gilbert GE; Strange C; Herpel L; Frye MD. Empiric auto-titrating CPAP in people with suspected obstructive sleep apnea. J Clin Sleep Med 2010;6(2):140-145.
Keywords: Auto-CPAP, OSAS, OSA, obstructive sleep apnea, Epworth sleepiness Scale, Functional Outcomes of Sleep Questionnaire
Untreated obstructive sleep apnea syndrome (OSAS) is associated with significant morbidity and mortality,1–8 mandating prompt recognition and timely treatment. Current standards of care include clinical assessment followed by 1 or more in-laboratory attended polysomnography studies.9
BRIEF SUMMARY
Current Knowledge/Study Rationale: We observed that the waiting times for overnight sleep studies can delay treatment of patients with obstructive sleep apnea and we wished to find a way to expedite treatment. This study aimed to evaluate the safety and efficacy of empiric auto-titrating CPAP in patients awaiting a sleep study who clinically had a high likelihood of having sleep apnea and no comorbidities.
Study Impact: This study suggests that empiric treatment with auto-titrating CPAP can reduce the time to effective treatment of OSA while awaiting overnight polysomnography. This study shows that empiric treatment of suspected OSA with auto-titrating CPAP is safe and effective.
Currently, the United States has the highest ratio of sleep laboratory beds per capita in the world, performing more than 1.1 million polysomnography annually.10 However, with obesity on an exponential rise, now estimated at 31% of all Americans,11,12 significant pressure on sleep-bed capacities exist.
A variety of alternatives to in-laboratory intervention have been proposed. Clinical prediction rules have helped target patients with OSA.13,14 Home monitoring is actively implemented in Europe. Although gaining momentum, evidenced-based US guidelines suggest that typical home monitoring is insufficiently robust for clinical use.15 Recent reimbursement approval may change this dynamic.
Some clinical trials16,17 have suggested that empiric treatment with automatically adjusting continuous positive airway pressure (auto-CPAP) is a reasonable choice for patients with a high clinical likelihood of having OSA. Other investigators have suggested the use of a CPAP-challenge as a potential diagnostic tool.18 Few have published objective efficacy outcomes using these approaches.
To evaluate the efficacy of empiric auto-CPAP in patients awaiting polysomnography, we conducted a trial comparing empiric auto-CPAP therapy to usual care in consecutive patients referred for polysomnography. The primary outcomes included the Epworth Sleepiness Scale (ESS) and Functional Outcomes of Sleep Questionnaire (FOSQ).
METHODS
Patients
Consecutive patients referred for polysomnography at the Ralph H. Johnson VA Medical Center in Charleston, SC, from April 2004 to February 2006 were evaluated. Patients were excluded for age greater than 80 years, a history of congestive heart failure, myocardial infarction in the prior 6 months, chronic obstructive pulmonary disease with a forced expiratory volume in 1 second of less than 60% predicted, stroke, alternate sleep diagnosis, or a prior diagnosis of OSA. Those responding to the telephone inquiry were screened with the Berlin questionnaire13 and offered enrollment if 2 or more categories of the Berlin questionnaire were positive.
Study Design
This prospective, randomized, controlled pilot trial was approved by the Medical University of South Carolina Institutional Review Board for Human Research and the Ralph H. Johnson Veterans Administration Research Committee. Once enrolled, subjects were randomly assigned by sealed envelope to either the auto-CPAP group or the usual-care group. Primary endpoints were the ESS score19 and the FOSQ score20 in the 2 groups at various time points. A secondary endpoint was the time to begin treatment of OSAS.
Instruments
The ESS
The ESS18 is a validated questionnaire that scores the subjective likelihood of dozing in 8 distinct situations ranging from 0 (no likelihood) to 3 (high likelihood). The maximum possible score is 24, and normal is considered by most investigators as 8 or less. Although an imperfect tool,21 the ESS is widely used to track changes in daytime hypersomnolence during therapy for OSAS.22,23
The FOSQ
The FOSQ is a 30-item self-report tool designed to assess the impact of excessive daytime somnolence on activities of daily living.19 Higher scores suggest less negative impact. FOSQ scores increase with OSAS therapy.24 A normal score has been estimated to be at least 18.20,25
Protocol
Eligible patients agreeing to participate were seen in an initial clinic visit during which informed consent was obtained and a physical examination performed. Patients completed the ESS and FOSQ prior to randomization. Patients were randomly assigned by sealed envelope to either the auto-CPAP group or the usual-care group. A flow diagram showing the study protocol and the number of patients at each point is presented as Figure 1.
Figure 1.
Flow diagram for the research protocol.
Auto-CPAP Group
Subjects randomly assigned to the auto-CPAP group were issued a cost-free auto-CPAP unit on the day of randomization (Respironics Remstar-Auto, Murraysville, PA).The pressure range was set from +5 to +20 cm H2O. Mask fitting and instructions on use were provided by a CPAP coordinator.
At 1 month from randomization and initiation of auto-CPAP, subjects returned to the clinic and completed a second ESS and FOSQ and a questionnaire about their symptomatic satisfaction with auto-CPAP and compliance. Subjects then remained on auto-CPAP and awaited an attended in-laboratory polysomnogram and CPAP titration. Approximately 1 month after polysomnography, patients returned to the clinic and completed the third and final ESS and FOSQ. At that time, they were placed on fixed CPAP based on the results of their in-laboratory studies, and their involvement in the study protocol ended.
Usual-Care Group
Subjects randomly assigned to the usual-care group completed the second ESS and FOSQ by mail approximately 1 month after randomization and continued to wait for in-laboratory polysomnography. Next, an attended in-laboratory polysomnogram was performed, and fixed-pressure CPAP was titrated via a split-night study or subsequent full-night CPAP titration. Fixed-pressure CPAP was then prescribed if indicated. Approximately 1 month after starting CPAP, patients were seen in the clinic and completed the third and final ESS and FOSQ. Their involvement in the study then ended.
Polysomnography and CPAP Titration
All patients underwent attended polysomnography and CPAP titration as they would have had they not been enrolled in the study. American Academy of Sleep Medicine scoring procedures were used. Hypopneas were scored with a 50% reduction in flow associated with an arousal or desaturation of 3%. Due to the high pretest probability for OSA and limited bed capacity, most sleep studies were split-night studies.
Data Analysis
The 2 primary endpoints were the ESS and FOSQ scores in the 2 groups. An intention-to-treat analytic strategy included all patients in each group.
Primary data were analyzed using a 2-tailed student t test or 2-tailed Fisher exact test for categorical data and reported as mean ± SD. Missing data was imputed from baseline data using last observation carried forward. Paired t tests were used to compare ESS and FOSQ scores with their corresponding previous time points using p values adjusted by Bonferonni correction for multiple tests. All statistical analyses were performed using SAS version 9.1.3 (SAS Institute, Inc., Cary, NC) and JMP version 5 (SAS Institute, Inc.).
RESULTS
Baseline Patient Characteristics
One thousand twenty patients were referred for polysomnography between April 2004 and February 2006. OSAS had been previously diagnosed in 447 (44%) and they were therefore excluded. Another 234 (23%) patients were excluded based on other screening criteria. The remaining 339 (33%) patients were potential research subjects. Of these, 109 responded to an initial telephone inquiry, were eligible, and enrolled. Subjects were randomly assigned to auto-CPAP (N = 54) or usual care (N = 55). Table 1 shows the enrollees' demographic features, which did not differ significantly between the 2 groups.
Table 1.
Baseline Characteristics
| Auto-CPAP (n = 54) | Usual Care (n = 55) | p value | |
|---|---|---|---|
| Age, y | 55.4 ± 10.3 | 55.0 ± 13.7 | 0.44 |
| Men (%) | 96 | 91 | 0.67a |
| Race (n) | 0.22a | ||
| African American | 21 | 14 | |
| Caucasian | 33 | 41 | |
| BMI, kg/m2 | 35.3 ± 6.8 | 34.9 ± 5.4 | 0.30 |
| Mallampati Score | 3.07 ± 1.0 | 3.25 ± 0.9 | 0.15 |
| Neck size, in | 18.0 ± 1.5 | 17.8 ± 1.5 | 0.27 |
| Baseline Questionnaires, scores | |||
| ESS | 14.8 ± 4.9 | 14.1 ± 5.0 | 0.23 |
| FOSQ | 14.0 ± 3.6 | 14.3 ± 3.3 | 0.30 |
Data are shown as mean ± SD, except men, which is percentage, and race, which is number. CPAP refers to continuous positive airway pressure; BMI, body mass index; ESS, Epworth Sleepiness Scale; FOSQ, Functional Outcomes of Sleep Questionnaire.
Two-tailed Fisher exact test.
Polysomnography
Eighty-six subjects (79%) completed the entire protocol, including polysomnography: 42 (78%) in the auto-CPAP group and 44 (80%) in the usual-care group. This 80% completion rate is comparable to the completion rate for sleep studies in our VA patient population. A total of 23 patients did not complete the protocol: 12 (22%) in the auto-CPAP group, and 11 (20%) in the usual-care group. Reasons given for not completing the protocol included patients seeking care elsewhere, moving outside of the service area, changing their minds about having a sleep study, and withdrawal from the research protocol.
Of the patients undergoing polysomnography, 82 (95%) met diagnostic criteria for OSAS with an apnea-hypopnea index (AHI) of more than 5 per hour and symptoms of excess daytime sleepiness. Four patients (5%) did not meet diagnostic criteria for OSAS: 3 in the usual-care group and 1 in the auto-CPAP group. The AHI for these 4 patients ranged from 3.2 to 4.3. The results of the attended polysomnograms for the 2 groups are collated in Table 2.
Table 2.
Results of Attended Polysomnography
| Auto-CPAP (n = 42) | Usual Care (n = 44) | p value | |
|---|---|---|---|
| AHI | 43.8 ± 30.9 | 37.0 ± 29.1 | 0.15 |
| AHI > 5/h | 97.6 | 95.1 | 0.62a |
| Min SaO2, % | 87.2 ± 6.7 | 81.4 ± 10.8 | 0.002 |
| CPAP pressureb | 10.3 ± 2.4 | 9.3 ± 2.5 | 0.07 |
Data are shown as mean ± SD, except apnea-hypopnea index (AHI) > 5, which is percentage. SaO2 refers to the minimum oxyhemoglobin concentration.
Two-tailed Fisher exact test.
The recommended continuous positive airway pressure (CPAP) pressure by titration included 32 in the Auto-CPAP group and 34 in the usual-care group.
Efficacy of Empiric Auto-titrating CPAP
At the baseline evaluation, the groups did not differ in ESS or FOSQ scores (see Table 1). At the second time point (approximately 1 month after enrollment), ESS scores improved in the auto-CPAP group from 14.8 ± 4.9 to 11.6 ± 5.4 (mean improvement 3.2, 95% confidence interval [CI] −1.6 to 4.8) but was unchanged in the usual-care group (14.1 ± 5.0 to 14.1 ± 4.7) (p < 0.001 in comparison of treatment effects).
FOSQ scores also improved in the auto-titrating CPAP group, from 14.0 ± 3.6 to 15.5 ± 3.0 (Mean improvement 1.5, 95% CI 0.5 to 2.7); whereas, in the usual-care group, the FOSQ score was unchanged (14.2 ± 3.3 to 14.2 ± 3.5; p = 0.02 in comparison of treatment effects).
At the final time point after the attended polysomnogram and CPAP titration, both the auto-CPAP and usual-care groups showed significant improvement over their respective initial ESS and FOSQ scores. The final ESS was not different between the auto-CPAP and usual-care groups (11.1 ± 5.6 vs 12.7 ± 5.0, respectively, p = 0.13). The final FOSQ was similar between auto-CPAP and usual-care groups (15.7 ± 3.1 vs 14.6 ± 3.8, respectively, p = 0.10)
In an effort to compare efficacy of empiric auto-CPAP more directly to usual care, the ESS and FOSQ data for the auto-CPAP group after 1 month of therapy (data point 2) were compared to the ESS and FOSQ data for the usual-care group after those patients had been on CPAP for approximately 1 month (data point 3). No difference was found between the ESS (11.6 ± 5.4 and 12.7 ± 5.0; p = 0.25) or the FOSQ (15.5 ± 3.0 and 14.6 ± 3.8; p = 0.17) for the auto-CPAP group and usual-care group, respectively. These data are presented in Figure 2.
Figure 2.
Results of the Epworth Sleepiness Scale (ESS) and Functional Outcomes of Sleep Questionnaire (FOSQ) for the auto-continuous positive airway pressure (CPAP) and usual-care groups (mean ± SD) at the 3 study time points.
These results show significant and comparable improvement following treatment in both groups. Improvement in the auto-CPAP group was achieved at an earlier time point.
Safety and Complications
There were no subject deaths or cerebrovascular accidents during the study period. Five patients (12%) in the auto-CPAP group and 4 (9%) in the usual-care group were admitted to the hospital for chest pain. All but 1 had negative cardiac workups. One patient in the usual-care group underwent coronary stent placement for non–ST-elevation MI. No motor vehicle crashes or other catastrophic adverse events were reported.
Time to Treatment
Patients randomly assigned to auto-CPAP began treatment for OSA on the day of randomization and waited an average of 184 ± 143 days for polysomnography. Patients randomly assigned to usual care waited an average of 144 ± 97 days for polysomnography and were started on CPAP within 30 days of polysomnography.
DISCUSSION
We found empiric auto-titrating CPAP to be effective in reducing sleepiness and improving the quality of life of patients with a high likelihood of having OSA while awaiting a polysomnogram. The degree of improvement was comparable to usual care with attended in-laboratory diagnostic polysomnography and CPAP titration. Furthermore, auto-CPAP appears to be safe when used empirically in select patients and resulted in a significant reduction in time to treatment.
Despite optimal therapy in both treatment groups, many patients did not achieve normal measures of wakefulness and sleep-related quality of life. This pattern has been observed in other studies as well.26 Weaver et al.27 assessed patients with OSA before and 3 months after treatment with CPAP using the ESS, FOSQ, and Multiple Sleep Latency Test. In that study, 52% of patients using CPAP for 6 hours per night remained sleepy by objective Multiple Sleep Latency Test measurement, and 22% remained sleepy by subjective assessment. Patients may report sleepiness due to other sleep-related problems, such as inadequate duration or frequent arousals. Patients may also perceive symptoms of unrelated comorbid illnesses, such as fatigue, lethargy, or weakness, as sleepiness. Permanent changes in the sleep and wake mechanisms of some patients with OSA are also implicated.28 In our VA population of predominantly older men with comorbid illnesses, the ability of the ESS and FOSQ to completely normalize with treatment of OSA may be limited despite effective therapy. Inadequate compliance may have also contributed to residual sleepiness in our study population.
We relied on the Berlin score to help determine OSA likelihood. The success of the Berlin instrument to identify OSA in this study was 95%, higher than many previous reports. This likely is due to the high prevalence of OSA in patients referred to our laboratory. It is unknown whether current screening tools are sufficiently robust to predict auto-CPAP responsiveness in populations with a lower prevalence of OSAS. Moreover, the success of empiric auto-CPAP in this study is at least in part related to the high pretest probability for OSA and the exclusion of patients at risk for having central apnea.
Treatment with CPAP prior to polysomnography has been associated with a reduction in the AHI felt to be related to a decrease in airway inflammation and edema.30 We did not observe any significant difference in the results of polysomnography in the 2 groups despite treatment with auto-CPAP for an extended period prior to polysomnography. This could be related to differences in auto-CPAP and fixed CPAP, differences in the severity of disease in the population studied, or that the population size was not adequate to show such differences.
Most studies of patients with confirmed OSA have shown comparable efficacy between auto-CPAP and fixed-CPAP.31–40 We evaluated efficacy of empiric auto-titrating CPAP in terms of participant sleepiness and quality of life, as measured by ESS and FOSQ. Although there is evidence to suggest variability in the ESS of individual patients over multiple administrations,41 such variability should have occurred in both groups equally.
A small group of our patients completely normalized their ESS and FOSQ on auto-titrating CPAP within 1 month of therapy. Although not evaluated in this study, individuals treated empirically with auto-CPAP who become completely asymptomatic might be able to entirely forgo an attended in-laboratory polysomnogram and CPAP-titration study. The safety and efficacy of long-term empiric auto-CPAP therapy or empiric fixed-CPAP therapy needs to be assessed.
There were no adverse events related to the use of empiric auto-titrating CPAP during this study. However, the study was not powered to directly compare survival or event-free survival. In the future, a longitudinal study of greater duration and magnitude could be conducted to directly compare long-term outcomes in empiric auto-titrating CPAP therapy and usual care. Improvement in mortality is proven for usual-care CPAP treatment of OSA but has not yet been studied in patients treated empirically with auto-CPAP.
Limitations
Although data from this study suggest a role for empiric auto-titrating CPAP, this study is limited in some ways. The study was conducted in a population with a high pretest probability for having OSA and in the setting of long wait times for diagnosis and treatment of OSA. These conditions may not exist at many sleep centers. The high pretest probability for having OSA was, however, ideal for evaluating efficacy of empiric treatment. Likewise, the long wait time resulted in empiric treatment lasting several months, whereas, at many sleep centers, it may have lasted only a few weeks. Although these factors make for an excellent population in which to study empiric treatment, it also limits the ability to generalize our findings. Similar studies in other patient populations and for longer periods are needed.
Furthermore, of the 1020 patients referred for a polysomnogram, only 109 were enrolled in the study. Many patients already had a diagnosis of OSA (n = 447). However, 234 were excluded due to comorbid illness. Although empiric treatment appears to be safe in the group studied, patients with comorbid disease that would put them at risk for having central apnea were excluded. This limitation of the study population was felt to be necessary for patient-safety reasons.
Objective measures of improvement and compliance were not utilized and would have considerably strengthened our findings. Objective compliance monitoring was not available at the study center at the time the study was conducted. Objective measures of improvement (e.g., maintenance of wakefulness testing or driving simulation) likewise were not available at the study center at the time of the trial.
Although patient follow-up was not perfect, the difference in ESS scores at 1 month is striking, despite statistical challenges imposed by an intention-to-treat study design. Furthermore, the completion rate for the study of about 80% mirrors the completion rate for patients referred for a sleep study.
In summary, both the degree of improvement and the number of patients who improved were similar between empiric auto-titrating CPAP and usual-care groups. Symptomatic benefit in ESS and FOSQ occurred in more than 80% of both groups, comparable with typical success rates of fixed-pressure CPAP.42 Further studies are needed to better define the role of empiric auto-CPAP in the treatment of patients with sleep disordered breathing.
DISCLOSURE STATEMENT
This was not an industry supported study. The authors have indicated no financial conflicts of interest.
ACKNOWLEDGMENTS
This material is the result of work supported with resources and the use of facilities at the Ralph H. Johnson VA Medical Center, Charleston, SC.
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