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* From the Departments of Medicine (Dr. Loredo) and Psychiatry (Dr. Ancoli-Israel), University of California San Diego, San Diego, CA; and the Department of Psychiatry (Dr. Dimsdale), Veterans Affairs San Diego Healthcare System, San Diego, CA.
Correspondence to: José S. Loredo, MD, UCSD Medical Center, Department of Medicine, 200 West Arbor Dr, San Diego, CA 92103-8378; e-mail: jloredo{at}ucsd.edu
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Abstract |
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Patients: Forty-eight CPAP-naive OSA patients were evaluated. None were receiving antihypertensive medications, and none had major medical illnesses.
Design: Patients were randomized to receive either CPAP or placebo CPAP (CPAP at an ineffective pressure) for 7 days in a double-blind fashion. Forty-one patients completed the protocol. Sleep quality variables, arousals, sleep arterial oxygen saturation (SaO2), and respiratory disturbance index (RDI) were assessed at baseline, after 1 day of treatment, and after 7 days of treatment. Repeated measures analysis of variance was used to evaluate the effects of treatment, time, and the interaction of the two.
Results: As expected, CPAP lowered RDI and number of arousals, and increased SaO2 over time (p = 0.001). Contrary to expectations, both CPAP and placebo CPAP had comparable effects on sleep quality as assessed by sleep architecture, sleep efficiency, total sleep time, and wake after sleep onset time.
Conclusions: This study confirms the effectiveness of CPAP in lowering the number of arousals and the RDI, and in raising SaO2. However, our data suggest that short-term CPAP is no different than placebo in improving sleep architecture. Further evaluation of the effectiveness of CPAP using a suitable placebo CPAP in prospective randomized studies is needed
Key Words: continuous positive airway pressure • obstructive sleep apnea • placebo continuous positive airway pressure • sleep architecture • sleep quality
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To determine the effectiveness of CPAP in improving sleep quality in patients with OSA, we randomly assigned OSA patients to receive CPAP or placebo CPAP in a double-blind fashion. We hypothesized that CPAP would improve sleep architecture, respiratory disturbance index (RDI), number of arousals, and arterial oxygen saturation (SaO2).
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Experimental Design
Potential OSA subjects were prescreened with an unattended
overnight home sleep study using a sleep recording system (NightWatch;
Healthdyne Technologies; Marietta, GA). If their RDI was 
20,
the subjects then were admitted to the clinical research center at 5
PM for a confirmatory overnight full polysomnography (PSG)
sleep recording. If on a preliminary interpretation of the PSG
recording the RDI was 20, subjects were considered to have
significant OSA and were admitted into the study.
On the second night of admission, qualifying subjects were randomized to receive either traditional nasal CPAP or placebo CPAP for 7 days in a double-blind fashion
PSG was repeated on the third night after admission (after 1 day of treatment), and patients then were discharged home for 1 week of continuing CPAP or placebo CPAP home treatment. Research staff were in frequent contact with patients to answer questions about mask placement and to encourage compliance with the therapy. All CPAP units (Horizon, model 7353D; DeVilbiss; Somerset, PA) had a hidden compliance clock, which allowed the measurement of the amount of time the CPAP units were switched on.
On the 11th day of the protocol (after 7 days of treatment) the subjects were readmitted to undergo a fourth sleep study
Sleep Recordings
Sleep was recorded using a polysomnograph (Model 4412P; Nihon
Koden; Irvine, CA) that recorded central and occipital EEG, bilateral
electrooculogram, submental and tibialis anterior electromyogram (EMG),
ECG, nasal/oral airflow using a thermistor, and respiratory effort
using chest and abdominal inductance belts.
SaO2 was monitored using a pulse
oximeter (Biox 3740; Ohmeda: Louisville, CO) and was analyzed using
computer software (Profox; Escondido, CA).11
Sleep records
were scored according to the criteria of Rechtshaffen and
Kales.12
Apneas were defined as decrements in airflow of 90% from baseline
for a period 10 s. Hypopneas were defined as decrements in airflow
of 50% but < 90% from baseline for a period 10 s. The
number of apneas and hypopneas per hour were calculated to obtain RDI.
The definition of an arousal from sleep was based on the criteria
published in the 1992 American Sleep Disorders Association
Report on EEG arousals13
with some modifications. An
arousal was defined as a shift in EEG frequency to alpha or theta for
1.5 s but < 15 s whether or not it was associated with a rise in
chin EMG amplitude, a rise in leg EMG activity, or both. Before an
arousal could be scored, the subject had to have been sleeping for a
minimum of 10 s in the same or the contiguous sleep epoch. A
minimum of 10 s of intervening sleep was necessary to score a
second arousal. Shifts in EEG frequency were scored from either or both
of the EEG derivations (occipital or central). The abrupt appearance of
K-complexes was scored as an arousal only if they were accompanied by
an obvious shift in EEG frequency. The total arousal index was
calculated by dividing the number of arousals by the total sleep time
(TST).
CPAP and Placebo CPAP Titration
In the CPAP-treated group, optimal effective nasal CPAP pressure
to minimize sleep apnea was obtained by conventional manual overnight
CPAP titration during monitoring with PSG. After standard PSG hookup,
the patient was fitted with an appropriately sized nasal CPAP mask
(Respironics; Monroeville, PA). After orientation to the function of
nasal CPAP, the patient was allowed to sleep while the CPAP pressure
was maintained at 2 cm H2O. On the appearance of
unequivocal obstructive apneas or hypopneas, the CPAP pressure was
increased in increments of 2 cm H2O until the
respiratory events were abolished or until a CPAP pressure of 8 to 10
cm H2O was reached. Further pressure titration
then was done in increments of 1 cm H2O based on
the presence of apneas, hypopneas, or snoring associated with arousals.
The titration was considered ended when most respiratory events were
controlled with CPAP while the patient was in the supine position and
in the second or third rapid eye movement (REM) sleep period, or until
a pressure of 20 cm H2O had been reached. If the
frequency of respiratory events was not reduced by > 50%, the CPAP
therapy was considered suboptimal and the patient was discharged from
the study.
Placebo-CPAP subjects underwent a mock titration night during which CPAP pressure was set at 2 cm H2O using a CPAP mask (Respironics) containing three 1/4-inch drill holes to create a large air leak. The pressure at the mask varied from 2 cm H2O at end-expiration to 1.5 cm H2O during inspiration. During this procedure, sleep was monitored with standard PSG as in the CPAP titration protocol, but the pressure was kept at 2 cm H2O.
Statistical Analysis
Only subjects with a confirmed RDI 20 on overnight PSG were
included in the analysis. Differences between and within the two
treatment groups over time were assessed using repeated-measures
analysis of variance. This analysis allowed us to test for a main
effect of treatment CPAP vs placebo CPAP, time effect (prior to
treatment, after 1 day of treatment, and after 7 days of treatment),
and the interaction of time by treatment. A time effect alone would
imply that CPAP itself had no specific effect on the variable of
interest. A CPAP-by-time interaction would imply that the CPAP-treated
group, in particular, responded to treatment over time with a
significant response. Statistical analyses were performed using a
statistical computer software package (SPSS for Windows 9.0; SPSS Inc;
Chicago, IL).
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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20. The subjects were
predominantly (75%) male. The subjects were moderately obese with an
average weight of 136% of ideal body weight using Metropolitan Life
Insurance Company norms.10
There were no differences
between groups in age, BP, and RDI at baseline. Subjects treated with
CPAP had a significantly greater body mass index (BMI; p = 0.024;
Table 1 ), and lower mean sleep SaO2
at baseline ( p = 0.011; Table 2 ). Both patient groups complied equivalently with CPAP or placebo
treatment over the 1-week interval at home (> 5 h per night use for
each group). The two treatment groups did not differ at baseline on
sleep architecture, TST, wake after sleep onset time (WASO), total
arousal index, or sleep efficiency (Table 2)
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There was a significant time effect on sleep latency (p = 0.027), percentage of stage 1 sleep (p < 0.001), percentage of slow-wave sleep (SWS; p = 0.001), percentage of REM sleep (p = 0.008), and sleep efficiency (p = 0.031). TST and WASO did not change with time or treatment. There was no correlation between compliance and the posttreatment sleep architecture variables. Using BMI as a measure of covariance did not alter the results.
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As expected, we found that CPAP effectively reduced RDI and increased mean nocturnal SaO2. CPAP also, as expected, effectively abolished arousals (Table 2) .
Contrary to our expectations, CPAP was not different than placebo CPAP in improving sleep quality as assessed by sleep architecture, sleep efficiency, TST, and WASO. The significant time effect noted in sleep architecture parameters suggests that the benefits noted in both treatment groups were not specific to a CPAP effect. Also, compliance was similar between the CPAP and placebo CPAP groups and was not related to sleep architecture.
Our findings differ from those reported in the literature regarding the effect of CPAP on sleep quality. Uncontrolled sleep studies have reported significant reductions in stage 1 sleep and increases in REM sleep and SWS in OSA patients treated with CPAP.1 2 Improvement in sleep architecture also has been reported in OSA patients using both standard CPAP units and auto-CPAP technology.3 Had we not used a placebo version of CPAP, we would have concluded that nasal CPAP had a robust effect in improving SWS and REM sleep and in reducing stage 1 sleep. That conclusion is not fully supported by our data.
There are two possible confounding factors affecting our findings1 : Laboratory-based sleep studies are known to have a first-night effect,16 17 in which sleep quality tends to be worse than usual during the first night due to the unfamiliar surroundings and equipment. This was suspected in our study, as noted by the high baseline sleep latencies in a population with moderate to severe OSA syndrome. Therefore, an acclimatization effect could have accounted for some of the changes noted in sleep architecture for both the CPAP- and placebo CPAP-treated subjects.2 Another possibility is that the small CPAP pressure (1.5 to 2 cm H2O) used in our placebo CPAP group was having a partial therapeutic effect, as suggested by a significant drop in RDI from baseline to day 1. However, CPAP in the range used in our placebo CPAP is much lower than would be expected to significantly reduce the RDI. Berry and Block18 showed that a minimum CPAP of 4 to 6 cm H2O was required to control the RDI in sleep apnea subjects of comparable weight to ours. Previous reports have demonstrated that a mean CPAP of 4 cm H2O (range, 2.0 to 6.0 cm H2O) is required just to prevent snoring in nonapneic subjects.19 In contrast, the average CPAP required to control sleep apnea in our CPAP-treated group was 10 cm H2O. Also, in a recent abstract publication, Stradling et al20 noted a significant placebo CPAP effect on quality of life using CPAP pressures of < 1 cm H2O.
Despite the intuition that wearing a CPAP mask with ineffective pressure and extra holes in the mask itself is sleep disruptive, placebo CPAP did not adversely affect sleep latencies, RDI, mean sleep SaO2, arousals, sleep architecture, TST, or WASO.
We found six studies in the literature examining the effects of CPAP on OSA that employed some form of placebo control. Four of these studies utilized an oral placebo,6 21 22 23 and one randomized patients to receive nasal cannula air as placebo.24 Only the report by Jenkinson et al20 used a placebo CPAP set-up that provided ineffective levels of CPAP (< 1 cm H2O). In our opinion, the literature pertaining to the effectiveness of nasal CPAP in the treatment of OSA suffers from a lack of appropriate placebo CPAP control trials. Despite the confounding effects of the first-night effect acclimatization and the possible partial treatment by the placebo CPAP set-up, our findings suggest that CPAP, when compared with a suitable placebo, may not be as effective as has been reported in improving sleep architecture abnormalities of the OSA patient.
This study has a number of limitations. We treated patients for only 1 week because we were concerned about exposing OSA patients to ineffective CPAP pressure for prolonged periods of time. It is possible that a longer trial of CPAP could have demonstrated a clear advantage over placebo CPAP in improving sleep architecture. Although the mean RDI was > 40, indicating moderate to severe OSA, we excluded individuals with major medical comorbidity and patients with severe obesity. Perhaps CPAP would have shown a clearer advantage over placebo CPAP in patients with more severe derangement of sleep architecture. As it turned out, subjects randomized to CPAP were more obese and had lower mean nocturnal SaO2, which could imply that their OSA was more severe.
Our null findings concerning CPAP efficacy could reflect insufficient sample size. However, we doubt that sample size accounts for our findings for a number of reasons: First, our sample size was comparable to or better than many studies of sleep architecture response to CPAP. Second, the p values (range, 0.125 to 0.85) for the null findings were far from significant. Third, if in fact we are committing a type II error that would be corrected by a larger sample size, we estimate that we would need to study many more subjects to perceive a significant CPAP by time interaction (sample size, approximately 80 to 330, depending on the variable in question). Such large sample size requirements suggest to us that the magnitude of the short-term effect of CPAP on sleep architecture, if significant, must be small.
Nevertheless, our study confirms the effectiveness of nasal CPAP in correcting OSA and the associated arousals and hypoxia. However, our results suggest that CPAP may not be as effective in improving sleep architecture in the OSA patient during the first 7 days of treatment. Further evaluation of the effectiveness of CPAP using a suitable placebo CPAP in prospective randomized studies is needed.
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Footnotes |
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This research was supported in part by National Institutes of Health grants HL44915, AG02711, AG08415, and RR00827.
Received for publication February 16, 1999. Accepted for publication June 30, 1999.
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This article has been cited by other articles:
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