Otolaryngol Clin N Am

40 (2007) 807–827

Continuous Positive Airway Pressure

for the Treatment of Sleep Apnea
Susmita Chowdhuri, MD
Department of Medicine (11M), John D. Dingell Veterans Affairs Medical Center
and Wayne State University, 4646 John R, Detroit, MI, USA

Obstructive sleep apnea (OSA) syndrome (OSAS) is a major public health

problem [1] with a high prevalence in adult men and women, 2% and 4%, re-
spectively [2]. It is characterized by repetitive closure of the upper airway dur-
ing sleep resulting in cyclical oxygen desaturations and arousals with
subsequent long-term adverse health consequences [3,4]. Continuous positive
airway pressure (CPAP) has become the treatment of choice since its introduc-
tion in 1981 [5]. A CPAP unit consists of a blower that generates positive pres-
sure, which is then delivered by way of a hose through an appropriate interface
to the patient. It functions as a pneumatic splint [6] thereby preventing the up-
per airway from collapsing cyclically during sleep in OSA. Continuous posi-
tive airway pressure is now considered the standard of treatment for OSAS
[7,8]. Although several studies have demonstrated the usefulness of CPAP
for treating OSAS, problems with appropriate patient–CPAP interface and
inadequate adherence often limit its efficacy.

Indications for continuous positive airway pressure therapy in obstructive

sleep apnea
Available evidence supports the use of CPAP for patients who have mod-
erate to severe OSA with respiratory disturbance index (RDI) 15/h or more.
RDI is defined as the number of respiratory events, including apneas, hypo-
pneas, and respiratory effort–related arousals per hour of sleep [9]. The term
RDI is used interchangeably with apnea hypopnea index (AHI) in this arti-
cle. By consensus [9], mild sleep apnea is AHI greater than 5 and 15 or fewer
episodes per hour; moderate sleep apnea, AHI greater than 15 and 30 or
fewer episodes per hour; and severe sleep apnea, AHI greater than 30

E-mail address: schowdh@med.wayne.edu

0030-6665/07/$ - see front matter. Published by Elsevier Inc.

doi:10.1016/j.otc.2007.04.011 oto.theclinics.com
808 CHOWDHURI

episodes per hour of sleep. CPAP probably functions by splinting the upper
airway open by raising the intraluminal upper airway pressure above the
positive critical transmural pressure of the upper airway [10] and increasing
lung volume [11]. In addition to acting as a splint [6,12] for the collapsible
upper airway tube and hence improving nocturnal oxygenation, CPAP pos-
sibly also works by increasing the awake ventilatory drive [13] and the air-
way tone [14]. CPAP eliminates both obstructive and mixed apneas [15].
Patients who have moderate to severe OSA should be treated with CPAP
[16]. In addition to moderate and severe OSA, patients who have mild
OSA in the presence of comorbid factors (eg, symptoms of daytime sleepi-
ness, impaired cognition, mood disorders, or documented cardiovascular
diseases) experience benefit from CPAP therapy [16]. Evidence from large
epidemiologic studies, including the Wisconsin Sleep Cohort [17] and the
Sleep Heart Health Study (SHHS) [18], demonstrated increased risk for hy-
pertension (HTN) even with a mild degree of OSA. The use of CPAP in pa-
tients who have mild OSA who do not have associated symptoms of
sleepiness, cognitive dysfunction, or underlying cardiovascular diseases is
controversial. Many patients who have a mild degree of abnormality do
not have subjective symptoms of sleepiness. In fact, some individuals who
have mild sleep apnea may have complaints of insomnia or may present
with neuropsychologic deficits that are evident only on objective testing
[19,20] that may also warrant therapy with CPAP. Additionally, the risk
for motor vehicle accidents correlates much more highly with AHI than
measures of sleepiness, with evidence of a marked increased risk even in
moderate OSA [21]. Studies have also shown that CPAP objectively im-
proves neuropsychologic functioning even in mild OSA [22,23]. In addition,
we now know from the Wisconsin Sleep Cohort [17] and the SHHS [18] that
even AHI as low as 5/h in asymptomatic subjects poses a risk for HTN,
ischemic heart disease, stroke, and other cardiovascular diseases [4]. In the
SHHS, however, there was no evidence of a dose–response relation between
the AHI and cognitive function between subjects who had mild to moderate
levels of OSA [24]. Controlled outcome studies demonstrating reversal of
cardiovascular morbidity and mortality are few in the mild OSA group.
Longitudinal studies are needed to evaluate these concerns.

Initiation of continuous positive airway pressure

Following a diagnostic nocturnal polysomnography or following the
diagnostic portion of a split-night study, patients who meet diagnostic crite-
ria for OSA and who opt for CPAP undergo CPAP titration in the sleep
laboratory [2,16]. This titration is done while monitoring electroencephalog-
raphy, electrooculography, oronasal airflow, chest wall effort, body posi-
tion, snoring microphone, electrocardiogram, and oximetry. The patient is
initially educated about the indications for CPAP and is allowed to adapt
 CPAP FOR THE TREATMENT OF SLEEP APNEA 809

to the equipment and different masks. An initial short period of desensitiza-

tion before the study is recommended, which allows the patient to get accus-
tomed to the idea of wearing the equipment through the night. An attended
study is most accurate and allows for technologist intervention for mask
leaks, lost leads, and adjustment of CPAP according to body positions
and rapid eye movement (REM) sleep [25,26]. No precise protocol for
CPAP titration exists, but general recommendations have been established.
Usually, one starts at a low pressure of 4 to 5 cm, gradually increasing by 1
to 2 cm every 15 to 20 minutes until the apneas, hypopneas, respiratory ef-
fort–related arousals, and snoring are abolished. Patients who hypoventilate
or who have other comorbidities (eg, chronic obstructive pulmonary disease,
congestive heart failure (CHF), neuromuscular disease) may require in-line
oxygen to correct hypoxia, but generally only after obstructive events have
been eliminated. There is less evidence for the efficacy of CPAP in central
sleep apnea syndromes.
Prediction equations, based on neck circumference, body mass index
(BMI), and AHI, have been suggested for empiric CPAP pressures but these
lack precision [27–29]. They are not accurate enough to distinguish between
patients who do or do not have OSA; however, they may be useful in prior-
itizing patients for split-night polysomnography [29]. In certain situations,
a re-titration study may be indicated, eg, when there is weight change greater
than 15%, persistent or recurrent symptoms, and for reassessment after up-
per airway surgery or treatment with oral appliances (OAs) [25]. During the
course of a titration study, positive airway pressure may need to be in-
creased in the supine position or during REM sleep. One study noted that
in most patients who had OSA, the optimal CPAP level was significantly
higher in the supine position than it was in the lateral position [26]. This
finding was true for REM and non-REM sleep, for obese and non-obese
patients, for patients who had different degrees of severity, and for young
and old OSA patients. The authors concluded that no CPAP titration
should be considered complete without the patient having slept in the supine
posture during REM sleep. Nevertheless, the differences in optimal CPAP
between the supine and lateral postures were similar, ranging between
2.31 and 2.66 cm H2O.
Frequently, diagnostic testing and CPAP titration can be accomplished in
a split-night fashion for patients who have moderate to severe OSA. A split-
night protocol, consisting of an initial diagnostic portion followed by a ther-
apeutic titration, can determine the effective CPAP pressure [8,30],
especially in patients who have an AHI greater than 20/h. But a split-night
study may be unsatisfactory in some situations, such as when the duration
of CPAP titration was short and when REM sleep was not achieved during
the titration. Patients who have mild OSA would be more likely to have un-
successful split-night studies because more prolonged monitoring would be
needed to establish the diagnosis [31]. Conversely, a study using classic symp-
toms of OSAS as the indication for split-night studies found that there were
810 CHOWDHURI

no differences in long-term CPAP use compared with full-night studies and

that it resulted in shorter time from referral to treatment [32].

Special positive airway pressure delivery systems

Bilevel positive airway pressure (PAP) systems allow for independent
adjustment of inspiratory and expiratory pressures and can provide partial
spontaneous ventilatory assist in various settings, including obesity
hypoventilation, neuromuscular disease, and reduced ventilatory drive [33].
Bilevel PAP may be indicated when patients cannot tolerate CPAP because
of discomfort while exhaling against positive pressure or when aerophagia is
problematic. Bilevel pressure is not routinely indicated as an alternative to
CPAP in OSA because, although the mean pressure used may be lower, in
most cases this does not affect compliance or increase the hours of usage [34].
Advances in CPAP technology have yielded CPAP devices with sensors,
which indirectly detect airflow and automatically adjust pressure according
to built-in algorithms. In theory, such autotitrating PAP (APAP) devices au-
tomatically adjust the pressure up or down to maintain upper airway pa-
tency at the lowest effective pressure. APAP devices differ greatly in their
detection algorithms, limiting comparison between machines. Devices using
differing technologies may yield dissimilar results in a given patient. The ef-
ficacy of APAP for the treatment of OSAS has been reviewed in detail
[35,36] and the American Academy of Sleep Medicine (AASM) has made
recommendations [37] regarding the use of these devices. APAP may be
used for treatment only after an attended titration with standard CPAP
or APAP is completed. It is not currently recommended for patients who
have CHF, significant lung disease, obesity, hypoventilation, or respiratory
failure. Patients who do not snore (because of surgery or naturally) should
not be titrated with an APAP device that relies solely on vibration or sound
to monitor compromised airflow. Mask leaks may prevent adequate titra-
tion with APAP. APAP is not recommended for use in split-night studies.
Studies have suggested that APAP therapy reduces the mean PAP require-
ments, which is believed to positively impact treatment adherence. The effi-
cacy of three different methods of CPAP deliverydautotitration pressure
throughout, autotitration pressure for 1 week followed by fixed pressure
thereafter (at 95th centile), and fixed pressure determined by an algorithmd
was assessed in a randomized prospective study over a period of 6 months,
with patients and investigators blinded to group allocation [38]. There were
no significant differences in any of the outcome measures, including indicators
of daytime sleepiness (Epworth Sleepiness Scale [ESS] scores), maintenance of
wakefulness test, 24-hour blood pressure, general health (short form-36
[SF-36]), and sleep apnea–related quality of life. The pressures in the 95th cen-
tile CPAP and 1 week autotitration pressure groups were higher than in the
algorithm group, but the median pressures were lowest in the 6-month auto-
titration group. A more recent meta-analysis investigated the question of the
 CPAP FOR THE TREATMENT OF SLEEP APNEA 811

efficacy of APAP over CPAP [39]. Specifically, the study investigated the rel-
ative effectiveness of devices in reducing the AHI, reducing the mean airway
pressure, improving subjective sleepiness, and improving treatment adher-
ence in patients who had OSA. Results from nine randomized trials with a to-
tal of 282 patients were analyzed. Compared with CPAP, there was no
significant advantage of APAP in reducing AHI or sleepiness (pooled
APAP-CPAP posttreatment RDI and ESS score ¼ 0.20 events per hour,
95% confidence interval:[0.74, 0.35], and 0.56 [1.4, 0.3], respectively).
The use of APAP reduced the mean applied pressure across the night by 2.2
cm water [1.9, 2.5] compared with CPAP. Adherence with therapy was not
substantially improved with APAP. Compared with standard CPAP,
APAP was associated with a greater reduction in mean pressure but there
were no differences in degree of adherence, ability to eliminate respiratory
events, or ability to improve subjective sleepiness. Given that APAP is
more costly than standard CPAP, the investigators suggested that APAP
should not be considered as first-line chronic therapy in all patients who
have OSA but could be considered in special situations (eg, home titrations,
detection of mouth leak) or in certain subgroups of patients who have
OSA, including patients intolerant of CPAP or patients who have posture-de-
pendent or sleep-stage dependent OSA. A recent Cochrane Review also con-
cluded that auto-adjusting and bilevel devices did not produce a significant
difference in adherence when compared with CPAP [40]. Studies investigating
long-term treatment outcomes with APAP versus CPAP are awaited.
A pressure-relief PAP device (C-Flex, Respironics) was introduced with the
aim of increasing comfort during exhalation to improve treatment adherence.
With C-Flex, the airway pressure alternates between exhalation and inhala-
tion on a breath-by-breath basis such that the pressure is reduced during early
exhalation and increased toward the end of inhalation. A nonrandomized trial
comparing this device with CPAP over a period of 3 months found that adher-
ence was higher in the C-Flex group (4.8  2.4 versus 3.1  2.8 hours, mean 
SD), but without significant differences in subjective sleepiness or functional
outcomes [41]. Additionally, two randomized, controlled, double-blind trials
[42,43] did not find any significant compliance differences at 1 month as deter-
mined by percentage of nights with at least 4 hours of use (80.5%  24% ver-
sus 77.6%  24.8%) and hours of use per night (5.6  1.4 versus 5.6  1.7
hours per night). Similar improvements were seen in scores on the ESS and
Functional Outcomes of Sleep Questionnaire (FOSQ) [42]. Oral dryness
with C-Flex was significantly lower than with constant CPAP but the effect
did not last after 7 weeks [43].

Potential problems with continuous positive airway pressure

The efficacy of CPAP as a treatment modality depends on long-term
compliance, which in turn is related to the frequency of side effects and
812 CHOWDHURI

discomfort with CPAP use, among other factors. The common side effects
of CPAP are related to nasal symptoms of dryness, congestion, sneezing,
and rhinorrhea, which may affect 25% to 65% of the users [44]. Patients
may also complain of sinusitis, conjunctivitis, sore eyes, and red eyes. Other
complaints include claustrophobia and discomfort from the pressurized air,
including difficulty exhaling. Pressure sores may develop on the face from
the mask. Some patients may complain of difficulty tolerating noise from
the equipment. In one study, 50% of the patients complained of at least
one side effect related to the mask, including allergic reaction, abrasion of
the bridge of the nose, or mask air leaks; 65% complained of dryness of
the nose or mouth; sneezing and nasal drip were noted in 35%, nasal con-
gestion in 25% of the subjects, air swallowing in 16%, sinusitis in 8%,
and nosebleed in 4% of the subjects [44]. There was no correlation between
the side effects and the level of pressure used during nasal CPAP. Although
machine noise was noted by 34% of patients in this study, it is probably less
of a problem today with newer, quieter machines. There have been case re-
ports of chest discomfort from the pressure, one case of pneumocephalus
[45], a postcoronary artery bypass pneumopericardium [46], and one case re-
port of meningitis related to recurrent sinusitis [47]. There are no absolute
contraindications for CPAP use but bouts of recurrent acute sinusitis fol-
lowing CPAP use may be a relative contraindication [47]. There is a potential
risk for rebreathing in the event of equipment or electric failure in the ab-
sence of an alarm system [48].

Optimizing continuous positive airway pressure use

Nonadherence patterns
Nonadherence with CPAP is a barrier to effective treatment of OSAS.
From a study of daily covertly monitored patients who had severe OSAS,
50% were consistent users of CPAP, using it more than 90% of the nights
for an average of 6.22  1.2 hours per night. The remaining 50% were in-
termittent users, averaging from 3.45  1.94 hours per night. Intermittent
users had more OSAS symptoms caused by inadequate therapy [49]. The
pattern of nonadherence was established early in treatment (ie, within the
first week of therapy) and compliance at 1 month predicted compliance at
3 months. Kribbs and colleagues [50] found that only 46% of patients
used at least 4 hours of CPAP on 70% of the nights. A 10% differential
existed between mask-on and machine-on time. Patients generally overesti-
mate the hours of CPAP use by about 1 hour. Individual patient self-reports
should thus be considered as unreliable for assessing compliance. Most
CPAP machines have built-in meters to record the duration of time that
the machine has been running or the duration that a mask has been in actual
use. These can be used to objectively measure adherence to CPAP. Monitor-
ing of CPAP adherence by these built-in timers has been recommended as
 CPAP FOR THE TREATMENT OF SLEEP APNEA 813

standard of practice by the AASM [51]. Adherence data can be obtained

and sent to the providers by way of a smartcard or transmission to a website.
This process allows monitoring of CPAP use with immediate intervention
when there is less than optimal use.

Predictors of continuous positive airway pressure compliance

Predictors of continued CPAP use include severity of sleepiness and se-
verity of AHI and snoring. The daily use of nasal CPAP was significantly
correlated to the initial AHI in one study (r ¼ 0.37, P ¼ .013) [52]. Others
have demonstrated that subjective CPAP use correlated with sleepiness
and ESS before treatment but not with any objective index of severity of
OSA [53–55]. Similarly, Scharf and colleagues [56] did not find that long-
term adherence was related to disease severity as measured by the AHI
but was related to an ESS score of more than 10. In one study, long-term
use could be predicted most reliably by the average nightly use of CPAP
during the first 3 months [55]; patients using CPAP for less than 2 hours
per night at 3 months were unlikely to continue with long-term treatment.
More than 85% of the long-term users had an average use of at least 3
hours, however. CPAP use was negatively correlated with ‘‘degree of nui-
sance’’ of CPAP therapy [54]. CPAP mask problems and side effects were
not associated with reduced CPAP use, but complaints of awakenings,
noise, and sore eyes from CPAP correlated negatively with reported use
[55]. In a separate study, frequently identified barriers to treatment use
were nasal stuffiness, claustrophobia, and disturbing the bed partner’s sleep
[54]. Age, gender, socioeconomic status, race, body mass index, or time
spent with oxygen saturation of less than 90% did not predict CPAP use
[56]. Patients used CPAP much more if they were aware of the beneficial ef-
fects of CPAP [52]. Perceived improvement in symptoms after CPAP use has
also been shown to be related to better adherence [56,57]. Although 50% of
the subjects did not perceive problems with concentration, sexual perfor-
mance, sleepy driving, or an accident as related to sleep apnea, more than
60% of the subjects acknowledged most of the benefits of CPAP presented
to them [54]. Overall CPAP use in those taking CPAP home was 68% at 5
years [55].
The type of device does not does not determine compliance. The Co-
chrane Review did not find a significant difference in adherence by type of
device used, whether auto-adjusting PAP, bilevel PAP, or fixed CPAP
[40]. A study investigating the contribution of flexible pressure (C-Flex)
and standard fixed pressure CPAP adherence [41] noted that compared
with fixed-pressure CPAP, adherence with devices using flexible pressure
was almost 1 hour longer during initial use (2 to 4 weeks) and 2 hours longer
with long-term use (9 to 12 weeks). This finding was not replicated in a more
recent study [43], however, where nightly use was similar with both devices
at 7 weeks.
814 CHOWDHURI

Strategies to improve adherence

Adequate education about the disease process and PAP device, mask in-
terface, humidification, and regular follow-up of patients with troubleshoot-
ing of problems can help to improve adherence with PAP use. Measures to
counteract the side effects of CPAP have been found to improve compliance
[58]. Proper mask selection, humidification (see later discussion), nasal ste-
roids and anticholinergic nasal sprays [51], use of chinstrap, pressure
ramp, and, in certain instances, bilevel airway pressure [40,51] or flexible
pressure [41–43] are some of the key interventions.

Type of interface and positive airway pressure device

Available interfaces include nose mask, nasal pillows, full-face mask, and
oral devices. The adequacy and comfort of mask fit and appropriate selection
of pressure level greatly affect compliance. Many different PAP interfaces are
available that are designed to increase compliance. Although the face mask
may be an alternative interface in patients who cannot tolerate nasal CPAP
because of nasal congestion, the number of nights on CPAP were similar re-
gardless of the type of mask used [59]. Conversely, another study noted greater
adherence with nasal versus a full-face mask because of greater comfort and
lower ESS scores [60]. The face mask was associated with fewer complaints
of dry mouth and dry nose, but more complaints of sore eyes, air leaks, and
claustrophobia [60]. Patients who complain of claustrophobia may be given
an oronasal mask, nasal pillows, or oral mask following a desensitization pro-
tocol. When claustrophobia or other CPAP use–related anxiety persists,
desensitization protocols often become essential [61]. Two randomized
controlled trials (RCT) comparing nasal versus the oral mask (Oracle,
Fisher-Paykel) in moderate [62] to severe [63] OSA found no significant differ-
ences in CPAP adherence at one month (0.3 hours per night) or side effects
[63]. Although polysomnographic variables, ESS scores, OSA-related symp-
toms, and CPAP compliance were significantly improved from baseline, these
were not significantly different between the two interfaces. In another study,
however, the main limitations of the Oracle mask were upper airway dryness
and ‘‘rain-out’’ associated with heated humidification, resulting in more drop-
outs [64]. A randomized controlled crossover trial comparing nasal pillows
and nasal masks [65] noted that the nightly minutes of use were similar (nasal
pillows: 223 minutes versus nasal mask: 288 minutes) over a 3-week period in
patients receiving CPAP at 14 cm or less with similar ESS and FOSQ scores.
On the other hand, fewer side effects with less sleep difficulty and air leak
occurred with nasal pillows [65].
Persistence of sleep apnea may occur in patients treated with CPAP. This
underscores the need for regular follow-up and adjustment of mask interface
to treat OSAS. In one study, persistence of sleep apnea was defined as AHI
greater than 10 per hour and occurred in 17% of the study subjects [66].
There were no significant differences between participants who had
 CPAP FOR THE TREATMENT OF SLEEP APNEA 815

persistent OSA and those who had AHI less than 5 per hour with regard to
age, sex, time since diagnosis, reported snoring, change in weight, or quality
of life. Persistence of sleep apnea was related to unresolved mouth or mask
leak [66]. These patients complained of morning headaches and nonrestor-
ative sleep. The AASM recommends close follow-up of patients to trouble-
shoot for mask and PAP device problems and manage side effects, especially
during the first few weeks of PAP use [51].

Heated humidification
The flow of cold air dries the nasal mucosa and may increase nasal airway
resistance. Excessive drying of nasal mucosa has been shown to induce the re-
lease of vasoactive leukotrienes leading to increased resistance and mouth
breathing, which in turn leads to drying of mouth mucosa [67,68]. Humidifi-
cation can be in the form of cold passover humidity or heated humidity. Al-
though both types of humidity provided greater satisfaction compared with
no humidity, patients were more refreshed and complained of fewer adverse
effects, such as dry mouth or dry nose, with heated versus cold humidification
[69,70]. Compliance was improved with heated but not cold humidity but
there was no change in the ESS scores. In these studies, the predictors for
the need for additional heated humidification with nasal CPAP included
age greater than 60 years, drying medication, symptoms of chronic mucosal
disease, and previous uvulopalatopharyngoplasty. Fifty-six percent of the pa-
tients described development of disabling nasal discomfort with nasal CPAP.
Heated humidification was necessary in 50% of the patients complaining of
nasal discomfort after failure of cold humidification [70]. In a recent study,
while heated humidity did not seem to improve long-term (3-month and 12-
month) compliance rates, individual symptoms of dry nose and dry mouth
and throat were significantly lower in the heated humidification group [71].
Radiofrequency reduction of nasal turbinate hypertrophy may benefit nasal
obstruction and hence compliance with CPAP use [72].

Education and cognitive behavioral therapy

Studies have also shown that consistent follow-up, troubleshooting, inten-
sive support, and regular feedback to patients and physicians can improve
CPAP compliance rates to 85% over a period of 6 months [73,74]. Patients
may lack appreciation for their own impairment and the consequences of un-
treated OSA; hence, it is possible that some patients may develop perceptions
that are not conducive to taking responsibility for their own treatment. Edu-
cation with an additional phone call or printed literature about CPAP use can
elicit greater compliance at 4 weeks from patients especially when applied at
the start of CPAP therapy compared with no additional intervention [75]. Ad-
ditionally, an investigator-developed 15-minute videotape, using patients
from different ethnicities discussing misconceptions about sleep apnea and
barriers to use, significantly increased CPAP compliance and return for
1-month clinic visit than that in the control group [76]. In patients who had
816 CHOWDHURI

OSA (mean RDI 54.2  25.5/h), active coping, which included confrontive
coping and planful problem solving, rather than passive coping, was associ-
ated with increased CPAP compliance (nightly CPAP use of 4.4 to 7.7 hours
per night) [77]. Individuals who engaged in active coping strategies with new
and difficult situations had greater CPAP compliance, whereas emotion vari-
ables, such as depressed mood, were unrelated to compliance. Active coping
independently explained 16% of the variance in CPAP compliance, whereas
more than 30% of the variance in CPAP compliance was explained by know-
ing the initial RDI, ESS, and compliance scores. Encouraging patients to use
coping techniques, such as planful problem solving, thus helps to improve
compliance with CPAP [77]. In addition, cognitive-behavioral therapy (two
45-minute sessions) with education regarding the consequences and efficacy
of CPAP has been shown to improve compliance [78]. After 12 weeks of use
subjects in the intervention group used CPAP 7.8 hours per night compared
with 4.6 hours per night in the control group [78]. Hoy and colleagues [74]
found that if patients themselves initiated treatment of sleep apnea, then
they were more likely to be adherent to treatment than if it was at the recom-
mendation of the bed partner.

Treatment outcomes
Several studies have documented that optimal CPAP implementation can
normalize AHI and oxygenation. This process in turn may ameliorate the
cardiovascular and neuropsychologic consequences of OSAS. Studies eval-
uating CPAP-related outcomes have used placebo tablets and sham or pla-
cebo CPAP (at 1 to 3 cm H2O) as control. Placebo tablets are given to the
subjects with the instruction that the tablets will improve their sleep apnea
syndrome [22]. Sham CPAP has been described by Farre and colleagues [79]
as a device that can be used as placebo when assessing the usefulness of
CPAP in treating OSAS. To implement sham CPAP, airflow resistance of
the exhalation port on the nasal mask is almost eliminated by drilling
a hole, leading to decreased pressure (0.4–1cm H2O). When comparing
sham CPAP with no treatment, no significant differences in sleep efficiency,
arousals, and AHI were found. Neither is a perfect placebo, however, be-
cause compliance rates are lower with sham CPAP, whereas a placebo tablet
does not produce the same absolute effect as CPAP. The subsequent para-
graphs summarize the effect of CPAP use on cardiovascular and neuropsy-
chologic outcomes in placebo-controlled studies.

Cardiovascular effects
Studies have demonstrated that OSA is associated with elevated blood
pressure (BP) [4,13]. Randomized placebo controlled trials of CPAP evalu-
ated treatment impact on BP [80–83]. Table 1 summarizes their findings.
 CPAP FOR THE TREATMENT OF SLEEP APNEA 817

Nighttime BP decreased significantly in patients who received active CPAP

versus sham CPAP [80,82,83]. Daytime mean BP also decreased significantly
in active CPAP and placebo CPAP groups [80] in one study, suggesting
a possible placebo response or an inadequate antihypertensive washout
period [80]. Subsequent trials [81,83] have shown that CPAP causes normo-
tensive patients who have sleep apnea to experience significant decreases in
24-hour diastolic BP compared with a placebo tablet over a period of 4 to 9
weeks. Becker [83] and colleagues reported the effect of CPAP on BP in 60
consecutive patients who had moderate to severe OSA (AHI ¼ 62.5  17.8/
h, mean  SD), randomly assigned, to either therapeutic (6–12 cm H2O) or
subtherapeutic nasal CPAP (3–4 cm H2O) for 9 weeks on average. After
treatment for 65.2  49.6 days, the mean arterial BP decreased significantly
by 9.9  11.4 mm Hg with effective CPAP treatment, whereas no relevant
changes occurred with subtherapeutic CPAP. Adequate therapy with nasal
CPAP also may lower nocturnal systolic and diastolic BP in hypertensive
patients who have occult, unrecognized OSAS compared with non-apneic
controls who have HTN [82]. It is postulated that CPAP may mediate these
changes by way of decreased sympathetic nerve activity [84], among other
mechanisms. In a shorter study of 4 weeks of therapeutic CPAP, there
was no significant decline in ambulatory BP in patients who had OSAS
and systemic arterial hypertension undergoing antihypertensive treatment
[85]. The authors noted, however, that the study was designed to specifically
analyze a sample of hypertensive patients who had already well-controlled
BP and may have been underpowered to demonstrate a treatment effect
over a short duration of 4 weeks. CPAP may also modify ejection fraction
in patients with CHF. One month of therapy with CPAP resulted in a 9%
absolute increase in left ventricular ejection fraction, with significant reduc-
tions in left ventricular end-systolic dimension, daytime systolic BP, and
heart rate [86]. CPAP therapy may also improve outcomes in ischemic heart
disease and stroke (see Table 1) [87–92].
Mortality rates in a historical cohort of 871 patients who did not receive
PAP therapy were higher compared with those treated with PAP. Patients
who had OSAS who used PAP for less than 1 hour per day had significantly
lower survival rates compared with patients who had high compliance (O6
hours perday) or even moderate compliance (1 to 6 hours per day) [93]. Pa-
tients died mainly of cardiovascular diseases. Variables that independently
correlated with mortality in a multivariate analysis were PAP use categories:
compliance for greater than 6 hours per day (odds ratio [OR], 0.10; 95% CI,
0.04 to 0.29); compliance for 1 to 6 hours per day (OR, 0.28; 95% CI, 0.11 to
0.69); HTN (OR, 3.25; 95% CI, 1.24 to 8.54); age (OR, 1.06; 95% CI, 1.01
to 1.10); and FEV1 percent predicted (OR, 0.96; 95% CI, 0.94 to 0.98). The
severity of OSAS was not a predictor of death in treated patients but HTN
was a strong predictor of mortality. Long-term prospective studies are
needed that will measure CPAP benefits in cardiovascular outcomes and
mortality rates.
 818
Table 1
Obstructive sleep apnea, risk for cardiovascular disease, and results of treatment with continuous positive air pressure
Author, study Measurements,
design, sample and duration
characteristics of CPAP use Results Comments
Dimsdale, et al [80], Ambulatory daytime Nighttime BP decreased to a greater extent in Possible carryover effect on daytime BP Sham
randomized and nighttime BP patients who received active CPAP (5 mm Hg fall CPAP was used as placebo.
placebo monitoring, 1 in BP, P ¼ .032). Daytime mean BP also
controlled trial, week of CPAP decreased significantly in both active CPAP and

CHOWDHURI
N ¼ 39 placebo CPAP groups.
Faccenda, et al [81], Ambulatory BP, 4 Small but significant drop in mean ambulatory The decline was also greater when CPAP use was
randomized weeks of CPAP diastolic BP after 4 weeks of CPAP (1.5 mm Hg R3.5 hours per night. Oral capsule was used as
crossover trial, fall in BP Hg; P ¼ .04). placebo.
N ¼ 68
Hla, et al [82], Ambulatory BP, 3 The mean nocturnal systolic and diastolic BP Adjusted for age and body mass index. Although
N ¼ 24 men, 14 weeks of CPAP decreased significantly in 14 subjects by 7.8 versus the daytime BP also tended to drop, the decline
had mild OSA þ0.3 mm Hg (P ¼ .02) and 5.3 versus 0.7 mm was small and insignificant. Sham CPAP was
controlled Hg (P ¼ .03), respectively, after 3 weeks of used as placebo.
interventional therapeutic CPAP.
trial
Becker, et al [83], Continuous BP AHI reduced by 95% in nasal CPAP group; AHI Reduction in mean, diastolic, and systolic BP
N ¼ 32, recording for 19 reduced by 50% in subtherapeutic group. Mean both at night and during the day. No change in
randomized hours before and BP reduced by 9.9 mm Hg in therapeutic group antihypertensive medications through the study.
placebo after treatment, 9 versus no significant change in subtherapeutic Sham CPAP served as control.
controlled trial weeks of CPAP group (P ¼ .01).
moderate to
severe OSA
Malone, et al [87], Overnight PSG, 4 Abolition of OSA (AHI 54.1 and 1.0 for Withdrawal of nasal CPAP for 1 week in four
N ¼ 8, CHF weeks of CPAP, pretreatment and nasal CPAP nights, patients was associated with a reduction in LVEF
with OSAS, LVEF measured respectively). Mean LVEF increased from from 53% to 45% (P!.001). Subjects were on
uncontrolled at baseline 37% to 49% after four weeks’ nasal stable medications.
study CPAP therapy (P!.0001).
Kaneko, et al [86], Overnight PSG, CPAP reduced OSA. CPAP significantly CPAP was used for 3 months in subjects. Controls
N ¼ 24, two-dimensional improved LVEF from, 25% to 33% (þ9%), received optimal medical management. Placebo
randomized ECHO, 4 weeks of P!.001; reduced LV end-diastolic dimensions was not used. Subjects had diagnosis of CHF and
controlled trial CPAP from 54 mm to 51 mm (P ¼ .009). OSAS.
Mansfield, et al Overnight PSG, Study group: LVEF improved 37% Placebo was not used. Subjects had diagnosis of

CPAP FOR THE TREATMENT OF SLEEP APNEA

[88], N ¼ 28 nuclear gated to 42% (þ5%), P ¼ .04; improved quality CHF and OSAS.
CPAP, 27 scan, nasal CPAP of life and lower urinary norepinephrine.
control for 3 months
Buckle, et al Overnight PSG, No significant differences in degree Treatment with nasal CPAP in patients who had
[89], N=8, nasal CPAP for of CSR between control and CHF did not improve CSR in this study. Controls
randomized 1 night treatment nights. received usual therapy.
cross-over trial
Naughton, et al Overnight PSG, LVEF increased þ7.7% in CPAP CPAP for 3 months; controls received optimal
[90], N ¼ 12 CPAP for versus control (P ¼ .019). therapy. Subjects had CHF with CSA.
CPAP, 3 months
randomized
controlled trial
Bradley, et al [91], Randomized to CPAP versus control group: reduction in AHI AHI was reduced by only 50%, with a residual AHI
N ¼ 258 with CPAP versus no (21  16 versus 2  18/h, P!.001), increases of 20/h while on CPAP; CPAP compliance was
CHF and CSA, CPAP; recorded in mean nocturnal oxygen saturation only 3.6 hours per night; baseline levels or changes
randomized PSG, ejection (1.6%  2.8% versus 0.4%  2.5%, P!.001) & in heart rate or BP were not addressed. No
controlled trial fraction (EF), EF 2.2%  5.4% versus 0.4%  5.3%, P ¼ .02). difference in quality of life and mortality/heart
6-minute walk, transplantation rates.
quality of life,
neurohormone
levels

819
(continued on next page)
 820
Table 1 (continued )
Author, study Measurements,
design, sample and duration
characteristics of CPAP use Results Comments
Bassetti, et al [92], Patients who had CPAP was started in 51% and continued OSA was associated with increased post-stroke
N= 152, acute stroke were chronically in 15% of patients who had OSA. mortality on long-term (60  16 months)

CHOWDHURI
Prospective placed on CPAP, Acutely, AHI was 18  16/h and 6 months later follow-up; however, in a logistic regression
observational portable decreased significantly compared with subjects model, age was the only independent
study, Follow-up: automatic CPAP who did not receive CPAP (subacute phase) predictor of mortality. Macroangiopathic
6016 months device was used (P!.001). cause of stroke was significantly
higher in patients who had AHIO30
than AHI!10.
Abbreviations: AHI, apnea hypopnea index; BP, blood pressure; CHF, congestive heart failure; CPAP, continuous positive airway pressure; CSA, central
sleep apnea; CSR, Cheynes-Stokes respiration; ECHO, echocardiography; EF, ejection fraction; LV, left ventricle; OSA, obstructive sleep apnea; PSG,
polysomnography.
 CPAP FOR THE TREATMENT OF SLEEP APNEA 821

Neuropsychologic functioning
Multiple case series and prospective studies provide evidence of the benefits
of CPAP therapy in restoring normal sleep architecture, cognition [94], day-
time functioning, and in relieving daytime sleepiness [95–97]. Neuropsycho-
logic test results improved in subjects receiving adequate treatment with
CPAP compared with sham CPAP [96]. CPAP use has been found to be cor-
related with improved psychosocial function as suggested by improved SF-36
and ESS scores and marital satisfaction compared with conservative treat-
ment at 3 months in a nonrandomized but controlled study [97]. Determinants
of usage were not identified, but benefits and usage were positively correlated.
Similar findings of general improvement in health status have been noted with
short-term (3 months) treatment and maintained with long-term (12 months)
CPAP use [98]. CPAP may also improve driving performance. Reduction in
motor vehicle accidnets with CPAP has been described following CPAP use
(CPAP use: averaging 5.8 days per week for an average of 5.9 hours per night)
[99]. CPAP treatment has also been found to improve subjective sleep quality
not only of patients who have OSAS but also of their bed partners [100]. A
meta-analysis of 11 trials assessing the effect of CPAP on subjective and objec-
tive sleepiness reported that CPAP reduced the ESS score an average of 2.94
points more than placebo (P!.001) [101]. CPAP increased sleep onset latency
by 0.93 minute (P ¼ .04) more than placebo and significantly improved sub-
jective and objective measures of sleepiness in patients who had OSA across
a diverse range of populations. Patients who had more severe apnea and sleep-
iness seemed to benefit the most.
Some patients who have OSA may have residual sleepiness and neuropsy-
chologic deficits despite adequate long-term treatment with CPAP [102,103].
Modafinil, a wake-promoting substance, has been FDA approved for the
treatment of residual sleepiness. Modafinil consistently [104–106] improved
subjective and objective sleepiness, quality of life, and vigilance compared
with placebo. The vast majority (75%) of subjects who had severe sleepiness
at baseline still had multiple sleep latency times of less than 10 minutes on
modafinil, however, despite effective CPAP and good compliance with
therapy. It is important to caution patients about the continued risk for
sleepiness and driving-related or other accidents. Given that sleep apnea pa-
tients use 23% to 50% more resources (defined by physician fees, physician
visits, and hospital nights) in the 5 years before diagnosis than do control
subjects [107], CPAP treatment decreases the excess health care costs for
cardiovascular disease and car accidents incurred by OSAS patients before
diagnosis and is a cost-effective investment. A recent cost-effectiveness anal-
ysis revealed that from a third-party payer or a societal perspective, CPAP
therapy was more effective but more costly than no CPAP in the context of
motor vehicle accidents [108]. When quality of life, costs of therapy, and
motor vehicle accident outcomes were considered, CPAP therapy for pa-
tients who had OSAS was economically effective.
822 CHOWDHURI

Summary
In summary, studies have demonstrated the efficacy of CPAP for the
treatment of OSAS. However, successful therapy depends on individual pa-
tient acceptance and compliance with this mode of therapy. Despite the re-
ported positive clinical response with CPAP, in certain situations excessive
daytime sleepiness and other neurocognitive symptoms may persist, necessi-
tating the use of wake-promoting drugs. The current indications of CPAP,
including those for mild OSA, may have to be revisited once results from the
longitudinal follow-up of the Wisconsin Cohort and SHHS are made avail-
able. Long-term outcome studies investigating the role of CPAP in reversing
the neurocognitive and cardiovascular sequelae and associated mortality are
needed. Further research providing greater insights into the pathophysiol-
ogy of OSAS will help in the development of more innovative modes of ther-
apy. In the interim, continued improvement in technology with better
machine–mask–patient interface, in conjunction with education and cogni-
tive behavioral therapy, may help to improve CPAP acceptance and
adherence.

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