Clin Chest Med 24 (2003) xi – xiii
Preface
Sleep-related breathing disorders: new developments
Teofilo L. Lee-Chiong, Jr, MD
Guest Editors
Obstructive sleep apnea (OSA) is defined as
recurrent episodes of airflow cessation during sleep
despite persistence of respiratory effort. It is common
in the general population—an estimated 15 million
people in the United States are believed to suffer from
the disorder. Furthermore, it is widely suspected that
sleep-disordered breathing is underdiagnosed in both
adults and children.
There are a variety of ways in which sleep-related
breathing disorders are classified. In one simple
schema, OSA may be considered the extreme end of
a spectrum of repetitive sleep-related upper airway
(UA) obstructions that includes, in order of severity,
intermittent snoring, continuous snoring, UA resist-
ance syndrome, asymptomatic hypopnea, and symp-
tomatic apnea-hypopnea. An American Academy of
Sleep Medicine Task Force Report published in 1999
defined four separate syndromes associated with
abnormal respiratory events during sleep among
adults, namely obstructive sleep apnea-hypopnea syn-
drome, central sleep apnea-hypopnea syndrome,
Cheyne-Stokes breathing syndrome, and sleep hypo-
ventilation syndrome. According to this classification,
the UA resistance syndrome was not regarded as a
distinct disease; rather, respiratory event related
arousals (RERAs) were considered part of OSA.
Sleep state dependency is one of the most impor-
tant and central features of OSA. During wakefulness,
ventilation and oxygenation are generally normal, only
0272-5231/03/$ – see front matter D 2003, Elsevier Inc. All rights reserved.
doi:10.1016/S0272-5231(03)00028-5
Vahid Mohsenin, MD
to be disrupted during sleep by repetitive UA narrow-
ing or obstruction. The diminished tone of the muscles
maintaining UA patency is part of the generalized
muscle hypotonia that occurs during sleep. Sleep
apnea is terminated by an arousal accompanied by
restoration of UA patency and airflow. Sleep state –
dependent changes in UA biomechanics and neuro-
physiology may lead to alterations in the balance
between inward forces that favor collapse of the air-
ways and outward forces that counter the former. Not
only do persons with OSA tend to have anatomically
narrower and physiologically more collapsible UAs,
they may also have decreased activity of the UA dilator
muscles with which to compensate for the collapse.
Persons with OSA commonly have alternating
episodes of loud snoring and periods of silence
during sleep due to marked diminution or total
absence of airflow. Blood oxygen saturation may
drop during the apneic phase. Respiratory events
typically recur throughout the evening, at times
reaching numbers substantial enough to produce
sleep fragmentation and subsequent daytime sleepi-
ness. There is increasing recognition of the potential
consequences of this disorder: neuropsychological
impairment, adverse effects on quality of life, and
seizure disorders, in addition to specific cardiovas-
cular diseases such as hypertension, atherosclerosis,
stroke, pulmonary hypertension, cardiac arrhythmia,
and congestive heart failure.
xii T.L. Lee-Chiong, Jr, V. Mohsenin / Clin Chest Med 24 (2003) xi–xiii
Technological innovations will likely transform
the recognition and diagnosis of sleep-disordered
breathing events. The overnight, attended, laboratory
polysomnography is the generally accepted reference
standard for diagnosis. Its limited availability and
high costs have prompted the search for alternative
sleep study protocols, such as portable sleep monitor-
ing. Accurate monitoring of respiration during sleep,
including measurements of airflow, respiratory effort,
oxygenation, and ventilation, is indispensable in the
identification of sleep-related respiratory events. In
particular, measurement of respiratory effort using
either esophageal pressure monitoring or surface
diaphragmatic electromyography is vital in distin-
guishing central from obstructive apneas. Today, the
sleep clinician has a wide variety of devices available
to monitor oro-nasal airflow, including pneumota-
chometers, nasal pressure monitors, thermal or ex-
pired carbon sensors, strain gauges, and respiratory
inductance plethysmography.
As we explore the indications for treatment and
various options for managing persons with OSA,
including behavioral modifications, pharmacological
interventions, positive airway pressure devices, oral
appliances, and surgery, the challenge is to provide a
framework within which we can integrate basic
research and clinical data with future therapies for
this disorder.
Obesity is strongly correlated with the prevalence
of sleep apnea, and weight reduction can be a highly
effective short-term treatment. However, recurrence
of sleep apnea appears to be common during long-
term follow-up, either because of a failure to maintain
weight loss or, for reasons that are unclear, despite
successful maintenance of weight loss.
Positional modification, using a variety of devices
such as posture alarms and wedge pillows to avoid
the supine sleep position, appear to be most effective
in persons with milder disease. Again, long-term data
are sparse and dishearteningly variable.
The search for effective pharmacological targets
continues. Currently, none of the agents that has
been evaluated to reduce sleep-disordered breathing
events is consistently effective to be considered as
standard therapy. Identification of excitatory neuro-
transmitters of the UA dilator motoneurons is ac-
tively being pursued. Another area of research is
pharmacological intervention using stimulant medi-
cations to attenuate residual daytime sleepiness that
may persist despite regular use of positive airway
pressure (PAP) therapy.
Since its first description in 1981, continuous
positive airway pressure (CPAP) therapy has become
the main therapy for OSA. It is highly effective, safe,
and reliable. PAP therapy most likely acts primarily as
a pneumatic splint; it may also decrease pharyngeal
collapsibility by augmenting lung volume as well as
increase UA length and tension. CPAP is typically
titrated during a formal sleep study, determining the
pressure at which it will effectively abolish all sleep-
disordered breathing in the supine position and in
REM sleep. Nevertheless, significant intra- and inter-
night variability exists in the severity of sleep-disor-
dered breathing and the corresponding corrective PAP
settings. A new generation of PAP devices, referred to
as automated PAPs, are capable of detecting signals
serving as surrogates of UA obstruction (eg, snores,
apneas, hypopneas, or airflow limitation) and, using
model-specific diagnostic and therapeutic algorithms,
responding to changes in airway resistance by either
increasing or decreasing the pressures generated.
Whether or not they are appropriate, automated-PAPs
are being increasingly used to diagnose and treat OSA
or to titrate pressures for conventional CPAP devices.
Oral devices, including tongue repositioning
devices and mandibular repositioning appliances,
are established therapies for primary snoring and
milder forms of OSA. Some persons with more
severe sleep-disordered breathing may also respond
favorably to these devices. Oral appliances are
becoming increasingly popular because of their ease
of use, portability, and reversibility. Increased under-
standing of their mechanisms of actions (including
effects of UA patency and muscle function), indica-
tions of therapy, predictors of treatment outcome,
and complications will help clarify their roles in the
management of patients.
Surgery remains an option for many patients,
especially those who are either unwilling to try, or
are intolerant of, positive pressure therapy. Advances
in surgical techniques have significantly improved
outcomes. Selection among the various surgical pro-
cedures is individualized, tailored primarily to the
anatomical region of narrowing or obstruction. Thus,
uvulopalatopharyngoplsty is commonly performed
for oropharyngeal obstruction, whereas surgical alter-
ations of the tongue, hyoid, and maxillomandibular
complex are attempted for hypopharyngeal airway
obstruction. The role of radiofrequency UA soft
tissue ablation is still being debated.
Dionysius of Heracleia (born 360 BC ) was
described by Athenaeus as ‘‘ . . . an unusually fat
man . . . sleepy, difficult to arouse and had problems
breathing . . .so [his] physicians prescribed . . . fine
needles, long enough that they thrust through his ribs
and belly when he happened to fall into a very deep
sleep . . . ’’ Could this be how OSA was treated then?
If so, we would like to believe that over the past
 T.L. Lee-Chiong, Jr, V. Mohsenin / Clin Chest Med 24 (2003) xi–xiii xiii

2400 years there has been some progress in our Teofilo L. Lee-Chiong, Jr, MD
understanding and management of this disorder. Sleep Medicine Center
The purpose of this issue of the Clinics in Chest Division of Pulmonary and Critical Care Medicine
Medicine is to provide a comprehensive discussion of University of Arkansas for Medical Sciences
the various aspects of OSA, focusing on new devel- Central Arkansas Veterans Healthcare System
opments and controversies and emphasizing trends 4301 West Markham Street, Slot 555
that may potentially offer a glimpse of the future of Little Rock, AR 72205, USA
the science and practice of sleep medicine. We hope E-mail address: leechiongteofilol@uams.edu
that readers find this issue to be clinically useful, and
we welcome all feedback. Vahid Mohsenin, MD
We wish to acknowledge our sincere gratitude to Director
the outstanding authors who have generously pro- Yale Center for Sleep Medicine
vided us with an array of excellent texts. We are Associate Professor of Medicine
especially indebted to Sarah Barth and the editorial Yale University
staff at W.B. Saunders for their expert counsel and 40 Temple Street, Suite 3C
unwavering support. Finally, we would like to thank New Haven, CT 06511, USA
our families: Grace and Zoe, Shahla, Amir, and
Neda—it is to them that we dedicate this issue.
 Clin Chest Med 24 (2003) 179 – 193
Molecular and physiologic basis of obstructive sleep apnea
Sigrid Carlen Veasey, MD*
Division of Sleep Medicine, University of Pennsylvania School of Medicine, 3600 Spruce Street, Philadelphia, PA 19104, USA
This is an exciting time to be involved in the
study of the obstructive sleep apnea-hypopnea syn-
drome (OSAHS) because characterization of the
diverse manifestations of this disorder continues to
evolve. One may be certain that the characterization
of this highly prevalent and disabling disorder is not
complete. There are many reasons why the defini-
tions and descriptions of the OSAHS will continue to
evolve. The syndrome-in-progress status may be
attributed, in part, to the relative newness of the
initial characterization of the OSAHS three decades
ago [1,2]. A more important reason, however, is that
this disease process, with repeated systemic oxy-
hemoglobin desaturations followed by reoxygenation
events and sleep disruption, has the potential to place
a substantial oxidative burden on many, if not all,
physiologic systems. Recently, researchers have be-
gun to recognize that included in the physiologic
systems impacted on by the repeated airway occlu-
sions and hypoxia/reoxygenation events are the
upper airway soft tissues and muscles and neural
control mechanisms. The disease process itself may
alter the molecular and physiologic mechanisms in-
volved in OSAHS.
This article summarizes the pathophysiologic
mechanisms of OSAHS and complements the phys-
iologic information with data concerning molecular
mechanisms involved in OSAHS and newer informa-
tion regarding the mechanisms through which the
disease process may alter obstructive sleep-disor-
dered breathing. An understanding of the pathophysi-
This work was supported in part by NIH HL 60287.
* Center for Sleep and Respiratory Neurobiology,
987 Maloney Building, 3600 Spruce Street, Philadelphia,
PA 19104.
E-mail address: veasey@mail.med.upenn.edu
0272-5231/03/$ – see front matter D 2003, Elsevier Inc. All rights reserved.
doi:10.1016/S0272-5231(03)00019-4
ology [3,4] has brought therapies such as continuous
positive airways pressure [5,6], surgical therapies for
the upper airway [7 – 10], and oral mandibular
advancement devices [11,12]. An understanding of
the molecular mechanisms may provide unique
approaches to therapies for this prevalent disorder,
including pharmacotherapies, and at the same time, a
comprehension of the molecular mechanisms may
afford insight into the differential vulnerability in
the severity and diverse manifestations of OSAHS,
so that we may better understand who is at risk for
this disease and its many morbidities.
An overview of the pathophysiology of obstructive
sleep apnea-hypopnea syndrome
One of the most remarkable features of the
OSAHS is the state dependency of this disorder.
Specifically, in persons with isolated OSAHS, ven-
tilatory patterns and arterial oxygen values during
wakefulness are completely normal. In contrast, dur-
ing sleep, the upper airway of persons with OSAHS
narrows or collapses or both [4], which results in
upper airway occlusion with large intrathoracic and
upper airway intraluminal pressure swings [13,14],
oxyhemoglobin desaturations [4], hypercapnia [15],
increases in sympathetic drive [16 – 18], and ulti-
mately, arousal with larger sympathetic surges [4]
and massive increases in upper airway dilator muscle
activity, which restores airway patency [4].
This state dependency in upper airway patency
and respiratory function suggests that state-dependent
changes in neural drive to the upper airway dilator
and pump muscles prompt obstructive upper airway
events. It is important to recognize that state-depen-
dent changes in neural drive to respiratory muscles
are not unique to sleep apnea. State-dependent reduc-
180 S.C. Veasey / Clin Chest Med 24 (2003) 179–193

tions in respiratory muscle activity are a normal
phenomenon of sleep [19,20]. The unique features
in individuals with OSAHS are a reliance on upper
airway dilator muscle activity and lung volume and a
greater magnitude of sleep state-dependent reductions
in muscle activity [20,21]. For these reasons, the
impact on airway caliber is larger [22 – 25].
State dependency of disease is a unique and
clinically important characteristic because it implies
that this disorder should be readily amenable to
pharmacologic therapies that effectively target state-
dependent neural changes. Understanding the mech-
anisms underlying OSAHS is essential for elucidating
safe, effective therapies for this syndrome. The key
components of this pathophysiology are (1) state-
dependent changes in respiratory drive to the upper
airway and pump muscles, (2) upper airway anatomy,
(3) upper airway mechanics, and (4) upper airway
muscle function.
Neural mechanisms underlying state-dependent
changes in upper airway and pump muscle activity
State-dependent upper airway obstruction in
OSAHS occurs most commonly within the pharynx
in the retropalatal or retroglossal regions or both
[26,27]. During inspiration, negative intraluminal
pressures in these regions exert centripetal forces that
must be countered by centrifugal forces of the upper
airway dilator muscles, particularly in persons with
upper airway narrowing or increased collapsibility.
The neurochemical control of upper airway motoneu-
rons is complex, and in this section the author works
backward from the upper airway dilator motoneurons
to reflexes and upper respiratory neural drive to
describe what is known of the neural and neurochem-
ical mechanisms that may contribute to state depen-
dency of the upper airway for each neural mechanism.
Many muscles contribute to centrifugal forces in
the upper airway (Fig. 1), whereas other muscles
that are important in phonation, deglutition, and
respiratory breaking act as constrictors within the
upper airway. When discussing neural mechanisms,
it is important to recognize that most upper airway
motor nuclei (cranial nuclei, V, VII, X, XI, and XII)
house motoneurons for upper airway dilators and
constrictors. Many researchers, including the author,
have chosen to focus first on XII, the hypoglossal
nucleus, because this collection of motoneurons
innervates the largest upper airway dilator muscles
in humans with OSAHS: the genioglossus and
geniohyoid [4,20]. The hypoglossal motoneurons
also innervate many more dilators than constrictors
[28]. The information gained concerning the state-
dependent control of hypoglossal motoneurons ulti-
mately must be addressed for other populations of
motoneurons, however. Recently, Kuna showed that

Fig. 1. Schematic of potential upper airway dilators in humans. Muscles surrounding the upper airway have the potential to dilate
or stent the upper airway in many different directions. Represented in this drawing are the force vectors for activation of specific
muscle groups. As a collapsible tube (gray), oropharyngeal patency is most effectively achieved by simultaneous activation of
muscles with vectors in different directions. As discussed in the text, elongation of the airway along with widening of the lateral
walls may be most effective in rendering the airway less collapsible.
 S.C. Veasey / Clin Chest Med 24 (2003) 179–193 181

electrical stimulation of the glossopharyngeal nerve
causes marked dilation of the pharynx (Fig. 2) [29].
Many excitatory and inhibitory neurotransmitters
and neuromodulators contribute to the activity of
hypoglossal and other upper airway dilator motoneu-
rons. Serotonin and its co-localized neuropeptides,
substance P, thyrotropin-releasing hormone, and nor-
adrenaline, orexin, acetylcholine (nicotinic receptors),
and glutamate may contribute to upper airway moto-
neuronal excitation, whereas acetylcholine (through
different receptor subtypes), glycine, GABA, and
perhaps enkephalin may contribute to upper airway
motoneuronal suppression [30 – 44]. Sleep state-
dependent reductions in upper airway motoneuronal
activity may reflect changes in inhibitory, excitatory,
or both inputs. One model used to explore the neuro-
chemical changes in motoneurons during sleep has
been the pontine carbachol model of rapid eye
movement (REM)-associated atonia. This model pro-
duces many of the phenomena of REM sleep, includ-
ing suppression in respiratory muscles in a manner
similar to natural, or spontaneous, REM sleep (upper
airway muscle activity is more suppressed than dia-
phragmatic activity) [32 – 35].
In models of carbachol REM atonia, serotonin and
noradrenaline delivery are reduced to hypoglossal
motor neurons coincident with upper airway motor
neuron suppression [32,35]. Kubin et al have shown
that carbachol suppression of hypoglossal nerve
activity may be largely prevented by pretreating the
hypoglossal nucleus with serotonin [31]. Further
evidence that sleep-dependent serotonin withdrawal
contributes to suppression of upper airway dilator
activity is shown in research on adult rats, in which
serotonin delivered by way of a chronic microdialysis
probe into the hypoglossal nucleus largely prevents
genioglossus suppression in spontaneous NREM
sleep and reduces the suppression in REM sleep,
albeit to a lesser extent [45]. Serotonin is important
for the maintenance of patent airways in an animal
model of obstructive sleep-disordered breathing, the
English bulldog [46], and a combination of seroto-
nergic drugs that increase serotonin production and
release within the brain and target multiple serotonin
receptor subtypes reduces obstructive sleep-disor-
dered events in the bulldogs [47]. Serotonin may
have excitatory and inhibitory effects at motoneurons
and on respiration [48,49], and there are at least 15

Fig. 2. The effects of glossopharyngeal nerve stimulation on pharyngeal patency in a decerebrate cat. Caudal view from
pharyngoscopy in a tracheostomized cat. The left panel shows velopharyngeal and oropharyngeal patency in the absence of nerve
stimulation. The right panel illustrates the large effect of glossopharyngeal nerve stimulation on the patency of the velopharynx and
oropharynx. Stimulation of the glossopharyngeal nerve extends most pharyngeal dimensions. Although this nerve innervates
primarily the stylophyryngeus, it also contributes to the innervation of the anterior digastric, levator palatine, and stylohyoid, a
collection of muscle that would extend all airway dimensions. (Courtesy of Sam Kuna, MD, University of Pennsylvania,
Philadelphia, PA)
182 S.C. Veasey / Clin Chest Med 24 (2003) 179–193
unique serotonin receptor subtypes within the central
nervous system in mammals [50]. Researchers re-
cently identified which excitatory serotonin receptor
subtypes are involved in postsynaptic serotonergic
excitation of hypoglossal motor neurons [51,52].
5-HT2A and 2C are the excitatory 5-HT receptors
transcribed in hypoglossal motoneurons and the only
functional excitatory receptors [51,52]. Kubin et al
identified a1B as the main postsynaptic noradrenergic
receptor subtype that mediates excitation [53]. Sub-
stance P excites hypoglossal motoneurons through
activation of the natural killer-1 receptor [42].
Glutamatergic excitation of hypoglossal moto-
neurons involves multiple receptor subtypes in the
hypoglossal nucleus [54,160 – 163], and although
reports have identified the presence of many different
receptor subtypes [55 – 59], it remains unclear what
the relative role of each subtype is. Recent studies
suggested that N-methyl-D-aspartate (NMDA) recep-
tor subtypes are particularly vulnerable to nitrosative
and oxidative stress and that the excitability of this
receptor is reduced in oxidative stress through nitro-
sative and oxidative changes in the sodium channel, a
mechanism believed to be protective in preventing
glutamatergic excitotoxicity [60]. Because glutamate
is involved in the respiratory drive to hypoglossal and
other respiratory neurons, it is essential to understand
glutamatergic control of upper airway motoneurons
and how OSAHS impacts on glutamate receptor
function [159].
Although glycine plays a major role in REM sleep
postural muscle suppression, it does not seem to
contribute significantly to either the pontine carba-
chol REM suppression of hypoglossal activity [61] or
spontaneous REM suppression of brain stem motor
reflex activity [62]. There are large hyperpolariza-
tions of brain stem motor neurons during phasic REM
sleep [63], which may occur when glycine contrib-
utes to upper airway dilator muscle suppression [64].
In summary, recent studies have identified the
subtypes for monoaminergic excitatory inputs to
hypoglossal motoneurons in an effort to identify drug
targets. Unfortunately, the predominant and non-
rapidly desensitizing serotonin receptor subtype
involved in excitation of hypoglossal motoneurons
in normal mammals, 5-HT2A, is not an ideal target for
pharmacotherapies, because activation of this receptor
subtype has been implicated in vasoconstriction of the
systemic and pulmonary beds, bronchospasm, and
thromboembolic disease [65]. The adrenergic receptor
subtype involved in hypoglossal excitation, alpha1B,
is also implicated in vasoconstriction [66]. A thyrot-
ropin-releasing hormone analog has been tried in the
English bulldog model of sleep-disordered breathing
and found to increase wakefulness without improving
sleep-disordered breathing (S.C. Veasey, unpublished
observations). To date, there are no ideal receptor
targets for pharmacotherapeutics for OSAHS.
With the certainty that the clinical description of the
manifestations of OSAHS is not complete, one also
may be sure that the list of neurochemicals involved
directly in the control of upper airway motoneurons is
not complete. Many ‘‘orphan’’ G protein-coupled
receptors and other potential targets for drug therapies
for OSAHS exist. Researchers currently are probing
upper airway motoneuronal tissue for novel receptors
with activity at upper airway dilator motoneurons
because they may provide additional avenues for
pharmacotherapies for this disorder.
It is crucial to determine how OSAHS alters
neuronal function. There are recent reports of long-
term intermittent hypoxia inducing neuronal injury
and reducing excitatory responsiveness in hippocam-
pal neurons [67,68]. There is at least one report of
patients with OSAHS showing delayed phrenic nerve
conduction, which is associated with severe oxy-
hemoglobin desaturations [69], suggesting that per-
haps oxidative injury occurs to the respiratory motor
neurons with severe OSAHS. Motor neurons are
sensitive to oxidative stress, and one likely mech-
anism of disease progression in persons with OSAHS
is oxidative injury to respiratory neurons and upper
airway dilator motor neurons. Advancing knowledge
concerning the neurochemical control of upper air-
way dilator motor neurons in sleep requires an un-
derstanding of the major inputs to motor neurons.
Respiratory neural inputs to the upper airway
motoneurons are numerous and include reflexes,
respiratory drive, and other central inputs. Responses
to reflexes may be excitatory or inhibitory, fast or
slow adapting responses. There is evidence that sleep
may modulate upper airway activity through many of
these mechanisms [70 – 88]. Readers are referred to
excellent review chapters [89]. One example in which
a rapid reflex response may play an important role in
upper airway patency in sleep is the immediate
response (first 200 – 300 milliseconds) to increased
respiratory loads. This augmentation of upper airway
muscle activity is not evident in non-REM sleep [70].
Loss of an initial powerful excitatory drive to the
upper airway muscles could reduce substantially the
effectiveness of pump muscle activity. In the English
bulldog model of obstructive sleep-disordered breath-
ing, the lead-time for upper airway muscles before
diaphragmatic activation that occurs upon waking is
lost in non-REM and REM sleep [21]. The relative
role that this reflex plays in waking respiratory drive
to upper airway muscles in persons with OSAHS is
 S.C. Veasey / Clin Chest Med 24 (2003) 179–193
largely unknown. There is evidence for a significant
contribution of a slow adapting reflex response,
mechanoreceptor reflex activation, to waking dilator
muscle activity in persons with OSAHS. When
topical anesthesia is applied to the pharyngeal
mucosa, electromyographic activity of upper airway
dilators and airway caliber declines in normal persons
and persons with OSAHS [71,72]. In both groups, the
apnea-hypopnea index increases [71,72].
Sleep also affects the pharyngeal muscle reflex
response to negative pressure [73 – 81]. Evidence that
this reflex contributes to waking genioglossus activity
is apparent because the application of positive pres-
sure abruptly (within a reflex latency) drops genio-
glossus activity in persons with OSAHS [75,81].
Effects of sleep on suppression of the negative
pressure reflex are more pronounced in REM sleep
than in non-REM sleep [77,78]. It is unclear, how-
ever, whether the sleep effect is a primary effect on
reflex inactivation or whether this is secondary to
sleep-induced reductions in upper airway motor neu-
ron excitability [79].
There is some evidence that reflex responses may
be impaired in persons with OSAHS. One recent
report suggested that long-term severe OSAHS is
associated with swallowing dysfunction [79]. The
swallowing reflex impairment was associated with
more frequent severe oxyhemoglobin desaturations
and is improved in patients after successful continu-
ous positive airway pressure (CPAP) therapy [79].
The negative pressure reflex response is also impaired
in OSAHS and improves with CPAP therapy [80]. It
is likely that in addition to impairments in respiratory
motor neurons, OSAHS may result in impairments in
important upper airway reflex responses. This is an
area in need of further exploration.
Another group of neurons affected by sleep and
likely by OSAHS is the upper respiratory neurons.
Collectively, the work from many studies suggests
that sleep may have larger suppressive effects on
pontine respiratory neurons [84,87], some of which
rely on serotonergic inputs [86]. There are little to no
suppressive effects on medullary neurons; in cats,
medullary respiratory neurons may increase firing
during REM sleep [83,85]. The large changes in
upper airway motor activity in sleep are most con-
sistent with tonic reductions in monoaminergic inputs
from nonrespiratory groups and perhaps phasic
increases in glycinergic drive through activation of
glycinergic interneurons. The reduced chemosensitiv-
ity in sleep is also poorly understood. It is not
because of sleep-related effects on nucleus tractus
solitarius response to hypercarbia [88]. Medullary
serotonergic neurons are chemosensitive, and because
183
firing of these neurons occurs less during sleep, this
could contribute to reduced chemosensitivity in sleep.
OSAHS may injure upper respiratory neurons and
alter drive to dilator and pump muscles. In neonatal
rats exposed to intermittent hypoxia, nucleus tractus
solitarius neurons show substantial injury, including
apoptosis [68]. Functional magnetic imaging in adults
with OSAHS reveals loss of grey matter in brain
regions involved in respiratory drive [90]. Whether
this is a consequence of OSAHS, or whether the
lesions render persons more vulnerable to OSAHS, is
presently unknown. The above referenced study in
young rats suggested a narrow window of increased
vulnerability, and whether clinically significant injury
may occur at later stages is presently unknown.
Overall, upper airway and other protective respi-
ratory reflexes are lost in sleep, and reduced or absent
reflex responses and respiratory neuronal injury may
contribute to the pathogenesis of OSAHS. How much
of a role these reflexes play remains unknown. It is
important to determine how much waking upper
airway dilator muscle activity is present because of
specific reflex activation in humans with OSAHS.
This is important to determine in persons with
OSAHS because the neurochemical control of reflex
activity may differ significantly from the neurochem-
ical control for central mechanisms. If reflexes con-
tribute substantially to upper airway activity in persons
with OSAHS, then the neurochemical basis for sig-
nificant reflexes may be determined in animals and
targeted to provide therapeutic targets. Differences
among patients in relative roles of reflex and central
inputs may explain partly the differential responses to
pharmacotherapies. At the same time, it is important to
understand which neurons are injured by OSAHS and
how this injury occurs.
The neurochemical control of upper airway re-
flexes is not well delineated, but it seems that nor-
adrenaline and serotonin may contribute to inhibitory
[91,92] and excitatory upper airway motor responses
for trigeminal nerve reflexes [93]. Serotonin does not
seem to contribute to the superior laryngeal nerve
stimulatory response of hypoglossal motor neurons
[94]. Glutamate contributes to excitatory responses
[95,96]; however, few other upper airway motoneuro-
nal excitatory receptor targets have been excluded
from reflex contribution, and this is an area in need
of further study.
Upper airway anatomy
One of the challenges for studying upper airway
anatomy in persons with OSAHS has been the state
184 S.C. Veasey / Clin Chest Med 24 (2003) 179–193
dependency of the upper airway anatomy. Specif-
ically, the upper airway is sufficiently patent in
wakefulness to allow normal ventilatory function,
and it is only during sleep, or anesthesia, that airway
collapse manifests. The following studies describe the
anatomy of the upper airway in awake normal sub-
jects and distinguish the unique features of the
waking upper airway in persons with OSAHS before
characterizing the features of the sleeping upper air-
way anatomy in persons with OSAHS.
The upper airway extends from the nares to the
vocal cords. Upper airway collapse, however, occurs
most frequently within the oropharynx, which
extends from the posterior edge of the hard palate
to the level of the cervical esophagus and glottic
inlet [97,164]. The anatomy described in this section
is the anatomy of the oropharynx with an emphasis
on the two more collapsible segments, the retropal-
atal and retroglossal airway, both of which are
surrounded by abundant soft tissues. The hypophar-
ynx has been identified as a site of collapse. Typ-
ically, however, the hypopharynx is not a primary
site of collapse. The posterior wall of the oropharynx
is comprised of mucosal tissue encompassed by
various posterior pharyngeal constrictors (muscles
that narrow the airway somewhat but also stiffen
the wall). The lateral walls of the oropharynx include
mucosal folds, a continuation of the constrictor
muscles, tonsils, tonsillar pillars, other lymphoid
tissue, and the parapharyngeal fat pads. The anterior
wall of the oropharynx consists of mucosa, the soft
palate, and the tongue. Many of the soft tissues that
surround the upper airway are surrounded, in turn,
by fixed skeletal structures, including the skull base,
maxilla, mandible, and cervical vertebral column.
There are many potential causes of upper airway
compromise, and many anatomic variations have
been associated with OSAHS, including retrogna-
thia, maxillary retropositioning, intranasal obstruc-
tion, caudal displacement of the hyoid bone,
macroglossia, a low-lying or enlarged soft palate,
enlarged lymphoid tissue in the upper oropharynx,
and brachycephalic posture [97 – 99].
Evidence supports the hypothesis that genetic
variations in skeletal head and neck structures con-
tribute to the likelihood of OSAHS. Several genetic
disorders with craniofacial anomalies are associated
with an increased risk of OSAHS, including cranio-
facial microsomia, Down syndrome, Pierre Robin
syndrome, Nager syndrome, Treacher Collins syn-
drome, and cri du chat syndrome [100 – 102]. There
are racial differences in the skeletal anomalies asso-
ciated with OSAHS. Hispanics, relative to white
adults, have on average smaller anteroposterior and
lateral dimensions for the maxilla and mandible [98].
Support that the smaller facial bones may contribute
to a predisposition to OSAHS stems from the in-
creased prevalence for OSAHS in Hispanics [98,103].
In many patients with OSAHS, however, obvious
craniofacial anomalies are not evident [98]. For
example, African Americans have on average larger
mandibular and maxillary inner dimensions relative
to whites, but the median respiratory disturbance index
is higher in African-American adult men compared
with white adult men [104]. Collectively, these data
suggest that the skeletal predispositions to OSAHS are
multifactorial; there are genetic influences on facial
skeletal structure that might increase the likelihood of
developing OSAHS, but skeletal structural variances
cannot explain all cases of OSAHS.
In addition to skeletal anatomic variations, there
are soft tissue differences in persons with OSAHS
(Fig. 3), and significant evidence supports the hy-
pothesis that changes in the upper airway soft tissue
anatomy also may predispose an individual to the
pathogenesis of OSAHS [98,99]. As with skeletal
changes, the sources of soft tissue abnormalities in
persons with OSAHS are numerous. It is difficult,
however, to determine which of the soft tissue
changes contribute to the disease process and which
are secondary to repeated upper airway obstruction.
For example, one tissue change in OSAHS is edema,
not only in the mucosa and submucosa but also in the
upper airway muscles, as evidenced by MRI of the
pharynx and neck muscles with T2 relaxation mea-
surements [105]. Edema could be caused by upper
airway negative pressure trauma but also could wor-
sen OSAHS by reducing airway caliber. Fatty infil-
tration of upper airway soft tissues is likely to play a
causal role in upper airway compromise. Obesity is a
significant risk factor for OSAHS [106], and signifi-
cant weight loss in obese persons with OSAHS
reduces the severity of sleep-disordered breathing
[107]. Of obesity parameters, neck size is the stron-
gest predictor of OSAHS [108,109], and neck cir-
cumference correlates with increased dimensions of
the parapharyngeal fat pads [110]. Increased weight
gain not only augments fat in mucosal tissue but also
increases adipose tissue within upper airway muscles
[111]. Weight gain may jeopardize the upper airway
caliber by increasing soft tissue confined by skeletal
structures surrounding the airway and causing poten-
tially deleterious effects on muscle function. A larger
upper airway soft tissue volume in men may contrib-
ute to the increased prevalence of OSAHS in men
compared to women [112].
One of the most striking differences in persons
with OSAHS in wakefulness is a marked narrowing
 S.C. Veasey / Clin Chest Med 24 (2003) 179–193 185

Fig. 3. Axial MRIs of the pharynx and all surrounding skeletal, soft tissue structures in a normal individual (left) and a person
with severe OSAHS (right). Notice the increased fat pads (white) in the person with OSAHS and compromise of the anterior
posterior and lateral pharyngeal walls. (Courtesy of Richard Schwab, MD, University of Pennsylvania, Philadelphia, PA)

of the lateral airway walls (Fig. 3) [113]. An increase
in the size of the parapharyngeal fat pads may
contribute to airway narrowing, but because the
increase in fat pad size cannot explain fully the
marked narrowing, there also must be an increase in
soft tissue edema or mucosa [158]. It is conceivable
that persons with mild upper airway narrowing mani-
fest a progression of OSAHS from soft tissue stress-
induced mucosal growth. Several growth factors in
mucosa elsewhere in the body respond to tissue
distortion with increased growth factor transcription
[114]. This concept has not been explored in human
upper airway soft tissues, however. Increased surface
area of mucosa would increase tissue collapsibility.
CPAP clearly affects soft tissue structures, and at
pressures effective to treat OSAHS, CPAP increases
the lateral wall soft tissue cross-sectional area more
so than anterior or posterior soft tissue, which sug-
gests that this region is more distensible in humans
with OSAHS [115]. An increase in upper airway
mucosal surface area may contribute to lateral wall
increased collapsibility in persons with OSAHS.
State-dependent imaging of the upper airway has
provided more clues concerning the pathogenesis of
OSAHS. By imaging persons during sleep, it is
possible to discern which structures surrounding the
upper airway might contribute to airway collapse or
narrowing. In normal persons, consistent with the
reduced upper airway muscle activity during sleep,
the upper airway dimensions decline in sleep [116].
The decline may be attributed to posterior positioning
of the tongue and soft palate and narrowing or folding
in of the lateral walls [116]. The posterior and lateral
changes are less likely to be explained by activity
reduction in one muscle. Presumably the narrowing
results from simultaneous reductions in several of the
following muscles: genioglossus, geniohyoid, tensor
veli palatini, and levator palatini. Similar dimensional
changes have been observed in persons with OSAHS
[117 – 119]. The reductions in upper airway caliber,
however, are more pronounced in persons with
OSAHS [117]. The larger changes in persons with
OSAHS may occur because of larger reductions in
upper airway muscle activity but also may occur as a
consequence of smaller lung volumes, which may
shorten the upper airway and allow the lateral walls to
collapse inward [120].
Imaging studies of the upper airway in persons
with and without OSAHS, particularly imaging stud-
ies performed during sleep, have provided a char-
acterization of many abnormalities of skeletal and
soft tissue origin that may contribute to OSAHS. The
abnormalities in waking are not sufficient to allow
diagnosis or consistently reliable predictions concern-
186 S.C. Veasey / Clin Chest Med 24 (2003) 179–193
ing which patients may benefit from various surgical
and nonsurgical therapies. Future imaging studies in
sleeping persons with OSAHS will be tremendously
insightful when measurement of specific muscle
activity and lung volume may be acquired simulta-
neously with dynamic breath-to-breath imaging
across states. The insight gained into neural control
of the upper airway and upper airway anatomy in
persons with OSAHS must be complemented with
data on mechanics to begin to approach unanswered
questions concerning state-dependent changes in
upper airway mechanics, because muscle activity
over several breaths before upper airway collapse
may not change in parallel with progressive reduc-
tions in upper airway caliber.
Upper airway mechanics
This article highlights the sleep state – dependent
reductions in upper airway dilator activity as normal
neurologic phenomena and phenomena that are more
pronounced in persons with OSAHS and result in
repetitive upper airway occlusions only in persons
with OSAHS. The author has discussed several
anatomic changes, including several genetically
determined bone and soft tissue features that may
predispose an individual to require increased upper
airway dilator activity to maintain a patent upper
airway. However, anatomy and muscle activity alone
are insufficient to explain fully the complicated
pathogenesis of OSAHS [121]. The mechanics of
the upper airway, particularly forces that alter com-
pliance and upper airway collapsibility, are equally
important in determining which patients snore and
which patients have occlusive apneas [122 – 124]. It is
difficult to predict reliably OSAHS severity with
either imaging or electromyographic studies. In con-
trast, several studies of upper airway biomechanics
help to distinguish snorers from persons with hypo-
pnea and persons with apnea [124 – 126].
The retropalatal and retroglossal regions of the
upper airway act much as a Starling resistor, a col-
lapsible passageway [127]. The clinical significance of
Starling properties is that variations in intraluminal
pressures, resistance, and airway collapsibility influ-
ence upper airway flow so that despite a high pulling
pressure (from inspiratory muscle activity), flow may
become limited [127,128]. Several factors influence
maximal flow in the upper airway through the col-
lapsible area [128]. First, a greater upstream (nasal)
driving pressure increases flow, because flow is some-
what proportional to the pressure gradient (nasal
pressure minus the critical closing pressure) [129].
Through this mechanism, positive airway pressure
therapies (CPAP, BiPAP, mask ventilation) work.
The increased driving pressure increases inspiratory
flow [130,131]. Nasal pressure does not differ in
normal persons and persons with OSAHS, however;
at end-expiration, this is simply atmospheric pressure.
One factor that varies among persons with and
without OSAHS is nasal or upstream resistance, and
as a Starling resistor, maximal flow is limited by
upstream resistance. If this resistance is too great,
flow ceases. In this manner, nasal obstruction may
contribute to OSAHS [132,133], although correction
of nasal resistance only rarely results in substantial
reductions in apnea/hypopnea frequencies [134]. The
third—and perhaps most influential—factor in per-
sons with OSAHS is the specific collapsing pressure
of the Starling segment [127,128]. This pressure is
termed the critical pressure, Pcrit, and is defined as the
upper airway pressure (nasal pressure) at which air
flow ceases in the collapsible segment. The upper
airway muscles come into play, and Pcrit is affected
by sleep state [121]. The dilator muscles act with
centrifugal force to produce a more negative closing
pressure, a less collapsible segment. Even in normal
persons, the effects of sleep are pronounced on upper
airway collapsibility and may change the Pcrit from
40 cm H2O when awake to 15 cm H2O during
sleep [121]. In sleep the Pcrit can be used to distin-
guish types of obstructive sleep-disordered breathing.
Snorers have a Pcrit closer to 6 cm H2O, whereas in
persons with hypopnea, the Pcrit is more positive,
closer to 2 cm H2O. In persons with predominantly
apneas, the Pcrit actually may be above atmospheric
pressure during sleep [121]. The frequency of
obstructive sleep-disordered breathing events corre-
lates somewhat with the Pcrit [123].
Collapsibility of a Starling resistor also may vary
with lengthening or shortening of the tube (pharyngeal
mucosa/submucosa). The collapsible portion of the
upper airway may be thought of as a tube that, under
some circumstances, is too long for the space within it
is housed, and under these circumstances the walls of
the tube are redundant with many folds of tissue. The
upper airway space may be shortened by reductions in
lung volume [135 – 142]. Sleep may impose reduced
lung volume through two mechanisms: reducing end-
expiratory lung volume and reducing tidal volume
[120,143]. Functional residual volume or end-expira-
tory volume may be reduced in sleep because of
supine posturing and less activity to tonic respiratory
muscles, including the external intercostals [143].
Phillipson et al examined the upper airway in awake
subjects with OSAHS and in controls at several lung
volumes using acoustic reflection, and they found
 S.C. Veasey / Clin Chest Med 24 (2003) 179–193
reductions in pharyngeal cross-sectional area in nor-
mal persons and in persons with OSAHS from total
lung capacity to residual volume [120]. The reduction
was greater in persons with OSAHS [120].
Begle et al extended these findings to show that
increasing lung volume (0.5 L) reduces the pharyn-
geal resistance in non-REM sleep despite reductions
in genioglossus electromyographic phasic and tonic
activity [137]. Increasing the functional residual
capacity reduces obstructive sleep-disordered breath-
ing event frequency [135]. A major effect of CPAP
therapy is pneumatic splinting [140]. The second
mechanism through which sleep reduces lung volume
is reduction in tidal volume [143]. Tidal volume is
reduced in non-REM sleep and reduced even further
in REM sleep in persons with OSAHS [144]. Sleep-
related reductions in lung volume impose additional
challenges on an already highly vulnerable airway in
persons with OSAHS. Through reduction in lung
volume it is possible to reduce the upper airway
caliber profoundly.
The effect of supine positioning on the pharyngeal
cross-sectional area is independent of the lung vol-
ume and is likely additive [145,146]. It is surprising
that little is known about the effects of upright
posturing on OSAHS (many patients prefer this
sleeping position). In one small study, resolution of
OSAHS was shown in half of the subjects, whereas
the rest of the subjects had significant reductions in
sleep-disordered breathing [147]. It is more likely that
upright posture for sleep might represent a supple-
mental therapy for patients in whom high positive
airway pressures are required or in whom other
therapies are only partially effective.
An additional factor for upper airway mechanics
is upper airway hysteresis. This is a minimally
explored area, with the exception of several topical
oropharyngeal lubricant therapy studies for sleep-
disordered breathing. In the upper airway, particularly
in the oropharynx, there are redundant folds. With
airway collapse and even with end-expiration when
the upper airway is smallest, the number of folds or
contact areas increases. Each of these folds represents
a potential contact area for the development of
hysteresis. Part of the airway compromise relates to
sleep state – dependent changes in upper airway
dilator activity [148]. Progressive hysteresis within
the upper airway would partially explain the dissoci-
ation between upper airway dilator activity and upper
airway caliber in the last few breaths preceding an
apneic event [121,149,150]. Lubricants that may
reduce surface tension on pharyngeal mucosa have
been shown to reduce apneic and hypopneic events
and snoring [151,152].
187
Upper airway muscle function
Many muscle disorders predispose to sleep apnea,
including OSAHS [153]. Evidence also exists that the
disease process itself may result in injury to the upper
airway dilator muscles. In individuals with OSAHS,
upper airway dilator muscle activity is required for
airway patency. In quiet wakefulness, the drive to
upper airway muscles is relatively constant compared
to sleep. During sleep, the drive to upper airway
muscles fluctuates with each obstructive event, some-
times reaching tremendously high levels of activity at
the termination of an event. Intense activation of
upper airway muscle activity at a time when intra-
luminal pressure is low may cause muscle injury.
That is, the centrifugal force of the dilator muscles is
opposed by the centripetal force of negative intra-
luminal pressure. Mechanical lengthening of a muscle
during contraction (eccentric contraction) may injure
the muscle [154].
Petrof hypothesized that eccentric contraction may
occur in persons and in English bulldogs with
OSAHS and that evidence of eccentric contraction
injury should be seen on biopsy specimens of upper
airway dilator muscles. Petrof also observed an
increased proportion of fast twitch fibers, increased
inflammation throughout the upper airway dilator
muscles, increased connective tissue, and a signifi-
cant reduction in muscle fibers in bulldog compared
to control dog airway muscles [155]. These findings
are consistent with an overuse injury [154] to upper
airway muscles in the bulldog. The increase in
myosin type II fibers in the sternohyoid muscle is
consistent with resistive load training of this dilator
muscle [156]. There were no differences in myosin
type in a non – upper airway striated muscle, the
anterior tibialis. Petrof concluded that eccentric con-
traction of upper airway muscles over a long time,
seen particularly in older dogs, may result in muscle
injury, which could help explain progression of
disease. Injury specific to upper airway muscles
rather than diffusely has been shown by Dr. Schot-
land and colleagues [165]. Intermittent hypoxia also
may increase fatigability of upper airway dilator
muscle, as shown recently in adult rats exposed to
5 weeks of intermittent hypoxia [157].
Summary
Obstructive sleep apnea-hypopnea syndrome
occurs because of various combinations of anatomic,
mechanical, and neurologic anomalies that jeopardize
ventilation only when normal state-dependent reduc-
188 S.C. Veasey / Clin Chest Med 24 (2003) 179–193
tions in drive to upper airway respiratory muscles and
pump muscles occur. A well thought out and carefully
described infrastructure of the normal and abnormal
physiology in persons with OSAHS has been
developed over the past few decades, which enables
the development of innovative and largely effective
therapies. The most recent data complement the infra-
structure with the neurochemical changes underlying
the state-dependent respiratory disorder and observa-
tions that the disease process itself can impair muscles,
neural inputs, and soft tissue in a manner that has the
potential to worsen disease. Oxidative and nitrosative
stress from the repeated oxyhemoglobin desaturations
and re-oxygenations is implicated in the injury to these
tissues. An improved understanding of the mecha-
nisms through which OSAHS progresses may lead to
alternative therapies and aid in the identification of
persons at risk for disease progression.
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 Clin Chest Med 24 (2003) 195 – 205

Cardiovascular consequences of obstructive sleep apnea

Robert Wolk, MD, PhD, Virend K. Somers, MD, PhD*
Mayo Clinic, Department of Medicine, Division of Cardiovascular Diseases and Division of Hypertension,
200 First Street Southwest, Rochester, MN 55905, USA

Sleep disorders are common, with an estimated
prevalence of approximately 40 million cases in the
United States alone. Fifteen million persons in the
United States are believed to have sleep apnea, which
is defined as recurrent episodes of cessation of respi-
ratory airflow during sleep, with a consequent decrease
in oxygen saturation. Sleep apnea can be considered as
central or obstructive. Central sleep apnea (CSA) is
characterized by periodic apneas and hypopneas sec-
ondary to diminution or cessation of respiratory
efforts. In contrast, obstructive sleep apnea (OSA) is
secondary to upper airway collapse during inspiration
and is accompanied by strenuous breathing efforts.
CSA and OSA often may coexist. There is an increas-
ing recognition of the widespread prevalence of OSA
and its potential cardiovascular consequences. CSA
also has been implicated in cardiovascular disease,
primarily in patients with heart failure. This article
addresses the association between OSA and specific
cardiovascular disease conditions and examines the
evidence that implicates OSA in the pathophysiology
and progression of these disorders.
Hypertension
Much work has focused on the link between sleep
apnea and hypertension, and the evidence that sug-
Work for this article was funded by the Mayo Foundation,
HL-61560, HL-65176, HL-70302, MO1-RR00585.
* Corresponding author. Mayo Foundation, St. Mary’s
Hospital, DO-4-350, 1216 Second Street SW, Rochester,
MN 55902.
E-mail address: somers.virend@mayo.edu
(V.K. Somers).
gests a causal association between these two condi-
tions is compelling. The prevalence of hypertension
is greater in patients with OSA, and hypertensive pa-
tients (especially the nondippers) have a higher inci-
dence of OSA [1,2], which suggests that OSA may be
etiologically linked to chronic daytime hypertension.
The evidence for a causal relationship between OSA
and daytime hypertension has been strengthened by
recent epidemiologic studies. The Wisconsin Sleep
Cohort Study demonstrated a dose-response associa-
tion between sleep-disordered breathing at baseline
(diagnosed by in-hospital polysomnography) and the
development of new hypertension 4 years later, inde-
pendent of other known risk factors [3]. Specifically,
the odds ratios for the presence of hypertension at fol-
low-up were 1.42, 2.03, and 2.89 with an apnea-hy-
popnea index of less than 5, 5 to 15, and more than
15 events/hour at baseline, respectively (Fig. 1). A
similar relationship between OSA and the risk of
hypertension was seen in other studies [4,5]. Further
support for some causal interaction between OSA and
hypertension is provided by evidence that successful
treatment of OSA with continuous positive airway
pressure (CPAP) reduces blood pressure, especially in
patients with hypertension [6 – 11]. Taken together,
these data suggest that OSA is likely to contribute to
hypertension in some patients and that the manage-
ment of hypertension in these patients may be aug-
mented by treating the underlying sleep apnea.
Neurogenic mechanisms may contribute impor-
tantly to the acute and chronic hypertensive effects of
OSA. Acute nocturnal surges in blood pressure occur
in response to chemoreflex-mediated hypoxic stimu-
lation of sympathetic activity [12 – 14]. These re-
sponses are potentiated in hypertensive subjects
[15]. Activation of the chemoreflex leads to an

0272-5231/03/$ – see front matter D 2003, Elsevier Inc. All rights reserved.
doi:10.1016/S0272-5231(03)00020-0
196 R. Wolk, V.K. Somers / Clin Chest Med 24 (2003) 195–205
Fig. 1. Odds ratios for the presence of incident hypertension
at 4-year follow-up according to the apnea-hypopnea index
(AHI) at baseline. The odds ratios are adjusted for baseline
hypertension status, age, gender, body habitus (body mass
index, waist and neck circumference), alcohol consumption,
and cigarette use. Data are shown as odds ratio (lower and
upper 95% confidence interval). P for trend = 0.002. (Data
from Peppard PE, Young T, Palta M, Skatrud J. Prospective
study of the association between sleep-disordered breathing
and hypertension. N Engl J Med 2000;342:1378 – 84.)
increase in vascular sympathetic nerve activity and
circulating catecholamines, which increase peripheral
vascular resistance. Upon termination of apnea, car-
diac output increases (caused by changes in intra-
thoracic pressures) in the presence of a constricted
peripheral vascular bed, which leads to dramatic
surges in blood pressure (sometimes to levels as high
as 240/120 mm Hg) [14]. There seems to be a
‘‘carry-over’’ effect, such that sympathetic activity
remains elevated even in normoxic conditions, serv-
ing as one of several possible mechanisms that
maintain elevated blood pressure even during day-
time wakefulness.
Daytime hypertension in OSA may be mediated
by enhanced sympathetic activity, as evidenced by
elevated circulating catecholamine levels, increased
sympathetic nerve activity [14,16 – 21], and other
mechanisms. Normotensive OSA patients, who are
free of any overt cardiovascular disease, have de-
creased heart rate variability and increased blood
pressure variability [22]—characteristics that may
predispose to the development of hypertension [23]
and end-organ damage [24]. These abnormalities in
daytime neural circulatory control may be related to
chemoreceptor resetting and tonic chemoreceptor
activation (even in normoxia) [21,25]. By attenuating
apneas, acute CPAP therapy prevents blood pressure
surges and nocturnal sympathetic activation. Long-
term CPAP therapy results in lower daytime sym-
pathetic traffic in OSA patients [26].
Other mechanisms are also important in contrib-
uting to hypertension in OSA. One such potential
mechanism is endothelial dysfunction, with a decrease
in endothelium-dependent vasodilatation [27 – 29]
(Fig. 2). OSA also may enhance production of vaso-
constrictor and trophic agents, such as endothelin
[30,31], and attenuate production of nitric oxide
[32,33], further favoring vasoconstriction. Metabolic
factors, such as those related to obesity, insulin
resistance, or hyperleptinemia [34 – 41], are also likely
to play a role. Finally, an intriguing but unprov-
en possibility is that OSA-induced neuroendo-
crine activation, together with the mechanical effects
of blood pressure surges, may lead to vascular re-
modeling, increased wall-to-lumen ratio, and sus-
tained hypertension.
From the clinical standpoint, OSA always should
be considered in the differential diagnosis of causes
of refractory hypertension, particularly in obese hy-
pertensive patients and in patients in whom there is a
blunted nocturnal blood pressure decline (nondip-
pers). Appropriate therapy is effective in decreasing
blood pressure acutely at night [14] and even during
the daytime [11].
Atherosclerosis
In patients with established coronary artery dis-
ease, severe OSA may trigger acute nocturnal cardiac
ischemia with ST-segment depression (predominantly
Fig. 2. Percent change in forearm blood flow (FBF) during
infusion of acetylcholine (ACh) and verapamil (VER)
in patients with OSA (circles) and matched normal control
subjects (squares). Data are mean F SEM. (Modified from
Kato M, Roberts-Thomson P, Phillips BG, Haynes WG,
Winnicki M, Accurso V, et al. Impairment of endotheli-
um-dependent vasodilation of resistance vessels in pa-
tients with obstructive sleep apnea. Circulation 2000;102:
2607 – 10; with permission.)
 R. Wolk, V.K. Somers / Clin Chest Med 24 (2003) 195–205
in rapid eye movement sleep) that is often resistant to
traditional therapy [42 – 44]. ST-segment depression
in association with OSA was also noted in patients
without clinically significant coronary artery disease
and was reduced by CPAP treatment [45]. Nocturnal
ischemia in these patients is probably a result of
simultaneous oxygen desaturation, increased sym-
pathetic activity, tachycardia and increased systemic
vascular resistance (all increasing cardiac oxygen
demand), a prothrombotic state (see later discussion),
and any underlying subclinical coronary artery dis-
ease and impaired coronary reserve. Cardiac ischemia
may be exacerbated further by left ventricular hyper-
trophy, especially in patients with OSA who have
long-standing hypertension. Conceivably, the hemo-
dynamic stress induced by apneas and arousals may
increase the risk of coronary plaque rupture.
Whether nocturnal ischemia is directly related to
cardiovascular endpoints or mortality in patients with
OSA has not been established. The observation that
untreated OSA may be associated with an increased
risk of cardiovascular mortality in patients with
coronary artery disease [46,47] argues for the recog-
nition and treatment of any sleep apnea in these
patients, however.
Clinical and epidemiologic evidence suggests a
possible direct role for OSA in the pathophysiology
of atherosclerosis and ischemic heart disease. First,
several studies have reported a high prevalence of
OSA in patients with coronary artery disease [48 –
51]. Second, several case-control studies of patients
with myocardial infarction or angina pectoris sug-
gested that the presence of sleep apnea is an indepen-
dent predictor of coronary artery disease [50 – 54].
Third, patients with OSA have a greater prevalence
of increased carotid wall thickness (a marker of gen-
eralized atherosclerosis) and calcified carotid artery
atheromas [55,56]. Finally, in a large cross-sectional
study of 6424 free-living individuals, sleep apnea
(diagnosed by unattended polysomnography at home)
was associated with increased multivariable-adjusted
relative odds of self-reported coronary heart disease
[57]. This observation has been supported by another
prospective study [5]. These findings suggest that
sleep apnea perhaps may be associated with, or even
predispose to, coronary artery disease. Any such
predisposition may be indirect (eg, through hyperten-
sion, dyslipidemia) or may be directly related to pro-
moting the process of atherogenesis independent of
other comorbidities.
Experimental studies lend further support to the
notion that there might be a cause-and-effect relation-
ship between OSA and atherosclerosis. In OSA, repet-
itive surges in blood pressure, sympathetic activity,
197
and increased oxidative stress [58,59] may lead to
vascular injury. Increased plasma endothelin levels
[30,31], decreased nitric oxide production [32,33],
and endothelial dysfunction [27 – 29] also may con-
tribute to the initiation and progression of atherogenic
lesions and vascular damage.
Atherogenic processes can be initiated and po-
tentiated by endothelial damage and the ensuing and
coexisting inflammatory response [60]. Specifically,
leukocyte accumulation and adhesion to the endo-
thelium (with consequent leukocyte-endothelial cell
interactions) may impair endothelial function and
promote atherogenic processes. It is possible that
OSA may influence atherogenesis by inducing such
inflammatory reactions. C-reactive protein level (an
index of the presence of systemic inflammation and
probably a direct mediator of vascular dysfunction,
damage, and atherogenesis) is elevated in persons
with OSA (Fig. 3) [61]. Elevated plasma levels of
various adhesion molecules, increased expression
of adhesion molecules on leukocytes, and their
enhanced adherence to endothelial cells also have
been reported in patients with OSA [59,62 – 64].
The correlation between these changes and OSA
severity [63] and their reversal after CPAP therapy
[59,63] point to a possible causal relationship
between OSA and the systemic activation of inflam-
matory processes.
Stroke
Several studies have investigated the association
between sleep-related breathing disorders and the
incidence of stroke. A history of snoring seems to
increase the risk of stroke, independent of other
cardiovascular risk factors. A recent large prospective
study in women also supported this conclusion [65].
Similarly, many studies that used polysomnography
noted that the prevalence of OSA is greatly elevated
in patients with stroke [66 – 71].
A high incidence of OSA in patients with stroke
raises the possibility that perhaps stroke may cause
OSA (rather than being a result of it), especially when
the evidence is based on case-control studies of
patients with and without a history of stroke. This
possibility cannot be excluded. However, it seems
that breathing disorders consequent on a cerebrovas-
cular accident are more likely to cause changes in
respiratory pattern leading to primarily central sleep
apnea [70,72]. These breathing disorders are most
likely to manifest in the first hours after stroke, but
may aggravate preexisting OSA or even cause ob-
198 R. Wolk, V.K. Somers / Clin Chest Med 24 (2003) 195–205

Fig. 3. Plasma CRP levels in OSA patients and controls. Middle horizontal line inside box indicates median. Bottom and top of the
box are 25th and 75th percentiles, respectively. (From Shamsuzzaman AS, Winnicki M, Lanfranchi P, Wolk R, Kara T, Accurso V,
et al. Elevated C-reactive protein in patients with obstructive sleep apnea. Circulation 2002;105:2462 – 4; with permission.)

structive apnea secondary to changes in tone of the
upper airway muscles and upper airway resistance.
The concept that OSA actually precedes and
predisposes to stroke is based on several lines of
evidence. First, in some studies the prevalence of
OSA has been shown to be equally high in patients
with transient ischemic attacks, which suggests the
possibility that OSA precedes stroke events [69,70].
Second, patients with stroke and OSA demonstrate
persistence of OSA when repeated polysomnographic
studies are performed several months after the acute
event (although the incidence of central apnea may
actually decrease) [67,70]. Third, the obstructive
events are independent of the type of stroke and its
location [70]. Finally, a possible causal relationship
between OSA and stroke is supported by several
pathophysiologic studies that investigated the actual
mechanisms whereby OSA may predispose to stroke.
For example, Doppler measurements of cerebral blood
flow suggest that obstructive apneas are associated
with blood flow reduction in association with in-
dividual apneic episodes [73 – 75] and, probably,
impairment of cerebrovascular autoregulation and
diminished cerebral vasodilator reserve. The decreases
in cerebral blood flow are most likely related to the
presence of negative intrathoracic pressures and
increased intracranial pressure. Ischemic effects of
decreased cerebral blood flow would be further poten-
tiated by hypoxemia secondary to apnea. Indeed,
cerebral tissue hypoxia has been recorded during
episodes of OSA [76]. OSA also is a prothrombotic
state that is characterized by higher levels of platelet
aggregation and activation [77 – 80], elevated fibrino-
gen levels (correlating with the severity of OSA) [81],
decreased fibrinolytic activity [82], and increased
whole blood viscosity—all of which may contribute
to thrombosis and ischemic stroke. It is relevant that
the cerebral hemodynamic changes may be reversed
[83], platelet aggregability can be decreased [79,80],
and the increase in morning fibrinogen levels can be
blunted [84] by CPAP treatment.
Atherosclerosis also may be an important factor
predisposing to stroke. Increased carotid wall thick-
ness (a marker of generalized atherosclerosis and a
risk factor for stroke) and calcified carotid artery
atheromas are significantly more prevalent in indi-
viduals with OSA [55,56]. Finally, hypertension, the
prevalence of which is high in OSA, is a known risk
factor for stroke and may contribute substantially to
any association between OSA and stroke.
Although OSA is an attractive potential contrib-
utor to stroke, the evidence that links OSA to stroke
is primarily observational, and any causality is
inferred from these data and the experimental data
that suggest that OSA contributes to abnormalities in
cerebral blood flow and a prothrombotic state. There
is a clear need for more definitive longitudinal
studies of stroke risk in patients with OSA, inde-
pendent of other risk factors, particularly hyperten-
sion and hyperlipidemia. Importantly, there is some
indication that OSA in stroke survivors may be
associated with increased mortality and a worse
long-term functional outcome [67,68,85]. Hence, it
may be prudent to use CPAP therapy in compliant
 R. Wolk, V.K. Somers / Clin Chest Med 24 (2003) 195–205 199

patients after stroke with documented evidence of

sleep-disordered breathing.

Heart failure

Patients with systolic heart failure have a signifi-

cant prevalence of sleep apnea (primarily CSA) [86 –
90]. OSA may be especially common in patients with
left ventricular diastolic dysfunction [91,92], al-
though not all studies are consistent [93]. The relative
contribution of CSA and OSA to sleep-disordered
breathing varies in different congestive heart failure
(CHF) populations studied, with a general predom-
inance of CSA. Recent observations suggest that
there may be an important pathophysiologic link
between OSA and CSA. Namely, it has been
observed that in heart failure patients the proportion
of OSA decreases and the proportion of CSA
increases from the first to the last quarter of the night,
with an accompanying decrease in transcutaneous
carbon dioxide levels and a significant lengthening
of circulation time [94]. This overnight shift from
OSA to CSA may be related to a deterioration of Fig. 4. Effects of nasal continuous positive airway pressure
cardiac function (caused by the assumption of a (nCPAP) therapy on improving left ventricular ejection
recumbent position and by the detrimental hemody- fraction (LVEF) and functional class (NYHA) in patients
namic effects of OSA), with a subsequent increase in with congestive heart failure. (Modified from Malone S, Liu
left ventricular filling pressures. PP, Holloway R, Rutherford R, Xie A, Bradley TD. Ob-
structive sleep apnea in patients with idiopathic dilated cardio-
The significance of OSA in CHF is twofold. First,
myopathy: effects of continuous positive airway pressure.
OSA might predispose a person to CHF. Some
Lancet 1991;338:1480 – 4; with permission.)
preliminary epidemiologic data suggest that the pres-
ence of OSA is associated with a relative odds for
self-reported CHF of 2.38 (independent of other risk tion and functional class in patients with CHF [96]
factors) [57]. Such a causal relationship between (Fig. 4).
OSA and CHF may be explained by the association
of OSA with other direct or indirect risk factors for
CHF (eg, hypertension, ischemic heart disease, ven- Pulmonary hypertension
tricular hypertrophy, oxidative tissue damage, sys-
temic inflammation, neuroendocrine activation, or Apnea and hypoxemia also may elicit acute el-
autonomic dysfunction). evations of pulmonary artery pressure during sleep.
Second, CHF might contribute to new-onset OSA, Conceivably, these nocturnal events of hypoxia and
especially in susceptible individuals. In this case, pulmonary hypertension might contribute to endothe-
OSA may be caused by the collapse of the upper lial damage and vascular remodeling, which may
airway because of soft tissue edema and changes in further lead to sustained pulmonary hypertension.
upper airway muscle tone. OSA superimposed on Several studies have reported the presence of daytime
CHF may lead to further deterioration of cardiac pulmonary hypertension in patients with OSA. In
function (caused by hypoxemia, sympathetic activa- many studies, however, other comorbidities were also
tion, vasoconstriction, endothelial dysfunction) and present (most notably lung disease, heart failure, or
set up a vicious cycle of progressing, refractory CHF. systemic hypertension), so that any independent con-
An independent association between the severity of tribution of OSA to chronic pulmonary hypertension
sleep apnea and depression of left ventricular ejection remains unclear.
fraction has been reported [95]. In small study sam- Several studies have investigated the occurrence
ples, treatment of OSA with CPAP has been shown of daytime pulmonary hypertension in patients with
to substantially improve left ventricular ejection frac- OSA in the absence of lung and heart disease. These
200 R. Wolk, V.K. Somers / Clin Chest Med 24 (2003) 195–205
studies generally support the concept that OSA is
associated with daytime pulmonary hypertension
[97 – 100]. The frequency of pulmonary hypertension
varies among various populations studied. It should
be noted that in several studies there was no differ-
ence between pulmonary hypertensive and normo-
tensive OSA subjects with respect to nocturnal
oxygenation and OSA severity [97,98,100], which
suggests that individual variation in pulmonary vas-
cular sensitivity to hypoxic stimuli may be important
or, alternatively, that factors other than OSA per se
may be responsible for the apparent increased pul-
monary artery pressures in patients with OSA.
Patients with OSA with daytime pulmonary hyper-
tension have been reported to have greater elevations
of pulmonary artery vascular tone during rapid eye
movement sleep, independent of the degree of hy-
poxia [101]. In some [100,102,103], although not all
[97,104] studies, patients with OSA and pulmonary
hypertension have been suggested to differ from their
nonhypertensive counterparts in that they tend to
have a greater body mass index and lower daytime
arterial oxygen saturation. It is possible, at least in
some patients with OSA, that mild daytime hypoxe-
mia caused by the obesity-hypoventilation syndrome
might play a role in increasing daytime pulmonary
artery pressures. Interestingly, CPAP therapy seems
to reduce pulmonary pressures in OSA patients with
either pulmonary hypertension or with normal pul-
monary pressures [100,105], which suggests the
possibility that in many cases even ‘‘normal’’ pul-
monary pressures may be elevated compared with
individual baseline values.
A recent report on subjects drawn from the general
population suggested that sleep-disordered breathing
is associated with increased right ventricular wall
thickness [106]. Right ventricular hypertrophy has
been found in selected subjects with OSA [107,108].
Depressed right ventricular ejection fraction and clin-
ical evidence of right ventricular failure also have been
reported in patients with OSA [109 – 111]. Echocardio-
graphic studies of right ventricular morphology and
function and Doppler estimates of right ventricular
systolic pressure (and hence pulmonary artery systolic
pressure) in OSA patients are limited by several
factors, however, including (1) the difficulty in obtain-
ing high-quality images in a population that is often
obese, (2) the potential influence of comorbidities and
medication on these measurements, (3) the difficulties
in selecting appropriate control subjects for compar-
ison, and (4) the natural scatter of measurements
within a population, together with margins of error
inherent in these measurements. As with other cardi-
ovascular conditions, there is a clear need for more
stringent longitudinal studies before any definitive
assessment of the risk of chronic pulmonary hyperten-
sion in patients with OSA can be made. Further studies
also are needed to investigate the relationship between
OSA, pulmonary hypertension, right ventricular
hypertrophy, and right ventricular failure and to estab-
lish whether these pathologic changes have any impact
on prognosis and require specific treatment.
Cardiac arrhythmias
Most studies that investigate the association
between OSA and cardiac arrhythmias have meth-
odologic limitations related to small sample sizes and
lack of control groups. The exact prevalence of
arrhythmias in patients with sleep apnea is also
difficult to assess because of comorbidities, medica-
tion, and differences among the populations studied.
There is nevertheless a general perception that sleep
apnea is associated with an increased incidence of
bradyarrhythmias and tachyarrhythmias (both supra-
ventricular and ventricular).
The most frequent arrhythmias described in asso-
ciation with sleep apnea are severe sinus bradycardia
and atrioventricular block (including sinus arrest and
complete heart block). These arrhythmias are purely
functional because they have been reported in the
absence of any primary disease of the cardiac con-
duction system and they readily respond to atropine.
The most important pathophysiologic mechanism of
bradyarrhythmias in OSA is a reflex (chemoreceptor
mediated) increase in vagal tone, which is elicited by a
combination of apnea and hypoxemia [112 – 115] that
activates the diving reflex (increased sympathetic
traffic to peripheral blood vessels and increased vagal
drive to the heart). The occurrence of OSA-related
bradycardia seems to be linked to apnea severity
[116 – 118]. Bradyarrhythmias also may be more
likely to occur in patients with impaired baroreflex
function (eg, persons with hypertension or heart fail-
ure) [115]. The number of bradyarrhythmias seems to
be greater in rapid eye movement sleep [118], which
may be related in part to greater OSA severity in this
sleep stage.
The causal relationship between these bradyar-
rhythmias and OSA is supported by the observation
that bradycardia occurs only during the night (in
association with nocturnal apnea episodes) in other-
wise asymptomatic subjects [119,120] and is readily
prevented by tracheostomy or CPAP therapy [116,
117,119 – 122]. CPAP therapy has been shown to
be curative in a sample of patients primarily referred
for pacemaker therapy with asymptomatic brady-
 R. Wolk, V.K. Somers / Clin Chest Med 24 (2003) 195–205
arrhythmias during sleep, most of whom were sub-
sequently diagnosed with OSA [123]. Although the
prognostic significance of severe nocturnal bradyar-
rhythmias in OSA is not known, it is prudent to
evaluate all patients with asymptomatic bradyarrhyth-
mias for the presence of sleep apnea, which should be
treated appropriately.
Cardiac tachyarrhythmias also have been reported
in OSA, including ventricular tachycardia [116,120,
124] and supraventricular tachycardias. The preva-
lence and severity of these rhythm disturbances are
low in otherwise healthy patients with OSA, how-
ever, and the clinical significance of these arrhyth-
mias is unclear. In contrast, sleep apnea may be an
important trigger for clinically significant arrhythmias
in the presence of serious comorbidities, such as
ischemic heart disease or heart failure. For example,
sleep apnea (central and obstructive) has been asso-
ciated with a greater prevalence of atrial fibrillation in
patients with heart failure [125,126] or after coronary
artery bypass surgery [127]. Similarly, CSA and OSA
are related to the occurrence of ventricular arrhyth-
mias in the heart failure population [126,128], with a
decrease in arrhythmias after CPAP therapy [129].
Summary
Sleep apnea is associated with several cardiovas-
cular disease conditions. A causal relationship be-
tween sleep apnea and each of these diseases is likely,
but remains to be proven. The clearest evidence
implicating OSA in the development of new cardio-
vascular disease involves data that show an increased
prevalence of new hypertension in patients with OSA
followed over 4 years [3]. Circumstantial evidence
and data from small study samples suggest that OSA,
in the setting of existing cardiovascular disease, may
exacerbate symptoms and accelerate disease progres-
sion. The diagnosis of OSA always should be con-
sidered in patients with refractory heart failure,
resistant hypertension, nocturnal cardiac ischemia,
and nocturnal arrhythmias, especially in individuals
with risk factors for sleep apnea (eg, central obesity,
age, and male gender). Treating sleep apnea may help
to achieve better clinical control in these diseases and
may improve long-term cardiovascular prognosis.
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 Clin Chest Med 24 (2003) 207 – 222

Heart failure and sleep apnea: emphasis on practical

therapeutic options
Shahrokh Javaheri, MDa,b,*
a
Sleep Disorders Laboratory, Department of Veterans Affairs Medical Center, 3200 Vine Street, Cincinnati, OH 45220, USA
b
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Cincinnati College of Medicine,
Cincinnati, OH 45220, USA

Heart failure is approaching epidemic proportions Epidemiology of heart failure

and has become a major public health problem. It is
the only cardiovascular disorder with increasing
incidence and prevalence, causing excessive morbid-
ity and mortality. The economic burden of heart
failure is also huge. It is the largest single Medicare
expenditure because it is the leading cause of hospi-
talization for individuals old than age 65.
Heart failure is a major risk factor for sleep-related
breathing disorders, which could adversely affect
cardiovascular function and contribute to morbidity
and mortality of heart failure. Unfortunately, in the
clinical management of heart failure, sleep-related
breathing disorders remain underdiagnosed. The
underdiagnosis is mostly caused by lack of education
and unfamiliarity with sleep apnea by primary care
physicians and cardiologists involved in care of
subjects with heart failure.
In this article, the author briefly reviews the
epidemiology of heart failure and sleep-related
breathing disorders and discusses some practical
therapeutic options. It is hoped that treatment of
sleep-related breathing disorders will decrease mor-
bidity and mortality and improve quality of life for
persons with heart failure. Treatment also may
decrease the economic burden. Long-term studies
with such endpoints as primary outcomes are needed.
* Pulmonary Section, Department of Medicine, Veter-
ans Affairs Medical Center, 3200 Vine Street, Cincinnati,
OH 45220.
E-mail address: Shahrokh.Javaheri@med.va.gov
Heart failure results from any cardiac disorder that
impairs the ability of the ventricle to eject blood [1].
Left heart failure may result from disorders of great
vessels, valves, myocardium, and pericardium. In
most adults with left heart failure, however, the
symptoms are caused by impairment of left ventricu-
lar function (myocardial failure). Left ventricular
failure could be predominantly diastolic in nature or
manifested by systolic and diastolic dysfunction. The
principal hallmark of diastolic dysfunction is an
elevation in left ventricular end-diastolic pressure
and pulmonary capillary pressure. The underlying
pathology in diastolic heart failure is a stiff non-
compliant left ventricle, with systolic function of the
left ventricle being preserved. In contrast, the hall-
mark of left ventricular systolic dysfunction is a
depressed ejection fraction, which is commonly asso-
ciated with an increase in left ventricular end-dia-
stolic and systolic volumes. Left ventricular systolic
dysfunction is most commonly caused by coronary
artery disease. There are several nonischemic causes
of left ventricular systolic dysfunction, such as myo-
carditis and alcohol ingestion. In idiopathic dilated
cardiomyopathy, no cause can be identified.
Coronary artery disease and heart failure are
progressive disorders. The progression of heart fail-
ure is associated with geometric remodeling of the
ventricle, characterized by the development of dilata-
tion, hypertrophy, and becoming more spherical.
Pattern of ventricular remodeling is load dependent,
with pressure overload resulting in systolic and
volume overload resulting in diastolic wall stress

0272-5231/03/$ – see front matter D 2003, Elsevier Inc. All rights reserved.
doi:10.1016/S0272-5231(03)00026-1
208 S. Javaheri / Clin Chest Med 24 (2003) 207–222
[1]. Activation of several endogenous factors, such as
neurohormones and cytokines, accelerates the process
of remodeling and contributes to progression of heart
failure. Elevated levels of neurohormones, particu-
larly the vasoconstrictors, norepinephrine, compo-
nents of renin-angiotensin-aldosterone system, and
endothelin adversely affect cardiovascular structure
and function, which ultimately results in myocyte
apoptosis and fibrosis.
For multiple reasons (Box 1), heart failure has
major impact on public health [2 – 8]. It is estimated
that 1.5% to 2% of the United States population has
heart failure. Heart failure is a disorder of elderly
persons, and its prevalence increases to approxi-
mately 6% to 10% in individuals older than 65 years.
Heart failure is the only major cardiovascular disease
with increasing incidence and prevalence. In this
regard, it is estimated that 20 million people may
have asymptomatic cardiac dysfunction, and with
time, these individuals are likely to become symp-
tomatic. Because of increased average life span and
improved therapy of ischemic coronary artery disease
Box 1. Heart failure in the United States,
present and future
 1.5% to 2% of population(5 million)
 6% to 10% of population older than
65 years
 400,000 to 700,000 new
cases annually
 11 million physician office
visits annually
 3.5 million hospitalizations annually
 Leading cause of hospitalization in
people older than age 65
 250,000 deaths annually (direct
and indirect)
 $40 billion direct cost annually
 $8 billion to $15 billion cost of
hospitalization annually
 Only cardiovascular disorder increas-
ing in incidence and prevalence
 20 million with asymptomatic car-
diac impairment, many of
whom will develop heart failure
 Increased average life span
 Improved therapy for ischemic
coronary disease, hypertension,
and stroke
 Prevalence and incidence will in-
crease into twenty-first century
and hypertension, which are risk factors for heart
failure, it is predicted that incidence and prevalence
of heart failure will continue to rise into the twenty-
first century.
Heart failure accounts for approximately 11 million
physician office visits. It is the leading cause of hos-
pitalization in people older than 65 years and accounts
for 3.5 million hospitalizations annually. The latter
may be underestimated by standard ICD coding sys-
tem [8]. Annually, heart failure may contribute directly
or indirectly to 250,000 deaths. The death rate in-
creases progressively, with advanced symptomatology
approaching 30% to 40% annually in patients with
heart failure in New York Heart Class IV.
The economic impact of heart failure is also huge
and accounts for approximately US$40 billion annu-
ally for direct cost. This cost accounted for approx-
imately 5.4% of the health care budget in 1991 [3].
The cost of hospitalization is approximately $8 bil-
lion to $15 billion annually and accounts for most of
the total cost of heart failure; the remainder of the
cost covers the care delivered by health care profes-
sionals, including physicians, cost of medications,
home health care, and other medical durables.
Epidemiology of sleep apnea in heart failure
Prevalence of sleep-related breathing disorders
has been studied in patients with heart failure due
to various causes [9], although most systematically in
heart failure caused by left ventricular systolic dys-
function [10 – 22]. The results of some of these
studies are depicted in Table 1. At least 45% have
an apnea-hypopnea index (AHI) of
10/hour, and
40% to 80% have an AHI of
15/hour.
Differences in prevalence rates of sleep-related
breathing disorders in systolic heart failure (Table 1)
can be attributed to differences in various aspects of
the studies, the various thresholds to define the
disorder, and the varied definitions of hypopnea.
For example, in one study [22], a minimum of a
2% drop in saturation was the criterion to define
hypopnea. In the author’s studies [12,13], a minimum
of 4% decrease in saturation or an arousal was
required for criteria to define hypopnea, and some-
what arbitrarily considered, a threshold index of

15/hour was considered to be clinically significant.
Regarding the AHI, in population studies of subjects
without heart failure, an index of
5/hour has been
used to define presence of a significant number of
disordered breathing events in obstructive sleep
apnea-hypopnea syndrome [23]. Results of recent
population studies [24 – 26] suggest that lower indi-
 S. Javaheri / Clin Chest Med 24 (2003) 207–222
Table 1
Prevalence of sleep-related breathing disorders in systolic and isolated diastolic heart failure
Reference n LVEF %
Systolic heart failure
[13]a 81 25 F
[14]a 34 30 F
[22]a 66 23 F
[18]a 20 < 25
[15]a 75 < 40
[16]b 450 27 F
Diastolic heart failure
[27]a 20 > 50
Abbreviation: LVEF, left ventricular ejection fraction.
a
Prospective.
b
Retrospective.
ces of disordered breathing events are also associ-
ated with cardiovascular pathology. Despite a wide
range in the reported AHIs in systolic heart failure
(see Box 1), these studies [10 – 22] collectively
showed a high prevalence of sleep-related breathing
disorders, which made systolic heart failure one of the
leading risk factors for sleep apnea-hypopnea.
The largest prospective study [13] (see Table 1)
involved 81 ambulatory male patients with stable,
treated heart failure. In the study, 92 consecutive
eligible patients who were followed in a cardiology
clinic were asked to participate (88% recruitment).
Using an AHI of
15/hour as the threshold, 41 pa-
tients (51% of all patients) had moderate to severe
sleep apnea-hypopnea, with an average index of
44 F 19 (1 standard deviation) per hour. The results
of that study [13] compared well with the results of
the largest retrospective study [16] using similar crite-
ria to define hypopnea. In the study of 450 patients
[16], which also included women, 61% had an AHI
of
15/hour. This prevalence, 61%, was expectedly
higher than the 51% prevalence rate in the author’s
study [13], because in Sin’s study [16], risk factors
for sleep apnea were among reasons for referral to the
sleep laboratory, whereas the author’s study sought
no information about symptoms or risk factors for
sleep apnea to recruit subjects.
The prevalence of obstructive and central sleep
apnea also varies widely among different studies. In
each study, obstructive sleep apnea-hypopnea/central
sleep apnea-hypopnea ratio depends on several fac-
tors, including the pattern of recruitment (consecutive
recruitment versus referral because of risk factor for
obstructive sleep apnea-hypopnea, such as snoring),
number of overweight and obese subjects, and the
cut-off point to define predominant obstructive ver-
sus central sleep apnea-hypopnea. Accurate differ-
entiation of hypopneas into central versus obstructive
209
AHI
10/h (%) AHI
15/h (%)
9 57 51
10 — 82
6 76 —
45 45
59 43
16 72 61
55 —
is difficult, much more so than differentiation of
obstructive from central sleep apnea. Undoubtedly
some degree of contamination occurs. With these
limitations in mind, in the author’s study [13],
approximately 40% of the patients had central sleep
apnea and 11% has obstructive sleep apnea. When
polysomnograms were decoded and matched with
demographics of subjects, patients whose polysom-
nograms were categorized to have obstructive sleep
apnea-hypopnea had a significantly higher preva-
lence of habitual snoring, obesity, and hypertension
[13]. In Sin’s study [16], the prevalence of obstruc-
tive sleep apnea (OSA) was 32%, compared with
11% in the author’s study [13]. This rate also was
expected because snoring, a risk factor for OSA, was
a reason for referral in Sin’s study [16] but not the
author’s [13].
Sleep-related breathing disorders in isolated
diastolic heart failure
A small study [27] reported that approximately
50% of persons with isolated diastolic heart failure
have sleep apnea-hypopnea defined by an AHI of

10/hour (see Table 1). Large-scale epidemiologic
studies are needed to define the prevalence of sleep
apnea-hypopnea in isolated diastolic heart failure.
This is important for two reasons. First, a large
number of old patients with symptoms of congestive
heart failure suffer from isolated diastolic heart failure
[28], and sleep-related breathing disorders also may
be prevalent in this cohort. Second, sympathetic
activation, nocturnal hypertension, and hypoxemia,
which are the immediate consequences of sleep-
related breathing disorders, could impair left ven-
tricular diastolic functions or contribute to diastolic
dysfunction [29,30]. In other words, sleep-related
210 S. Javaheri / Clin Chest Med 24 (2003) 207–222
breathing disorders could be a cause of diastolic
dysfunction or contribute to its progression.
Pathophysiologic consequences of sleep apnea
and hypopnea
There are three major adverse cardiovascular con-
sequences of sleep apnea and hypopnea: (1) intermit-
tent alterations in arterial blood gases, (2) arousals and
shift to light sleep stages, and (3) large negative inspir-
atory deflections in intrathoracic pressure [31 – 33].
Intermittent alterations in arterial blood gases
Periodic breathing is characterized by episodes of
apnea and hypopnea, which cause hypoxemia and
hypercapnia, and hyperpnea, which results in reoxy-
genation and hypocapnia. Hypoxemia may affect the
cardiovascular system adversely in multiple ways,
such as by decreasing myocardial oxygen delivery,
promoting endothelial cell dysfunction, and increas-
ing sympathetic nervous system activity.
Decreased oxygen delivery is most detrimental to
myocardium if there is established coronary athero-
sclerosis, which could limit myocardial blood supply.
In this regard, myocardium has the highest oxygen
extraction, as evidenced by a low coronary sinus
partial pressure oxygen (PO2). Hypocapnia, which
occurs because of hyperpnea after apnea or hypo-
pnea, may further impair myocardial oxygen delivery
and uptake by coronary artery vasoconstriction [34]
and shifting the oxygen-hemoglobin dissociation
curve to the left. Decreased myocardial oxygen
supply may impair systolic and diastolic function
and cause myocardial ischemia and arrhythmias.
Hypoxia also may promote coronary endothelial
dysfunction. Endothelial dysfunction has been dem-
onstrated in several cardiovascular disorders, includ-
ing hypertension, myocardial infarction, and stroke
[35 – 37], disorders that also have been associated with
OSAH [24 – 27]. Hypoxia causes an imbalance in
vasoregulatory agents and promotes coagulation and
inflammation. As an example, through activation of
hypoxia-inducible factor-1 [38,39], hypoxia increases
the expression of several genes, such as genes that
encode endothelin-1, a potent vasoconstrictor with
proinflammatory properties. In contrast, hypoxia sup-
presses transcriptional rate of endothelial nitric oxide
synthase [40,41] and results in decreased production
of nitric oxide (NO), which is vasodilatory and has
antimitogenic properties. By enhancing expression of
adhesion molecules and promoting leukocyte rolling
and endothelial adherence [42], hypoxia may mediate
coronary artery inflammation. Hypoxia is also in-
volved in induction of cardiac and endothelial cells
apoptosis [43,44].
Most studies that show adverse effects of hypoxia
have been performed with sustained and severe hy-
poxia. Because in sleep apnea-hypopnea hypoxemia is
intermittent, the results of studies with sustained hy-
poxia might not be necessarily applicable to sleep-
related breathing disorders. Recent studies [45 – 47]
have shown that intermittent hypoxia (ie, hypoxia-
reoxygenation) also results in gene activation. In this
context, intermittent hypoxia may be analogous to
ischemia-reperfusion syndrome, and it has been pro-
posed to be more deleterious than sustained hypoxia
[48 – 50]. Support for a causative role of intermittent
hypoxia in induction of these abnormalities stems from
studies on treatment of OSAH with nasal continuous
positive airway pressure (CPAP). Several adverse
effects of hypoxia (eg, platelet activation [51], hyper-
fibrinogenemia, increased factor VII activity [53],
abnormal endothelium-dependant vasodilation [54],
and leukocyte activation [55,56]) observed in OSAH
are reversed by treatment with nasal CPAP. Enhanced
sympathetic activity, another neurohormonal con-
sequence of sleep-related breathing disorders that
results in adverse structural and functional cardiac
alterations, decreases after treatment of OSA and
central sleep apnea in heart failure.
It is conceivable that endothelial dysfunction
caused by sleep-related breathing disorders contrib-
utes to worsening of atherosclerosis, atherothrombo-
sis, and left ventricular dysfunction (Fig. 1). In this
regard, one study [57] has shown that untreated OSA
is a risk factor for cardiovascular disease, and two
prospective studies [58,59] of persons with myocar-
dial infarction have shown increased mortality rates
in persons with sleep apnea when compared with
individuals without it.
Finally, hypoxemia by stimulation of the carotid
bodies [60] causes sympathetic activation. In contrast
to the inhibitory function of the baroreceptors,
increased carotid body activity augments central
nervous system sympathetic outflow. In heart failure
with left ventricular systolic dysfunction, sympathetic
activity may be increased partly because of blunting
of baroreceptor activity and partly because of
increased carotid body stimulation [29].
There are multiple adverse cardiac consequences
of increased sympathetic activity. At cellular level,
increased catecholamines may cause myocyte apop-
tosis and fibrosis [61 – 63], both of which are inhibited
by b-adrenergic blockade [61,62]. Hemodynamically,
sympathetic activation increases systemic vascular
resistance and left ventricular afterload, myocardial
 S. Javaheri / Clin Chest Med 24 (2003) 207–222
Fig. 1. Proposed mechanisms by which sleep-related breathing disorders may cause or contribute to progression of ather-
osclerosis. ḊO2, oxygen delivery; CBF, coronary blood flow; z, increase; #, decrease.
contractility, and heart rate, all of which increase
myocardial oxygen demand. As a consequence of
hypoxemia, myocardial oxygen delivery may de-
crease, whereas consumption may increase and result
in an imbalance in supply/demand ratio. Adverse
consequences include myocardial cell hypoxia, sys-
tolic and diastolic dysfunction, angina, myocardial
infarction, and arrhythmias.
Arousal and shift to light sleep stages
In addition to hypoxemia and hypercapnia causing
increased sympathetic activity, arousals also increase
sympathetic activity. Comparing wakefulness to
sleep, there is a reduction in sympathetic activity
and increased parasympathetic activity [64 – 66].
These changes in autonomic nervous system during
sleep are reflected in a decrease in heart rate, blood
pressure, and cardiac output [67]. Sleep is peaceful for
the heart; however, arousals and awakenings result in
reversal of autonomic nervous system activity [68].
In patients with heart failure and systolic dys-
function, sleep is disturbed. This was evidenced in
studies that included a first night stay in the sleep
laboratory for adaptation to minimize sleep frag-
mentation [12,13]. Considerable sleep fragmentation
was observed in the second night polysomnography.
211
Arousals, insomnia, and shift to light sleep stages
that were observed in patients with systolic heart
failure were further exaggerated by presence of
sleep-related breathing disorders. Approximately
half of the sleep-disordered breathing events caused
cortical arousals [13]. In patients with OSAH,
arousals commonly occurred immediately before
termination of the breathing disorder and resulted
in patency of the upper airway and resumption of
breathing. In central sleep apnea, however, arousals
occurred at the peak of hyperventilation and served
no purpose but to fragment sleep and increase
sympathetic activity.
In the presence of sleep apnea-hypopnea, for
various reasons such as arousals, shift to light sleep
stages, hypoxia, and hypercapnia, nocturnal sympa-
thetic activity is elevated, which makes sleep not so
peaceful for the cardiovascular system. Increased
sympathetic activity is a predictor of poor survival
in systolic heart failure. Sleep-related breathing dis-
orders, by augmenting sympathetic activity, may
contribute to mortality in systolic heart failure. Impor-
tantly, treatment of sleep-related breathing disor-
ders—OSA [69,70] and central sleep apnea [71]—
decreases sympathetic activity and conceivably
improves survival of subjects with systolic heart
failure, in a manner similar to b-blockers.
212 S. Javaheri / Clin Chest Med 24 (2003) 207–222
Large negative deflections in intrathoracic pressure
Sleep-related breathing disorders are associated
with exaggerated negative inspiratory intrathoracic
pressure deflections. High negative intrathoracic pres-
sures may be generated during episodes of obstruc-
tive apnea [33]. After central apnea, hyperpnea occurs
and relatively large negative pressure deflections
[33], particularly in the face of stiff lungs and chest
wall, also may be observed. Pleural pressure changes,
however, are generally less pronounced in central
sleep apnea than in OSA [33].
The exaggerated negative intrathoracic pressure
increases the transmural pressure (pressure inside
minus pressure outside) of the intrathoracic vascular
structures including aorta, ventricles, and pulmonary
vascular bed. The consequences of exaggerated nega-
tive intrathoracic pressure include increased venous
return, increased left ventricular afterload, and pul-
monary congestion and edema [72 – 74].
Treatment of sleep-related breathing disorders
Obstructive sleep apnea
Treatment of OSAH in heart failure is similar to
that in the absence of heart failure (Box 2). The two
main therapeutic approaches are weight loss and
nasal mechanical devices.
Obesity is the major known risk factor for OSAH
[23,75,76] in the general population and in persons
with heart failure [13,16]. Importance of weight loss
in heart failure is particularly evident from recent data
from the Framingham Heart Study [77], which
showed that excess weight and obesity are associated
with and presumably cause heart failure. Another
study [78] showed that obesity was associated with
increased mortality, primarily because of cardiovas-
cular causes. Undoubtedly, however, several obese
persons in these two studies suffered from OSAH.
Undiagnosed OSAH could have been an important
contributing factor, linking obesity to heart failure
and cardiovascular mortality reported in these two
studies [77,78]. OSAH was not mentioned in these
two reports [77,78]. This observation is consistent
with the author’s earlier remarks regarding unfamili-
arity of physicians with sleep-related breathing dis-
orders and importance of education. Overweight and
obese subjects with heart failure should get dietary
consultation and be encouraged to lose weight, which
has been shown to decrease OSAH index [76].
Noninvasive mechanical devices have been used
most successfully to treat OSAH in the general popu-
Box 2. Potential treatment options for
sleep apnea-hypopnea in heart failure
Obstructive sleep apnea-hypopnea
Optimization of medical therapy for
heart failure
Weight loss
Mechanical devices (CPAP,
bi-level pressure for
CPAP noncompliance)
Oxygen for subjects noncompliant
with mechanical devices
Central sleep apnea
Optimization of medical therapy for
heart failure
Cardiac transplantation
Mechanical devices (CPAP, bi-level
pressure, and adaptive pressure
support servoventilation)
Medications (eg, oxygen,
theophylline)
lation [79 – 81]. There are limited reports on the use
of nasal CPAP for treatment of OSA in heart failure
[82 – 84]. Application of nasal CPAP results in sig-
nificant improvement in obstructive disordered breath-
ing events and arterial oxyhemoglobin desaturation.
Left ventricular ejection fraction increases with long-
term use of CPAP [83]. This is an important finding
because left ventricular ejection fraction is a predictor
of survival in systolic heart failure. Application of
nasal CPAP to treat OSAH in the general population
reverses several neurohormonal abnormalities, such
as abnormal endothelium-dependent vasodilata-
tion, hypercoagulopathy, and leukocyte activation
[51 – 56]. If, as expected, treatment of OSA in heart
failure results in reversal of the aforementioned patho-
logical process, progression of coronary artery inflam-
mation, thrombosis, and atherosclerosis may subside.
Rarely in congestive heart failure may treatment with
CPAP convert OSA to central sleep apnea [82].
Central sleep apnea
The approach to treatment of central sleep apnea
in systolic heart failure is somewhat different from
that of OSA [31,33]. Of utmost importance is
 S. Javaheri / Clin Chest Med 24 (2003) 207–222
improving cardiorespiratory function before per-
forming polysomnography.
Optimization of cardiopulmonary function
Early studies by Harrison et al [85] and more
recent studies [86 – 88] showed that treatment of heart
failure may improve or even eliminate periodic
breathing. Given the limited manpower and the cost
of polysomnography, the author suggests that in
congestive heart failure polysomnography be per-
formed only after optimization of cardiorespiratory
functions. Optimal treatment of heart failure with
diuretics, angiotensin-converting enzyme inhibitors,
cardiotonic drugs, and b-blockers may improve or
eliminate periodic breathing by several mechanisms,
including normalization of partial pressure carbon
dioxide in the arterial blood (PaCO2), improved
arterial circulation time, and normalization of func-
tional residual capacity.
Although a low arterial PCO2 is not a prerequisite
for development of central sleep apnea [89,90],
several studies [89,91,92] have shown that a low
arterial PCO2 while awake highly predicts central
sleep apnea. In the author’s study [89], many patients
with central sleep apnea had normal PaCO2; however,
the predictive value of a low arterial PCO2 defined as
35 mm Hg or less was approximately 80%.
Multiple mechanisms may contribute to hyper-
ventilation in congestive heart failure. The most
commonly quoted factor is pulmonary congestion.
It is believed that stimulation of pulmonary juxta-
capillary receptors by pulmonary vascular congestion
and edema causes tachypnea. The rise in respiratory
rate may result in an increase in alveolar ventilation
and hypocapnia. Another cause of hyperventilation in
heart failure could be increased sympathetic activity.
Limited data in humans [93] show that intravenously
infused sympathomimetic agents increase ventilation
and lower PCO2; this action is blocked by pretreat-
ment with propranolol [93].
How does a low PaCO2 predispose subjects with
heart failure to central sleep apnea? The difference
between two PCO2 set points (the baseline prevailing
PCO2, PCO2 at the apneic threshold) is critical for the
genesis of central apnea [94,95]. The smaller the
difference, the greater the likelihood of the person
having central apnea. Normally, in transition from
wakefulness to sleep, the prevailing PCO2 increases
and the difference between the prevailing PCO2 and
the PCO2 at the apneic threshold increases. As long as
the prevailing PCO2 remains above the apneic thresh-
old, central apnea does not occur. Limited studies
[92,94,96] showed that patients with heart failure and
central sleep apnea, in contrast to patients without
213
central sleep apnea, are unable to increase their
prevailing PCO2 in transition from wakefulness to
sleep. Because sleep unmasks the apnea threshold,
such persons become prone to developing central
apnea during sleep. It is conceivable that because of
cardiorespiratory effects of advanced heart failure
(particularly in patients with hypocapnia), PaCO2 fails
to rise with sleep onset. If true, this occurrence may
relate specifically to severity of the left ventricular
diastolic dysfunction. In the supine position, as
venous return increases, left ventricular end-diastolic
and pulmonary capillary pressures rise if the left
ventricle is noncompliant. As a result of the rise in
pulmonary capillary pressure and consequent conges-
tion and edema, juxta-capillary receptors are stimu-
lated, which causes tachypnea and hyperventilation.
In this regard, a negative correlation between arterial
PCO2 and wedge pressure has been reported [15].
Another factor that increases the likelihood of
periodic breathing is increased arterial circulation
time, which delays the transfer of information regard-
ing pulmonary capillary PO2 and PCO2 to the con-
trollers (the chemoreceptors). Increased arterial
circulation time converts a negative feedback system
into a positive one. In heart failure, arterial circulation
time may be increased for various reasons, including
a low stroke volume and increased intrathoracic
blood volume (pulmonary congestion, increased left
atrial and left ventricular volumes).
A third factor that increases the likelihood of
developing periodic breathing in heart failure is a
low functional residual capacity, which results in
underdampening. In heart failure, functional residual
capacity could be low [13] for various reasons, such as
pleural effusion, pulmonary edema, and cardiomegaly.
Pharmacologic treatment of heart failure with
diuretics, angiotensin-converting enzyme inhibitors,
and b-blockers could normalize PCO2 by decreasing
pulmonary congestion and decreasing sympathetic
activity. Treatment also could decrease arterial cir-
culation time as stroke volume increases and cardio-
pulmonary blood volume decreases and increase
functional residual capacity as cardiac size, pleural
effusion, and intravascular and extravascular lung
water decrease, all of which should stabilize breath-
ing during sleep.
b-blockers have been added to pharmacologic
treatment of heart failure [3,4] and have been shown
to improve survival considerably. The additional
beneficial effect of b-blockers over angiotensin-con-
verting enzyme inhibitors relates to their counterbal-
ancing of increased sympathetic activity, which is
present in congestive heart failure and could be
augmented further by consequences of sleep-related
214 S. Javaheri / Clin Chest Med 24 (2003) 207–222
breathing disorders. The improvement in survival for
heart failure with the use of b-blockers may be partly
caused by counterbalancing the sympathetic activity
caused by sleep-related breathing disorders. If
increased sympathetic activity causes hyperventila-
tion, which promotes central sleep apnea, b-blockers
may normalize PCO2 by decreasing sympathetic
activity and decrease the likelihood of occurrence of
central sleep apnea. b-blockers could improve or
eliminate sleep-related breathing disorders by
improving cardiac function and normalizing PCO2.
Any residual breathing disorders result in failure of
maximal sympathetic deactivation by b-blockers.
It is important to emphasize that aggressive treat-
ment of heart failure with various medications may
decrease or even eliminate central sleep apnea. This
result has been shown with use of salt restriction,
diuretics, ionotropes, and angiotensin-converting
enzyme inhibitors. Ironically, there are no studies
with b-blockers, although b-blockers may improve
cardiorespiratory functions more than angiotensin-
converting enzyme inhibitors and result in consid-
erable improvement in central sleep apnea. As left
heart structure and function deteriorate with time,
even in the presence of b-blockers, central sleep
apnea worsens or recurs. Patients who have heart
failure and whose central sleep apnea is initially
improved by b-blockers must be followed serially
for recurrence of central sleep apnea.
Regarding b-blockers, the author also emphasizes
one side effect that relates to their effect on melato-
nin. Secretion of melatonin, a sleep-promoting chem-
ical, is via cyclic AMP-mediated b-receptor signal
transduction system, and b-blockers have been shown
to decrease melatonin secretion [97,98]. Carvedilol is
an exception [97].
Oxygen
Systematic studies of subjects with systolic heart
failure [99 – 103] have shown that nocturnal admin-
istration of supplemental nasal oxygen improves
central sleep apnea, eliminates desaturation, and
may decrease arousals and light sleep. Pembrey
[104] should be credited with the observation approx-
imately 100 years ago, and Hanly et al [99] should be
credited for the first randomized, placebo-controlled
study of nocturnal oxygen versus compressed nasal
air. In a study [99] of nine subjects with systolic heart
failure (mean left ventricular ejection fraction was
12% F 5%) that compared one night of nasal oxygen
versus air, AHI (30 F 5 versus 19 F 2) and arousal
index (30 F 8 versus 14 F 2) decreased and sleep
architecture improved significantly. In the largest
study [103], with 36 subjects with systolic heart
failure (mean left ventricular ejection fraction approx-
imately 22%), central apnea index decreased signifi-
cantly from approximately 28/hour to 10/hour [100].
In a randomized, placebo-controlled, double-blind
study, Andreas et al [101] showed that short-term
(1 week) administration of supplemental nocturnal
oxygen improved maximum exercise capacity. This
is an important finding because V̇O2max is an inde-
pendent predictor of survival in heart failure [106] and
coronary artery disease [105]. Another randomized,
placebo-controlled study of 4 weeks’ duration showed
that nocturnal administration of oxygen decreased
overnight urinary norepinephrine excretion [102].
Overnight urinary norepinephrine excretion may be
a better indicator of the overall nocturnal sympathetic
activity than a single venous blood sample of norepi-
nephrine obtained in the morning. Recently, Andreas
et al showed that nasal oxygen decreased the aug-
mented muscle sympathetic activity caused by vol-
untary central apnea in persons with systolic heart
failure [107].
Potential adverse effects of oxygen. Long-term
nocturnal and diurnal nasal oxygen has been used
extensively in chronic obstructive pulmonary disease
and has been shown to increase survival [108,109]. It
is remarkably free from side effects [108,109]. In
heart failure, however, oxygen may have adverse
hemodynamic effects in heart failure. This was
studied in seven awake subjects with class III and
IV heart failure in a cardiac catheterization laboratory
[110]. After baseline (breathing room air) hemody-
namic variables were obtained, subjects breathed
graded amounts of nasal oxygen, 24%, 40%, and
100%, each for 5 minutes [110]. Oxygen breathing
resulted in a progressive dose-dependent increase in
systemic vascular resistance and pulmonary capillary
pressure and a decrease in stroke volume. Regarding
the results of this study, however, several important
issues must be emphasized. The study lacked appro-
priate control, and the hemodynamic effects of lying
supine for the same period of time in these patients
with class III and IV heart failure were not available.
The duration of each trial was 5 minutes, during
which time steady state may not be achieved. The
hemodynamic effects of oxygen were most pro-
nounced with administration of 40% to 100% oxy-
gen, and more therapeutic ranges of nasal oxygen (ie,
28%, 32%, and 36%, equivalent to 2 – 4 L/minute)
were not studied.
Careful studies (placebo controlled) are necessary
to determine any hemodynamic effects of therapeutic
amounts of nasal oxygen (24% – 36%) in patients
with heart failure. Finally, the mechanisms for the
potential hemodynamic effects also must be studied
 S. Javaheri / Clin Chest Med 24 (2003) 207–222
because increased oxidative stress is present in con-
gestive heart failure, and administration of additional
oxygen provides substrate for production of oxygen
radicals. The results of this study [110] may not apply
to subjects with heart failure and periodic breathing
who may be treated with lesser amounts of oxygen
therapeutically because of desaturation during sleep.
Several studies have shown that nocturnal oxygen
results in improvement in central sleep apnea, sleep
characteristics, exercise tolerance, and a reduction in
sympathetic activity. In this regard, nocturnal and
diurnal use of oxygen has proven useful for heart
failure in patients with cor pulmonale secondary to
chronic obstructive pulmonary disease.
Mechanisms of therapeutic effect of nasal oxygen
on central sleep apnea are multiple and include a
small rise in PCO2 [100,111], which presumably
increases the difference between the prevailing
PCO2 and the PCO2 at the apneic threshold, a
reduction in ventilatory response to CO2 [112], and
increasing body tissue stores (eg, lung and blood
contents) of oxygen, which increase damping. Con-
sequently, breathing during sleep should stabilize.
Short-term studies show that nocturnal oxygen
improves or eliminates central sleep apnea and asso-
ciated arousals, eliminates arterial oxyhemoglobin
desaturation, improves sympathetic activity, and
increases exercise capacity. Prospective, placebo-con-
trolled, long-term studies are necessary to determine
if nocturnal oxygen therapy has the potential to
decrease morbidity and mortality of patients with
systolic heart failure [113].
Nasal positive airway pressure devices
Various positive airway pressure devices have
been used to treat central sleep apnea in congestive
heart failure [82,114 – 118]. Nasal CPAP has been
studied most extensively. Several laboratories have
reported on acute and chronic use of CPAP in patients
with central sleep apnea with differing results
[82,114,117 – 121].
The author’s experience with acute (one night)
effect of CPAP on central sleep apnea has been
reported elsewhere [82]. The author studied 21
patients with central sleep apnea, 9 of whom (43%)
responded to CPAP. In these patients, CPAP virtually
eliminated disordered breathing (AHI decreased from
36/hour F 15/hour to 4/hour F 3/hour) and arterial
oxyhemoglobin desaturation. An important finding in
the author’s study was the effect of CPAP on ven-
tricular irritability during sleep [82]. In patients whose
sleep apnea-hypopnea responded to CPAP, the number
of premature ventricular contractions, couplets, and
ventricular tachycardias decreased. In contrast, CPAP
215
had no significant effect on ventricular irritability in
patients whose disordered breathing did not improve.
Although the author’s study enrolled the largest num-
ber of patients in an acute CPAP trial [82], the number
of patients was small, and the electrocardiographic
findings must be confirmed in a large study.
Chronic effects of CPAP on central sleep apnea
have been studied by Naughton et al [114] and Sin et
al [120]. In a randomized, parallel design, controlled
trial [114], heart failure patients were assigned to
either nasal CPAP (n = 14) or served as controls
(n = 5). Patients were followed for 3 months, and 12
subjects (in each arm) completed the study. Com-
paring paired variables obtained initially and after
1 month use of CPAP at approximately 10 cm H2O,
the AHI (43/hour F 5/hour versus 15/hour F
5/hour) and arousal index (36/hour F 6/hour versus
24/hour F 4/hour) decreased significantly with
CPAP. There was an increase in left ventricular
ejection fraction from 21% F 4% to 29% F 5%
noted at 3 months after use of CPAP. Ejection fraction
did not change significantly in the control group.
Naughton et al [71] reported that use of CPAP
decreases sympathetic activity as measured by
plasma norepinephrine level and urinary norepineph-
rine excretion. These are important observations
because left ventricular ejection fraction and plasma
norepinephrine are predictors of survival in systolic
heart failure.
Sudden death (presumably caused by ventricular
arrhythmias) and pump failure are the two major
causes of death in systolic heart failure. By decreas-
ing ventricular arrhythmias [82] and improving ejec-
tion fraction [120], nasal CPAP may improve survival
in patients with systolic heart failure. In this regard, in
a randomized, controlled trial [117] of 29 patients
with central sleep apnea (n = 15 in control and 14 in
CPAP group), treatment analysis (ie, excluding the 2
CPAP noncompliant patients) showed a significant
reduction in 3-year mortality-cardiac transplantation
( P = 0.017, n = 12 in CPAP group and 15 in control
group). With intention to treat analysis (which
includes all patients enrolled), a similar trend was
observed ( P = 0.06) [120].
There are several unresolved issues about the use
of CPAP for central sleep apnea in heart failure, and
further large studies [122] are necessary to confirm the
effects of CPAP on central sleep apnea in heart failure.
Researchers [82] found that 57% of patients with
central sleep apnea did not respond to CPAP (one
night). These patients had the most severe central sleep
apnea and had a tendency to have a low PaCO2.
Negative studies from some other laboratories have
been reported [117 – 119]. Davies et al [117] random-
216 S. Javaheri / Clin Chest Med 24 (2003) 207–222
ized eight patients with mean left ventricular ejection
fraction of 18% to either 2 weeks of CPAP (7.5 cm
H2O) or placebo (sham CPAP). Two patients withdrew
from the CPAP trial because of worsening of heart
failure, and one patient died. There were no significant
changes in periodic breathing in the remaining sub-
jects. Buckle et al [118] reported that one night’s use of
CPAP (5 – 7.5 cm H2O) had no significant effect on
periodic breathing in eight patients with heart failure
and systolic dysfunction. Guilleminault et al [117]
studied nine patients with systolic heart failure and
central sleep apnea. Titration (5 – 12 cm H2O) with
CPAP failed to eliminate periodic breathing and
arousals. One study reported increased muscle sym-
pathetic activity with short-term use of CPAP in
subjects with chronic heart failure [123].
Another concern with long-term use of CPAP is
compliance. In OSAH syndrome, compliance varies
and is probably related to several factors, particularly
patient perception of improvement. Because imme-
diate improvement in symptoms is often not observed
in heart failure patients with central sleep apnea,
high-level compliance may not be achieved.
Because of an increase in intrathoracic pressure,
venous return may decrease with CPAP, which results
in decreased stroke volume and hypotension. Heart
failure patients with atrial fibrillation [124], intra-
vascular hypovolemia, and normal left ventricular
end-diastolic blood pressure may be more vulnerable
than others. For these reasons, successful use of
CPAP in heart failure is not easily achieved and
requires a skillful team. Acute (first night) titration
is not necessary. Gradual (during a few weeks)
titration, treatment of complications, particularly
nasal clogging, and repeated follow-ups with encour-
agement are key factors for success.
The mechanisms by which CPAP improves cen-
tral sleep apnea are complex and probably multi-
factorial. Upper airway closure has been shown to
occur in central sleep apnea [125,126], and in a full-
night polysomnographic study [11] and a nap study
[127], obstructed breaths were observed at the end of
some central apneas. CPAP could stabilize breathing
by increasing transmural pressure of upper airway, a
mechanism similar to that in obstructive apnea. It is
also possible that pressure stimulation of various
receptors in the upper airway could improve central
apnea because upper airway (laryngeal and pharyn-
geal) receptors are important in regulating the timing
and amplitude of breathing.
Another set of mechanisms by which CPAP may
improve central apnea may relate to improvement in
pathogenic factors that predispose subjects with sys-
tolic heart failure to central sleep apnea. Prolonged
arterial circulation, decreased functional residual
capacity, and a low arterial PCO2 are among predis-
posing factors that could be reversed toward normal
by application of CPAP. Nasal CPAP may shorten
arterial circulation time by decreasing afterload and
increasing stroke volume. By increasing intrathoracic
pressure, CPAP may decrease intrathoracic blood
volume (pulmonary intravascular and intracavitary
blood volume), which also should shorten circulation
time and stabilize breathing. Nasal CPAP increases
functional residual capacity, which should increase
damping and stabilize breathing. Although long-term
use of CPAP has been shown to increase PaCO2,
which should decrease the likelihood of developing
central sleep apnea, acute use of CPAP does not
significantly increase PaCO2 in patients with heart
failure and central sleep apnea [116]. By increasing
dead space and ventilation/perfusion ratio of some
areas of the lung, however, application of nasal CPAP
could increase PCO2 acutely. Further careful studies
with change in PaCO2 as the outcome parameter are
necessary to determine acute effects of CPAP on
PaCO2. The author noted that application of positive
end-expiratory pressure in adult respiratory distress
syndrome does not significantly change extravascular
lung water but affects its redistribution [128 – 132].
The same also could be true for effects of CPAP on
lung water in congestive heart failure, which may
further improve PO2 and increase damping.
Continuous positive airway pressure is uniformly
effective in treating OSAH in patients with heart
failure. It also could be effective in treating central
sleep apnea. The approach in the use of CPAP is
different in these two disorders, however. Acute
CPAP titration is necessary to determine the precise
upper airway pressure required to eliminate OSAH in
heart failure in a similar manner used to eliminate
OSAH in the absence of heart failure. For central
sleep apnea, the author suggests gradually increasing
the pressure from 5 to 10 to 12 cm H2O over many
days to weeks as tolerated by the patient. The
author’s protocol requires initiation of CPAP during
daytime in the laboratory. While the patient is in the
supine position, blood pressure and saturation are
monitored for 30 minutes to 1 hour as CPAP
increases from 5 to 7 cm H2O. Further increments
are made a few days apart, usually under similar
circumstances. Immediate overnight CPAP titration in
the sleep laboratory, particularly in persons with
severe central sleep apnea, is not necessary. Careful
follow-ups with frequent phone calls and visits for
aggressive treatment of complications (eg, nasal
clogging) and encouragement to use CPAP are neces-
sary to improve long-term compliance.
 S. Javaheri / Clin Chest Med 24 (2003) 207–222
Another noninvasive device used to treat central
sleep apnea is adaptive pressure support servoventi-
lation. This device provides varying amounts of
ventilatory support during different phases of periodic
breathing. The support is maximal during central
apnea and minimal during the hyperpneic phase of
periodic breathing [116]. The device provides a con-
stant positive expiratory pressure that should be
enough to eliminate obstructive apneas when present,
and pressure support ventilation is provided by super-
imposing additional, although variable, inspiratory
pressure. For example, if expiratory pressure is set at
6 cm H2O, when ventilation is stable, the inspiratory
pressure could be approximately 9 cm H2O; however,
inspiratory pressure quickly increases further if central
apnea develops. The inspiratory pressure returns to
9 cm H2O when breathing stabilizes.
This pattern of pressure support should be easier
to tolerate, particularly for patients with severe peri-
odic breathing and repetitive episodes of hyperpnea.
In an acute (one-night) study [116] of 14 subjects
with systolic heart failure and central sleep apnea,
the AHI decreased significantly from approximately
45/hour to 6/hour. The improvement by the adaptive
pressure support servoventilation was better than that
observed with either CPAP or oxygen. The author
believes that the adaptive pressure support servoven-
tilation device should be particularly helpful in heart
failure patients with severe central sleep apnea who
may be nonresponsive [82] or noncompliant to CPAP.
An adaptive pressure support servoventilation device
could be used initially and then replaced later by
CPAP as cardiopulmonary function and central sleep
apnea improve. Large-scale studies are needed.
Theophylline
Open studies [11,133] have shown the efficacy of
theophylline in the treatment of central sleep apnea
in heart failure. In a double-blind, randomized, pla-
cebo-controlled, cross-over study [134] of 15 patients
with treated, stable systolic heart failure, theophyl-
line, twice daily by mouth, at therapeutic plasma
concentrations (average, 11 mg/mL; range 7mg/mL –
15/mg/mL) decreased the AHI by approximately 50%
and improved arterial oxyhemoglobin saturation
[133]. Theophylline significantly decreased central
apnea but had no effect on OSA [134].
Mechanisms of action of theophylline in improv-
ing central apnea remain unclear [134]. At therapeutic
serum concentrations, theophylline increases ventila-
tion [134]. This action probably is caused by com-
petitive inhibition of adenosine, which is a respiratory
depressant [135,136]. An increase in ventilation by
theophylline could decrease the likelihood of occur-
217
rence of central apnea during sleep. Although theo-
phylline slightly decreases end-tidal and arterial
PCO2 [128,129], the assumption is that theophylline
also decreases PCO2 at the apneic threshold, and the
difference between the two PCO2 set point does not
decrease or may even increase. This could be similar
to the action of almitrine [95], another respiratory
stimulant. Theophylline does not increase ventilatory
response to CO2 [135].
Potential arrhythmogenic effects and phospho-
diesterase inhibition are common concerns with
long-term use of theophylline in patients with heart
failure. Further controlled studies are necessary to
ensure its safety. If theophylline is used to treat
central sleep apnea, frequent and careful follow-ups
are necessary.
Summary
Heart failure is a highly prevalent problem asso-
ciated with excess morbidity and mortality and eco-
nomic impact. Because of increased average life
span, improved therapy of ischemic coronary artery
disease and hypertension, the incidence and preva-
lence of heart failure will continue to rise into the
twenty-first century.
Multiple factors may contribute to the progres-
sively declining course of heart failure. One such
cause could be the occurrence of repetitive episodes
of apnea, hypopnea, and hyperpnea, which frequently
occur in patients with heart failure. Episodes of
apnea, hypopnea, and hyperpnea cause sleep disrup-
tion, arousals, intermittent hypoxemia, hypercapnia,
hypocapnia, and changes in intrathoracic pressure.
These pathophysiologic consequences of sleep-
related breathing disorders have deleterious effects
on cardiovascular system, and the effects may be
most pronounced in the setting of established heart
failure and coronary artery disease. Diagnosis and
treatment of sleep-related breathing disorders may
improve morbidity and mortality of patients with
heart failure [34]. Large-scale, carefully executed
therapeutic studies are needed to determine if treat-
ment of sleep-related breathing disorders changes the
natural history of left ventricular failure.
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 Clin Chest Med 24 (2003) 223 – 237

Sleep-disordered breathing and stroke

Henry Yaggi, MD, MPHa, Vahid Mohsenin, MDa,b,*
a
Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, 333 Cedar Street,
Post Office Box 208057, New Haven, CT 06520-8057, USA
b
Yale Center for Sleep Medicine, 333 Cedar Street, LCI 105, Post Office Box 208057, New Haven, CT 06520-8057, USA

Care-charming Sleep, thou easer of all woes, Brother
to Death, sweetly thyself dispose. John Fletcher
(1579 – 1625), The Tragedy of Valentinian (V, ii).
It is fascinating to consider that something as
basic as the way we breath during sleep is associated
with conditions that account for several of the leading
causes of mortality in adults in this country: hyper-
tension, cardiovascular, and cerebrovascular disease.
When considered separately from other cardiovascu-
lar diseases, stroke ranks as the third leading cause
of death, and it is the leading cause of serious long-
term disability [1]. Stroke constitutes several different
types of cerebrovascular disease: ischemic stroke,
embolic stroke, transient ischemic attack (TIA), and
hemorrhagic stroke. There are currently few effective
therapies for stroke, so understanding underlying
pathophysiologies, promoting preventative behaviors,
and developing novel therapeutic approaches for the
treatment of stroke are of crucial importance.
Like stroke, sleep-disordered breathing is highly
prevalent [2] and constitutes a spectrum of diseases:
primary snoring, upper airway resistance syndrome,
obstructive sleep apnea (OSA), central sleep apnea,
and obesity-hypoventilation syndrome. The high prev-
alence of stroke and sleep apnea could cause an
overlap of these two diseases just by chance alone.
There are several reasons to suspect a direct relation-
ship between stroke and sleep-disordered breathing,
* Corresponding author. Section of Pulmonary and
Critical Care Medicine, Yale University School of Medi-
cine, 333 Cedar Street, Post Office Box 208057, New
Haven, CT 06520-8057.
E-mail address: vahid.mohsenin@yale.edu
(V. Mohsenin).
however. In the authors’ clinical experience, apneic
spells and snoring are frequently observed on the
stroke rehabilitation service. Patients who suffer from
cerebral infarction often complain of diffuse cerebral
symptoms and cognitive problems, such as impaired
memory, inability to concentrate, emotional instability,
and excessive daytime sleepiness [3]. In large part,
these symptoms have been attributed to structural
damage to brain tissue; however, many of these
symptoms are also pervasive in patients with sleep-
disordered breathing [4]. There are several overlap-
ping risk factors and consequences of both diseases,
such as gender, age, hypertension, obesity, smoking,
and alcohol use. Finally, some of the physiologic
consequences of OSA, such as cyclic oxygen desatu-
rations and labile blood pressure, are known to be
poorly tolerated in patients with stroke.
Identifying and treating underlying sleep-dis-
ordered breathing ultimately may represent a novel
management strategy for reducing the large morbidity
and mortality burden of stroke. Over the past decade,
the understanding of the strength of the association
between sleep-disordered breathing and stroke has
grown considerably, as has the understanding of the
physiologic, autonomic, humoral, and vascular con-
sequences of this breathing disorder. Several challeng-
ing questions persist with respect to any causal
inference between sleep-disordered breathing and
stroke, however: What is the temporal relationship
between sleep apnea and stroke? In other words, does
sleep-disordered breathing cause stroke, or does
stroke cause sleep disordered-breathing? Is sleep-
disordered breathing an independent risk factor for
the development of stroke in the setting of confound-
ing overlapping risk factors, or is the association with
stroke simply mediated by higher levels of cardio-

0272-5231/03/$ – see front matter D 2003, Elsevier Inc. All rights reserved.
doi:10.1016/S0272-5231(03)00027-3
224 H. Yaggi, V. Mohsenin / Clin Chest Med 24 (2003) 223–237
vascular risk factors in patients with sleep-disordered
breathing? Does the presence of sleep-disordered
breathing influence the morbidity or mortality from
stroke, and does treatment of sleep disordered breath-
ing influence this risk?
The primary objective of this article is to explore
these questions by critically reviewing the current
literature. First, epidemiologic studies about the rela-
tionship between sleep-disordered breathing and
stroke are analyzed with respect to issues regarding
the strength of the association, temporal relationship,
dose-response relationship, and consistency of the
association using different study designs and different
populations. Subsequently, the biologic plausibility of
the relationship is explored by reviewing studies that
examine the pathophysiology of sleep-disordered
breathing and stroke focusing on cerebral hemody-
namic and humoral mechanisms.
Epidemiologic studies
Several studies have sought to determine the
presence and extent of a causal interaction between
sleep-disordered breathing and stroke independent of
frequently coexisting and potentially confounding
variables common to both conditions. Established
modifiable risk factors for stroke include hyperten-
sion, hypercholesterolemia, smoking, and diabetes for
atherosclerotic cerebrovascular disease; atrial fibril-
lation and myocardial infarction for cardiogenic
embolism; and hypertension for intracerebral hemor-
rhage. Established risk factors for sleep-disordered
breathing include excess body weight, age, gender,
estrogen depletion, smoking, and alcohol. To com-
plicate matters further, the adjustment for potential
confounding factors is open to criticism, because
these factors may be on the causal pathway of the
relationship between OSA and stroke. This applies
especially to hypertension, because removal of its
effect might overadjust the apparent risk and negate a
true cause-effect relationship between sleep-dis-
ordered breathing and stroke.
An investigation from the Sleep Heart Health
Study, a cohort of 6440 men and women over age
40, explored the associations between sleep-dis-
ordered breathing and cardiovascular risk factors and
found that the respiratory disturbance index (RDI, the
number of apneas and hypopneas per hour sleep) was
cross sectionally associated with age, body-mass index
(BMI), waist-to-hip ratio, hypertension, diabetes, and
lipid levels [5]. This risk factor pattern of hyperten-
sion, diabetes, and hypertriglyceridemia is commonly
seen in people who are obese, and the multivariate
models in this study suggest that the degree of obesity,
age, and gender explain most of the elevation in these
cardiovascular risk factors, with the exception of
hypertension. The presence of an independent asso-
ciation of the RDI with hypertension suggests that it
may be in the causal pathway. As discussed elsewhere
in this issue, because of the acute and profound effects
of sleep-disordered breathing on vascular tone, hyper-
tension is believed to be a major mechanism by which
sleep-disordered breathing might influence future car-
diovascular and cerebrovascular disease risk [5].
Snoring and stroke
Early epidemiologic studies that examined the
relationship between sleep-disordered breathing and
cerebrovascular disease used self-reported snoring as
the primary exposure variable. Self-reported ‘‘habit-
ual snoring,’’ usually defined as subjects who snore
‘‘often’’ or ‘‘always,’’ is a sensitive measure of true
heavy snorers based on all night recordings [6]. The
specificity is low, however, with many patients being
misclassified as snorers. The consequence of such
misclassification is the reduction of a potential rela-
tionship and bias toward the null hypothesis.
Despite this failing, most of these studies clearly
show an association between snoring and stroke
(Table 1) and demonstrate that the strength of this
association is on the same order of magnitude as
traditional risk factors for stroke, such as hypertension,
smoking, cardiac arrhythmia, and hypercholesterol-
emia. Even when adjusted for confounding risk factors
such obesity, hypertension, age, and gender, an inde-
pendent association remained between snoring and
stroke. The designs of these initial studies were pre-
dominantly case control or cross-sectional [7 – 12] and
were subject to criticism with respect to recall bias and
establishing the temporal relationship between stroke
and sleep-disordered breathing, because snoring and
sleep apnea can be consequences of stroke [13].
More convincing evidence comes from several
large, prospective studies that seemed to corroborate
these case-control and cross-sectional studies. In an
early cohort study exclusively of men that used a
Finnish nationwide registry, there was a twofold
increase in the relative risk for the combined outcome
of stroke and ischemic heart disease in habitual
snorers compared with non-snorers [14]. A smaller
but still significant positive association (relative
risk = 1.33) between regular snoring and the com-
bined cardiovascular outcome of stroke and ischemic
heart disease was seen exclusively in women in the
Nurses Heath Study [15]. In this large cohort, the age-
adjusted relative risk for stroke alone in regular
Table 1
Selected studies of snoring and stroke
Study Study design No. of subjects Exposure assessment Disease assessment Confounding assessment Relative risk (95% CI)
Partinen [9] Case control 50 Personal interview, Stroke patients admitted Age, BMI 10.3 (3.5 – 30.1)
habitual snoring to hospital, neurologic

H. Yaggi, V. Mohsenin / Clin Chest Med 24 (2003) 223–237

exam, CT/MRI
Koskenvuo [14] Cohort, 3-year 4388 Mailed questionnaire, Finish registry, death, Age, BMI, hypertension, 2.08 (1.5 – 3.77)
follow-up habitual snoring ischemic heart smoking, alcohol
disease, stroke
Spriggs [11,12] Case control 400 Personal interview, Stroke patients admitted Age, gender 3.2 (2.3 – 4.4)
regular snoring to hospital, neurologic
exam, CT/MRI
Palomaki [8] Case control 177 Standardized Stroke patients admitted Age, gender, alcohol, hypertension, 2.13 (1.29 – 3.52)
questionnaire, to hospital, neurologic ischemic heart disease
habitual snoring exam, CT/MRI
Smirne [10] Case control 330 Personal interview, Stroke patients admitted Age, gender, BMI, diabetes, 1.86 (1.2 – 2.87)
habitual snoring to hospital, Neurologic dyslipidemia, smoking,
exam, CT/MRI alcohol, hypertension
Jennum [63] Cohort 6-year 804 Personal interview, Cardiovascular outcome based Hypertension, BMI, diabetes, 1.26 (1.3 – 6.8)
follow-up habitual snoring on Danish Health Registry smoking, alcohol, hyperlipidemia,
catecholamines
Neau [7] Case control 133 Personal interview, Stroke patients admitted Gender, age, hypertension, 2.9 (1.3 – 6.8)
habitual snoring to hospital, Neurologic obesity, cardiac arrhythmia
exam, CT/MRI
Hu [15] Cohort 8-year 71,779 Mailed questionnaire, Follow-up questionnaire to Smoking, age, BMI, alcohol, 1.33 (1.06 – 1.67)
follow-up regular snoring determine cardiovascular physical activity, menopausal
(Nurses Health Study) outcome confirmed by status, family history of
medical record review myocardial infarction, diabetes,
high cholesterol

225
226 H. Yaggi, V. Mohsenin / Clin Chest Med 24 (2003) 223–237
snorers was 1.88 (1.62 – 2.53), which became non-
significant when adjusted for BMI and other cardio-
vascular covariates.
These initial studies of the association between
snoring and stroke on balance supported a positive
association and served to raise some important meth-
odologic issues. First, if hypertension is on the
intermediate causal pathway between sleep-disor-
dered breathing and stroke, should it be adjusted for
and considered a confounder? Second, self-reported
habitual snoring may not be a reliable measurement
of true snoring. Although self-reported habitual snor-
ers seemed to be true heavy snorers when validated
against overnight recordings, a large percentage of
self-reported never-snorers were not aware of their
snoring, which resulted in exposure misclassification
and bias toward the null hypothesis [6]. The pre-
sumed mechanism for the association between snor-
ing and stroke is that snoring serves as a marker for
OSA. Although heavy snoring invariably accompa-
nies sleep apnea [16], most snorers do not have sleep
apnea. In some of the case-control studies discussed
previously [8,17], the authors attempted to identify
within their populations those snoring subjects more
likely to have OSA by identifying snorers who also
have apneas, excessive daytime sleepiness, and obe-
sity. The addition of these potential markers for OSA
increased the odds ratio in these studies.
A different approach to assessing exposure to
sleep-disordered breathing occurred in a study that
used data from the First National Health and Nutri-
tion Examination Survey (NHANES I) cohort [18].
Instead of self-reported snoring, other clues to pre-
existing OSA were used: self-reported sleep duration
and daytime somnolence. Sleep duration and symp-
toms of daytime somnolence were significantly asso-
ciated with the development of stroke and coronary
heart disease adjusted for potential confounding car-
diovascular risk factors. Although these symptoms
are assumed to serve as markers for sleep apnea, the
validity of this assumption is questionable, and it is
conceivable that these symptoms of increased sleep
duration and daytime somnolence serve as general
markers of disease and disability.
Sleep apnea and stroke (the temporal relationship)
Several studies have used overnight polysomno-
graphy to define OSA more precisely in an attempt to
sort out whether it is the minority of patients with
OSA who account for the apparent increased risk of
sleep-disordered breathing with stroke (Table 2).
These studies have focused on OSA as a risk factor
for the development of stroke and as an outcome and
consequence of stroke.
A study by one of the authors (V.M.) in 1995 of
ten patients who were recovering from hemispheric
stroke revealed a high prevalence (80%) of OSA
compared with age- and BMI-matched controls with
similar frequency of hypertension and smoking with-
out stroke [19]. The mean RDI for the control and
stroke group was 3 and 52 events per hour, respec-
tively. Predominantly obstructive events were found
in seven patients. Because none of the study subjects
had a previous history of significant snoring, apnea,
obesity, hypersomnolence, or neurologic impairment,
the conclusion was that OSA might be a sequela of
stroke. It is known that repeated upper airway
obstruction in patients with OSA occurs as a con-
sequence of reduction in pharyngeal muscle tone
during sleep. The pharyngeal muscles may be affect-
ed in stroke; neurologic dysphagia has been demon-
strated in 30% to 40% of patients admitted to the
hospital with unilateral hemispheric stroke [20,21].
A subsequent case-control study of consecutively
admitted inpatients with stroke [22] speculated that
the hypoxia and hemodynamic responses in OSA
may have predisposed to the development of stroke
rather than the other way around. This study com-
pared the polysomnograms of 27 healthy age- and
gender-matched controls recruited from the local pop-
ulation to 24 inpatients with recent stroke confirmed
by neurologic examination and imaging studies of the
brain. Overall, OSA was diagnosed in 19% of the
controls and 71% of the stroke patients. The mean
lowest oxygen saturation level was 91% in the con-
trol group and 85% in the stroke group, and the mean
RDI was 4 events per hour for controls and 26 events
per hour for stroke patients. Once again, predomi-
nantly obstructive apneas were found as opposed
to central or Cheyne-Stokes respirations. 4 stroke
patients were reevaluated at 5 months with polysom-
nography, and they demonstrated OSA on reevalua-
tion. The 4-year mortality rate for patients with stroke
was 21%, and all patients with stroke who died (of
various causes) had OSA. These findings led the
authors to propose that OSA predisposes patients
to stroke.
Although case-control studies generally are effi-
cient study designs for evaluating strength of asso-
ciation, they have a significant limitation in their
ability to establish the temporal course in a cause-
effect relationship. When comparing hospitalized
inpatients to healthy community-dwelling controls,
a selection bias known as Berkson’s Bias may distort
the actual association in that patients who are admit-
ted to the hospital or rehabilitation unit also may have
 H. Yaggi, V. Mohsenin / Clin Chest Med 24 (2003) 223–237
Table 2
Selected studies of sleep apnea and stroke using polysomnography
Study date Study design No. stroke/controls no. Mean RDI Study population Confounding assessment Prevalence sleep apnea in stroke (%)
Mohsenin [19] Case control 10/10 52 Predominantly hemispheric Age, BMI, 80% with RDI 20
stroke in a rehabilitation unit hypertension, smoking
Good [34] Descriptive 47 (19 underwent NA Rehabilitation patients NA 32% had 10 desaturation events/h
polysomnography) recently hospitalized for stroke based on computerized
overnight oximetry
Dyken [22] Case control 24/19 26 Recently hospitalized for stroke Age, gender 71% with RDI 10
Bassetti [24] Case control 128/25 (80 underwent 28 Inpatients with stroke and TIA Age, BMI, diabetes, 63% with RDI 10
polysomnography) severity of stroke
Parra [28] Descriptive 161 21 Inpatients with stroke and TIA NA 71% with RDI 10 (acute phase)a
61% with RDI 10 (stable phase)
Shahar [23] Cross-sectional 6424 NA Assembled from several ongoing Age, race, gender, NA (see text) relative risk of stroke
(Sleep Heart (see text) population based studies of smoking, diabetes, comparing lowest quartile to highest
Health Study) cardiovascular disease in the hypertension, BMI, quartile = 1.58 with 95% CI (1.02 – 2.46)
United States cholesterol
a
‘‘Acute phase’’ after admission and ‘‘stable phase’’ indicate > 3 months later.

227
228 H. Yaggi, V. Mohsenin / Clin Chest Med 24 (2003) 223–237
pathology in addition to the stroke (ie, OSA), which
increases the chance of admission.
Perhaps the strongest epidemiologic evidence dem-
onstrating the association between sleep-disordered
breathing and cerebrovascular disease comes from
the initial results of the Sleep Heart Health Study
[23]. This study explored the cross-sectional associ-
ation between sleep-disordered breathing and preva-
lent self-reported cardiovascular disease (myocardial
infarction, angina, coronary revascularization proce-
dures, heart failure, or stroke) in a large cohort of 6424
individuals who underwent overnight polysomnogra-
phy at home. By comparing the upper apnea-hypopnea
index (AHI) severity quartile (>11) to the lower AHI
severity quartile (0 – 1.3), the most parsimonious
logistic regression model revealed an odds ratio of
1.58 (1.02 – 2.46) for the association of stroke with
sleep-disordered breathing adjusted for age, race, sex,
smoking status, self-reported diabetes, total choles-
terol, and HDL lipoprotein cholesterol. Unlike cor-
onary heart disease and congestive heart failure,
in which much of the risk associated with sleep-
disordered breathing came from mild sleep apnea
(RDI < 10), there seemed to be an incremental increase
in risk of stroke associated with increasing AHI
severity (Fig. 1). Support of this finding is limited,
however, by the small number of subjects at higher
AHI severity in this population-based study. Hypoxe-
mia seemed to explain 10% to 40% of the AHI effect,
and sleep fragmentation per se, as measured by the
arousal index, was not associated with cardiovascular
Fig. 1. Predicted log odds (a measure of risk) of stroke as a
function of AHI. AHI indicates the number of apneas and
hypopneas per hour of sleep. The histogram is adapted from
regression of the log odds of stroke. (From Shahar E, Whitney
CW, Redline S, et al. Sleep-disordered breathing and
cardiovascular disease: cross-sectional results of the Sleep
Heart Health Study. Am J Respir Crit Care Med 2001;163:19;
with permission.)
disease in these data. If the associations observed in
this study are causal, it seems that even a modestly
elevated risk of stroke coupled with the high preva-
lence of mild/moderate sleep-disordered breathing will
have considerable public health implication.
Cross-sectional associations might reflect reverse
causal pathways, whereas sleep-disordered breathing
has been the consequence rather than the cause of
stroke. The direction of this arrow of causation
ultimately can be determined definitively only by
analysis of incident cerebrovascular disease events,
and it awaits the results of future prospective follow-
up studies. To the authors’ knowledge no study has
investigated prospectively the relationship between
polysomnographic indices of sleep-disordered breath-
ing and stroke, several investigations have taken
creative approaches to gaining insight into this tem-
poral relationship.
One study that provided some insight into the
causal pathway of stroke and OSA was a retrospec-
tive cohort study of patients who were diagnosed
with OSA by using polysomnography in the 1970s
before the availability of continuous positive airway
pressure (CPAP), when the only known aggressive
therapy for OSA consisted of tracheostomy [17].
7 years of follow-up was provided on 198 patients,
of whom 71 received tracheostomy (considered
‘‘effective treatment’’) and 127 received ‘‘conservative
treatment’’ that consisted of recommended weight loss
(the only alternative). Any new hypertension, myocar-
dial infarction, or stroke that occurred since the orig-
inal polysomnography was considered the main
vascular morbidity outcome. Despite the fact that at
study entry the tracheostomy group included more
patients with a history of hypertension, myocardial
infarction, or stroke, the conservatively treated group
presented with significantly more vascular morbidity.
Patients with TIA potentially represent another
unique opportunity to delineate the directionality of
the cause-effect relationship between OSA and cere-
brovascular disease. TIA represents an intermediate
stage of disease in the natural history of ischemic
stroke, and by definition, patients with TIA have no
residual neuromuscular side effects, which makes the
causal pathway of TIA leading to OSA less plausible.
Demonstrating an increased prevalence of OSA
among cases of TIA bolsters the theory that OSA
leads to the ultimate development of ischemic stroke
rather than the other way around. In follow-up studies
of patients with acute TIA or ischemic stroke [24,25]
researchers demonstrated a similar elevated frequency
and severity of OSA. In one of these studies [24],
adequate polysomnography was performed in 80
subjects (stroke = 48, TIA = 32) and the prevalence
 H. Yaggi, V. Mohsenin / Clin Chest Med 24 (2003) 223–237
and severity of OSA were compared in patients with
stroke, TIA and ‘‘normal’’ healthy controls from the
Michigan Alcohol Research Center. Stroke and TIA
patients differed significantly from normal controls in
measurements of AHI, maximal apnea duration, and
minimal oxygen saturation. Stroke and TIA patients
also were similar in all variables considered, including
habitual snoring, AHI, maximal apnea duration, mean
apnea duration, and minimal oxygen saturation.
Although the face validity of these studies of TIA
and OSA is high with respect to clarifying the
temporal relationship between OSA and cerebrovas-
cular disease, there are several limitations with
respect to internal and external validity. Most impor-
tantly, patients with TIA may represent a heteroge-
neous group of individuals. Symptoms of TIA, a
clinical diagnosis, are mimicked by multiple other
disease entities, which may result in disease misclas-
sification. Strictly defining and validating the defini-
tion of TIA for clinical research is of the utmost
importance. Because the traditional definition of TIA
requires the resolution of signs and symptoms within
a 24-hour period, generally it has been assumed that
TIAs leave no residual damage. Cerebral infarctions
have been demonstrated by neuroimaging techniques
in 5% to 10% of patients with clinically defined TIA,
however [26], and some estimates of unrecognized
infarctions by CT (32%) and MRI (77%) are even
higher [27].
Another approach used to gain some insight into
the temporal relationship between sleep-disordered
breathing and stroke prospectively followed 161
consecutive patients with first-ever stroke or TIA
admitted to a stroke unit [28]. TIA was strictly
defined according to the National Institute of Neuro-
logic Disease and Stroke classification [29]. In
this study, previously validated portable respiratory
recordings were performed within 48 to 72 hours
after admission (acute phase) and subsequently after
3 months (stable phase). The important findings of
this study included lack of significant differences
in OSA severity according to stroke subtype (TIA,
ischemic stroke, or hemorrhagic stroke) or brain
parenchymatous location. The study also found that
the frequency of obstructive apneas did not signifi-
cantly decline from the period immediately after stroke
to 3 months later. Because there were no significant
differences in obstructive apneas between baseline and
3 months later or between different stroke subtypes
and locations, the findings led the authors to conclude
that obstructive events seem to be a condition predat-
ing the development of cerebrovascular disease and
they act as a risk factor for rather than a consequence of
cerebrovascular disease.
229
Sleep-disordered breathing and hypertension
Further evidence in support of the causal pathway
of sleep-disordered breathing leading to stroke comes
from recent large cross-sectional and cohort studies in
support of OSA being an independent risk factor for
the development of hypertension. From the Sleep
Heart Health Study [30], sleep-disordered breathing
was associated with prevalent hypertension even after
controlling for potential confounders, such as age,
gender, BMI (and other measures of adiposity), alco-
hol, and smoking. The relative risk for the highest
category of AHI (>30/hour) compared with the lowest
category (< 1.5/hour) was 1.37 (95% CI, 1.03 – 1.83).
Overall, the odds of hypertension seemed to increase
with increases in AHI in a dose-response fashion.
More compelling data that lends support to the
evidence of a causal role of sleep-disordered breathing
in hypertension comes from the prospective findings
of the Wisconsin Sleep Cohort Study [31]. The
presence of sleep-disordered breathing at baseline
was accompanied by a substantially increased risk
for future hypertension at 4 years of follow-up. Even
after adjusting for baseline hypertension status, age,
gender, BMI, waist and neck circumference, and
weekly alcohol and cigarette use, the risk was ele-
vated, with an odds ratio of 2.89 (95% CI, 1.46 – 5.64)
for subjects with an AHI of more than 15/hour
compared with patients without any nocturnal apnea.
It should be noted that for many of the aforementioned
studies (see Tables 1, 2), the risk of stroke from sleep-
disordered breathing was independent of coexisting
hypertension. The presence of hypertension further
enhances the risk.
Functional outcome after stroke
Previous studies reported that up to 43% of stroke
patients will have a progression of their neurologic
deficit [32,33]. Regardless of whether OSA precedes
or follows stroke, it is associated with unfavorable
clinical outcomes after stroke, including early neu-
rologic worsening, delirium, depressed mood, poor
functional status, and impaired cognition [12,34 – 36].
In one study [34], the functional status, as assessed
by the Barthel Index (a multifaceted scale that
measures mobility and activities of daily living), in
patients with stroke and OSA was significantly lower
compared with patients with stroke but no evidence
of sleep-disordered breathing at discharge and 3 and
12 months (Fig. 2). Death at 1 year was negatively
correlated with percentage of time spent at less than
90% SaO2. Whether sleep-disordered breathing is an
independent predictor of poor functional outcome or
230 H. Yaggi, V. Mohsenin / Clin Chest Med 24 (2003) 223–237

Fig. 2. The Barthel Index (BI) scores on admission and discharge and 3- and 12-month follow-up for patients with sleep-
disordered breathing (OSA group) compared with other stroke patients without sleep-disordered breathing. Lower BI scores
indicate worse cognitive impairment and activity of daily living impairment. (From Good DC, Henkle JQ, Gelber D, et al. Sleep-
disordered breathing and poor functional outcome after stroke. Stroke 1996;27:252 – 9; with permission.)

simply a marker for more severe stroke is not clear
from this study.
Predictors of upper airway obstruction in stroke
Typical OSA-type risk factors, such as elevated
BMI and neck circumference, seem to be the best
predictors of the development of upper airway
obstruction in acute stroke. Limb weakness also
seemed to be an independent predictor of OSA in
acute stroke, but other stroke characteristics, such as
severity and subtype, do not seem to be associated
with the development of upper airway obstruction
[37]. Of clinical relevance in this study was that most
of the sleep-disordered breathing occurred while the
subjects were supine. Whether simple maneuvers
targeted at preventing upper airway obstruction, such
as position therapy, may improve outcomes in acute
stroke remains an important unanswered question.
Continuous positive airway pressure treatment trials
Two CPAP treatment trials of patients who exhibit
sleep-disordered breathing after stroke recently were
published and have provided insight into whether
sleep-disordered breathing is truly an independent
cause of worse outcome after stroke and the effective-
ness and acceptance of CPAP [12,34,35,38]. Although
the trials only reflect short-term use of CPAP, the
results are encouraging because they demonstrated
beneficial effects and comparable compliance rates to
OSA patients without stroke. In one trial [39],
although not randomized, there was a significant
reduction in nocturnal blood pressure (8 mm Hg) after
10 days of treatment in comparing CPAP-compliant
and CPAP-noncompliant patients. There was
improvement in subjective well-being (although this
later finding is based on less well-validated neuro-
psychiatric testing). In a logistic regression model,
aphasia and the severity of motor disability as quan-
tified by the Barthel index were significant negative
predictors of acceptance of CPAP.
The second CPAP study was a randomized treat-
ment trial [38], and although it was not double-
blinded, it demonstrated that depressive symptoms
are reduced in patients who are treated with nasal
CPAP at 7 and 28 days compared with controls who
are not treated. There was no significant improvement
in delirium, activities of daily living, or cognitive
functinoning. Compliance was lower in this study
(approximately 50%), perhaps partly related to the
fact that this was an older population.
Overall, the primary acceptance of CPAP (at least
in the first treatment study) seems comparable to
patients with OSA without stroke, and CPAP seems
to exert a beneficial influence in terms of well-being,
hypertension, and depression. Long-term compliance
is not certain, however, especially in a population of
patients with more functional and cognitive disability.
As suggested elsewhere [40], bearing in mind that
 H. Yaggi, V. Mohsenin / Clin Chest Med 24 (2003) 223–237
obstructive apneas result in recurrent hypoxemia and
cerebral blood flow fluctuations that could damage
the area of the ischemic penumbra, one possible
argument in favor of CPAP treatment is to prevent
stroke recurrence. Patients with TIA or minor non-
disabling stroke may represent an important target
group for CPAP treatment for secondary prophylaxis
because they may be a younger and more compliant
group with fewer deficits.
Circadian variation in ischemic events
The relation between the time of stroke symp-
toms and the time of day may relate to the under-
lying pathophysiology of stroke. Early studies of the
timing of acute stroke indicated that acute strokes
tend to occur either during the evening hours or
during sleep, and many afflicted patients reported
awakening with new neurologic deficits [41 – 43]. A
metaanalysis of 11,816 strokes revealed that similar
to myocardial infarction and sudden cardiac death, a
‘‘morning excess’’ of all types of stroke (including
TIA) is seen between 6:00 AM and 12:00 PM and is
significantly higher than would be expected by
chance (Fig. 3) [44].
It is of interest that the most prolonged rapid eye
movement (REM) sleep period occurs in close tem-
poral proximity to this circadian preference for ische-
mic stroke (the early morning hours). Specifically,
during REM sleep there are significant hemodynamic
changes [45] with increases in cerebral blood flow
[46] and blood pressures, which can reach near-
normal waking levels [47]. The early morning hours
are associated with decreased fibrinolytic activity
[48], increased platelet aggregability, and peak levels
of catecholamines [49].
Fig. 3. Circadian variation in ischemic stroke and cardiovascular events. (From Mohsenin V. Sleep-related breathing disorders
and risk of stroke. Stroke 2001;32:1271; with permission.)
231
As is described in the following sections, many of
these same autonomic, hemodynamic, and physiologic
mechanisms are heightened in patients with OSA.
Mechanism studies
During sleep in OSA, repetitive episodes of air-
way occlusion with resulting hypoxemia, hypercap-
nia, and significant changes in intrathoracic pressure
elicit a wide variety of autonomic, hemodynamic,
humoral, and vascular perturbations that serve as
plausible biologic mechanisms whereby OSA may
cause stroke (Table 3). Large variations in intratho-
racic pressure with nadirs during inspiratory effort
increase the filling of the right heart and cause a
leftward shift of the interventricular septum [50]. The
resulting reduction of stroke volume is one probable
cause of the decreased arterial pressure seen early
during apnea. Changes in autonomic activity influ-
ence blood pressure variability by vasoconstriction,
with increased levels of circulating catecholamines
and increased endothelin-1 production (a potent vaso-
constrictor) likely contributing to diurnal hyper-
tension [51]. Impaired endothelial function and
accelerated atherogenesis, which may theoretically
result from the repetitive hypoxia and pressure
surges, are also evident in patients with OSA. Finally,
altered cerebral blood flow, fluctuations in intracra-
nial pressure, impaired cerebrovascular autoregula-
tion combined with increased platelet aggregability,
increased fibrinogen, and increased plasma homocys-
teine levels are also likely contributory mechanisms.
Because autonomic mechanisms that contribute to
diurnal hypertension are discussed elsewhere in this
issue, the following discussion of physiologic mech-
232 H. Yaggi, V. Mohsenin / Clin Chest Med 24 (2003) 223–237

Table 3 activity. For example, if metabolic activity increases

Mechanisms whereby sleep-disordered breathing may as a result of strenuous activity, then blood flow
cause stroke increases proportionately to meet the increased meta-
Mechanism Consequence bolic demand. Finally, reactive hyperemia is an
Negative intrathoracic Decreased stroke increase in blood flow in response to or as a reaction
pressure created volume, increased to a prior period of decreased blood flow. For
from inspiratory venous return/central example, reactive hyperemia is the increase in blood
effort against venous pressure flow to an organ that follows a period of arterial
closed airway occlusion. During the occlusion, an oxygen ‘‘debt’’ is
Autonomic mediated Hypertension, increased accumulated. The longer the period of occlusion, the
increases in intracranial pressure greater the oxygen debt and the greater the sub-
circulating
sequent increase in blood flow above the preocclu-
catecholamines
sion levels. The increase in blood flow continues until
and endothelin-1
Impaired autoregulation, Alterations in cerebral the oxygen debt is ‘‘repaid.’’ In the cerebral circula-
active/reactive hyperemia blood flow, increased tion the major vasoactive metabolites are CO2 and
intracranial pressure H + . In addition to these local control mechanisms,
Increased platelet Impaired endothelial mechanical effects, such as changes in intracranial
aggregation, fibrinogen, function, accelerated pressure, can cause changes in cerebral blood flow.
homocysteine, vascular atherogenesis, thrombosis Sleep state has a profound effect on cerebral
cell adhesion molecule-1, hemodynamics. Multiple studies using various meth-
intracellular adhesion ods, including transcranial Doppler ultrasonography
molecule-1, and L-selectin
[54], Xe inhalation, and single photon emission test-
Right-to-left shunting through Paradoxic embolism
a patent foramen ovale
ing, have shown a 5% to 28% reduction in cerebral
blood flow during non-REM sleep and a 4% to 41%
increase in REM sleep compared with wakefulness in
anisms focuses on cerebral hemodynamic and hu- normal persons [46,54 – 61].
moral factors.
Intracranial hemodynamics in sleep apnea
Cerebral hemodynamics and their changes during Individual episodes of sleep apnea are accompan-
normal sleep ied by marked episodic elevations of cerebrospinal
fluid pressure and decreases in SaO2 (Fig. 4) [62].
Changes in blood flow to individual organs are Cerebrospinal fluid pressure in patients with OSA was
achieved by altering arteriolar resistance. The mech- monitored via a pressure transducer and a plastic tube
anisms that regulate blood flow are broadly catego- inserted into the subarachnoid space at the lumbar
rized as local (intrinsic) control and neural or level. Another study that invasively monitored radial
hormonal (extrinsic) control (ie, sympathetic innerva- artery pressure, central venous pressure, and intra-
tion). The cerebral circulation is controlled almost cranial pressure (ICP) [63] confirmed the previous
entirely by local control mechanisms. Many circulat- findings and demonstrated that values of ICP were
ing vasoactive substances do not affect the cerebral also elevated in patients with OSA even while awake.
circulation because their large molecular size pre- ICP increases further during sleep, and there was a
vents them from crossing the blood-brain barrier. strong correlation between duration of apnea and ICP
Mechanisms for the local control of blood flow elevations. These increases in ICP were attributed to
include autoregulation, active hyperemia, and reac- (1) increases in central venous pressure, which causes
tive hyperemia. Autoregulation is the maintenance of an increase in cerebral vascular volume, (2) increased
constant blood flow to an organ in the face of systemic arterial pressure, which causes an increase in
changing arterial pressure [52,53]. For example, if cerebral perfusion pressure, and (3) hypoxic and
arterial pressure in a cerebral artery suddenly hypercapnic cerebral vasodilation, which causes an
decreases, an attempt is made to maintain constant increase of the intracranial blood volume. It was
blood flow through this artery by the immediate suggested that these ICP elevations may be of impor-
compensatory dilation of cerebral arterioles decreas- tance in understanding the cerebral symptoms in
ing the resistance of the cerebral vasculature and patients with sleep apnea, such as morning headache
keeping flow constant in the face of decreased and cognitive impairment. The mechanical effects of
pressure. Active hyperemia is the concept that blood increased ICP may impede cerebral blood flow and
flow to an organ is proportional to its metabolic predispose to cerebral ischemia.
 H. Yaggi, V. Mohsenin / Clin Chest Med 24 (2003) 223–237 233

Fig. 4. Polysomnographic recordings during REM sleep and in the waking state in a patient with OSA. The nasal oral flow,
thoracic and abdominal wall movements, cerebrospinal fluid pressure at the lumbar level, and SaO2 (%) were recorded and are
presented simultaneously. Apneic events are indicated by diamond marks in the upper part of the recording. A 60-second time
scale is indicated in the upper left part of the figure. The SaO2 (%) scale is indicated by the left vertical axis, and the
cerebrospinal fluid pressure scale is indicated by the right vertical axis. As evident in the recording, each apneic event is
accompanied by marked cerebrospinal fluid pressure changes. (Adapted from Sugita Y, Susami I, Yoshio T, et al. Marked
episodic elevation of cerebral spinal fluid pressure during nocturnal sleep in patients with sleep apnea hypersomnia syndrome.
Electroencephalogr Clin Neurophysiol 1985;60:214 – 9; with permission.)

Several recent studies have attempted to gain
insight into the regulation of cerebral flow during sleep
by measuring middle cerebral artery blood flow veloc-
ities noninvasively using transcranial Doppler. One
study [64] revealed that the overall cerebral blood flow
velocities in patients with sleep apnea were signifi-
cantly reduced during all phases of sleep compared
with control subjects with no polysomnographic evi-
dence of sleep apnea. They postulated that this may be
caused by impaired autoregulatory and active/reactive
hyperemic mechanisms in patients with OSA given
that PCO2 was noted to rise in these patients. Of
therapeutic interest is that impairment of cerebrovas-
cular reactivity to elevated CO2 in patients with OSA
may be reversed by treatment with nasal CPAP [55].
Another study [65] that examined more specif-
ically cerebral blood flow velocity in direct relation to
individual obstructive apneic events demonstrated a
biphasic pattern with a concomitant increase in mean
arterial pressure and cerebral blood flow velocity
during early apnea followed by a subsequent decrease
of almost 25% below baseline after apnea termina-
tion. The authors suggested that the period immedi-
ately after the apneas, after the resumption of
ventilation in combination with hypoxemia, poten-
tially would make individuals with OSA vulnerable to
nocturnal cerebral ischemia.
Obstructive apneas and hypopneas compared with
central apneas lead much more frequently to a reduc-
tion in cerebral blood flow, and the longer the
obstructive event the greater the likelihood for a
reduction in blood flow [66]. The relationship
between airway obstruction and decreased perfusion
of the middle cerebral artery was attributed to the
negative intrathoracic pressure generated by the
increased respiratory effort against an obstructed air-
way. Increased time of obstruction could lead to the
development of a high cardiac preload, lower cardiac
afterload, activation of carotid body receptors, and
vasodilation by increasing arterial carbon dioxide and
decreasing oxygenation, all of which can contribute
to a reduction in cerebral blood flow.
Effect of aging on cerebral blood flow
Several cross-sectional studies have demonstrated
an age-related reduction in regional cerebral blood
flow in the range of 20% to 24% in normal aging
individuals [67,68]. This reduction in regional blood
flow has been attributed to age-related brain atrophy
and increased cerebral vascular resistance secondary
to cerebral arteriosclerosis [68]. The mechanism
underlying this change is attributed to altered endo-
thelium function. Relaxation of the basilar artery in
humans [69] and cerebral arterioles [70] and the
234 H. Yaggi, V. Mohsenin / Clin Chest Med 24 (2003) 223–237
carotid artery in rats [71] in response to endothelium-
dependent agonists is impaired with aging. Deposits
of b-amyloid in brain and cerebral vessels are seen in
aging individuals. Recent data suggest that b-amyloid
may impair endothelium-dependent relaxation by
generation of superoxide anion. This impaired endo-
thelium-dependent relaxation has been attributed to
degradation of nitric oxide by generation of reactive
oxygen species in the vessel wall [71]. Similar impair-
ment of vasoconstrictor responses to several stimuli
has been reported in the human basilar artery [69].
These age-related changes in cerebral blood flow and
the alterations during normal sleep may predispose the
brain to compromised blood supply during sleep.
Humoral mechanisms
In addition to physiologic mechanisms that alter
cerebral blood flow and contribute to hypoperfusion,
several humoral mechanisms may contribute to
increased hypercoagulability in patients with sleep-
disordered breathing and predispose to ischemic and
thromboembolic stroke. Elevated plasma fibrinogen
levels are believed to be associated with increased risk
of stroke and other cardiovascular events [72 – 77].
Plasma fibrinogen is an acute-phase protein that is
synthesized in the liver and is intrinsically involved in
coagulation. It enhances thrombosis and atheroscle-
rosis by effects on platelet aggregation, blood vessel
wall, and endothelial cell injury [78,79].
Patients with OSA have been shown to have
increased morning levels of fibrinogen [80]; there-
fore, elevated fibrinogen levels may be one mech-
anism that links OSA to stroke. Further evidence of
the association between OSA and increased fibrino-
gen levels and stroke comes from a cross-sectional
study of 113 stroke patients who underwent neuro-
logic rehabilitation. Fibrinogen level was positively
correlated to RDI and length of respiratory events
and negatively correlated with oxygen desaturation
during sleep [81]. As suggested elsewhere [82],
given the cross-sectional nature of this latter study,
it is not clear whether the higher fibrinogen levels
are a reflection of the acute-phase reaction to the
stroke insult, with stroke being worse and fibrinogen
levels being higher in patients with preexisting
OSA. Alternatively, could airway inflammation
associated with OSA induce increases in plasma
fibrinogen? Although it is widely held that BMI
and other measures of obesity may be determinants
of fibrinogen [83], this study showed that OSA, not
BMI, was independently associated with increased
fibrinogen. Whether fibrinogen is simply a marker
for stroke is yet to be determined, but it is provoc-
ative to consider it as a potential intermediate step
of the pathophysiologic pathway between OSA and
stroke. Further studies that explore the effects of
fibrinogen with treatment for sleep apnea should
prove informative.
Increases in platelet reactivity have been associ-
ated with increased risk of cardiovascular event and
death [84 – 87]. The ability of aspirin, a recognized
inhibitor of platelet function, to prevent stroke, myo-
cardial infarction, and death can be interpreted as
additional evidence linking platelets to these disor-
ders. It also has been demonstrated that platelet
aggregability increases significantly during the pe-
riod from 6:00 AM to 9:00 AM, which is temporally
related to rising plasma catecholamine levels and the
circadian period. This period has the highest risk for
cardiovascular/cerebrovascular events and sudden
cardiac death [49] (see Fig. 3). A small prospective
study of men who underwent polysomnography for
suspected sleep apnea demonstrated significantly
increased spontaneous platelet activation and ag-
gregation in patients with OSA compared with con-
trols without OSA [88]. Although no relationship
could be established between the level of sponta-
neous platelet activation and specific markers of sleep-
disordered breathing, a second important finding
of the study was a reduction of platelet reactivity
after the application of CPAP. The authors speculated
that the mechanisms for increased platelet reactivity
in patients with OSA are possibly the cyclic hypo-
xemia, hypercarbia, and catecholamine surges that
are part of OSA, which also have been reported to
cause enhanced platelet reactivity [89 – 91]. Several
other humoral factors associated with cardiovascular
morbidity and mortality have been demonstrated to
be increased in patients with OSA, including plasma
homocysteine [92], circulating endothelin-1 (a potent
vasoconstrictor) [93,94], vascular cell adhesion mol-
ecule-1, intracellular adhesion molecule-1, and L-se-
lectin [95].
A last mechanism whereby OSA may increase the
risk of stroke relates to it being provocative of right-
to-left shunting through a patent foramen ovale [96].
The increased right heart pressure – associated apneic
events may serve to increase the exposure time of
right-to-left shunting through a patent foramen ovale,
which increases the risk of paradoxic embolism.
Patients with sleep apnea may have an increased
prevalence of patent foramen ovale [97].
Taken together, cerebral hypoperfusion, sympa-
thetic activation, hypertension, hypercoagulabity, hy-
poxemia, endothelial impairment, and right-to-left
shunting via patent foramen ovale all likely have a
role in pathogenesis of cerebrovascular disease in
patients with sleep-disordered breathing.
 H. Yaggi, V. Mohsenin / Clin Chest Med 24 (2003) 223–237
Summary
Sleep-related breathing disorders are strongly
associated with increased risk of stroke independent
of known risk factors. The direction of causation
favors sleep-disordered breathing leading to stroke
rather than the other way around, although definitive
proof of this awaits the results of prospective cohort
studies. If causal, even a moderately elevated risk of
stroke coupled with the high prevalence of sleep-
disordered breathing could have significant public
health implications. The relationship between sleep-
disordered breathing and stroke risk factors is com-
plex, and likely part of the risk for cerebrovascular
events is because of higher cardiovascular risk factors
in patients with increased RDI. The mechanisms
underlying this increased risk of stroke are multi-
factorial and include reduction in cerebral blood flow,
altered cerebral autoregulation, impaired endothelial
function, accelerated atherogenesis, thrombosis, and
paradoxic embolism. Because of the effects of sleep-
disordered breathing on vascular tone, hypertension
is believed to be a major mechanism by which sleep-
disordered breathing might influence risk of stroke.
Because sleep-related breathing disorders are treat-
able, patients with stroke/TIA should undergo inves-
tigation, with a thorough sleep history interview,
physical examination, and polysomnography. Treat-
ment of sleep apnea has been shown to improve
quality of life, lower blood pressure, improve sleep
quality, improve neurocognitive functioning, and
decrease symptoms of excessive daytime sleepiness
[98]. Further treatment trials are needed to determine
whether treatment improves outcome after stroke and
whether treatment may serve as secondary prophy-
laxis and modify the risk of recurrent stroke or death.
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 Clin Chest Med 24 (2003) 239 – 248

Obstructive sleep apnea in epilepsy

Bradley V. Vaughn, MDa,*,1, O’Neill F. D’Cruz, MDa,b,2
a
Division of Sleep and Epilepsy, Department of Neurology, University of North Carolina School of Medicine,
Chapel Hill, NC 27599-7025, USA
b
Division of Pediatric Neurology, Department of Neurology, University of North Carolina School of Medicine,
Chapel Hill, NC 27599-7025, USA

The dramatic interplay of sleep and epilepsy has
been known since antiquity. In the fourth century,
Aristotle noted, ‘‘sleep is similar to epilepsy and in
some way, sleep is epilepsy’’ [1]. Even in the second
century, the importance of sleep in the treatment of
epilepsy was observed. Galen cautioned his patients
with seizures against sleepiness, and Soranus noted
that sleep ‘‘must be undisturbed’’ [2]. These early
observations demonstrated the importance of sleep
quality to patients with seizures.
Although sleep apnea is a common disorder, the
first report of treatment of sleep apnea in a patient
with epilepsy was in 1981 by Wyler and Weymuller
[3]. Their patient underwent tracheotomy and attained
control of the generalized seizures and improvement
in the partial seizures. Subsequent reports suggested
significant benefits of treating sleep apnea in patients
with epilepsy [4 – 7]. Hypotheses of the mechanism
by which sleep apnea seems to exacerbate epilepsy
rest on the physiologic consequences of sleep apnea.
In this article the authors explore these observations
* Corresponding author.
E-mail address: vaughnb@glial.med.unc.edu
(B.V. Vaughn).
1
Dr. Vaughn has research funding from Cyberonics
Inc., UCB Pharma, and GlaxoSmith Kline and is a member
of the speaker’s bureau for Glaxo Smith Kline, Cyberonics,
Abbott, and Sanofi.
2
Dr. D’Cruz has research support from UCB Pharma,
Cyberonics, and GlaxoSmith Kline and is a member of the
speaker’s bureau for OrthoMcNeil and Shire.
that have led to many questions underlying the
prevalence, mechanisms, and potential therapeutic
relationships of sleep apnea to epilepsy.
Epilepsy
The term ‘‘epilepsy’’ is derived from the Greek
work epilambanien, which means to seize or to attack
[8]. Although epilepsy patients were believed in this
time to be seized by demons, science has come to the
understanding that epileptic seizures are the clinical
manifestations of excessive hypersynchronus central
neuronal activity. The clinical diagnosis of epilepsy is
defined as the chronic condition of recurrent unpro-
voked epileptic seizures. Epileptic seizures typically
are divided into partial and generalized seizures.
Partial seizures start in one location and potentially
spread to other regions of the brain. This seizure type
may be subdivided into simple partial (retention of
memory and consciousness), complex partial (impair-
ment of memory or consciousness), or secondarily
generalized. Primary generalized seizures begin
simultaneously over both hemispheres and comprise
various types of behavior. Absence seizures are
characterized by brief staring episodes. Atonic sei-
zures erupt as a sudden loss of tone that results in a
patient falling, whereas tonic seizures produce diffuse
stiffening from increase in muscle tone. Clonic sei-
zures are associated with repetitive jerking, and
myoclonic seizures are single rapid jerks. Tonic-
clonic seizures start with generalized tonic posturing
that progresses to clonic activity. A summary is
provided in the Box 1 [9].

0272-5231/03/$ – see front matter D 2003, Elsevier Inc. All rights reserved.
doi:10.1016/S0272-5231(03)00023-6
240 B.V. Vaughn, O.F. D’Cruz / Clin Chest Med 24 (2003) 239–248

by increased airway resistance in sleep, this disorder

Box 1. Seizure types
is associated with nocturnal oxygen desaturation or
frequent arousals. The disorder is arguably a com-
I. Generalized seizures of Non-Focal
bination of altered central nervous system control
Origin
over state-dependent regulation of breathing and
1. Tonic-Clonic
predisposition of airway structure [15]. Regardless
2. Tonic
of the underlying cause, this disorder influences the
3. Clonic
prevalence of hypertension, diabetes mellitus, and
4. Absence
stroke and produces significant neurologic manifes-
5. Atonic/akinetic
tations of cognitive decline and changes in autonomic
6. Myoclonic
regulation [16,17]. These neurologic manifestations
II. Partial Seizures
may be a result of sleep deprivation, oxygen desatu-
1. Simple partial (without loss
ration, or disturbance of other systems, such as
of consciousness)
neuroendocrine, required for the maximal perform-
a. motor symptoms
ance of the brain.
b. sensory symptoms
Conversely, diseases that alter the central nervous
c. autonomic
system increase the likelihood of disturbing regu-
d. psychic symptoms
lation over sleep-related respiration and propagating
e. compound forms
upper airway obstruction. Disorders such as stroke,
2. Complex partial
Alzheimer’s disease, and myotonic dystrophy have a
(impaired consciousness)
higher prevalence of sleep apnea [18 – 20]. The cir-
a. simple partial seizure
cular argument of central nervous system involve-
followed by loss
ment in OSA and disorders of the central nervous
of consciousness
system having a higher association of sleep apnea is
b. Impairment of
not surprising. Neurologic disorders are likely to alter
consciousness at onset
the function of the neurons involved in state-depen-
c. Automatisms
dent regulation of breathing just as neurons are
3. Partial seizures evolving to
susceptible to the deleterious effect of sleep apnea.
secondary generalization
We have become conscious of the importance of
III. Unclassified Seizures
sleep for maximal performance of the central nervous
system. Treatment of OSA may improve some of the
central nervous system function but not cure the
In 1881, Gower reported on the relationship of underlying neurologic process.
sleep and awake states to epilepsy. He noted that 21%
of patients had seizures solely during sleep [10]. He
also found that 42% patients had seizures only during Effect of obstructive sleep apnea on epilepsy
the awake state, whereas a third group of 37% had
seizures during the awake and asleep states. Later Clinicians have inferred that OSA exacerbates
investigation by Janz revealed that some individuals epilepsy from the beneficial effect of treatment of
have seizures primarily in the first 2 hours after OSA in patients with epilepsy [4 – 7]. Several studies
awakening [11]. Janz coined the term ‘‘awakening’’ have shown that for some patients, treatment of OSA
epilepsies for these individuals and referred to seizures resulted in the reduction of seizures in patients with
that occur without dependence on the sleep-awake focal-onset seizures and generalized seizures. This
state as the diffuse epilepsies [11,12]. The state- was seen in adults and children [4,5,7]. The authors
dependent types of epilepsy may be more susceptible noted a reduction in number of seizures in patients
to alteration in sleep than the diffuse epilepsies. with state-dependent seizures, whether focal-onset or
generalized seizures, and Devinsky et al and Vaughn
et al reported a greater reduction in the number of
Obstructive sleep apnea adult patients with generalized seizures [4,5]. Koh
et al demonstrated that 56% of children with various
Obstructive sleep apnea (OSA) is a common neurologic disorders had a reduction in seizure fre-
disorder seen in as many as 9% of adult women, quency [7]. Oliveira found that patients with focal-
24% of adult men, and 2% of children [13,14]. onset epilepsy have fewer epileptiform discharges on
Defined by repetitive apneas or hypopneas caused their electroencephalogram after treatment of their
 B.V. Vaughn, O.F. D’Cruz / Clin Chest Med 24 (2003) 239–248
OSA [21]. These studies uniformly found that some
patients had significant benefit in seizure control with
the treatment of sleep apnea.
In addition to the effect OSA has on seizure
frequency, sleep apnea can deter from a patient’s
quality of life. As seen in patients with OSA without
epilepsy, patients with epilepsy frequently complain
of excessive daytime sleepiness, unrefreshing sleep,
and low energy [5,22]. These symptoms were
improved after the initiation of therapy for OSA
[4,5,22]. Although no quality-of-life studies have
been performed in patients with epilepsy and OSA,
these patients conveyed subjective improvement in
their sleep.
Prevalence
The prevalence of epilepsy in the general popu-
lation is approximately 1%. Epilepsy most frequently
begins in childhood and later adult years [23]. Middle
age adulthood holds the lowest incidence of epilepsy.
OSA, however, has a peak incidence in middle age and
occurs predominantly in adult men. Patients with
neurologic disorders seem to have a greater prevalence
for sleep disturbance than normal subjects. This
increase in prevalence seems to extend to patients with
epilepsy. Miller showed that more than two thirds of
patients with epilepsy seen at a university center had
complaints regarding sleep [24]. Polysomnographic
investigation by Malow et al showed that nearly one
third of patients with medically refractory epilepsy had
a respiratory disturbance index of more than 5 [22]. In
the authors’ cohort of 25 patients with intractable
epilepsy, they found that 36% had a respiratory dis-
turbance index of more than 10. This may have male
gender predominance. In the three adult studies that
showed the effect of treatment of OSA in patients with
epilepsy, men were strikingly more affected than
women. Nine of the ten patients in the authors’ cohort
were men, eight of the nine in Malow’s series were
men, and six of the seven in Devinsky’s report were
men [4,5,22]. This may be caused in part by selection
bias. These patients also may not be obese or have the
‘‘typical’’ body habitus associated with OSA. Two of
the authors’ ten patients had normal body habitus and
did not have features upon examination that suggested
sleep apnea [5]. Although all of these studies are
compelling, larger cohorts are needed to elucidate
the true prevalence and age and gender distribution
of sleep apnea in patients with epilepsy.
The apparent increased prevalence of sleep apnea
in patients with epilepsy may be from several etiol-
ogies. These factors may be inherent in the epileptic
241
disorder or result from the treatment of the epilepsy.
Disorders of the central nervous system may affect
the regulation of respiration and increase the risk of
sleep apnea. This is seen in patients with other
neurologic disorders, such as Alzheimer’s disease,
strokes, cerebral palsy, and myotonic dystrophy
[18 – 20,25]. Therapeutic intervention for epilepsy
also may increase the risk of sleep apnea. Some
anticonvulsant medications promote weight gain
and may alter respiratory regulation. Valproate, viga-
batrin, and gabapentin are well known to accelerate
obesity, which increases the likelihood for sleep
apnea. Vigabatrin has been reported to cause a
significant weight gain, which results in a patient
developing overt signs of OSA [26]. Patients who are
given medications that promote weight gain should
have regular visits to monitor their weight and be
queried regarding symptoms of sleep apnea. Benzo-
diazepines and barbiturates may cause suppression in
responsiveness of carbon dioxide and oxygen desatu-
ration and increase upper airway musculature relaxa-
tion [27]. The changes in regulation of breathing may
be more sensitive to these inhibitory medications and
exacerbate underlying sleep-related breathing distur-
bance during certain stages of sleep. Another form of
therapy for epilepsy, vagus nerve stimulation, has
been reported to increase airway disturbance poten-
tially during sleep in some patients [28]. This therapy
may increase airway resistance from stimulation of
recurrent laryngeal nerve or interfere with the respi-
ratory sensory feedback.
Obstructive sleep apnea also may influence the
prevalence of epilepsy. Seizures as a direct result of
apnea are rare. In one patient, apnea in sleep report-
edly caused a seizure after severe oxygen desatura-
tion and cardiac arrest [29]. In another study of
patients with OSA, Sonka et al found that 4% of
their cohort had epilepsy [30]. This prevalence
exceeds that of the general population. Most
(78.9%) of these patients had seizures only during
sleep, and most of the events were generalized
seizures. This study may be skewed by variances in
referral patterns, but the elevated prevalence raises
interesting question of sleep apnea provoking sei-
zures or unmasking a potential for seizures.
Mechanisms
The treatment of sleep apnea seems to reduce the
recurrence of seizure in some patients. The subsequent
inference is that the presence of sleep apnea increases
the recurrence of seizures in these same patients. The
mechanism by which sleep apnea influences the sei-
zure disorder is unclear, however, some observations
242 B.V. Vaughn, O.F. D’Cruz / Clin Chest Med 24 (2003) 239–248
may provide clues to this relationship. Many patients
who responded to OSA therapy had a reduction of
seizures away from the period of sleep [5]. The
potential mechanism of this influence must take into
account the effect on seizure induction away from the
individual apnea. Potential mechanisms for sleep
apnea increasing the likelihood of seizures rest on
two general hypotheses, which are derived from the
pathologic consequences of the apnea: sleep depriva-
tion and oxygen desaturation. Sleep deprivation and
sleep fragmentation may increase the vulnerability to
seizure recurrence similarly to other potential distur-
bances of sleep. The second hypothesis is based on
apnea producing hypoxemia, which subsequently dis-
rupts the mechanisms inhibiting seizures.
Sleep and sleep deprivation in epilepsy
Sleep can play an important role in the seizure
discharge. This effect can be seen in the interictal and
ictal discharge. Interictal discharges are the electro-
encephalographic signature of epilepsy away from
the seizure. Sleep may activate interictal activity in
approximately one third of patients with epilepsy and
up to 90% of subjects with state-dependent epilepsies
[31 – 34]. For focal-onset seizures, the interictal dis-
charge may have little to do with the actual seizure.
The focal discharges may increase with the onset of
light sleep and demonstrate a greater frequency and
spatial and morphologic variability with stage 3 and
4 sleep. Rapid eye movement (REM) sleep is asso-
ciated with relative suppression of interictal dis-
charges. The epileptiform discharges that occur in
REM sleep are briefer and have less variability in
morphology and location than those seen in non-
REM sleep. Overnight studies of interictal activity
demonstrated that the focal interictal activity
increases with the entrance into the deeper stages
of non-REM sleep [35]. These stages of sleep are
physiologically linked to greater thalamocortical
neuronal synchronization, when fewer neurons are
engaged in active membrane depolarization [36].
More neurons are in the resting membrane state
and can be recruited into the discharge. This greater
availability of neuronal recruitment may account for
the greater spatial and morphologic variability of the
focal interictal discharge.
For primary generalized epilepsies, little distin-
guishes ictal from interictal discharges in that in-
terictal discharges are shorter and have no clear
behavioral manifestations. These generalized dis-
charges are more common during light sleep and
after awakening, however. Horita found that the
discharges are longest in stage 1 sleep [37]. The
deeper non-REM stages of sleep, stages 3 and 4,
are less likely to activate the generalized discharges,
and REM sleep has a further suppressive action.
Seizures have a slightly different pattern than
interictal discharges in relation to sleep. Focal and
generalized seizures are more likely to occur out of
light sleep or soon after awakening and rarely occur
in REM sleep [38]. Generalized seizures also occur
frequently near arousals or soon after awakenings.
Potential exists that the thalamocortical relay neu-
rons are more vulnerable at these times to hyper-
excitable synchronization and allow for generalized
discharges to propagate into seizures. Shouse has
postulated that a synchronous bursts-pause pattern of
entrained thalamocortical neurons extends beyond
the normal firing and can generate into a spike-wave
discharge [38].
Sleep deprivation can bring out seizures and
increase the frequency of interictal activity. Sleep
deprivation has been used extensively in long-term
epilepsy monitoring settings to trigger seizure activity.
In some patients, sleep deprivation is a powerful
provocative agent, whereas other patients demonstrate
little change in seizure frequency [31,39 – 41]. Rajna
and Veres found that in 9 of 14 patients with temporal
lobe epilepsy, seizures occurred on more than half of
the days after sleep deprivation [41]. Sleep deprivation
is also noted to increase the frequency of generalized
seizures and increase the interictal discharges in
patients with generalized epilepsies [42]. Although it
is still debated, activation of interictal activity from
sleep deprivation may be related to the promotion of
the onset of sleep or the disruption of central nervous
system processes that inhibit seizures [43].
Obstructive sleep apnea disrupts sleep and can
cause significant sleep deprivation. Janz noted that
sleep deprivation frequently provokes seizures in
patients with the awakening epilepsies. These epi-
lepsies are frequently characterized by generalized
seizures [11,12]. The first case report of OSA and
epilepsy showed a resolution of the generalized sei-
zures after tracheotomy [3]. Devinsky et al found that
the patients with generalized seizures were more
likely to have a reduction in seizure frequency after
the treatment of the OSA than their patients with
focal-onset seizures [4]. Two of their patients, who
had only generalized tonic-clonic seizures, became
seizure free after appropriate continuous positive
airway pressure (CPAP) therapy. The decrease in
seizure frequency in response to treatment of sleep
apnea also seems to extend to children. In their
cohort of 12 children with primary generalized epi-
lepsy and absence seizures, Carney and Kohrman
reported an average of 92% reduction in seizures
 B.V. Vaughn, O.F. D’Cruz / Clin Chest Med 24 (2003) 239–248
with appropriate treatment of the OSA [44]. None of
these children had oxygen desaturation below 87%,
which supported the idea that some mechanism other
than oxygen desaturation was playing a role for
seizure provocation and recurrence (Carney, personal
communication, 2002).
Patients with focal-onset epilepsy also seem to
have a reduction in their seizures after treatment of
OSA. In a cohort of patients who had focal-onset
seizures, more than half had a more than 50%
reduction in seizure frequency with no alteration in
medication [5]. Although they had a reduction in
seizure frequency, two patients who became seizure
free did not have oxygen desaturation below 88% on
polysomnographic examination. Pediatric patients
with presumed focal-onset epilepsy also showed
improvement in seizure frequency with treatment of
the OSA. Koh et al reported that one patient with
focal-onset seizures had near complete control of
seizures after tonsillectomy [7]. This patient had
oxygen desaturation only to 96%, which supported
the hypothesis that something other than low oxygen
plays a role for the increase in seizure frequency.
In the context of sleep apnea, the changes in sleep
architecture caused by the repetitive apnea increases
the vulnerability to seizures. The patient with sleep
apnea has more frequent arousals, greater percent of
time awake and light sleep, and less REM sleep. The
increased number of arousals and increased amount
of time awake and in light sleep afford a greater
chance of seizure initiation by increasing the percent
of time in a state that is more vulnerable to seizures.
Sleep fragmentation may allow a greater opportunity
for seizure initiation. Most patients with OSA also
have either disrupted REM sleep or diminished time
in REM sleep. REM sleep seems to have an anticon-
vulsant effect and increases the threshold for seizure
occurrence [45]. Patients with REM sleep disruption
have less of the antiseizure effect of this state. REM
sleep is important in reducing seizure recurrence and
may play a role in the provocative seizure effect of
sleep deprivation.
Shouse showed that the propensity for generaliza-
tion of epileptic discharges increases after sleep
deprivation, as seen by the susceptibility of cats to
penicillin-induced seizures after sleep deprivation
[46]. Sleep deprivation also affects the development
of a seizure focus. Animals can be kindled to develop a
seizure focus by repetitive exposure to epileptigenic
chemicals or electrical stimulation. This model for
epilepsy has been correlated to human focal-onset
epilepsy. Total sleep deprivation causes an increase
in the rate of kindling, and REM sleep deprivation
accelerates kindling of amygdala [47,48]. Conse-
243
quently, sleep fragmentation may increase seizure
frequency by interfering with seizure inhibitory mech-
anisms, and potentially increasing kindling and sleep
deprivation may accelerate the progression of the
epileptic focus. The clinical application of these find-
ings raises a concerning issue regarding progression of
the epileptic process in humans with epilepsy and sleep
deprivation. It also suggests that sleep fragmentation
and sleep deprivation may have a differentiating effect
on focal and generalized epilepsies.
Hypoxia
Many of the patients described in reports by
Devinsky et al, Vaughn et al, and Koh et al had
significant oxygen desaturations [4,5,7]. Several of
these patients had dramatic improvement in seizure
frequency after therapeutic intervention of the apnea.
The effect of hypoxia must be considered as one
potential mechanism for the improvement in seizure
frequency. Seizures are not a common manifestation
of brief periods of hypoxia, but they are frequently
seen in individuals who suffered anoxic encephalop-
athy. The effect of hypoxia on lowering the seizure
threshold seems to be most prominent in the devel-
oping brain. Hypoxia induces a hyperexcitable state
in the immature hippocampus [49]. This effect seems
to be most significant and long lasting if the hypoxia
occurs during the perinatal period. Animal studies
have shown that hypoxia produces a profound effect
on glutamate synapses and leads to the cascade of
events that ends in cell death and reorganization that
promotes epileptogenesis [50].
Although these findings may have some applica-
tion to children with nocturnal hypoxia, their
application to adults with OSA is unclear. Adult
mice made hypoxic may be more susceptible to
certain types of seizure induction. In adult mice,
hypoxia induced by breathing a 5% oxygen prepara-
tion lowered the seizure threshold to several con-
vulsant agents [51]. This phenomenon was blocked
by the application of adenosine A1 receptor ant-
agonist. In certain mutant mice that lack the Kir6.2
subunit of the potassium sensitive ATP channels,
brief hypoxia can lead to generalized seizures. These
mice lack the ability to enhance the substantia nigra
pars reticulata’s role in seizure suppression [52].
Emerson et al also found some evidence to suggest
that hypoxia preconditioning may enhance the pro-
tective mechanisms of the brain [53]. These studies
suggested that hypoxia may alter the seizure thresh-
old, but we have limited understanding of how
hypoxia influences seizure induction and recurrence
in humans.
244 B.V. Vaughn, O.F. D’Cruz / Clin Chest Med 24 (2003) 239–248
Epilepsy causing a breathing disorder
The article has focused thus far on patients who
have epilepsy and developed OSA (Figs. 1, 2). There is
a need to address the possibility that the seizure focus
may cause apneas. Respiratory disturbances related to
seizures are not uncommon. Oxygen desaturation
frequently is found during seizures in individuals
who are in an epilepsy monitoring unit [54]. Snoring
and apneas that occur with seizures may be part of
the ictus or may occur as a postictal phenomenon (see
Figs. 1, 2). Repetitive nightly seizures can be mis-
taken for sleep apnea [55]. Seizures also can cause
nocturnal choking, as seen in rolandic epilepsy and
epileptic operculum syndrome [56]. The clinician must
be alert for the occurrence of seizures. This is one reas-
on that adequate electroencephalographic monitoring
should be included in the overnight polysomnogram.
Clinical manifestations and evaluation
The disruption of restorative sleep by OSA results
in excessive daytime sleepiness and other symptoms
reminiscent of sleep apnea. Patients with epilepsy and
sleep apnea frequently complain of excessive daytime
sleepiness, unrefreshing sleep and loud snoring. They
may have witnessed apneas or periods in which they
have awoken themselves from horrific snoring or
gasping. The clinician must ask about hypersomno-
lence, snoring, and other symptoms of increased
upper airway resistance and obstruction. The clinician
Fig. 1. The patient has an apnea after the initiation of the seizure.
also should ask about recurrence of seizure, trends of
seizure frequency especially associated with the
symptoms of sleep disturbance, time of seizures,
and intensity of seizure and look for potential
increase in seizures that may suggest a relationship
of OSA to seizures. Patients must relate their current
medication regimen and changes that have occurred
even before the onset of sleep-related symptoms. The
clinician should note weight changes, pattern and
time of sleep, and concurrent use of herb or food
supplements. The differential diagnosis of hypersom-
nolence includes sedating medications, sleep depriva-
tion, circadian rhythm disorders, and other causes of
sleep disruption. Recurrence of seizures also should
be considered. As with any other complex medical
condition, patients should undergo a thorough sleep
history and physical examination before considera-
tion for polysomnography. The polysomnography
should include more extensive electroencephalo-
graphic coverage of the frontal and temporal head
regions [57]. These patients also should be screened
for thyroid abnormalities and other medical disorders
that may increase the likelihood of disturbed sleep. A
complete review of potential causes for the symptoms
offers a better chance for successful identification and
treatment of the underlying cause.
Therapeutic options
Various therapeutic interventions have been used
in patients with OSA and epilepsy. The sleep
 B.V. Vaughn, O.F. D’Cruz / Clin Chest Med 24 (2003) 239–248
Fig. 2. This figure demonstrates an apnea occurring at the end of a seizure.
specialist, epileptologist, and patient should work
together with the goal of determining a treatment
option that corrects the breathing disturbance with-
out exacerbating the underlying seizure disorder.
Optimization of medications to avoid progressive
weight gain or sedation should be considered if it
could be accomplished without exacerbating the
seizures. Making sure the patient is educated
regarding sleep apnea and becomes vested in the
therapy is a fundamental feature to ensure high
patient compliance and satisfaction. Patient involve-
ment is an intricate factor in determining the best
treatment option.
The most common intervention for treating OSA in
adults has been CPAP, which can be used safely in
patients with epilepsy. Close and frequent follow-up
that focuses on identifying issues that interfere with
CPAP use and educating patients have been key to
improving compliance. Patients may experience the
predictable difficulties with CPAP and respond to
similar interventions. The authors have not had any
patients become entangled in the tubing or injured with
the device during a seizure. The authors also have used
positional therapy with success. Two patients from
their original series responded well to positional ther-
apy using a tennis ball in the middle of the back of a
nightshirt. These patients had clear positional-related
sleep apnea defined on an overnight study and were
motivated to continue the therapy.
Other investigators have promoted the use of
medications such as protriptyline or acetazolamide
245
[4,58]. Devinsky et al reported that two of their
patients noted benefits in seizure frequency and
symptoms of OSA with use of protriptyline [4]. They
also noted trying acetazolamide in three patients, but
the results of seizure reduction and symptoms of OSA
were mixed. Acetazolamide has the attractive benefit
of being a mild anticonvulsant and may improve
seizure control by more than one mechanism. On
the other hand, theophylline should be used with care
in patients with epilepsy because of its potential for
lowering the seizure threshold. Anticonvulsant ther-
apy should be directed toward complete seizure
control with no side effects. If possible, patients
may improve by avoiding any sedating and weight-
enhancing medications. Alternatively, the epileptolo-
gist may consider the use of anticonvulsant agents
that promote weight loss, such as topiramate. Medi-
cations should be optimized to improve respiration
without impairing seizure control.
Airway surgery also has been used successfully
to treat OSA. Wyler and Weymuller’s first report
used the correction of airway obstruction by means
of tracheotomy [3]. Although tracheotomies are
preformed for only the most severe cases of OSA,
alternative surgeries are available and can improve
the sleep apnea and compliance with CPAP. Ton-
sillectomy can be performed safely and is the
treatment choice for many children with OSA.
Whatever the surgery, the operation should be
tailored to the patient, and close postoperative moni-
toring may be required. A team that includes the
246 B.V. Vaughn, O.F. D’Cruz / Clin Chest Med 24 (2003) 239–248
epileptologist, sleep specialist, surgeon, and anes-
thesiologist should discuss the potential benefits and
risks for the patient with the goals of correction of
the airway disturbance.
Oral devices have been proposed as a viable option
in patients with epilepsy [58]. Although these devices
are an alternative therapy for OSA, patients with
history of mastication during or after a seizure should
be counseled on the potential risk of the device being
fractured during a seizure and the possibility of airway
occlusion. Hard, nonpliable dental devices that have a
high retention of the teeth may have lower likelihood
of becoming dislodged and fractured. Another concern
is for patients who have postictal vomiting. A dental
device may impede the ability for the patient to clear
the airway, which should be especially concerning if
the patient has impaired sensorium from the seizure
and postictal somnolence.
The patient with epilepsy and OSA has many
therapeutic options and considerations to maximize
the potential for improvement. Optimal care for the
epilepsy and OSA reduces the chance of untoward
effects of either disease process. Regardless of the
therapy chosen, the patient must be vested in the
therapy, and close follow-up is crucial to success.
Summary
Obstructive sleep apnea can affect an individual
with epilepsy profoundly. These relatively common
disorders can coexist and potentially exacerbate each
other. The identification and appropriate treatment
of OSA may have far-reaching consequences in
improving a patient’s quality of life and recurrence
of seizures. Clinicians must be aware of the relation-
ship of these disorders and keenly question epilepsy
patients, regardless of their body habitus, regarding
potential symptoms of sleep apnea. Although the
underlying pathogenic mechanisms are unclear, we
can model the information gained from the observa-
tions to further the understanding of the relationship
between sleep and epilepsy.
Acknowledgment
The authors wish to extend their great apprecia-
tion to Michelle Wrightsell for her administrative and
editorial assistance that made this article possible.
The authors also wish to extend their appreciation to
Beth Malow for her thoughtful input regarding issues
discussed in the manuscript.
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 Clin Chest Med 24 (2003) 249 – 259

Neuropsychological impairment and quality of life in

obstructive sleep apnea
Michael J. Sateia, MDa,b,*
a
Department of Psychiatry, Dartmouth Medical School, 1 Medical Center Drive, Lebanon, NH 03756, USA
b
Sleep Disorders Center, Dartmouth-Hitchcock Medical Center, 1 Medical Center Drive, Lebanon, NH 03756, USA

Obstructive sleep apnea (OSA) is characterized by
repetitive partial or complete airway obstructions
during sleep, with associated sleep disruption and
varying degrees of transient oxygen desaturation. The
indications for treatment of OSA fall into three broad
categories: (1) social complications, such as spousal
disturbance or patient embarrassment related to snor-
ing, (2) daytime dysfunction, including sleepiness,
psychological disturbance, cognitive impairment, or
quality-of-life issues, and (3) cardiovascular conse-
quences (eg, risk of systemic or pulmonary hyper-
tension, congestive heart failure, or arrhythmia). Of
these three categories, the daytime disturbances, in all
likelihood, are the most frequent motivations for
physicians and patients to pursue definitive treatment
for OSA. Although much attention has been paid to
excessive sleepiness as a complication of this con-
dition, there is less understanding about the relation-
ships between OSA and various cognitive and
psychological disturbances and the relationship of
these disturbances to quality of life.
Although research directed to the issue of cogni-
tive and psychological consequences of OSA has been
ongoing for more than 20 years, a clear picture has yet
to emerge, mainly because the area is complex and
study designs have varied significantly, which makes
comparisons between studies problematic. The pop-
ulations assessed in these investigations have varied
with respect to severity of their respiratory distur-
This work was supported by Grant No. K07-HL03646
from the National Heart, Lung, and Blood Institute.
* Sleep Disorders Center, Dartmouth-Hitchcock Medi-
cal Center, 1 Medical Center Drive, Lebanon, NH 03756.
E-mail address: michael.j.sateia@dartmouth.edu.
bance, age, baseline physical characteristics, coexist-
ing medical illness, and other measures. Hypoxemia,
obesity, medications, and psychiatric state all have
potential bearing on the outcome of neuropsycholog-
ical assessment. To date, the nature of the relation-
ships between these factors and daytime impairments
in obstructive sleep apnea is not clearly defined.
This article summarizes current information re-
garding OSA and quality of life, cognitive disturbance,
and psychological factors, identifies limitations of the
available data, draws tentative conclusions, and dis-
cusses future research considerations.
Neuropsychological function
Background considerations
Cognitive function and neuropsychological testing
have been assessed in numerous studies over the past
20 years. In evaluating the results of these investi-
gations, differences in sampling and study design
must be considered. The characteristics of study
populations vary significantly across these studies.
The most obvious source of variation is the severity
of respiratory disturbance, as dictated by defined
inclusion criteria and sampling pool. A recent review
[1] noted that the effect size of cognitive impairment
in OSA correlated highly with the severity of breath-
ing disturbance, with effect size ranging from 0.2 to
0.3 standard deviations in samples with milder apnea
[2,3] to 2 to 3 standard deviations in clinical pop-
ulations with moderate to severe OSA [4,5]. As
detailed later in this section, severity also influenced
the type of cognitive impairment observed [1,6].

0272-5231/03/$ – see front matter D 2003, Elsevier Inc. All rights reserved.
doi:10.1016/S0272-5231(03)00014-5
250 M.J. Sateia / Clin Chest Med 24 (2003) 249–259
Assessment of cognitive function also may be
influenced by other subject characteristics that vary
across studies. For example, early work by Findley et
al demonstrated significant cognitive impairment in a
population of 26 patients with OSA [7]. These
patients demonstrated daytime CO2 retention and
hypoxemia, which may play a role in the genesis of
cognitive dysfunction independent of sleep apnea.
Many studies have failed to assess or control for
other pertinent variables that may impact cognitive
performance, such as the psychological state of sub-
jects, particularly the degree of depression. As noted
by Bliwise [8] and Telakivi et al, [9] age and baseline
cognitive function of subjects also may play an
important role in determining degree of identified
neuropsychological impairment in OSA. Individuals
with high baseline function may have the ability to
compensate for the effects of mild to moderate OSA
on standard evaluation instruments that have been
designed primarily to detect dementia.
Box 1. Neuropsychological instruments in assessment of obstructive sleep apnea patients
Instrument
Wechsler Adult Intelligence
Scale-Revised (WAIS-R)
Simple Reaction Time (SRT)
Four Choice Reaction Time (FCRTT)
Continuous Performance Task (CPT)
Critical Flicker Fusion (CFF)
Digit Span (DS)
Digit Symbol Substitution (DSS)
Trail-Making (TM)
Stroop Color-Word
Paced Auditory Serial
Addition (PASAT)
Wisconsin Card Sorting (WCS)
Tower of Toronto / London
Verbal Fluency
Picture Completion
Block Design (BD)
Picture Arrangement
Object Assembly
Wechsler Memory Scale (WMS)
Benton Visual Retention
Rey Auditory Verbal Learning
Purdue Pegboard
Finger Tapping
A range of comparison groups has been used in
these investigations. Comparisons include use of
published normative data [7], healthy controls
[4,5,10,11], and other groups, such as insomniacs
[12,13], persons with other hypersomnolence disor-
ders [5], and patients with treated chronic obstructive
pulmonary disease [14].
An array of neuropsychological instruments has
been used in the assessment of patients with OSA.
Although there has been some overlap in the particu-
lar performance batteries used in these investigations,
the inevitable differences in such batteries, coupled
with other design variations, make comparisons
among studies difficult. In developing a specific
battery for research purposes, the neuropsychologist
chooses from a large number of individual tests, each
of which is purported to measure a specific domain or
domains of performance. Commonly used tests and
the primary domain(s) that they assess are listed in
Box 1. Decary et al have reviewed the subject of
Function
General intelligence
Alertness/vigilance
Alertness/vigilance
Alertness/vigilance
Alertness/vigilance; visual motor function
Attention/short-term memory
Attention/concentration/psychomotor
Attention/executive function
(sequencing/visual search)
Attention/executive function (response inhibition)
Attention/executive function
Executive function
Executive function (problem solving)
Executive function
Executive function (concept formation/reasoning)
Executive function (constructional ability)
Executive function (planning/organization/
concept formation)
Executive function (concept formation/
constructional ability)
Immediate/delayed memory (logical/figure [visual])
Short-term memory (figure [visual] retention)
Memory (Immediate/delayed verbal learning)
Executive function (planning)
Psychomotor coordination
Psychomotor coordination
 M.J. Sateia / Clin Chest Med 24 (2003) 249–259
neurocognitive function in OSA and note the most
relevant areas of assessment: (1) general intellectual
function, (2) attention/vigilance/concentration, (3)
memory (working/episodic/procedural) and learning,
and (4) executive and motor function [15]. It is
important to note that because many of these tools
involve multiple functions, there is not always uni-
form agreement as to the significance and meaning of
impaired performance on a given test. The authors
have suggested a standard battery for neuropsycho-
logical assessment of sleep apnea patients that
includes measures in each of these areas.
The following issues are most commonly ad-
dressed in studies of neuropsychological impairment
in obstructive sleep apnea: (1) Is significant impair-
ment of neuropsychological function associated with
obstructive sleep apnea and what is the nature of
that impairment? (2) What is the relationship
between the severity of apnea and the type/degree
of dysfunction? (3) Which aspects of OSA (eg,
hypoxemia, frequency of events, disturbances of
sleep architecture) are most predictive of dysfunc-
tion? (4) Do different types of dysfunction correlate
with different characteristics of the sleep apnea? (5)
Is functional impairment reversible with treatment
and, if so, what is the pattern and time course
associated with that reversal?
General intellectual function
Numerous studies have identified a significant
degree of neuropsychological impairment with OSA
[4,5,7,11,16,17]. Deficits in global intellectual func-
tioning, typically assessed by IQ scores of the Wechs-
ler Adult Intelligence Scale (WAIS-R), have been
demonstrated [4,5,7,16]. For the most part, these
studies have suggested that deterioration in general
intellectual function in OSA is a function of hypox-
emia [4,7,16], although not all analyses have demon-
strated such an association or explored possible
correlation with other variables.
Attention and concentration
Measures of attention and concentration likewise
have yielded indication of impairment associated
with sleep apnea. Significant differences between
apnea subjects and controls have been described on
Trail Making [4,5,7,16], Stroop Color Test [11], Digit
Symbol [4,16], Paced Auditory Serial Addition Test
[7], and Letter Cancellation [4,5]. Similarly, mea-
sures of vigilance, such as Choice Reaction Time
[4,7,18], Continuous Performance Test [3,14], and
Steer Clear [18,19], document impairment, which is
251
consistent with the sleepiness manifested in most
sleep apnea patients.
Memory
Assessment of memory function in OSA has
suggested deficits in short- and long-term memory.
Bedard et al described diminished performance on a
short-term memory measure in patients with mod-
erate and severe sleep apnea, although only the
severe group demonstrated evidence of impairment
in delayed recall [4]. These disturbances were pri-
marily associated with decrease in vigilance. Green-
berg et al found no differences between patients with
OSA and controls on subscales of the Wechsler
Memory Scale (in either immediate or delayed con-
ditions) but did demonstrate a modest impairment in
immediate recall on digit span [5]. Short-term mem-
ory deficit has been noted by others [7,11]. Naegele
et al also demonstrated significant abnormalities in
long-term memory [11]. They argued, however, that
the apparent long-term disturbance reflects the defi-
cit in initial learning and that, in this respect, patients
with OSA more closely resemble persons with
frontal lobe lesions than persons with temporal
lesions, for whom true forgetting is a core feature.
Others have reported short- and long-term memory
problems [10,14,20].
Executive function
From a neuroanatomic standpoint, disturbances in
executive function and problem-solving areas are
associated with frontal lobe dysfunction. Although
the available data do reveal disturbance in executive
function in some cases, results are mixed and suggest
that these abnormalities are most evident in patients
with more severe sleep apnea. One group reported
mild performance deficits on standard measures of
executive function (Wisconsin Card Sorting [WCS]/
Tower of Toronto) [11]. Others found impaired per-
formance on Paced Auditory Serial Addition Task
(PASAT) in hypoxemic sleep apnea patients com-
pared with a nonhypoxemic group [7]. Bedard et al
described widespread deficits in various executive
functions (verbal fluency, planning, sequential think-
ing, and constructional ability), with extent and
severity of impairment apparently advancing in asso-
ciation with severity of the breathing abnormality [4].
In a more recent study, Salorio et al found no
difference in performance in WCS between patients
with OSA and controls, although results on verbal
fluency measures were mixed [10]. Studies of older
subjects with mild apnea have not revealed signifi-
252 M.J. Sateia / Clin Chest Med 24 (2003) 249–259
cant disturbance in executive function, memory, or
other aspects of cognitive performance [21,22].
Cognitive impairment and severity
For purposes of comparison, OSA severity data,
as addressed in studies of cognitive impairment, are
usually based on frequency of respiratory events
(apnea-hypopnea index [AHI]). One should note that
this measure might best serve as a proxy for sleep
disruption and does not consistently reflect severity
of hypoxemia. Many of these studies, however, do
include analyses of the relative effects of hypoxemia
versus sleep disturbance on cognitive function. Eng-
leman et al, in reviewing case-control studies, noted a
distinct trend toward increasing effect size of cogni-
tive impairment with increasing AHI [1]. Other
researchers found only limited and relatively mild
differences between patients with moderate OSA and
controls, whereas the severe group had more wide-
spread and obvious dysfunction [4].
Analysis of correlations between specific physio-
logic parameters associated with OSA and disturbed
neuropsychological function is complicated by the
choice of physiologic parameters for analysis and the
definitions of those parameters. For example, an
assessment of the role of hypoxemia in generation
of impairment may use the number of desaturations
of 4% or more, the percentage of time spent below
specific thresholds, or the minimum saturations per
event. Likewise, exploration of the impact of sleep
disturbance on neuropsychological function may use
AHI, numbers of arousals (of varying definitions), or
direct measures of daytime vigilance/sleepiness, such
as reaction times or multiple sleep latency tests. The
outcome of these investigations depends—at least to
some extent—on the choice of measures. Which
measures produce the most significant and accurate
correlations remain unclear.
Not surprisingly, the investigations of correlations
among sleep, respiratory variables, hypoxemia, and
various neuropsychological tests have demonstrated
mixed results (Table 1). Correlations between global
intellectual impairment and hypoxemia have been
noted in several investigations. Other investigations
have described an association between executive func-
tion (eg, WCS or Block Design) and oxygen desatura-
tion in OSA. Measures of sleep disruption or direct
assessments of daytime sleepiness/alertness (eg,
arousals or Multiple Sleep Latency Test [MSLT]) have
been noted to correlate most closely with memory
disturbance (eg, digit span, Wechsler Memory Scale)
and tests of vigilance/alertness/ concentration, such as
Four Choice Reaction Time, Critical Flicker Fusion,
Digit Symbol Substitution, or Simple Reaction Time.
These relationships, however, are variable, overlap-
ping, relatively weak, and, as Englemann et al point
out, not strongly predictive of specific dysfunction [1].
The evidence of general intellectual slowing and,
more specifically, disturbance in executive functions
has led to the suggestion that OSA (and specifically
hypoxemia) may be associated with frontal lobe
dysfunction [4,23]. Others have postulated distur-
bance in neurotransmitter synthesis as the basis for
cognitive dysfunction [4], but the precise mecha-
nisms of these disturbances are not known.
Treatment and reversibility
Trials that examine the reversibility of cognitive
dysfunction in patients with OSA have used various
treatments (primarily continuous positive airway pres-
sure [CPAP]) and study designs (including normal
controls, placebo CPAP groups, and cross-over
designs). Bedard et al assessed ten patients with
moderate to severe OSA at baseline and 6 months after
CPAP treatment and compared them to ten control
subjects [24]. Significant baseline deficits in function
normalized to near control levels in most cases, but
tests of executive function (Trail Making Test [TMT]/
verbal fluency) did not significantly improve. The
investigators suggested that this continued impair-
ment might reflect irreversible hypoxic damage.
Naegele et al studied ten patients treated with
CPAP for 4 to 6 months and compared them to ten
controls [25]. At baseline, subjects demonstrated
significant differences from controls in multiple areas
of cognitive function. After treatment, these subjects
differed from controls only in persistence of short-
term memory deficits. The investigators argued that
persistent frontal lobe disturbance may be the basis of
the ongoing memory problems. Lojander et al eval-
uated the impact of surgical treatment (23 patients)
and nasal CPAP (27 patients) on cognitive function
[26]. In this group of patients with moderate sleep
apnea, CPAP treatment at 3 and 12 months was
associated with significantly greater improvement
(versus conservative management) on the Benton
Visual retention Test only. Patients who were treated
surgically did not differ from the conservative treat-
ment group on any psychometrics. These patients
showed only mild impairment at baseline, however.
Other researchers have found varying degrees of
improvement with CPAP in uncontrolled investi-
gations [23,27]. Only two recent studies have used
a credible placebo (subtherapeutic or sham CPAP) in
assessing effect of treatment on cognitive function. A
subtherapeutic CPAP-controlled, randomized cross-
Table 1
Correlation of neuropsychological performance with obstructive sleep apnea variables
Source Hypoxemia
Kingshott et al [58] Intellectual ability component
score correlates with min.
O2 (0.15)
Greenberg et al [5] Perceptual organization/motor
speed correlate with min. O2; global
performance shows no correlation
Telakivi et al [20] Logical memory correlates
with DESA4 (snorers)
Berry et al [59] Logical memory/WMS/WAIS-PS/
verbal fluency correlates with
number of desaturations
Yesavage et al [60] NA
Findley et al [7] Short-term memory/problem solving/
attention impaired in hypoxemic vs.
nonhypoxemic group; global
performance impairment correlates
with median sleep SaO2
Verstraeten et al [12]
Bedard et al [4] General intellectual function
(WAIS) and executive functions
may be associated with hypoxemia
(cumulative % below threshold)
Cheshire et al [16] Attention/executive function
(TMT)/global IQ correlates with min.
O2; executive function (BD)/attention
(SRT)/global IQ correlates with DESA4
Telakivi et al [9] No cognitive function correlates
with DESA4 or median SaO2
Redline et al [3]
Naegele et al [11] Executive function associated with
hypoxemia in logistic regression
Other respiratory variables
Intellectual ability component
score correlates with AHI
( 0.14)
Logical memory/visual memory/
WMS correlates with AI
Concentration/response inhibition/
eye-hand coordination/ (Raven)/
(Peabody) correlate with RDI
Attention/executive function/
global IQ correlates with AHI
Short-term memory impairment
associated with AHI in
logistic regression
Sleep variables
Sleep variables not correlated
with global cognitive function
Executive function correlates
with arousals ( 0.41)
Upward sleep stage shifts correlate
with executive function
Alertness variables
Response slowing component
score correlates with wakefulness
component score ( 0.34)
NA
Spatial skills/memory retention/
WAIS-VS correlate with sleepiness
M.J. Sateia / Clin Chest Med 24 (2003) 249–259
Psychomotor function/attention
correlates with alertness (FCRTT)
Vigilance (MSLT/FCRTT) associated
with attention/verbal memory
Subjective sleepiness estimates show
no correlation with any impairment
Sleepiness (MSLT) correlated with
executive function (WCS)/
short-term memory
253
254 M.J. Sateia / Clin Chest Med 24 (2003) 249–259
over study of 46 patients demonstrated significant
improvements in multiple areas of cognitive function
from baseline to treatment condition, as had been
demonstrated in previous studies [28]. No difference
in improvement was observed between CPAP and
placebo groups, however. Similarly, Bardwell et al
found that only 1 of 22 neuropsychological test
scores showed a difference between CPAP and sham
groups, a result attributable to chance alone, although
rank-sum analysis did suggest a greater overall
improvement in general cognitive function in the
treatment group [29].
The mean treatment periods for these studies were
only approximately 2 weeks and 1 week, respec-
tively, which leaves open the possibility that cogni-
tive functional improvement in response to CPAP
may require more extended periods of treatment. In
the Bardwell study, AHI on the sham CPAP was
reduced from 44 to 28, which raised the consideration
that this is actually ‘‘partially therapeutic’’ as opposed
to subtherapeutic. No reduction was observed in
another CPAP placebo investigation [28]. Although
numerous uncontrolled studies show improvement in
cognitive function after initiation of CPAP, the results
of placebo-controlled investigations do not provide
unequivocal support for the hypothesis that this
change is directly attributable to CPAP.
Psychological factors
Most of the studies that examine psychological
variables and OSA have focused on depression,
including baseline and posttreatment analyses. The
results have been mixed. Early studies identified
evidence of increased depression in patients with
OSA on Minnesota Multiphasic Personality Inventory
(MMPI) [30,31]. Reynolds noted that 20% of patients
with OSA met criteria for a past or present episode of
depression and noted increased likelihood of depres-
sion in the sleepier group [32]. Millman found that
45% of 55 patients with OSA generated scores of more
than 50 on the Zung Depression Self-Rating Scale
[33]. Statistically significant correlation between AHI
and depression was not identified, although a trend
toward higher Respiratory Disturbance Index (RDI) in
the depressed group was noted. In a controlled MMPI
study, investigators noted elevation on multiple scales,
including depression, in patients with moderate to high
severity OSA compared with controls [34].
Mosko et al used a questionnaire based on Diag-
nostic and Statistical Manual of Mental Disorders
(DSM-III) to assess depression [35]. They reported
that 58% of the OSA group met DSM-III criteria for
major depression of four or more depressive symp-
toms. Similar results were noted for narcolepsy and
periodic limb movement patients. Only 26% of
patients described themselves as currently depressed,
however. Dahlof et al found that 34% met criteria for
depression using the Comprehensive Psychiatric Rat-
ing Scale and clinical interview [36].
Several other investigations have failed to find
significant increases in depression associated with
sleep apnea. In a 5-year longitudinal study, Phillips
found no evidence of significant psychopathology in
a population of older adults, although this population
had relatively mild OSA [22]. An investigation of
2271 patients screened for sleep apnea found no
significant association between breathing disturbance
and depression or other psychopathology, as assessed
by the Symptom Check List-90 [37]. Although
women with simple snoring and patients with severe
sleep apnea were noted to have elevated depression
scores, the investigators did not find a consistent
relationship between depression and apnea in this
group and concluded that the higher rates of depres-
sion are related to gender and personality differences
rather than sleep apnea. Likewise, other investigators,
using various assessment instruments, discovered no
association between OSA and depression [38,39].
Treatment and reversibility
If sleep apnea does significantly predispose to
depression, one would expect at least some degree of
improvement in mood as a result of treatment for OSA.
Several studies have demonstrated this. Most treat-
ment response studies unfortunately are not well
controlled. Derderian described a reduction of Profile
of Mood States (POMS) depression scores in seven
patients with moderate to severe apnea and noted that
improvement in depression correlated with increase in
slow-wave sleep [40]. In the Dahlof study [36], the
percentage of persons who meet criteria for depression
fell from 34% to 10% after uvulopalatopharyngo-
plasty. Similarly, Mosko’s patient group had signifi-
cant reduction of depression (and fatigue and anger)
POMS scores 2 to 3 months after various corrective
upper airway surgeries [35]. Millman also found
substantial reduction in Zung Self-Rating Scale scores
in his sample after initiation of nasal CPAP [33].
Positive airway pressure resulted in modest but
progressive improvement of the MMPI depression
scale and several other scales in 23 apnea patients
described by Platon and Sierra [34]. Of note, the
improvement did not reach statistical significance until
the third follow-up, which occurred at 11 to 14 months
after initiation of nasal CPAP. More recently, others
 M.J. Sateia / Clin Chest Med 24 (2003) 249–259
have reported improvement at 1 and 3 months on nasal
CPAP using the Beck Depression Inventory [41].
Recent placebo-controlled (oral placebo or subthera-
peutic nasal CPAP) studies that examined change in
depression in response to treatment have cast some
doubt on the earlier results. Engleman et al did find
significant improvement in Hospital Anxiety and
Depression Scale depression ratings in a population
of patients with mild OSA treated with CPAP for
4 weeks versus a group treated with oral placebo [6].
Barnes et al noted no difference between patients
who received CPAP and the oral placebo group for
POMS or Beck depression scores [42]. Henke et al
saw no difference between CPAP and subtherapeutic
(0 – 1 cm H2O) CPAP groups using the Geriatric
Depression Scale [28]. Yu et al also used subther-
apeutic CPAP as a placebo control [43]. They found
improvement in the active treatment and placebo
groups, which suggested that the improvement is
primarily placebo response. Several design limita-
tions of this study, as noted by the authors, suggest
a need for caution in interpretation of these results.
Patients with more severe depression were excluded
from the study, which produced a study population
with relatively low depression POMS scores. Post-
treatment assessment was conducted at 1 week,
whereas most treatment studies have used follow-up
evaluation at 1 to 14 months. The placebo group did
show an almost 30% reduction in RDI, which raised
the possibility that there may have been a partial
therapeutic response to the ‘‘placebo.’’
Although the standard clinical perspective regard-
ing psychological function and OSA suggests that the
disorder is commonly associated with some degree
of depression that typically remits with treatment,
the evidence, particularly from placebo-controlled
treatment trials, is mixed. Numerous variables must
be considered in assessing the methodology of
these investigations. The length of treatment period
for these studies varied from 1 week to more than
1 year. At least one study suggested that full treatment
response may not occur for months, which raised
some question about those studies with short follow-
up periods. The baseline severity of apnea and the
severity of depression may impact outcomes assess-
ment. Although effect may be more apparent in
populations with more severe breathing disturbance
and associated symptoms, it is important to define the
lowest level of severity at which treatment interven-
tion effects significant change. Not all studies report
compliance with CPAP (which typically is moderate,
at best). Any assessment of outcome clearly must
include determination of compliance. Finally, it has
been demonstrated that these patients exhibit substan-
255
tial placebo response, which underscores the necessity
of placebo controls in these investigations. Subther-
apeutic CPAP seems the most appropriate placebo
intervention, although further understanding of the
extent to which a partial therapeutic response to this
‘‘placebo’’ may compromise distinctions between
treatment and control groups would be helpful.
Quality of life
Patents who are treated for moderate to severe
obstructive apnea typically note marked subjective
improvement in quality of life. The baseline disturb-
ance and the treatment response have been well
documented in numerous quality-of-life assessment
studies. Most of these studies have used the Short Form
36 (SF-36), a 36-item subscale of the Medical Out-
comes Survey (MOS), which measures physical func-
tioning, role limitations caused by physical and
emotional difficulties, mental health, physical
pain, vitality/energy, and general health perception.
Although there is variance across studies with respect
to the particular areas of disturbance, almost all studies
demonstrated some impairment in one or more areas.
Some studies suggested a linear relationship between
the severity of apnea and breadth and degree of
functional disturbance. Most of the studies also
revealed marked improvement—if not complete res-
olution—of the dysfunction with effective treatment.
The Wisconsin Sleep Cohort Study evaluated
738 patents with the SF-36 [44]. Although the qual-
ity-of-life assessment was not conducted until some
time after the sleep study, diminished general health
was correlated with apnea in dose-response fashion,
even after controlling for age, body mass index, and
other health factors. Increasing impairments in phys-
ical function, mental health, role function associated
with physical problems, social role, and energy were
associated with increasing severity of OSA. A trend
toward diminished life satisfaction correlated with
breathing disturbance also was noted. An investigation
of 5816 patents from the Sleep Heart Health Study
found that energy/vitality was the only scale that
demonstrated a linear relationship with apnea [45].
Severe sleep apnea, however, was associated with
significant abnormalities in multiple SF-36 scales,
including physical and social function, vitality, and
general health. The investigators also identified asso-
ciations between insomnia and sleepiness complaints
and disturbance on all SF-36 scales. Both of these
groups point out that the degree of impairment noted in
the samples is on the same order as that noted in other
populations of patents with significant medical illness,
256 M.J. Sateia / Clin Chest Med 24 (2003) 249–259
such as diabetes, heart disease, arthritis, or clinical
depression. Several other investigations have de-
scribed decrements in various domains of the SF-36
[46 – 50]. These disturbances have been seen in cohorts
of persons with mild sleep apnea [48] and in persons
with more severe apnea. Some of these studies iden-
tified a relationship between severity and degree
of disturbance.
Analysis of predictors of daytime dysfunction does
not provide a clear conclusion. The Finn et al study
found that AHI correlated significantly with multiple
SF-36 scales [44]. Baldwin et al analyzed data by RDI
4% and by clinical categories of severity and found
only a linear relationship between the latter and vitality
[45]. Reports of difficulty initiating or maintaining
sleep and excessive sleepiness did predict widespread
disturbance in quality-of-life measures. Moore et al
found that RDI did correlate with health distress,
energy/fatigue, mobility, and social function when
age and gender were controlled [51]. Finally, Bennett
noted only a weak relationship between pretreatment
SF-36 scores and sleep fragmentation indices [50].
Treatment and reversibility
Studies of the impact of treatment on quality of
life have focused primarily on CPAP. Bolitschek et al
and Bennett et al described normalization of daytime
function after 3 months and 4 weeks of nasal CPAP,
respectively [50,52]. Others found broad improve-
ment in quality-of-life measures after 6 months on
CPAP [47]. No relationship between arousals and
change in daytime function was identified, but a
correlation between hypoxemia indices and quality-
of-life improvement was noted. Two studies have
examined the issue of CPAP response in placebo-
controlled trials. Engleman et al, in an oral placebo
investigation of subjects with mild sleep apnea,
reported improvement in Nottingham Health Profile
total score for the CPAP versus placebo group,
although this reached statistical significance only
for the better CPAP compliers [6]. An earlier inves-
tigation by the same group revealed significant
improvement versus placebo in patients with mod-
erate to severe OSA [53]. Jenkinson et al adminis-
tered CPAP and subtherapeutic CPAP in randomized
fashion to a total of 107 patients with moderate OSA
[54]. They found significantly greater improvement
in the CPAP group for numerous SF-36 scales, with
effect sizes of 1.02 for mental component summary
and 1.68 for energy/vitality. Other researchers have
described an association between degree of improve-
ment in quality-of-life measures and severity of
baseline impairment [46].
Other instruments
Flemons et al, noting that generic instruments
such as the SF-36 or Nottingham Health Profile
may not be optimal instruments for identifying and
tracing symptoms of sleep apnea, have developed the
Calgary Sleep Apnea Quality of Life Index [55]. This
35-question instrument addresses four domains,
including daily function, social interaction, emotional
function, and symptoms. Correlations between the
Sleep Apnea Quality of Life Index and SF-36 total
scores at baseline were relatively low (0.21). Change
scores for the two instruments showed significant
correlations for total scores and for several SF-36
subscales, however. In an expanded study they
described assessment of 90 patients before and after
CPAP [56]. The Sleep Apnea Quality of Life Index
did not correlate with severity of OSA but did show
moderate (0.36 – 0.71) correlations with various
SF-36 scales. Based on 62 subjects who completed
at least 4 weeks of CPAP, they found that changes in
Sleep Apnea Quality of Life Index were most
strongly associated with change in RDI, global qual-
ity of life rating, and vitality and social function
scales of SF-36. Another sleep apnea-specific instru-
ment, the Obstructive Sleep Apnea Patient-Oriented
Severity Index, assesses 32 items and demonstrates
significant correlation with patients’ subjective global
assessment of quality of life [57].
The available data strongly suggest that even mild
sleep apnea is associated with some degree of impair-
ment in quality of life. Although the exact nature of
the impairment may vary from study to study depend-
ing on the characteristics of the patient sample, the
severity of apnea, and the specific instrument(s) used
to measure quality of life, the weight of evidence
supports significant dysfunction, possibly on the order
of that observed in common chronic illnesses. Several
considerations must be weighed in interpreting these
data, however. The specific evaluation tool may
influence substantially the outcome of such studies.
Although instruments such as the SF-36 or Notting-
ham Health Profile are well-validated and widely used
devices, they may not provide the most accurate
evaluation of quality of life in patients with sleep
apnea, as Flemons and others [55] have pointed out.
Not only do they fail to assess directly many symp-
toms of potential relevance but they also demonstrate
a ceiling effect in healthy controls and treatment
responders that may obscure significant differences
between controls/responders and untreated apnea
patients. Other instruments designed to measure more
specific symptoms in OSA show promise, but further
assessment is required.
 M.J. Sateia / Clin Chest Med 24 (2003) 249–259
Quality-of-life data do not consistently dem-
onstrate a strong association between impairment
and severity of sleep apnea, as measured by AHI or
degree of sleep fragmentation. As several investiga-
tors pointed out, the absence of a strong correlation
between a particular OSA symptom or symptom
cluster and a specific index of respiratory or sleep
disturbance is hardly unprecedented. The same holds
true for other symptoms, such as sleepiness. Numer-
ous factors contribute to these symptom presenta-
tions, and perhaps it is unrealistic to expect high
degrees of association between these symptoms and
any one variable.
Future studies of quality of life in OSA must focus
on several issues to strengthen further a demonstra-
tion of dysfunction. A single, well-recognized assess-
ment tool would allow ready comparison of results
among investigators. Although the SF-36 has played
that role to some extent thus far, an instrument more
specific for OSA may be conducive to more accurate
and efficient identification of differences. Any anal-
ysis of this sort must control for the variety of
confounding variables, such as age, gender, body
mass index, smoking, alcohol consumption, and the
potential contribution of co-varying medical or psy-
chiatric disorders that may, in their own right, be
associated with significant quality of life impairment.
Studies of treatment response must use adequate
placebo controls, such as subtherapeutic CPAP.
Cross-over designs should use adequate washout
periods to reduce the risk of carry-over effects that
might contaminate results.
Summary
Although clinical experience has suggested for
more than two decades that OSA is associated with
impairment of cognition, emotional state, and quality
of life and that treatment with nasal CPAP produces
significant improvements in these areas, sound empir-
ical evidence to support this view, especially regard-
ing treatment outcome, has been lacking. More recent
investigations have begun to provide this support
from randomized, adequately controlled studies.
These assessments suggest that some degree of cog-
nitive dysfunction is associated with OSA. The
effects are most apparent in the severe cases, whereas
results in mild cases are more equivocal. Reported
impairments include global intellectual dysfunction
and deficits in vigilance, alertness, concentration,
short- and long-term memory, and executive and
motor function. Considerable discrepancy exists
across studies with respect to type and degree of
257
dysfunction, however. Disturbances in general intel-
lectual function and executive function show stron-
gest correlations with measures of hypoxemia. Not
unexpectedly, alterations in vigilance, alertness, and,
to some extent, memory seem to correlate more with
measures of sleep disruption. Although many inad-
equately controlled investigations have demonstrated
reversibility of most or all of these deficits with
effective treatment, more recent placebo-controlled
studies have raised doubts regarding whether the
observed changes are truly a function of treatment.
This issue requires further systematic exploration
with adequate controls and step-wise analysis of
treatment duration effects.
A similar set of considerations exists with respect
to the relationship between psychological distur-
bance, primarily depression, and OSA. Although
several studies suggest significant depression in these
patients, the results are mixed. Placebo-controlled
treatment trials fail to demonstrate consistently a
difference in mood improvement between active
treatment groups and controls, although several meth-
odologic considerations suggest that these results
should be interpreted with caution.
Numerous investigations leave little doubt about
the issue of quality of life impairment among persons
with OSA. Further characterization of impairment,
particularly in areas specific to this population, will
provide clearer understanding of the problem.
Preliminary investigations of treatment response in
controlled studies indicate significantly greater
improvement of quality of life in response to CPAP.
Although patients with OSA commonly report
disturbances in cognitive and psychological function
and general quality of life, the increased rates of
obesity, hypertension, diabetes, cardiovascular dis-
ease, medication use, and related psychosocial com-
plications present a host of potential etiologies that
might explain the impairments noted. There can be
little doubt that these covariants do, in some cases,
contribute to neuropsychological dysfunctions. It is
essential that future studies continue to define those
disturbances that are specific to OSA, the relationship
between levels of severity and impairment, the role of
treatment in reversing these dysfunctions, and the
correlation between test results and significant day-
to-day social and occupational functional impairment.
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 Clin Chest Med 24 (2003) 261 – 282
Obstructive sleep-disordered breathing in children:
new controversies, new directions
John L. Carroll, MD
Pediatric Sleep Disorders Center, Division of Pediatric Pulmonary Medicine, University of Arkansas for Medical Sciences,
Arkansas Children’s Hospital, 800 Marshall Street, Little Rock, AR 72202, USA
Obstructive sleep-disordered breathing (SDB) in
children was characterized until recently as obstruc-
tive sleep apnea syndrome (OSAS), usually treated by
surgical adenotonsillectomy, versus primary snoring,
which was believed to be of no clinical significance
and did not require treatment [1].
Although classic childhood OSAS is estimated to
occur in approximately 2% of children, the reported
prevalence of loud nightly snoring is much higher,
ranging to more than 20% in children [2 – 10].
Nightly snoring is common in children and, if asso-
ciated with significant morbidity, could represent an
enormous public health problem.
In the past, the pathophysiology of childhood ob-
structive SDB was believed to be relatively straight-
forward; sleep disruption was the likely cause of
daytime sleepiness and hypoxemia was believed to
result in growth impairment and cardiovascular com-
plications [1]. Other daytime symptoms of childhood
SDB were not widely recognized. Diagnosis of ob-
structive SDB in children was also believed to be
straightforward until recently, with polysomnography
touted as the ‘‘gold standard’’ for neatly separating
snoring children into categories of childhood OSAS
versus clinically benign ‘‘primary snoring.’’ Al-
though this approach was simple and straightforward,
recent advances suggest that it was incorrect or, at
best, incomplete.
The clinical picture of childhood SDB was com-
plicated in the late 1990s by general acknowledgment
that upper airway resistance syndrome (UARS) occurs
E-mail address: carrolljohnl@uams.edu
0272-5231/03/$ – see front matter D 2003, Elsevier Inc. All rights reserved.
doi:10.1016/S0272-5231(03)00024-8
in children. That is, snoring children without classic
OSAS could exhibit significant daytime symptoms
related to increased upper airway resistance during
sleep. In 1999, an American Thoracic Society (ATS)
workshop summary on sleep studies in children
included childhood UARS and obstructive hypoven-
tilation in the classification of childhood SDB but
retained the concept of ‘‘primary snoring’’ [11].
Recent evidence indicates that childhood
obstructive SDB is not easily categorized into simple
clinical entities and that symptoms in children may
be varied, subtle, and difficult to detect. Far from
being ‘‘straightforward,’’ the area of childhood SDB
is currently characterized by a lack of consensus on
definitions, lack of diagnostic criteria, numerous
unanswered mechanistic questions, and several excit-
ing new directions. Because many reviews of child-
hood OSAS have been published [12 – 18], this article
focuses on new developments and controversies.
Clinical picture of childhood obstructive sleep-
disordered breathing: then and now
Snoring always indicates some degree of partial
airway obstruction. Although once believed to be
‘‘benign,’’ it is currently recognized that snoring, in
the absence of obstructive sleep apnea (OSA) or
hypoxemia during sleep, may be associated with
sleep disruption and daytime symptoms as severe or
worse than symptoms associated with full-blown
‘‘classic’’ childhood OSAS. From a respiratory per-
spective, childhood obstructive SDB is continuum,
with snoring on one end and complete upper airway
262 J.L. Carroll / Clin Chest Med 24 (2003) 261–282
obstruction, hypoxemia, and obstructive hypoventila-
tion on the other (Fig. 1). The relationship among
daytime symptoms, nighttime breathing patterns, and
physiologic abnormalities is not simple. In the
absence of apnea, hypopnea, hypoxemia, or hyper-
capnia, a child with snoring may have disturbed sleep
and severe daytime symptoms, whereas a child with
severe sleep-related upper airway obstruction may
have minimal or no discernible daytime symptoms.
Even the absence of discernable daytime symptoms
(see Fig. 1B) does not rule out a pathologic condition
associated with snoring. The snoring ‘‘C student’’
may have been an ‘‘A student’’ were it not for subtle
sleep disruption associated with ‘‘apparently’’ benign
snoring [19 – 21]. The child who grows along the fifth
percentile for height and weight may have been in the
fiftieth percentile were it not for ‘‘apparently’’ benign
snoring [22,23]. The behavior of the ‘‘difficult’’ child
may have been better were it not for ‘‘apparently’’
benign snoring [6,24,25].
Classically, childhood OSAS was defined as par-
tial or complete upper airway obstruction during
sleep, usually associated with some combination of
sleep disruption, hypoxemia, hypercapnia, or daytime
symptoms attributable to the sleep-related airway
obstruction (see Fig. 1D, E). Normative polysomno-
graphic data for children were published in the 1980s
and 1990s [26], and as in adults, the diagnosis of
‘‘childhood OSAS’’ was based on threshold criteria
such as apnea index and degree of oxygen desatura-
tion. Children who snored but did not meet the
Fig. 1. Continuum of upper airway resistance and airway obstruction.
threshold criteria for childhood OSAS were classified
as ‘‘primary snorers,’’ which was believed to be
clinically insignificant (see Fig. 1B).
In recent years UARS has been used to describe
daytime symptoms caused by nighttime breathing-
related sleep disruption but without OSA or hypopnea
(see Fig. 1C) [13,27 – 30]. Guilleminault et al de-
scribed the clinical picture of childhood UARS as
early as 1982 [31], although it was not termed
‘‘UARS’’ until the 1990s [29]. It is currently widely
accepted that snoring children may exhibit a range of
daytime symptoms from subtle to disabling, regard-
less of whether they meet criteria for classic OSAS.
Despite these advances, the use of unvalidated thresh-
old indices (eg, apnea-index) and other unvalidated
‘‘diagnostic criteria’’ for childhood SDB continues.
‘‘New’’ perspective on daytime symptoms
More than 25 years ago it was recognized that
childhood obstructive SDB was associated with im-
paired daytime neurocognitive function and behavior
[31 – 35]. These observations had little effect on
diagnostic testing, however, which continued to focus
almost entirely on nighttime breathing measurements
and unvalidated threshold criteria to ‘‘score’’ the
degree of sleep disruption and abnormal breathing.
Although it was has been known for decades that
severe childhood OSAS could cause developmental
delay and cognitive impairment [35], little attention
 J.L. Carroll / Clin Chest Med 24 (2003) 261–282
was given to mild OSAS or snoring children without
OSAS. Despite several additional studies in the 1990s
that explored behavioral effects associated with snor-
ing [6,23 – 25], diagnosis and treatment practices
remained unchanged.
In 1998, Gozal reported that first grade children
with poor school performance had a higher-than-
expected prevalence of snoring and sleep-related
hypoxemia. Children treated with adenotonsillectomy
showed a statistically significant improvement in
school grades, whereas untreated children with SDB
showed no improvement [21]. This study marked a
turning point, with the full realization that ‘‘classic’’
childhood OSAS (see Fig. 1D, E) probably represents
only the ‘‘tip of the iceberg’’ [15]. Recently, the
major focus has shifted to the other end and middle
of the spectrum: children with snoring and important
but subtle and nonspecific behavioral and neurocog-
nitive daytime symptoms (see Fig. 1). A clear result
of this shift is the recognition that current approaches
to the identification and diagnosis children with
obstructive SDB are inadequate and much in need
of revision and standardization.
Childhood obstructive sleep-disordered breathing
A growing body of evidence suggests that the
traditional diagnosis of childhood OSAS encom-
passed only a small proportion of children with SDB
[13,15,36]. Nearly all of the existing literature on
childhood obstructive SDB is based on arbitrary, non-
validated criteria for classic OSAS and primary snor-
ing that were borrowed from the adult medical
literature decades ago, however. To complicate matters
further, even in the ‘‘classic’’ childhood OSA litera-
ture, data are highly variable because of lack of stan-
dardized definitions and diagnostic criteria [37,38].
Definitions
Discussion of childhood obstructive SDB should
start with the definition. Currently, however, there is
no standard, widely accepted definition. Given that
clinical symptoms can result from the entire spectrum
of childhood obstructive SDB, it seems reasonable to
consider classical OSAS, obstructive hypoventilation,
and snoring with daytime symptoms (UARS) as
manifestations of the same underlying pathophysiol-
ogy, under the heading ‘‘childhood obstructive SDB.’’
Currently, there are no officially endorsed diagnostic
criteria for childhood SDB similar to those published
for adult OSAS [39]. Although a ‘‘consensus confer-
ence’’ on childhood OSAS was held in the early 1990s
263
[1], an evidence-based ‘‘definitions conference,’’ sim-
ilar to the one convened to clarify definitions of adult
SDB [40], has never been organized.
Childhood obstructive SDB may be defined as a
disorder of breathing during sleep characterized by
prolonged increased upper airway resistance, partial
upper airway obstruction, or complete obstruction
that disrupts pulmonary ventilation, oxygenation, or
sleep quality. Nighttime manifestations include some
combination of snoring, increased respiratory effort,
episodic hypoxemia, CO2 retention, restless sleep,
and increased numbers of arousals and awakenings
from sleep. Daytime symptoms include excessive
daytime sleepiness, daytime tiredness, fatigue, poor
school performance, inattention, hyperactivity, oppo-
sitional behavior, and other subtle behavioral distur-
bances. This definition, modified from the American
Thoracic Society definition [1], encompasses all
childhood SDB diagnoses, including childhood
OSAS, obstructive hypoventilation, and UARS.
Because there is no consensus on diagnostic
criteria, practitioners are still faced with basic, fun-
damental questions, such as ‘‘What are the diagnostic
criteria for obstructive SDB in children?’’ ‘‘How to
identify children with obstructive SDB?’’ ‘‘What are
the indications for testing?’’ ‘‘What are the appropri-
ate methods of testing?’’ ‘‘What are the indications
for treatment (including avoidance of future morbid-
ity)?’’ ‘‘What are the short- and long-term outcomes
of treatment versus no treatment?’’ It is particularly
important for parents, teachers, family practitioners,
pediatricians, and third-party payors to discard the old
‘‘mindset’’ of childhood obstructive SDB manifesting
only as severe nighttime airway obstruction or overt
daytime sleepiness [41,42].
Epidemiology
The prevalence of snoring ‘‘often’’ or ‘‘nightly’’
(so-called ‘‘habitual snorers’’) ranges from 3.2% to
21% in children [2 – 4,6 – 9,43,44], and little is known
about the natural history of snoring in children. Ali et
al studied the natural history of snoring in a group of
children from age 4 to 7 years and found that the
overall prevalence of snoring did not change (12.1%
in 1989 – 1990 versus 11.4% in 1992) [5]. More than
half of the children who snored habitually at age 4 to
5 no longer did so by age 7, however. Although the
overall prevalence of daytime sleepiness decreased
with age, hyperactivity, excessive daytime sleepiness,
and restless sleep were more common in snoring
children compared with children who reported never
snoring. The prevalence of snoring in adolescents
and adults is higher than that reported for preadoles-
264 J.L. Carroll / Clin Chest Med 24 (2003) 261–282
cent children, which suggests that snoring increases
with age.
Nothing is known about the prevalence of UARS
in children. The prevalence of ‘‘classic’’ childhood
OSAS is believed to be approximately 1% to 3% and
occurs in children of all ages. In children with normal
craniofacial structure, the peak incidence occurs
between approximately 3 and 6 years of age, which
corresponds to the age range when upper airway
lymphoid tissue enlargement, relative to craniofacial
size, is greatest [45]. OSAS seems to be more
frequent in African-American children, children with
respiratory disease, obese children, and children with
a family history of OSAS [46]. It is unclear whether
gender is a predisposing factor for OSAS in children.
Clinical features
Nighttime symptoms
Snoring is the most common nighttime symptom
of OSAS in children. The snoring sounds made by
children may have a higher pitched, more guttural, or
harsh sound than classic ‘‘nasal’’ snoring, however,
and some parents may not identify their child’s noisy
breathing during sleep as snoring. Simple questions
such as ‘‘Does your child snore?’’ may fail to identify
children with significant SDB. Parents usually do not
sleep in the same room as the child and may be
unaware of the child’s breathing sounds and pattern
during sleep.
Children may exhibit the classic adult pattern of
continuous snoring interrupted by pauses. In children,
however, OSAS tends to occur mainly in rapid eye
movement (REM) sleep; therefore, the snoring or
pauses may be absent for significant periods of the
night. Children with SDB also tend to exhibit a pattern
of prolonged partial upper airway obstruction and may
have few or even no complete obstructive apneas
[42,47]. Children may manifest SDB by making other
sounds, such as stridor, snorting, gasping, or grunting.
Loud gasping often accompanies arousals after
obstructive episodes. Children with SDB may have
obviously increased respiratory effort, which is often
manifested as paradoxical inward rib cage motion, and
some parents may describe this as ‘‘struggling’’ to
breathe during sleep [30]. Paradoxical inward rib cage
motion is normal in children during REM sleep until
age 3. Cyanosis is rarely observed by parents, even in
cases of severe childhood OSAS.
Sleep disturbances caused by SDB may be man-
ifested as restless sleep, increased movement during
sleep, ‘‘bed thrashing,’’ frequent arousals (sometimes
accompanied by gasping noises), frequent awakening,
and unusual sleeping positions (eg, sitting, propped up
on pillows). Other signs may be observed, such as
increased sweating during sleep or sleeping with the
neck hyperextended. Although enuresis has been
associated with OSAS in children [48], subsequent
studies have not confirmed the association [8].
Daytime symptoms
The most prominent daytime symptom of SDB in
adults—excessive daytime sleepiness—is absent in
most children with polysomnography-proven OSAS
[30,49]. A recent study using multiple sleep latency
testing confirmed that most children with OSAS
do not exhibit excessive daytime sleepiness [50]. This
is a major difference between children and adults
with SDB.
If children with SDB are not overtly sleepy during
the day, what are their daytime symptoms? The ef-
fects of obstructive SDB on mental development in
children were well recognized more than 100 years
ago [51 – 53]. Studies from the early 1980s showed
that children with OSAS may exhibit daytime behav-
iors, such as pathologic shyness, social withdrawal,
hyperactivity, aggressiveness, tiredness, and fatigue
[31,33,35,49,54]. Older children were reported to
exhibit lethargy, excessive ‘‘daydreaming,’’ rebellious
behavior in school, ‘‘phasing out,’’ ‘‘lapses’’ in aware-
ness, or being unresponsive to questions [31,54].
Numerous more recent studies of symptoms [6,24,
25,55 – 62] and objective measures [20,21,24,56,63]
have confirmed and expanded early observations that
SDB in children is associated with behavioral symp-
toms or impaired cognitive or school performance (eg,
the 1998 study by Gozal [21]). In children with classic
OSAS, there is clearly an important association be-
tween SDB, poor school performance, and other man-
ifestations of impaired daytime cognitive function.
The larger question is whether similar daytime
neurocognitive impairment occurs in children with
SDB who do not meet the criteria for classic OSAS.
Twenty years ago, Guilleminault et al reported on 25
children with heavy snoring and daytime symptoms,
including abnormal behavior and excessive daytime
sleepiness, but without OSA or oxygen desaturation
on polysomnography [31]. In every case, tonsillec-
tomy or adenoidectomy resulted in improvement or
complete disappearance of daytime symptoms [31].
Other studies also suggested that snoring children who
did not fit criteria for classic OSAS, may have clini-
cally significant daytime dysfunction (UARS) [27,36].
Morning headaches have been reported by several
authors to be a symptom of childhood OSAS, al-
 J.L. Carroll / Clin Chest Med 24 (2003) 261–282 265

though one of the few controlled studies of childhood

Box 1. Predisposing factors for childhood
OSAS did not confirm this association [49]. Compar-
obstructive sleep apnea syndrome
ison of children who underwent adenoidectomy with
‘‘normal’’ controls also revealed no difference in the
Nasal Rhinitis
incidence of morning headaches [64]. Daytime mouth
Nasal polyps
breathing is a common finding in children with
Adenoid hypertrophy
adenotonsillar hypertrophy and is a common finding
Pharyngeal flap surgery
in OSAS.
Nasal stenosis
Because children may have significant daytime
Choanal atresia
symptoms (eg, neurocognitive impairment, behavioral
Pharyngeal Tonsil enlargement
abnormalities, poor school performance, poor growth)
Micrognathia
even if the polysomnography does not indicate OSAS,
Retrognathia
is it unfortunate that the 2002 Academy of Pediatrics
Lingual tonsil
(AAP) Clinical Practice Guideline for Diagnosis and
enlargement
Management of Childhood Obstructive Sleep Apnea
Cleft palate repair
simply recommends ‘‘further clinical evaluation and
Airway narrowing
treatment as warranted’’ for such a child [65].
caused by obesity
Although the prevalence of UARS in children is
Tissue infiltration (eg,
unknown, data from a large study of children referred
mucopolysaccharidoses)
to a pediatric sleep center suggested that UARS may be
Laryngeal Laryngeal web
present in most children referred for snoring [36].
Subglottic stenosis
Presentation of childhood SDB as UARS seemed to
Vocal cord paralysis
be much more common than classic OSAS [36].
Laryngomalacia
Laryngeal masses
and tumors
Predisposing factors for childhood obstructive
Inflammation caused
sleep apnea syndrome
by gastroesophageal
reflux
Obesity
Neurologic Cerebral palsy
Arnold-Chiari
Although obesity predisposes to sleep-related
malformation
upper airway obstruction in children, most children
Pharmacologic Sedation
with OSAS are not obese. A study of OSAS in obese
Anesthesia
Singapore children estimated the prevalence to be
Other Allergy/atopy
5.7% overall and 13.3% in morbidly obese children
Cigarette smoke
(percent ideal body weight >180) [66]. Redline et al
exposure
found obesity to be a significant risk factor (odds
Sleep deprivation
ratio, 4.59; 95% confidence interval 1.58 to 13.33)
for OSAS in children and adolescents [46], and
numerous studies have found that obese children
are overrepresented in groups of children referred achondroplasia, Arnold-Chiari syndrome, and myelo-
for suspected OSAS [42]. meningocele. SDB is common in children with
cerebral palsy [67]. Any syndrome or disorder that
Other factors affects one or some combination of upper airway
structure, airway muscle tone, upper airway muscle
Snoring increases during upper respiratory tract control, or sleep may predispose to OSAS in children.
infection in children. Various nasal, oropharyngeal, Obstructive sleep apnea syndrome in children with
laryngeal, and neurologic problems also may predis- Down syndrome is especially noteworthy. Marcus et al
pose to sleep-related airway obstruction (Box 1). A found a high incidence of OSAS in patients with Down
long list of syndromes and other medical conditions syndrome 2 weeks to 52 years of age, even in persons
are known to be associated with an increased inci- in whom it was not clinically suspected [68]. Children
dence of childhood OSAS. Major genetic syndromes with Down syndrome also tend to have significant
and disorders associated with SDB in children sleep fragmentation that is only partly explained by
include Down syndrome, Prader-Willi syndrome, SDB [69]. Practitioners should have a low threshold
266 J.L. Carroll / Clin Chest Med 24 (2003) 261–282

for performing a detailed sleep assessment in patients
with Down syndrome.
Complications of obstructive sleep apnea
syndrome in children
Growth
Growth impairment is a well-documented com-
plication of OSAS in children. OSAS may result in
failure to thrive. Not all children with growth impair-
ment caused by SDB are below the fifth percentile on
growth charts for height or weight, however. Some
children with SDB demonstrate increased growth
velocity after adenotonsillectomy, even if they were
not less than fifth percentile before surgery [22,23,70].
From a practical point of view, SDB should be con-
sidered in any child with questionable weight gain or
stature and snoring.
Cardiovascular complications
It has been known for five decades that severe
OSAS in children may lead to congestive heart failure
and cor pulmonale. In the 1950s, childhood OSAS
was diagnosed mainly by cardiologists and endocri-
nologists when children presented in heart failure or
severe growth impairment. The more relevant ques-
tion currently is whether milder forms of childhood
SDB are associated with cardiovascular morbidity.
Tal et al, using radionuclide ventriculography to
study children with OSAS, found significant reduc-
tions in right ventricular ejection fraction that were
reversible after adenotonsillectomy [71]. Children
with polysomnographic-proven OSAS have been
shown as a group to have higher diastolic blood
pressures compared with children with snoring but
without OSAS [72]. Amin et al recently reported
abnormal left ventricular geometry in approximately
40% of children with OSA and approximately 15% of
children with snoring alone [73]. Whether such
changes are a precursor for cardiovascular disease
in adults remains to be determined.
Mortality
The mortality rate for childhood SDB or OSAS is
unknown. Death during sleep caused by OSAS in
children is apparently rare, and most deaths are
believed to be perioperative after adenotonsillectomy.
Children with unrecognized OSAS and cardiovascu-
lar compromise may decompensate during general
anesthesia [74,75]. Death caused by OSAS may occur
after surgical correction of velopharyngeal incompe-
tence [76].
Pathophysiology of childhood obstructive sleep
apnea syndrome
Sleep-related airway obstruction
Given the wide variety of predisposing factors for
childhood SDB, no single pathophysiology accounts
for all cases (Fig. 2). Sleep-related upper airway

Fig. 2. Pathophysiology of childhood SDB. Any one factor alone (eg, adenotonsillar hypertrophy) may not be sufficient to cause
obstructive SDB. The same degree of hypertrophy may cause SDB when combined with predisposing factors such as abnormal
arousal mechanisms, decreased neural drive to upper airway muscles, or abnormal load compensation mechanisms, however.
 J.L. Carroll / Clin Chest Med 24 (2003) 261–282
obstruction in children is not simply a matter of big
tonsils and adenoids; it is dynamic airway collapse
related to muscle tone, motor control, and structure.
Children with SDB do not exhibit upper airway
obstruction while awake, which indicates that sleep-
related dynamic factors responsible for maintaining
airway patency are involved. The other clear evidence
in support of this view is that OSAS in children is
highly state related and occurs largely during REM
sleep [77]. A child with severe REM-related OSAS
may have minimal upper airway obstruction during
non-REM sleep, which indicates that state-related
upper airway control plays a major role.
Numerous studies have failed to find a simple
relationship between adenotonsillar size (or volume)
and the occurrence of OSAS in children. This has led
to the speculation that children who develop OSAS
must have an underlying abnormality of upper airway
structure, muscle tone, or upper airway reflex muscle
control [13,78,79]. In otherwise normal children with
OSAS the current view is that adenotonsillar hyper-
trophy causes airway narrowing that, when super-
imposed on subtle abnormalities of upper airway
motor control or tone (neural drive), leads to clin-
ically significant dynamic airway obstruction during
sleep (see Fig. 2) [79].
Daytime symptoms and complications
The pathologic mechanisms underlying daytime
symptoms of childhood OSAS are unknown,
although intermittent hypoxia and sleep fragmenta-
tion likely play a role [19]. Snoring children without
OSAS may have debilitating daytime symptoms.
Conversely, children with severe OSAS and severe
hypoxemia during sleep may have minimal daytime
symptoms. Proposed mechanisms have included
sleep disruption or fragmentation, nighttime hypox-
emia, hypoxia, or sleep fragmentation – induced
alterations in brain neurochemistry, inflammation,
hormonal changes caused by sleep fragmentation or
deprivation, and changes in cerebral blood flow
caused by blood gas changes or altered cerebral
perfusion pressure [15,19]. In reality, how childhood
SDB leads to complex behavioral and neurocognitive
derangements remains unknown. Additional research
in this area is critically important to determine appro-
priate thresholds for the treatment of various aspects
of childhood SDB.
Complications of SDB, such as cardiovascular
compromise, hypertension, and growth failure or
impairment, are likely caused partly by known effects
of intermittent hypoxia during sleep [73,80]. Large
swings in intrathoracic pressure may affect cardiac
267
afterload directly, hypoxemia or sleep fragmentation
may affect brain neurochemistry in cardiovascular
control areas, and growth hormone secretion may be
affected by sleep fragmentation. Potential mecha-
nisms by which intermittent hypoxia may lead to such
derangements recently were reviewed in detail [81].
Relationship between childhood sleep-disordered
breathing and attention deficit disorders
Children with attention deficit hyperactivity dis-
order (ADHD) have difficulty sustaining attention,
attending to details, finishing tasks, listening to
others, and organizing behaviors. These children are
easily distracted, forgetful, and impulsive and have
difficulty sitting still. Reported symptoms of child-
hood SDB include hyperactivity, inattention, im-
pulsive behavior, and oppositional behavior. It is
reasonable to assume that SDB in some children
may exacerbate ADHD or that some children with
hyperactivity caused by SDB may be misdiagnosed as
having ADHD. The possible relationship is strength-
ened by the observation that children with ADHD
have high rates of sleep complaints and disturbances.
The medications used to treat ADHD also can inter-
fere with sleep, and the behavior problems manifested
by these children may interfere with sleep hygiene.
There is evidence that children diagnosed with
ADHD have increased rates of snoring or sleep
disturbances, such as periodic limb movement dis-
order [55 – 57,82 – 84]. Although the precise relation-
ship between SDB and ADHD is unknown, because
of the symptom overlap, snoring children with a
diagnosis of ADHD are commonly evaluated for the
possibility that SDB is causing or exacerbating their
behavioral symptoms.
Polysomnographic findings in childhood
obstructive sleep-disordered breathing
Procedure and limitations
Polysomnography originally was developed for
adults and later adapted for use in children. As a
diagnostic test for childhood SDB, polysomnography
has numerous shortcomings. Polysomnography
focuses heavily on breathing during sleep, with only
a few crude measures of sleep quality. More impor-
tantly, no studies have documented the relationship
between anything measured by polysomnography
and daytime sleepiness, impaired neurocognitive
function, behavioral abnormalities, or other adverse
outcomes related to SDB in children. Finally, no
268 J.L. Carroll / Clin Chest Med 24 (2003) 261–282
studies have validated whether polysomnography has
any ability to predict which children need (or do
not need) treatment to avoid adverse clinical conse-
quences. One of the few studies that examined this
question reported that conventional polysomno-
graphic scoring criteria failed to identify children
with significant sleep-related upper airway obstruc-
tion [47]. Classic scoring and interpretation of poly-
somnography for children does not identify children
with UARS.
Polysomnography, although considered by many
to be the ‘‘gold standard,’’ is one of several poorly
validated tests for childhood SDB. The ability of
polysomnography to identify children at risk (or
not) for significant adverse clinical outcomes is
unknown. In reality, most children who undergo
adenotonsillectomy for apparent symptoms of child-
hood SDB do not receive any diagnostic studies. For
the small fraction of children who are tested before
adenotonsillectomy for ‘‘obstructive symptoms,’’
practitioners in pediatric sleep laboratories worldwide
use different clinical and laboratory testing proce-
dures and diagnostic criteria.
Guidelines for polysomnography in children were
published by the American Thoracic Society based
on a consensus of opinion in the early 1990s [1].
Because of a lack of data on polysomnography in
children at that time, however, the guidelines are not
definitive. After an exhaustive review of the litera-
ture, the 2002 AAP Technical Report on the Diagnosis
and Management of Childhood Obstructive Sleep
Apnea Syndrome concluded that the ‘‘gold standard’’
is poorly validated and that normative standards for
polysomnography in children have not been shown to
have any validity as predictors of the occurrence
complications [37]. Because the scope of childhood
SDB has been expanded beyond OSAS to include
UARS, the use of polysomnography as a ‘‘gold
standard’’ becomes even more dubious because of
its heavy focus on breathing and minimal measures of
sleep quality.
Most pediatric laboratories record standard elec-
troencephalogram leads for sleep staging, chest/abdo-
men motion by strain gauges or respiratory inductance
plethysmography, extraoccular muscle electromyo-
gram, submental and limb electromyogram, electro-
cardiogram, a measure of nasal/oral airflow (eg,
thermistor), pulse oximetry, and a method of detecting
CO2 retention (end-tidal or transcutaneous CO2).
Some laboratories include esophageal pressure mon-
itoring for detection of UARS [36]. With the
expanded scope of clinically significant SDB, much
more research is needed on methods for identification
and diagnosis of children with all forms of SDB,
particularly methods that do not meet criteria for
classic childhood OSAS.
What is normal?
The field of childhood obstructive SDB includes
the following major problems: (1) ‘‘Normal’’ has
never been defined with respect to childhood obstruc-
tive SDB. (2) Normative data are not available for
many polysomnographic measures. (3) Existing nor-
mal values are limited to classic OSAS. During the last
two decades, when most studies on childhood SDB
were conducted, snoring was believed to be ‘‘benign’’
and the behavioral symptoms of SDB were unrecog-
nized. Although normal polysomnographic values for
children and adolescents were published in a landmark
paper by Marcus et al [26], that study included snoring
children and possibly included children with UARS.
Currently, polysomnographic diagnostic criteria for
childhood UARS have not been developed, and nor-
mal polysomnographic values for asymptomatic, non-
snoring children are lacking. In the discussion that
follows, where possible, normative polysomnographic
values were extracted from the asymptomatic control
groups of several studies.
Sleep
Pediatric sleep laboratories analyze polysomno-
graphic data to derive arousal index (arousals/hour of
sleep time), sleep efficiency (time asleep/time in bed),
number of awakenings per hour, and time spent in
stages 1, 2, 3, 4 non-REM sleep and REM sleep. No
data exist on the relationship between sleep architec-
ture variables and daytime symptoms or other adverse
outcomes of childhood SDB, however. The positive
and negative predictive values of polysomnographic
sleep data are simply unknown.
Arousal index was reported by Goh et al to be
5/hour F 2/hour (mean F SD) in ten nonsnoring,
prepubertal children [77]. Guilleminault et al, in 36
asymptomatic prepubertal children with no evidence
of SDB, reported an electroencephalogram arousal
index of 2.7/hour F 1.9/hour [85]. These data suggest
that an arousal index of ten or more arousals/hour is
clearly outside of the normal range for asymptomatic
children (excluding infants). Goh el al found that
sleep efficiency was 84% F 13% (mean F SD) in
nonsnoring control children and that sleep architec-
ture, with respect to sleep stages and sleep efficiency,
was the same in nonsnoring controls versus children
with polysomnographically proven OSAS [77]. Mean
arousal index reported for children with classic OSA
was 11/hour F 4/hour in the study of Goh et al but
 J.L. Carroll / Clin Chest Med 24 (2003) 261–282 269

ranged from 2.5/hour up to 17/hour in other studies
[27,30,77,86]. Although it seems that normal children
should have an arousal index of less than ten
arousals/hour, some children with classic OSAS have
an arousal index within the normal range. Because
excessive daytime sleepiness and various other
daytime symptoms are known to occur in children
with UARS and OSAS, either current polysomno-
graphic techniques fail to detect significant sleep
disruption in children or other mechanisms underlie
these daytime symptoms.
Breathing pattern
Respiratory rate is usually normal in children with
OSAS unless they have lung disease or breathing
control abnormalities. Children with classic OSAS
exhibit obstructive apnea and hypopnea, defined
essentially as they are for adults except for duration.
In children, artificial time limits (eg, 10 seconds) are
usually not placed on obstructive apnea or hypopnea.
A standard approach is to consider significant any
obstructive episode that lasts longer than two respi-
ratory cycle times [87]. Young children may exhibit
oxygen desaturation with apnea as brief as 3 to
5 seconds. Fig. 3 shows classic OSA in a 4-year-
old boy that consisted of no airflow for 20 seconds
while paradoxical respiratory efforts continued. This
event was accompanied by a fall in oxygen saturation
from 96% to less than 80%. Fig. 4 shows a 2-minute
sample from the same child’s polysomnograph,
which indicates repetitive obstructive apnea associ-
ated with a ‘‘saw tooth’’ pattern of oxygen desatura-
tion and five arousals in 2 minutes. Children with
OSAS may exhibit obvious patterns of obstruction
similar to that observed in adults, and in such cases,
the diagnosis is not difficult.
One of the most remarkable findings in childhood
OSAS is the clustering of events in REM sleep [77]. It
is common in childhood OSAS to find most obstruc-
tive apnea, hypopnea, hypoxemia, or hypercarbia
occurring during REM sleep. Fig. 5 shows a 1-minute
sample from an 8-year-old child with obstructive
hypoventilation. This child had a normal apnea-
hypopnea index, with only two obstructive apneas
the entire night, yet during each REM period he
exhibited severe obstructive hypoventilation without
any complete obstructive apnea. As shown in the
figure, end-tidal CO2 exceeded 76 mm Hg and oxygen
desaturation was moderately severe despite continued

Fig. 3. Typical obstructive apnea in a 4-year-old boy. (A) Absence of flow in end-tidal CO2 tracing. (B) Paradoxical inward rib
cage motion during period of airway obstruction. (C) Oxygen desaturation from 96% at the beginning to approximately 75% by
the end of the obstructive apnea. (D) Arousal from sleep at end of obstructive apnea.
270 J.L. Carroll / Clin Chest Med 24 (2003) 261–282

Fig. 4. Repetitive obstructive apnea in a 4-year-old boy. (A) Obstructive apnea with absent airflow. (B) Paradoxical inward
rib cage motion during airway obstruction. (C) In phase rib cage and abdomen motion during nonobstructed breathing.
(D) Oxygen desaturation from 98% at the beginning to less than 75%. (E) Arousal from sleep at end of obstructive apnea.
There were five arousals during the 2-minute period. Note ‘‘sawtooth’’ pattern of severe oxygen desaturation after each ob-
structive apnea.

Fig. 5. Continuous obstructive hypoventilation. (A) No interruption of oronasal airflow. (B) Continuous paradoxical inward rib
cage motion. (C) End-tidal CO2 between 72 and 76 mm Hg. (D) Oxygen saturation 84% to 88% without recovery to normal.
This child, despite severe hypoventilation and persistent hypoxemia, simply would seem to be snoring if observed by parents
during sleep.
 J.L. Carroll / Clin Chest Med 24 (2003) 261–282
airflow with each breath. It is generally accepted that
some measure of CO2 is necessary to detect obstruc-
tive hypoventilation in children, and many pediatric
sleep laboratories measure end-tidal CO2.
Sleep-related upper airway obstruction may be
worse during the second half of the night [77]. A
significant proportion of children with classic OSAS
exhibit most of their obstructive episodes during the
second half of the polysomnograph. This has several
important implications. First, brief studies (eg, nap
studies) are relatively insensitive for detecting OSAS
in children [88]. Second, unless parents stay up or
wake up to observe their child sleeping during the
second half of the night, they may be unaware of the
severity of their child’s SDB. Finally, any attempt to
perform ‘‘split night’’ studies (eg, continuous positive
airway pressure [CPAP] titration during the second
half of the polysomnograph) results in a high prob-
ability of missing the child’s worst SDB.
By definition, children with UARS do not exhibit
hypoxemia, hypercapnia, or obstructive apnea during
sleep, although they may snore and may seem to have
increased respiratory effort or disrupted sleep. The
diagnosis of childhood UARS is controversial cur-
rently, and there are no diagnostic standards. The most
comprehensive study to date indicated that children
with UARS exhibit several patterns of sleep-related
increased respiratory effort that are best detected using
esophageal pressure monitoring [13,36,78]. Children
may not tolerate esophageal pressure monitoring, and
more research is needed to determine the best methods
and criteria for diagnosis of UARS in children.
Hypoxemia
Oxygen saturation measured by pulse oximetry
during sleep generally remains approximately 95% or
more in children [26,77], and numerous studies have
reported oxygen desaturation in children with classic
OSAS. Children with OSAS or obstructive hypoven-
tilation may experience episodic or continuous hypox-
emia during sleep that can range from minimal to
severe. Most pediatric sleep laboratories record oxy-
gen saturation continuously all night using pulse
oximetry (SpO2) and report nadir SpO2, respiratory
events associated with oxygen desaturation more than
4%, and percent of total sleep time spent with SpO2
less than 90%, 92%, or other threshold values. It is
generally assumed that hypoxemia is bad for children
and oxygen saturations less than 90% or 92% are
considered harmful. The positive or negative predic-
tive values of polysomnographic oximetry data in
children are unknown, however. Oxygen saturation
during sleep is normal in children with UARS.
271
Hypercapnia
Normal children maintain end-tidal CO2 less than
53 mm Hg and do not spend more than 10% of total
sleep time with an end-tidal CO2 more than 50 mm
Hg according Marcus et al [26,77]. As seen in Fig. 5,
some children exhibit obstructive hypoventilation
without apnea. Other children present a mixed picture
of obstructive apnea, hypopnea, and elevated end-
tidal CO2. As with hypoxemia, numerous studies
have reported hypercapnia in children referred for
suspected OSAS [30,35,47]. These groups are highly
selected, and the actual prevalence of hypercapnia in
children with obstructive SDB is unknown. Obese
children and children with genetic abnormalities may
be more likely to exhibit sleep-related hypercapnia.
Silvestri found that three quarters of obese children
with OSAS were hypercapneic during sleep [89].
These authors reported that OSAS with hypercapnia
was significantly more likely if weight was 200% or
more than ideal body weight.
Scoring polysomnography for childhood obstructive
sleep apnea syndrome
There are no widely accepted standardized guide-
lines or diagnostic criteria for classic OSAS in
children. The 2002 AAP Clinical Practice Guideline
for the Diagnosis and Management of Childhood Ob-
structive Sleep Apnea Syndrome [37,65] acknowledg-
ed that polysomnography remains unvalidated. The
AAP technical report on childhood SDB [37] states:
‘‘It is assumed that PS is a benign condition and
OSAS is associated with undesirable complications.
Normative standards for their polysomnographic
determination have been chosen on the basis of
statistical distribution of data, but it has not been
established that those standards have any validity as
predictors of the occurrence of complications.’’
The AAP Clinical Practice Guideline [65] sum-
marizes their findings by stating that in children:
‘‘Although we know which polysomnographic
parameters are statistically abnormal, studies have
not definitively evaluated which polysomnographic
criteria predict morbidity.’’
Pediatric sleep laboratories choose threshold val-
ues, usually based on the ATS standards for cardio-
respiratory sleep studies in children [1], that they
consider to be diagnostic or strongly suggestive of
significant childhood SDB (typical values shown in
Box 2). Polysomnography also yields data on the se-
verity of the sleep-related airway obstruction, hypox-
272 J.L. Carroll / Clin Chest Med 24 (2003) 261–282
Box 2. Abnormal values on pediatric
polysomnography (example)
Obstructive apnea index (AI) >1/h
Apnea-hypopnea index >5/h
Peak end-tidal CO2 >53 mm Hg
End-tidal CO2 >50 mm Hg for >10%
of total sleep time
Minimum SpO2 < 92%
emia, hypercapnia, and degree of sleep disruption.
Severity criteria have been shown to correlate with the
probability of postoperative complications [90 – 95]
and response to treatment [96].
Scoring polysomnography for childhood upper
airway resistance syndrome
Currently there are no polysomnographic criteria
or guidelines for diagnosing UARS in children. By
definition, children with UARS do not meet criteria
for classic OSAS (see Box 2). Guilleminault et al
recommend esophageal pressure monitoring during
polysomnography to diagnose several distinct patterns
of increased respiratory effort during sleep in children
with UARS [13,36,78]. There are no widely accepted,
validated standards for interpretation of esophageal
pressure measurements on polysomnography, how-
ever, and their diagnostic and predictive value (of
adverse outcome) has not yet been determined. Some
adult sleep laboratories measure respiratory effort-
related arousal index [97]. There are no evidence-
based guidelines for respiratory effort-related arousal
index use in children. Some pediatric sleep labora-
tories, based on experience, determine a threshold for
nocturnal awakenings (eg, <1/hour), arousal index
(eg, <10/hour), and sleep efficiency (eg, >80%) and
consider these ‘‘suggestive’’ of UARS when
exceeded. Finally, even if polysomnography is ‘‘nega-
tive’’ for classic OSAS, the interpreter often can get a
strong impression of increased upper airway resist-
ance from viewing the video/audio tape, reviewing the
technician’s comments, and reviewing the tracings.
Such values and impressions are not evidence-based,
however, and in reality, UARS in children remains an
individualized clinical diagnosis based on judgment
and experience.
Other diagnostic tools for childhood obstructive
sleep apnea syndrome detection
Various alternatives to polysomnography for diag-
nosis of classic OSAS in children have been pro-
posed, including simple video or audiotaping and
analysis of snoring patterns. Videotaping a child at
home can be useful if it shows obvious sleep-related
upper airway obstruction. Simple videotaping by
parents does not allow assessment of severity and
provides no data on degree of hypoxemia. Unless the
parents happen to film the child during REM sleep,
significant SDB easily can be missed. Sivan et al
studied the predictive value of video, taken by parents
of their sleeping child, for diagnosing childhood
OSAS [98]. The authors analyzed a 30-minute video-
tape for noisy breathing, movement, arousals, and
other signs of OSAS. The results of the videotape
analysis correlated with polysomnography diagnosis
of classic OSAS in 84% of cases. This study did not
address the important issue of UARS, however.
Simple audio recordings, although touted by some
as useful for detecting SDB in children, are probably
not useful and may be misleading. A recent study that
compared home audiotape analysis with polysomno-
graphy found that the sensitivity rate of audiotape for
diagnosis of OSAS was only 46% [99].
A more sophisticated video-based home sleep
study methodology was described by Brouillette
et al [100 – 103]. These authors developed a home
sleep study system that uses a simple cardiorespira-
tory montage (EKG, respiratory inductance plethys-
mography, SpO2) combined with videotaping. The
videotapes are analyzed using a computerized move-
ment detection system. This system’s ability to detect
OSAS in children with adenotonsillar hypertrophy
has been validated relative to polysomnography and
it has several advantages. The child can be studied in
his or her natural sleeping environment at home and
there are no leads or sensors on the face. The utility of
this system for diagnosis of UARS is unknown, and
the authors are careful to point out that this system is
not appropriate when detailed information on sleep
staging, ventilation, or respiratory muscle function is
required. Once fully validated with respect to daytime
symptoms of UARS and OSAS, it may prove to be an
alternative to polysomnography.
Other home study approaches, which range from
overnight oximetry to complex multichannel record-
ings, recently were reviewed by the AAP subcom-
mittee on OSAS [37]. Oximetry alone should be used
with caution, although it may provide useful screen-
ing information [90,104,105]. A ‘‘negative’’ over-
night oximetry study does not rule out significant
sleep disturbance, hypoventilation, or significant
increased upper airway resistance. All of these meth-
ods currently suffer from the same shortcomings as
full polysomnography; that is, they lack ability to
predict daytime symptoms, complications, and other
 J.L. Carroll / Clin Chest Med 24 (2003) 261–282
adverse outcomes, and threshold levels of abnormal-
ity that merit treatment remain unknown.
In summary, there is no ‘‘gold standard’’ for the
diagnosis of childhood SDB (UARS and OSAS). As
Ali and Stradling recently observed, polysomnogra-
phy is not the ‘‘gold standard’’ methodology against
which other techniques must be compared, it is
simply the oldest [106]. Polysomnography can
identify statistically abnormal breathing that suggests
classic OSAS, but it is certainly not a ‘‘gold stan-
dard’’ for diagnosis of UARS in children. As new
approaches to the diagnosis of childhood SDB are
developed, critical evaluation and validation—par-
ticularly with respect to their ability to predict clinical
symptoms, adverse outcomes, and response to treat-
ment—will be essential.
Tests for daytime symptoms of
sleep-disordered breathing
None of the subjective scales commonly used for
adults with SDB (eg, Epworth Sleepiness Scale) has
been validated for children. Quality-of-life assess-
ment tools, such as the Child Behavior Checklist,
OSA-18, and CHQ-PF50, may be valid for detecting
signs of impaired health or improvement in symp-
toms after adenotonsillectomy [107 – 111]. The diag-
nostic value of such tools is unknown for children.
Similarly, the Maintenance of Wakefulness Test also
has not been validated for children with SDB. Cur-
rently, the only standardized test for daytime sleepi-
ness in children is the multiple sleep latency test.
Diagnosis of childhood obstructive
sleep-disordered breathing
Presenting symptoms and signs
Children with obstructive SDB may present with
any combination of snoring, noisy breathing during
sleep, restless sleep, daytime fatigue, excessive day-
time sleepiness, abnormal or difficult behavior,
impaired school performance, attention problems,
developmental delay, and impaired growth. Children
with UARS may not even snore. The diagnosis of
obstructive SDB in children often requires a high level
of suspicion and detailed clinical history. The symp-
toms of childhood SDB clearly overlap with numer-
ous other potential causes, and they usually cannot be
attributed to SDB on the basis of history alone.
Excessive daytime sleepiness, the hallmark of
OSAS in adults, occurs in only a small proportion of
children with obstructive SDB. Children do present
273
with excessive daytime sleepiness as the chief com-
plaint, however, and may turn out to have UARS,
OSAS, idiopathic hypersomnia, narcolepsy, poor sleep
hygiene, some combination of the above diagnoses, or
various other causes of excessive daytime sleepiness.
History and physical examination
The value of clinical history for diagnosing classic
childhood OSAS has been questioned by numerous
studies [30,96,112 – 115], all of which were per-
formed before childhood UARS became widely
acknowledged. These studies, including one from
the author’s laboratory [30], examined the ability of
limited clinical history (focused mostly on breathing
symptoms and excessive daytime sleepiness) to dis-
tinguish classic OSAS from snoring without OSAS,
whereas the question of UARS was not addressed. In
retrospect it is likely that the ‘‘primary snoring’’
groups in such studies included children with UARS.
The relevant question is whether clinical history (or a
clinical ’’score’’ based on history/examination) has
predictive validity with respect to symptoms or com-
plications of childhood obstructive SDB (including
UARS). The answer to this question remains
unknown, and research in this area is critically
important for the field to advance toward a definitive
diagnostic approach.
Despite the limitations and controversy, the
evaluation for suspected SDB should begin with a
detailed history of the child’s sleep, breathing during
sleep, and daytime symptoms. Sleep history should
start by defining where the child sleeps in relation to
the caregiver being interviewed and the degree to
which the caregiver is aware of the child’s sleep
problems. This is not trivial. Parents may be unaware
of the child’s nightly sleep/breathing patterns (eg, the
child lives with grandmother, is brought by the
mother but lives five nights/week with the father)
or daytime symptoms (eg, at school). The same
parent will answer ‘‘no’’ to ‘‘does your child snore’’
and similar questions rather than reveal that he or she
simply does not know. Taking a detailed sleep/
breathing history of a child from adult caregivers is
fraught with pitfalls for the unwary. Suggested points
to cover in the history are outlined in Table 1.
Research is badly needed to develop validated,
age-specific, standardized questionnaire tools ca-
pable of identifying neurobehavioral abnormalities
and other symptoms or sequelae in children with
obstructive SDB.
Physical examination is also important for assess-
ing airway structure and exacerbating factors (Table 2).
The possible significance of abnormal craniofacial
274 J.L. Carroll / Clin Chest Med 24 (2003) 261–282

Table 1
Clinical history of the child with snoring and suspected sleep-disordered breathing
Sleeping environment Usual sleeping location; does child sleep in bed? age of mattress, type of pillow(s),
age of pillows, pillow/mattress covers? Bed sharing, room sharing, bed location,
distracting factors in sleeping environment (eg, television, outside noises, lights),
smoke exposure, pets in home
Sleep history Usual bedtime, bedtime behavior (eg, resistance), usual sleep onset time, nighttime
awakenings, parasomnias (sleep talking, walking, nightmares), usual sleeping
position, unusual sleeping positions, movement during sleep, enuresis (primary or
secondary), usual time of awakening, problems with awakening in morning
Snoring/breathing history Age at onset of snoring, frequency (nightly, most nights of week, only with upper
respiratory infection), proportion of night spent snoring, quality (pitch, harshness,
loudness, whether it disturbs others), pauses in snoring, observed struggle to breathe
or increased breathing effort during sleep, observed paradoxical inward rib cage mo-
tion, neck position (eg, hyperextended), parental interventions to improve breathing
(eg, change head position, prop up on pillows, awaken child)
Daytime symptoms Excessive daytime sleepiness: daytime sleepiness, inappropriate naps (for age),
falling asleep in school, inappropriately early bedtime (for age)
Behavioral/functional: cranky, irritable, oppositional, inattentive, hyperactive, poor
school performance, morning headaches, difficulty awakening in morning
Neurocognitive: loss of developmental milestones, poor school performance, mem-
ory problems, ‘‘blank’’ periods during day, oppositional behavior
Other: daytime mouth breathing, nasal obstruction, constant runny nose, frequent
sore throats, poor eating (likely related to tonsil/adenoid hypertrophy), poor growth,
allergies, nasal congestion
Medications Current medications, with focus on medications that may affect nasal resistance,
upper airway tone, or sleep quality; also important for planning polysomnography
(eg, medications that interfere with sleep)
Past medical and surgical history Previous airway manipulation (eg, intubation in neonatal intensive care unit),
previous airway surgery (adenoidectomy, tonsillectomy, uvulopalatopharyngoplasty),
previous cleft lip and/or palate repair, previous nasal surgery, recent weight gain,
thyroid or other metabolic problems
Family history Snoring, OSAS, UARS, obesity, family members on CPAP
Review of systems Thorough review of systems to elucidate any possible exacerbating factors (eg,
smoke exposure) or complications (eg, signs of cor pulmonale, congestive heart fail-
ure, seizures)

morphology and airway anatomy in childhood SDB
recently was reviewed [13,78]. Some children fall
asleep during the office visit and exhibit overt OSAS
or obviously abnormal upper airway resistance. Most
of the time, however, even children with severe OSAS
appear normal while awake. The visit is an opportu-
nity to observe the child for subtle signs of excessive
daytime sleepiness, developmental impairment, or
behavior problems.
Approaches to diagnosis of childhood obstructive
sleep-disordered breathing
Despite the confusion, lack of data, and lack of
validated diagnostic approaches, physicians still must
evaluate snoring children and recommend treatment.
The 2002 AAP Clinical Practice Guideline for Dia-
gnosis and Management of Childhood Obstructive
Sleep Apnea proposes an algorithm for diagnosis and
management of uncomplicated childhood OSAS [65].
The reader is referred to the AAP guidelines [65] and
the accompanying technical report [37] for extensive
review of evaluation options for snoring children.
The main highlights of those guidelines for diagnosis
are as follows: (1) all children should be screened for
snoring; (2) complex patients should be referred to a
specialist; (3) patients with cardiorespiratory failure
cannot await elective evaluation; (4) diagnostic evalu-
ation is useful to distinguish ‘‘primary snoring’’ from
OSAS; and (5) polysomnography is the ‘‘gold stan-
dard’’ [65].
Unfortunately, although the 2002 AAP technical
report [37] provided an outstanding review of the
research literature on childhood SDB, there are sig-
nificant gaps and limitations in the resulting AAP
Clinical Practice Guideline for Diagnosis and Man-
agement of Childhood Obstructive Sleep Apnea [65].
The guidelines acknowledge repeatedly that neuro-
 J.L. Carroll / Clin Chest Med 24 (2003) 261–282
Table 2
Physical examination of the child with snoring and suspected
sleep-disordered breathing
Examination Focus of examination
Vital signs Include height, weight, growth curve,
blood pressure
Body habitus Obesity, neck anatomy (eg, short neck)
Ear, nose, throat Emphasis on oropharyngeal size, tonsil
size (0 – 4+), adenoid enlargement,
nasal patency, evidence for chronic
nasal congestion, neck masses,
thyroid examination
Craniofacial Facial shape/features (eg, ‘‘adenoid’’
facies, long face), mid-face hypoplasia,
micrognathia, retrognathia, elongated
soft palate, small triangular chin,
steep mandibular plane, narrow
intermolar width
Cardiovascular Emphasis on signs of cor pulmonale
Other The remainder of the examination may
focus on features associated with SDB,
such as neuromuscular weakness,
spasticity, cerebral palsy, and other
associated conditions (eg, genetic)
cognitive impairment and behavior problems may be
a symptom or complication of childhood SDB, yet
they never explicitly acknowledge the existence of
UARS, nor do they provide any guidance in cases in
which the child is symptomatic but the ‘‘gold stand-
ard’’ polysomnography is ‘‘negative’’ for OSAS. The
current polysomnographic diagnostic criteria for
childhood OSAS are based on statistical norms (from
limited, small studies) and never have been shown to
have any diagnostic validity with respect to symptoms
or complications. Symptomatic snoring in children
who do not meet the current diagnostic criteria for
OSAS may be a common presentation of childhood
SDB [13,19,27,36,85]. Diagnosing classic OSAS
by polysomnography is easy when the polysomno-
gram is abnormal. When a symptomatic child’s poly-
somnogram does not demonstrate classic OSAS,
the AAP guidelines simply recommend ‘‘further clin-
ical evaluation and treatment as warranted,’’ which
leaves the practitioner without guidance for the most
difficult cases.
In reality, most children with snoring and daytime
symptoms of childhood SDB never see a sleep spe-
cialist; they are either referred to an otolaryngologist
or remain unidentified. For the snoring child with
daytime symptoms and enlarged tonsils or adenoids, it
has been argued that the diagnosis is likely UARS or
OSAS and polysomnography is not indicated [116].
The same author further suggested that polysomno-
275
graphy, as currently performed for children (without
esophageal pressure monitoring or detailed analysis of
sleep microarchitecture), does not detect UARS
anyway. The latter assertion has merit and should be
resolved with appropriate research studies. Adenoton-
sillectomy is a procedure with risk of morbidity and
mortality, however, and should not be undertaken
without the clearest diagnosis possible. The daytime
symptoms of childhood SDB, particularly neurobe-
havioral symptoms, are all nonspecific and possibly
the result of various causes. The major dilemma in
this field currently is that the so-called ‘‘gold stan-
dard’’ diagnostic test, traditional polysomnography,
fails to identify children with significant morbidity
caused by SDB (UARS).
Approaches to this diagnostic dilemma to date
have included measurement of esophageal pressure
during polysomnography to detect UARS [13,36],
attempts to detect increased ‘‘airway resistance’’
using nasal pressure measurements [117,118], use of
unvalidated locally derived criteria to diagnose
UARS, and surgical adenotonsillectomy without di-
agnostic testing. As acknowledged by the AAP
Clinical Practice Guideline for Diagnosis and Man-
agement of Childhood Obstructive Sleep Apnea [65],
there is currently a shortage of pediatric sleep labo-
ratories to perform polysomnography. For evaluation
of the snoring child, many if not most otolaryngolo-
gists only use polysomnography for children deemed
to be borderline or high risk for adenotonsillectomy
[18,116]. In the absence of guidelines, some pediatric
sleep laboratories make up diagnostic standards for
childhood UARS based on experience. For example,
in a symptomatic snoring child who does not meet
ATS criteria for classic OSAS, a diagnosis of UARS
may be made based on arousal index, number of awak-
enings, sleep efficiency, number of sleep stage shifts,
severity of snoring, technician observations of in-
creased respiratory effort, and ‘‘gut feeling’’ of the
interpreting physician. It is critically important to
develop unambiguous definitions, effective diagnostic
tools (including quality-of-life assessment, symptom
questionnaires, clinical scores), and validated guide-
lines for diagnosis of UARS in children.
Management of obstructive sleep-disordered
breathing in children
Despite the lack of diagnostic criteria for child-
hood SDB, practitioners must make difficult manage-
ment decisions. Which snoring child needs treatment
and which treatments are indicated? How should
polysomnographic data be used to guide treatment
276 J.L. Carroll / Clin Chest Med 24 (2003) 261–282

of obstructive SDB in children? What follow-up Table 3

measures are appropriate for the child with obstruc- Laboratory evaluation of the child with suspected sleep-
tive SDB? disordered breathing
The 1996 ATS Consensus Statement on Standards Type of test Test
and Indications for Cardiopulmonary Sleep Studies in To identify Lateral neck radiographs
Children outlined a few polysomnographic findings predisposing Laryngoscopy/bronchoscopy
that ‘‘should be considered abnormal’’ but stopped conditions Upper airway fluoroscopy
short of treatment recommendations. The 1996 con- Sleeping MR cine-fluoroscopy
sensus statement concludes with the following Cephalometric assessment
‘‘research question’’ [1]: of radiographs
To identify daytime Neuropsychological testing
‘‘Which PSG abnormalities (number of respiratory symptoms or Multiple sleep latency testing
events, cumulative hypercapnia, severity of desatu- complications Actigraphy
ration, and degree of sleep disruption) in infants and Maintenance of wakefulness testing
children with OSAS correlate with morbidity?’’ Electrocardiogram
Echocardiogram
The relationship of polysomnographic findings to Hematocrit
treatment was left as an open question because of a To determine Studies for screening or to provide
lack of data in 1992, when the conference actually diagnosis complementary information
took place. 10 years later, on the question of poly- Questionnaire or
somnography interpretation, the 2002 AAP Clinical history-based scores
Practice Guideline for Diagnosis and Management of Videotaping by parents
Audiotaping by parents
Childhood Obstructive Sleep Apnea [65] recom-
Overnight oximetry
mends following the ATS Consensus Statement [1] Daytime nap polysomnography
which did not provide guidelines for polysomno- Other: combinations of oximetry,
graphic interpretation with respect to treatment. In videotaping, other channels
other words, there are no accepted guidelines on how Diagnostic studies
to relate polysomnographic results to treatment deci- Conventional fully polysomnography
sions for children with obstructive SDB. Cardiorespiratory video system
Generally speaking, diagnostic criteria such as (see text)
those outlined in the previous box are used to deter- Some multichannel home
mine that polysomnographic results fall outside of study methodologies
the normal range. In reality, practitioners combine
‘‘abnormal polysomnographic results’’ with data
gleaned from history, physical examination, and other obstruction with fluticasone is promising, which
testing (Table 3) and make a decision based on clinical suggests that effective nasal steroid therapy may
judgment. On choice of treatment, the AAP 2002 suffice for some children with mild UARS or mild
Clinical Practice Guideline recommends the follow- OSAS. Further study of this approach is needed
ing: (1) Adenotonsillectomy is the first line of treat- before it can be recommended, however. Obese
ment for most children, and CPAP is an option for children with OSAS will benefit from weight loss
children who are not candidates for surgery or do not and adenotonsillectomy [120].
respond to surgery. (2) High-risk patients should be
monitored as inpatients postoperatively. (3) Patients Surgical treatment
should be reevaluated postoperatively to determine
whether additional treatment is required [65]. For otherwise normal children with adenotonsillar
hypertrophy and OSAS or UARS, the current surgical
Medical treatment treatment of choice is tonsillectomy and adenoidec-
tomy [65,96,121 – 125]. It is important to note, how-
Any child with obstructive SDB may show some ever, that adenotonsillectomy does not resolve
degree of improvement with nonsedating deconges- obstructive SDB fully in all children, particularly
tants or nasal steroid sprays. A recent study by children with severe preoperative symptoms. Some
Brouillette et al showed significant improvement in children with persistent SDB after adenotonsillectomy
obstructive event indices but not resolution of OSAS may benefit from uvulopalatopharyngoplasty, lingual
in children after treatment with nasal fluticasone tonsillectomy, maxillary or mandibular surgery, or
[119]. The significant improvement in upper airway tracheostomy. Alternative surgical procedures for
 J.L. Carroll / Clin Chest Med 24 (2003) 261–282
obstructive SDB in children were reviewed recently
[18,126].
Children with SDB and genetic craniofacial
anomalies, cerebral palsy, very young age, lung dis-
ease, and other medical conditions present special
problems with respect to treatment. When the tonsils
and adenoids are enlarged, simple adenotonsillectomy
or other procedures can be beneficial or even curative
of SDB in a substantial proportion of these complex
patients without resorting to long-term tracheostomy
[123,127 – 132].
Mechanical treatment
Obstructive SDB in children is not always cor-
rectable with medical or surgical treatment. In such
cases, CPAP or bi-level positive airway pressure
(BiPAP) may be indicated and can be used success-
fully by children of all ages, including infants [133].
CPAP provides positive pressure to the lumen of the
airway, which supports soft tissues and decreases
airway collapsibility. In most children, CPAP by
nasal mask is tolerated and effective [134 – 136]. It
is important that the initial approach to the family and
child be performed correctly and successfully by
practitioners experienced in techniques of desen-
sitization, parent training, and modeling [135]. CPAP
therapy should be titrated during polysomnography to
determine effective pressures, and children on CPAP
therapy should be followed regularly to ensure com-
pliance and proper fit of masks, headbands, straps,
and other equipment as the child grows.
Bi-level positive airway pressure is more comfort-
able to use, especially with higher pressures, and
children may tolerate it better. BiPAP also allows
higher inspiratory pressures to be used, allows setting
of a backup rate, and provides some ventilatory
assistance. BiPAP therapy is particularly appropriate
for the child who will not use CPAP and patients with
sleep-related hypoventilation caused by muscle
weakness, neurologic disease, or obesity. One poten-
tial complication of long-term nasal mask CPAP or
BiPAP is mid-face hypoplasia. Li et al recently
reported the case of a 15-year-old boy who received
face-mask CPAP for 10 years and developed severe
mid-face hypoplasia [137]. In children on long-term
nasal mask CPAP or BiPAP, maxillomandibular
growth should be monitored carefully.
Supplemental oxygen
There are no widely accepted guidelines or stan-
dards for the use of supplemental oxygen in children
with obstructive SDB. Supplemental oxygen may be
277
used as a temporary treatment for children with SDB
who are awaiting surgery or may be used postoper-
atively if sleep-related hypoxemia persists after thor-
ough evaluation and treatment. Oxygen also can be
used in combination with CPAP and BiPAP when
needed in children with nonobstructive causes of
hypoxemia (eg, lung disease). Caution is strongly
advised when starting supplemental oxygen in patients
with SDB. Although most patients tolerate supple-
mental oxygen well [138,139], some children develop
hypoventilation, and a small subgroup of children are
at risk for developing frank respiratory failure when
placed on supplemental oxygen [140]. Experience
suggests that the children at highest risk for hypoven-
tilation with supplemental oxygen tend to be children
with the most severe, long-standing SDB. The safest
approach is to start oxygen therapy during polysomno-
graphy (or at least while monitoring PCO2).
Follow-up
Some children continue to have upper airway
obstruction, increased upper airway resistance, hyper-
capnia, hypoxemia, and daytime symptoms after
surgery [141,142]. Follow-up is critically important
when the SDB is moderate to severe [96,143] or
when the risk of surgical treatment failure is high (eg,
Down syndrome, cerebral palsy, severe obesity).
Even when therapy of SDB is successful, the original
presenting symptoms may not resolve. Children with
excessive daytime sleepiness may have narcolepsy,
idiopathic hypersomnia, or other sleep disorders.
Follow-up is important, regardless of the treatment
used for childhood SDB.
Summary
Although it may seem that confusion and uncer-
tainty reign in the field of pediatric sleep medicine,
the recent realizations that the scope of childhood
SDB is wider, the symptomatology is broader, and
the prevalence is higher than previously believed are
major advances. Likewise, recent acknowledgment of
the lack of true ‘‘gold standards’’ for diagnosing
UARS and OSAS in children is also a major advance-
ment in this field. Critical assessment of the current
‘‘state of the art’’ by the 2002 AAP Technical Report
on the Diagnosis and Management of Childhood
Obstructive Sleep Apnea Syndrome [37] is another
major advance that sets the stage for the next steps.
The field needs an evidence-based definitions con-
ference, standardization of definitions across all
research studies, and much more research on clinical
278 J.L. Carroll / Clin Chest Med 24 (2003) 261–282
features, pathophysiology, diagnosis, and treatment of
the ‘‘new’’ obstructive SDB, including the full range
of morbidity caused by increased upper airway re-
sistance. This should include further inquiry into the
origins of adult morbidity that resulted from child-
hood SDB and how it can be prevented.
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 Clin Chest Med 24 (2003) 283 – 295

State of home sleep studies

Christopher K. Li, MD, W. Ward Flemons, MD*
Division of Respiratory Medicine, Department of Medicine, Foothills Hospital, University of Calgary, #211,
108 Edgeridge Terrace Northwest, 1403 29th Street Northwest, Calgary, Alberta, T3A 6C4 Canada

‘‘Sleep is a reward for some, a punishment for
others.’’
Isidore Ducasse
Monsieur Ducasse, a nineteenth century French
poet, recognized a subset of the population with
badly troubled sleep. Some of these people must
have had obstructive sleep apnea, a common dis-
order defined by recurrent apneas or near-apneas
(hypopneas) during sleep. Obstructive sleep apnea is
suspected especially in obese patients who snore,
have systemic or pulmonary hypertension, or are
hypersomnolent [1]. In the Wisconsin Sleep Cohort
study, a working population aged 30 to 60 years was
surveyed to determine the prevalence of sleep apnea
and commonly associated symptoms. Sleep apnea,
defined as an apnea-hypopnea index (AHI, the
number of apneas and hypopneas per hour of sleep)
more than 5, was present in 24% of male subjects
and 9% of female subjects [2]. The prevalence of
symptomatic sleep apnea (AHI > 5 with excessive
daytime somnolence) was 4% and 2%, respectively;
habitual snoring, 44% and 28%, respectively; and
self-reported hypersomnolence, 16% and 23%,
respectively [2]. The prevalence of hypertension in
this study group was 34% [3], whereas the preva-
ence of obesity (body mass index >30 kg/m2) in
the general population aged 20 to 74 is approxi-
mately 27% [4]. The percentage of the population
who are ‘‘at risk’’ of having sleep apnea is high.
Because it is expected that treatment would make a
significant difference in quality of life for many of
* Corresponding author.
E-mail address: flemons@ucalgary.ca (W.W. Flemons).
these people, there is a steadily increasing demand
for investigation.
The widely accepted reference standard for the
diagnosis of sleep apnea is the polysomnogram [5];
however, this labor-intensive test is time consuming
and requires considerable technical expertise to per-
form and interpret. As a result, most health care
jurisdictions have unacceptably long waiting times
for sleep studies, which causes many clinicians to
seek simpler, more accessible tests. In 1992, Douglas
et al reported in a sample of 200 consecutive patients
who underwent diagnostic polysomnography that the
omission of the electroencephalogram, electromyo-
gram, and electrooculogram, which allow staging of
sleep and detection of arousals, had little or no
influence on their diagnostic conclusions [6]. This
strongly suggested that devices that monitor only
respiration might well prove to be satisfactory for
investigating many cases of suspected sleep apnea.
Diagnosis could be more accessible in simpler cases,
and waiting times for polysomnography might be
reduced in more complicated cases. With this in
mind, numerous devices designed to monitor respira-
tion at home have been developed.
Compared with polysomnography, portable mon-
itors are less costly, do not require a technician in
attendance, and record patients in the natural envi-
ronment of their own beds. Most of the devices are
more prone to technical failures, give no information
about sleep state or even whether the patient was
asleep, fail to detect problems other than sleep apnea,
and have not been shown to distinguish central from
obstructive apneas. Use of portable monitors at home
for managing sleep apnea patients remains controver-
sial and is not currently considered accepted practice
by any specialty group.

0272-5231/03/$ – see front matter D 2003, Elsevier Inc. All rights reserved.
doi:10.1016/S0272-5231(03)00018-2
284 C.K. Li, W.W. Flemons / Clin Chest Med 24 (2003) 283–295

Classification of portable monitors
The technology for data acquisition and analysis
for home monitors has evolved rapidly, and several
devices have been modified repeatedly over the
years. The American Academy of Sleep Medicine,
formerly the American Sleep Disorders Association,
developed a classification system for portable mon-
itors based on the number and type of parameters
recorded (Table 1) [7].
Defining breathing-disordered events
Although polysomnography is widely recognized
as the reference standard for evaluating patients who
are suspected of sleep apnea, the methods and criteria
for defining events are not standardized across sleep
laboratories or research studies [5]. In general, breath-
ing disturbances are identified during polysomnogra-
phy by a clear reduction in a measurement of
breathing, with or without an accompanying decrease
in oxygen saturation or arousal [5]. The most com-
mon method for detecting reductions in airflow dur-
ing polysomnography is a nasal thermistor, which
detects changes in air temperature. Thermistors are
nonquantitative, however, and some experts recom-
mend that they not be used [5].
Type 2 monitors use the same bioelectric signals
as standard polysomnography, which allows quan-
tification of total sleep time and calculation of the
AHI. Type 3 monitors use similar channels and
definitions for detecting breathing events as type 1
and 2 monitors but lack the bioelectric signals for
sleep staging. Because electroencephalogram, elec-
trooculogram, and electromyogram are not recorded,
arousals cannot be used to identify respiratory dis-
turbances and total sleep time cannot be determined.
Types 3 and 4 monitors most commonly divide the
number of events by total monitoring time to derive a
respiratory disturbances index (RDI), which neces-
sarily underestimates AHI to some degree. To address
this potential problem, White et al used a combina-
tion of electrooculogram channels and anterior tibialis
electromyogram channels to estimate total sleep time;
the correlation with electroencephalogram-based
scoring of sleep time was 0.72 [8]. Others have used
leg movements on electromyogram alone to estimate
periods of wakefulness and subtracted these from the
total monitoring time [9]. It is not clear how such
estimates of total sleep time affect the diagnostic
performance of portable monitors.
Type 4 monitors have used several methods to
define breathing disturbances. Most methods use
oxygen saturation as the primary parameter, but there
are many different techniques for analyzing the data.
The various oximeters use different algorithms for
calculating oxygen saturation, have different sam-
pling frequencies, and store or display the signal at
different intervals. Some oximeters take multiple
readings, store them in memory, average them, and
report a value every 21 seconds [10]; others sample

Table 1
American Academy of Sleep Medicine classification system for sleep apnea evaluation studies
Type 4
Type 1 Type 2 Type 3 Continuous single
Standard Comprehensive Modified portable or dual parameter
polysomnography portable polysomnography sleep apnea testing recording
Parameters Minimum of 7, Minimum of 7, including Minimum of 4, Minimum of 1:
including EEG, EEG, EOG, chin EMG, including ventilation oxygen saturation,
EOG, chin EMG, ECG, airflow, respiratory (at least 2 channels flow, or
ECG, airflow, effort, oxygen saturation of respiratory movement, chest movement
respiratory effort, or respiratory movement
oxygen saturation and airflow), heart rate or
ECG, oxygen saturation
Body position Documented or Possible Possible No
objectively measured
Leg movement EMG or motion sensor Optional Optional No
desirable but optional
Personnel Yes No No No
in attendance
Interventions during Possible No No No
the study
Abbreviations: EEG, electroencephalography; EOG, electrooculography; EMG, electromyography; ECG, electrocardiography.
 C.K. Li, W.W. Flemons / Clin Chest Med 24 (2003) 283–295
and report each value at a frequency up to 10 Hz [11].
A sampling rate of every 12 seconds has been shown
in one study to give falsely low rates of oxygen
desaturations per hour [12].
Methods of automated analysis of the oxygen satu-
ration signal are also variable: most rely on detection
of a drop in oxygen saturation from 2% to 5%, some
detect resaturation [13], and others are designed to use
both criteria [14]. Some automated analyses calculate
baseline oxygen saturation [14], but most do not.
Some oximetry-based monitors do not score dis-
crete events but instead identify sleep apnea from an
overall pattern or distribution of oxygen saturations.
The CT90 is the cumulative percentage of time that
oxygen saturations are below 90%; a CT90 that
exceeds 1% has been used as a criterion for diagnos-
ing sleep apnea [15]. The delta index is a measure of
variability in oxygen saturation over constant time
intervals; the higher the delta index, the higher the
likelihood of sleep apnea [16].
Some type 4 monitors are oximetry based but also
record snoring [17] and heart rate variability [18].
Using a nasal pressure cannula, one type 4 monitor
detects reduction in nasal airflow as the primary
criterion for breathing-disordered events [19 – 21].
There is no consensus about the best method for
interpreting data from home monitors. Some methods
identify and count events automatically, but these
may fail to identify poor quality recordings and can
give misleading results. Others depend on manual
review by a sleep technician or physician, which
raises the issue of interobserver and intraobserver
variability. Still others score events automatically
but produce printouts of raw data that can be
reviewed manually to detect problems, such as
artifact or poor quality data. So far, researchers using
manual scoring or manual review have not published
data on the reliability of their scoring methods.
Existing guidelines and reviews
In 1994, the American Sleep Disorders Asso-
ciation practice parameters recommended that poly-
somnography remain the standard for the diagnosis,
determination of severity, and treatment of sleep
apnea [22]. Unattended portable recording was
viewed as an acceptable alternative only under the
following circumstances: (1) when initiation of treat-
ment was urgent and polysomnography unavailable,
(2) when patients could not undergo polysomnogra-
phy because of mobility issues, or (3) as a follow-up
to treatment study. The use of type 4 studies was not
considered acceptable at that time. Since 1994, many
285
validation studies for various types of portable mon-
itoring and three reviews have been published; an
update of the existing guidelines is warranted.
In 1994, the American Sleep Disorders Asso-
ciation reviewed 23 studies [7], and in 1997 it pub-
lished a review [23] and practice parameters [24] for
polysomnography and related procedures that in-
cluded a section on type 3 and 4 monitors. These
practice parameters suggested that attended type 3
monitors might be appropriate in patients with a high
pretest probability (eg, >70%) of sleep apnea and that
negative type 3 monitor studies in symptomatic
patients should be followed up with a full polysomno-
gram [24]. Also in 1997, the Agency for Healthcare
Research and Quality (formerly the Agency for Health
Care Policy and Research) commissioned a systematic
review of the research on the diagnosis of sleep apnea.
The section of that review devoted to portable mon-
itors reviewed 25 studies of multi-channel devices,
including 12 studies on oximetry alone [25]. The
quality of each reviewed study was rated using a scale
developed by the authors. The system for assigning
‘‘quality ratings’’ to the articles was somewhat differ-
ent from published methods for rating evidence on
diagnostic studies, however [26]. Higher rated (ac-
cording to the system of Sackett et al [26]), quality
research studies that compared portable monitoring to
polysomnography will be the focus of this article. A
complete, updated systematic review of the literature
on portable monitoring for sleep apnea is required but
is beyond the scope of this article.
Evidence
Rating the evidence
To avoid bias in assessing a diagnostic test such as a
portable monitor, several key factors must be consid-
ered. Selection bias may be introduced if consecutively
referred patients are not used. Verification bias may be
introduced if the decision to perform a reference
standard (in this case, polysomnography) is influenced
by the results of the test being evaluated (a portable
monitor). Table 2 depicts how the system by Sackett
et al [26] for rating evidence would apply to studies
evaluating a portable monitor.
Comparing results of portable monitoring
to polysomnography
Several methods are in use for evaluating agree-
ment between the results of two diagnostic tests, such
as the AHI from polysomnography and the RDI from a
286 C.K. Li, W.W. Flemons / Clin Chest Med 24 (2003) 283–295
Table 2
Levels of evidence for studies of portable monitors for the
diagnosis of sleep apnea
Level
of evidence Criteria
1 Independent, blind comparison
between the PM and PSG
Appropriate spectrum of
consecutive patients
PM and PSG performed on
all patients
2 Independent, blind comparison
between the PM and PSG
Narrow spectrum of individuals or
nonconsecutive patients
PM and PSG performed on
all patients
3 Independent, blind comparison
between the PM and PSG
Appropriate spectrum of
consecutive patients
PSG not performed on all patients
4 Comparison between the PM and
PSG was not independent or blind
Abbreviations: PM, portable monitor; PSG, polysomno-
graphy.
portable monitor. The product-moment (Pearson) cor-
relation coefficient is most commonly used but is not
recommended [27]. Although it describes how closely
the two test results are associated (ie, how closely they
cluster along a straight line when one result is plotted
against the other), it does not indicate whether one
result is the same as the other. For example, a monitor
that always gives an RDI exactly half the AHI would
have the same high correlation coefficient as one that
gives an RDI equal to the AHI. Correlation coefficients
also are strongly influenced by the range of values of
the test results. The coefficient might be high in cases
with a high AHI and RDI, but there may be a great deal
of scatter at the lower end of the AHI range (impor-
tantly, near the diagnostic cut-off), which makes the
portable monitor useless at identifying anything other
than severe disease.
The Bland Altman approach is to calculate the
difference between each pair of results (AHI and
corresponding RDI) and plot that against the mean of
the two numbers [27]. The ‘‘limits of agreement’’ (ie,
the mean F 2 standard deviations of the differences)
can be misleading, however, because they are often
strongly influenced by data in the range of high AHI,
where it is irrelevant. The limits of agreement in the
important low range of AHI, near the diagnostic cut-
off, may be better than the statistic calculated for the
whole group.
Because ultimately a clinician’s main concern is
whether a test correctly classifies patients as having
or not having sleep apnea, sensitivity, specificity, and
likelihood ratios for the RDI as a predictor of the AHI
seem more appealing. This approach dictates that a
patient be classified with or without sleep apnea
based on an arbitrary cut-off, such as an AHI of 10;
by dichotomizing results into simply positive or
negative, a good deal of information is lost. Most
research studies on portable monitoring report sen-
sitivity and specificity; some studies also list mean
differences and limits of agreement. The only way to
compare the performance of most portable monitors
is to use their reported sensitivity and specificity and
their calculated likelihood ratios.
Sensitivity is the proportion of patients with
disease who have a positive test result, or the ‘‘true-
positive’’ rate, whereas specificity is the proportion of
patients without disease who have a negative result,
or the ‘‘true-negative’’ rate. These numbers indicate
the probability that the test result will be positive if
the patient has the disease and the probability that the
test result will be negative if the patient does not have
the disease, respectively. These numbers by them-
selves are not sufficient to guide a clinician’s deci-
sion-making process, however, because clinicians do
not know whether a patient has the disease. What a
physician must know is the probability that the
patient has the disease if the test result is positive
or negative (positive and negative predictive values
of the test, respectively).
Sensitivity and specificity can be determined by
analyzing columns in a 2  2 table (Table 3), whereas
the positive and negative predictive values are
obtained by analyzing rows. By convention, the
reference standard is at the top; for sleep apnea this
is usually based on the AHI (the most common cut-
offs used are 10 or 15). The new diagnostic test to
which it is being compared is on the side; for sleep
apnea these are the results of the portable monitor
or RDI.
Changing the threshold of what constitutes a
normal or abnormal diagnostic test changes the
sensitivity and specificity. Lowering the threshold
increases sensitivity but lowers specificity, which
causes more true-positive results (and fewer false-
negative results) but also more false-positive results.
The converse—increasing the threshold—has the
opposite effect (it lowers sensitivity and increases
specificity). Because positive and negative predictive
values depend on the combination of sensitivity and
specificity, using either of these statistics in isolation
to infer the usefulness of a diagnostic test for ruling in
or ruling out a disorder can be misleading.
 C.K. Li, W.W. Flemons / Clin Chest Med 24 (2003) 283–295 287

Table 3
Calculating sensitivity, specificity, positive and negative predictive values, and the effect of prevalence
(prevalence = 150/1000 or 15%) (prevalence = 600/1000 or 60%)
RS + ve RS ve RS + ve RS ve
DT + ve 135TP 100FP 235 DT + ve 540 47 587
DT ve 15FN 750TN 765 DT ve 60 353 413
150 850 1000 600 400 1000
In this hypothetical example (left side), 150 patients have sleep apnea (prevalence = 15%) and 135 of these patients have a
positive diagnostic test result (sensitivity = 135/150 = 90%). Of the 850 patients who do not have the disease, 750 have a
negative test result (specificity = 750/850 = 88.2%). The positive predictive value is 135/235 (57.4%). The negative predictive
value is 750/765 (98%). In the example on the right side, the prevalence has increased to 60% with no change in sensitivity or
specificity; however, the positive predictive value has increased substantially to 92%, and the negative predictive value has
dropped to 85.5%. The formulas are as follows:
Sensitivity: TP/TP + FN
Specificity: TN/TN + FP
Positive predictive value: TP/TP + FP
Negative predictive value: TN/TN + FN
Abbreviations: TP, true positives; FP, false positives; TN, true negatives; FN, false negatives; RS, reference standard
(polysomnography); DT, diagnostic test (portable monitor).

The utility of a test is best captured in a single
number, the likelihood ratio. The likelihood ratio for
a positive test result is the ratio of the proportion of
patients with disease who have a positive test (true-
positive rate or sensitivity) to the proportion of people
without disease who have a positive test (false-
positive rate). Similarly, the likelihood ratio for a
negative test result is the ratio of the proportion of
patients with disease who have a negative test (false-
negative rate) to the proportion of people without
disease who have a negative test (true-negative rate or
specificity). Using the example of the 2  2 table
(see Table 3), the likelihood ratio for a positive result
is 0.9/0.112, which is 8; the likelihood ratio for a
negative result is 0.1/0.882, which is 0.11. Mathemat-
ically, when using likelihood ratios to convert pretest
to posttest probabilities, the pretest probability esti-
mate (ie, the estimated prevalence) is first converted
to an odds expression (pretest odds = pretest prob-
ability/1 pretest probability) and then multiplied by
the likelihood ratio to obtain the posttest odds, which
are then converted back to a probability statement
(posttest probability = posttest odds/posttest odds + 1).
This process can be simplified greatly with the use of
a nomogram (Fig. 1) [28]. The nomogram also high-
lights the interaction between pretest probability and
likelihood ratio on posttest probability.
A guide to the interpretation of likelihood
ratios follows.
Likelihood ratio influence on disease probability
< 0.05 Very large reduction
0.05 – 0.1 Large reduction
0.1 – 0.2 Modest reduction
0.21 – 5 Little change
5.1 – 10 Modest increase
10.1 – 20 Large increase
>20 Very large increase
In this article the authors have included the best
reported sensitivity and specificity for the portable
monitors evaluated. In some studies, the best sen-
sitivity and best specificity are obtained at different
RDI cut-offs. If this is the case, then some patients in
the study population will have a ‘‘negative’’ result (an
RDI below the cut-off for best sensitivity) and others
will have a ‘‘positive’’ result (an RDI above the cut-
off for best specificity), but a certain percentage of
patients will have an RDI between these cut-offs and
will have neither a negative nor positive result. If this
percentage of ‘‘unclassified’’ patients is high, then the
portable monitoring test may have little clinical use
despite having a high sensitivity and specificity. This
potential problem is circumvented if the best sen-
sitivity and specificity occur at the same RDI cut-off,
in which case all patients can be classified as either
negative or positive.
Type 2 monitors
A potential advantage of type 2 monitors is that
they provide information about non – sleep apnea dis-
orders, such as periodic limb movements. Patients
usually must come to the laboratory to have electrodes
applied by a technician before the home study, how-
ever. Data loss rates of 20% have been reported in the
unattended setting [29], and patients may sleep poorly
288 C.K. Li, W.W. Flemons / Clin Chest Med 24 (2003) 283–295
Fig. 1. A nomogram for converting pretest to posttest
probability (probabilities listed as percentages), using
likelihood ratios. To use the nomogram, anchor a straight
edge at the pretest probability and direct it through the
appropriate likelihood ratio. The intersection of the straight
edge with the third (right) line produces the probability
result. (From Fagan TJ. Nomogram for Bayes’ theorem.
N Engl J Med 1975;293:257; with permission.)
because of concerns about safety or equipment fail-
ures. Two studies found that patients preferred labora-
tory polysomnography to a type 2 portable monitor
[29,30]. The best quality study (level 2 evidence) had
only 20 patients, from which only gross estimates of
sensitivity (80%) and specificity (90%) can be drawn.
The calculated likelihood ratio for a positive test result
was 8, and the likelihood ratio for a negative test result
was 0.22 [31]. Currently, it is not proven that type 2
monitors are reliable or offer any advantage over
laboratory polysomnography.
Type 3 monitors
With fewer channels, type 3 monitors are easier
for patients to sleep with, and technicians are not
required for the initial set up. One study reported an
at-home failure rate of 10% [32]. Three studies that
were Level 1 evidence compared type 3 monitors to
simultaneous laboratory polysomnography. Sensitiv-
ity rates ranged from 92% to 100%, and specificity
rates ranged from 96% to 100% [9,33,34]. Calculated
likelihood ratios were more than 20 for a positive test
result and less than 0.10 for a negative test result. One
study noted that the sensitivity rate dropped to 55% at
an AHI cut-off of 40 when events were scored
automatically, but visual editing of the raw data
improved the sensitivity rate to 91% [33].
To date, no level 1 studies have compared un-
attended type 3 monitors to laboratory polysomnog-
raphy. Two level 2 studies reported best sensitivity
rates of 91% to 95% and best specificity rates of 83%
to 93%, with likelihood ratios of 5.1 to 9 for a
positive test result and 0.13 to 0.15 for a negative
test result; however, it should be noted that 22% to
37% of patients would have been ‘‘unclassified’’ in
these studies [8,32].
Overall, type 3 monitors have been shown in
level 1 attended laboratory studies to have like-
lihood ratios that can alter substantially the posttest
probability of sleep apnea. Manual scoring or
review of raw data with editing seems to improve
the specificity of some of these devices at higher
AHI cut-offs; however, it is not clear that this would
have an impact on clinical decision making. In the
home setting, level 2 evidence has shown low
likelihood ratios for negative tests, and these mon-
itors could be used to ‘‘rule out’’ sleep apnea. In
these studies, portable monitoring and polysomnog-
raphy were performed on different nights, and night-
to-night variation in a patient’s disease may have
played a role in explaining the modest likelihood
ratios for a positive result. Some authors also have
postulated that patients may have slept more in the
 C.K. Li, W.W. Flemons / Clin Chest Med 24 (2003) 283–295
home environment and experienced more breathing-
disordered events, which lead to ‘‘false-positive’’
results on portable monitoring but were in fact
true-positive results with a falsely negative poly-
somnogram result [8].
All type 3 monitors evaluated in the literature have
used thermistors as a measurement of flow. Limited
data are available on their accuracy, but laboratory
models that compared thermistors to pneumotacho-
graphs suggest that thermal signals are nonlinearly
related to actual airflow and tend to overestimate
ventilation [35]. Nasal pressure has been shown to
have excellent agreement with a pneumotachograph
[36], and although theoretically some false-positive
events may result from mouth breathing, this tech-
nology seems superior to thermistors for detecting
apneas and hypopneas. Type 3 monitors might be
improved by substituting nasal pressure for thermis-
tors, but to date no unattended study using nasal
pressure-based monitors has been reported.
Type 4 monitors
Oximetry alone
In 1993, Sériès et al published a level 1 study that
compared nocturnal home oximetry to subsequent
polysomnography in 240 patients with suspected
sleep apnea [37]. Oximetry, with a sampling rate of
0.5 Hz using a finger probe, was classified as ‘‘nor-
mal’’ or ‘‘abnormal’’ according to the absence or
presence of repetitive episodes of transient desatura-
tion; no minimum decrease in saturation levels or
threshold saturation was used. Repeat oximetry was
required in 8% of patients. The authors reported a high
sensitivity (98%) but a low specificity (48%), which
corresponded to calculated likelihood ratios of 1.88
for a positive test result and 0.037 for a negative test
result. The low likelihood ratio for a negative test
result indicates that this approach was useful for
‘‘ruling out’’ sleep apnea; however, a positive test
result would have required additional testing.
Most other studies of oximetry alone have used a
desaturation threshold to identify and quantify breath-
ing-disordered events, including two level 1 evidence
studies. In a home setting, Gyulay et al reported a best
sensitivity rate of 93% and a best specificity rate of
98% (calculated likelihood ratio of 20 for a positive
test result and 0.14 for a negative test result), although
49% of patients would have been ‘‘unclassified’’ using
these RDI cut-offs [15]. A study by Chiner et al in a
laboratory setting reported a best sensitivity rate of
82% and best specificity rate of 93% (calculated
likelihood ratio of 8.9 for a positive test result and
289
0.24 for a negative test result); 19% of these patients
would have been ‘‘unclassified’’ [38].
Snoring and oximetry
Issa et al reported on a monitor that measured
snoring via a laryngeal microphone and 1 Hz oxime-
try [17]. In their level 2 evidence study, they reported
a best sensitivity rate of 89% and a best specificity
rate of 98% (calculated likelihood ratio of 45 for a
positive test result and 0.12 for a negative test result),
although 22% of patients would have been ‘‘unclas-
sified.’’ A subsequent version of the device modified
the automated oximetry analysis algorithm and elim-
inated snoring from the definition of a breathing-
disordered event. A level 1 validation study of the
newer device compared with simultaneous polysom-
nography reported a best sensitivity rate of 97% and a
best specificity rate of 88% (calculated likelihood
ratio of 8.2 for a positive test result and 0.04 for a
negative test result), with 11% of tests ‘‘unclassified’’
[14]. The increased specificity of this device com-
pared with other oximeters is likely a result of the
unique analysis software, which uses a moving base-
line and desaturation and resaturation criteria for
defining an event. Both of these studies took place
in a laboratory setting, and their results must be
confirmed in a home study.
Nasal pressure
Several published studies that are level 2 evidence
have been conducted using a monitor that measures
nasal flow via a pressure transducer [19 – 21]. In
these studies, an RDI was defined by a reduction
in nasal flow of 50% or more. Oximetry also was
measured but was not one of the criteria for defining
an event. On comparison with simultaneous labora-
tory polysomnography, best sensitivity rate ranged
from 97% to 100%, and best specificity rate ranged
from 77% to 93% (calculated likelihood ratio of
4.2 – 12.5 for a positive test result and 0 – 0.06 for a
negative test result). In one study, 48% of patients
would have been ‘‘unclassified’’ [20]; in the other
two studies the best sensitivity and specificity rates
were obtained at the same RDI cut-off. These prom-
ising likelihood ratios must be confirmed by level 1
studies, and the devices should be tested unattended
in the home.
Oximetry, snoring, and heart rate variability
A 1992 level 2 evidence study reported a device
that measured oximetry, snoring, heart rate, and body
290 C.K. Li, W.W. Flemons / Clin Chest Med 24 (2003) 283–295
position but used only oximetry in the algorithm for
defining a breathing-disordered event [39]. The oxy-
gen saturation sampling frequency was not reported.
When compared with simultaneous laboratory poly-
somnography, the best sensitivity rate was 97% and the
best specificity rate was 92% (calculated likelihood
ratio of 12.1 for a positive test result and 0.03 for a
negative test result). A subsequent study (level 2
evidence) used snoring pauses in the scoring algorithm
and had a higher calculated likelihood ratio for a
positive result (34.5) and a similar calculated like-
lihood ratio for a negative result. However, 26% of the
patients would have been ‘‘unclassified’’ [18]. The
most recent version of this monitor used an algorithm
that combined oximetry with heart rate. The best
reported sensitivity and specificity rates were lower,
which resulted in less useful likelihood ratios, but it
has only been evaluated in a level 4 evidence, unat-
tended home study [40].
In summary, oximetry has demonstrated use for
‘‘ruling out’’ sleep apnea in the attended and unat-
tended settings. The sampling rate and interpretation
algorithm of the particular device must be considered
carefully. In devices that measure other channels,
such as snoring and heart rate variability, the best
likelihood ratios for a positive test result were
obtained using algorithms that used oximetry alone
to define breathing-disordered events. Limited data
are available on oximetry-based portable monitors in
the unattended setting for ‘‘ruling in’’ sleep apnea.
Further research is required to determine if the find-
ings in the attended setting remain valid in the
unattended setting. Nasal pressure-based monitors
also have useful negative likelihood ratios and rea-
sonably helpful positive likelihood ratios. There is a
pressing need for further validation studies of type 4
monitors in the unattended setting.
Further research directions
Additional research on portable monitors is
required to address several issues. Most monitors
have been studied by only a single group of inves-
tigators. All studies have taken place on patients
referred to a sleep center. It is yet to be proven what
the effect of changing the studied clinical population
would have on the diagnostic performance of these
monitors. Primary care populations, women, non-
whites, and patients with comorbid illness have not
been studied adequately; therefore, the published
results on portable monitoring cannot necessarily
be generalized to these groups. Changing the popu-
lation of patients could have two effects: (1) it could
alter prevalence (pretest probability) of the condition
and impact positive and negative predictive values
and (2) it could affect the operating characteristics
(sensitivity, specificity, likelihood ratios) of the
monitor. Studies published in the future should plan
to address key methodologic issues such as selection
bias, verification bias, and blinded data interpre-
tation. Investigators are encouraged to provide
detailed information on their study population,
methods used for acquiring and analyzing portable
monitoring data, and polysomnography data.
Using laboratory polysomnography as a reference
standard is often criticized because many patients do
not sleep well in a laboratory and it is difficult to
account for night-to-night variability. Although a dif-
ference of 5 between the AHI and RDI may not be
clinically significant, it can result in a portable moni-
toring study being labeled ‘‘falsely’’ positive or nega-
tive. A more rigorous validation study would address
important clinical outcomes, such as improvement in
quality of life (including symptoms such as daytime
sleepiness) and compliance with treatment.
Portable monitors in a clinical decision algorithm
Like any diagnostic test, the results of testing
with portable monitors are most useful when applied
to the appropriate clinical context. The results of a
negative portable monitoring study would have
different implications for a mildly symptomatic
patient with a low pretest probability compared with
a symptomatic patient with a high pretest probabil-
ity. The probability that a patient has sleep apnea
based on clinical factors alone can be estimated
using one of several clinical prediction rules [41].
The sensitivity rate of a risk stratification algorithm
that combined a clinical prediction rule and oxime-
try has been reported by Gurubhagavatula et al [42]
to be 95% for detection of sleep apnea (AHI  5)
and 85% for severe sleep apnea (AHI  30). Cor-
responding specificity rates were 68% and 97%,
respectively. Although this is a well-validated
method, the complexity of it may limit its clinical
application. A simplified approach to assigning
clinical probability and incorporating it into a strat-
egy for managing patients with suspected sleep
apnea recently was published (Fig. 2) [1]. It is
derived from a sleep apnea clinical prediction rule
that was developed using multiple linear regression
[43]. The ‘‘adjusted neck circumference’’ in centi-
meters is calculated by adding 4 cm if the patient
has hypertension, 3 cm if the patient is a habitual
snorer, and 3 cm if the patient is reported to choke
 C.K. Li, W.W. Flemons / Clin Chest Med 24 (2003) 283–295 291

Fig. 2. A suggested clinical decision algorithm for evaluating patients with suspected sleep apnea. (From Flemons WW.
Obstructive sleep apnea. N Engl J Med 2002;347:498 – 504; with permission.)

or gasp most nights [1]. Table 4 illustrates how the Example 1

adjusted neck circumference corresponds with a
patient’s clinical probability of having a positive
test result for sleep apnea.
The following scenarios are examples of how
this clinical decision algorithm might be applied
to patients.
Mrs. A is a healthy 53-year-old schoolteacher
whose husband has complained of her heavy snor-
ing. They have started to sleep in different rooms
because of this. Her neck circumference is 40 cm,
she does not have systemic hypertension, and she
292 C.K. Li, W.W. Flemons / Clin Chest Med 24 (2003) 283–295
Table 4
Adjusted neck circumference and corresponding clinical
probability
Adjusted neck circumference (cm) Clinical probability
< 43 Low
43 – 48 Intermediate
> 48 High
has not been reported to choke or gasp while
sleeping. She does not complain of significant
daytime somnolence.
Mrs. A’s adjusted neck circumference is 43 cm
(40 cm + 3 cm for snoring), and she has an inter-
mediate clinical probability of sleep apnea. Testing at
home with a portable monitor similar to the one
studied by Vazquez et al [14] produced results illus-
trated in Fig. 3. Although this monitor has more
channels than the one reported by Vazquez et al,
the automated scoring algorithm based on the oxygen
saturation signal is identical. The updated monitor
records and reports airflow (using nasal pressure) and
heart rate in addition to the standard signals of
oxygen saturation, snoring, and body position. The
tracing in Fig. 3 demonstrates snoring but normal
flow and oxygen saturation. The patient’s RDI was
4.1, which, combined with her low pretest probabil-
ity, is sufficient to ‘‘rule out’’ clinically important
sleep apnea. Because she is asymptomatic, further
investigations are not indicated, and a discussion of
her treatment options for primary snoring can ensue.
Example 2
Mr. B is a 37-year-old executive who presents
because of excessive daytime somnolence. He has
Fig. 3. Heavy snoring; no evidence of sleep apnea. The oxygen saturation profile (red tracing), air flow (blue tracing), and
heart rate (green tracing) are all normal. The patient is lying in a nonsupine position as indicated by the lack of a horizontal
line adjacent to the ‘‘Supine’’ label (compare with Fig. 5). The vertical black lines at the bottom indicate heavy snoring. (Time
frame = 10 minutes.)
been falling asleep in meetings and in front of his
computer at work. On several occasions, he has
dozed off while driving home and swerved off the
road. He has systemic hypertension and a neck
circumference of 41 cm. His wife describes him as
an occasional snorer, but she does not report choking
or gasping during sleep.
The patient has an adjusted neck circumference of
45 cm (41 cm + 4 cm for hypertension), and thus an
intermediate clinical probability of sleep apnea. Fig. 4
is taken from his portable monitor study, which
demonstrates no snoring, normal flow, and a normal
oxygen profile. The RDI was 1.8.
Mr. B’s portable monitor study makes sleep apnea
an unlikely cause of his daytime symptoms. Because
of the severity of his somnolence, further investi-
gations such as polysomnography and a multiple
sleep latency test are indicated.
Example 3
Mr. C is a 49-year-old carpenter who is referred
for assessment of excessive daytime somnolence. He
can fall asleep in any situation if he is not physically
active or mentally stimulated. His wife claims that he
is a ‘‘heroic’’ snorer who frequently chokes, gasps,
snorts, and stops breathing when he is asleep. He has
mild type II diabetes mellitus and a blood pressure of
160/90. His neck circumference is 47 cm.
Mr. C has a high clinical probability of sleep
apnea, with an adjusted neck circumference of
57 cm (47 cm + 4 cm for hypertension + 3 cm for
snoring + 3 cm for choking/gasping). His portable
monitor study, shown in Fig. 5, demonstrates fre-
quent, cyclic oxygen desaturations associated with
 C.K. Li, W.W. Flemons / Clin Chest Med 24 (2003) 283–295 293

Fig. 4. No evidence of sleep apnea. The oximetry recording (red tracing), air flow (blue line), and heart rate (green line) are all
normal. The patient is lying in a nonsupine position as indicated by the lack of a horizontal line adjacent to the ‘‘Supine’’ label
(compare with Fig. 5). There are no vertical bars adjacent to the ‘‘Snore’’ label, which indicates that the patient was not snoring.
(Time frame = 10 minutes.)

intermittent snoring and reductions in flow. He has an
RDI of 65 and clinically important daytime som-
nolence, so a trial of CPAP is indicated. It is impor-
tant for him to have a follow-up test to ensure that
these abnormalities normalize on CPAP.
Summary
Many different portable monitors have been used
to assess patients with suspected sleep apnea. There is
limited evidence for the use of type 2 monitors,
especially in the unattended setting in which there
may be high rates of data loss. Type 3 monitors have
low likelihood ratios for negative tests and can be
used to ‘‘rule out’’ sleep apnea. The ability of type 3
monitors to ‘‘rule in’’ sleep apnea is less convincing,
but this may improve with the use of improved
technology, such as nasal pressure transducers. Type
4 monitors usually use oximetry and can be used to
‘‘rule out’’ sleep apnea. Higher sampling rates and
improved analysis algorithms can improve the spe-
cificity of these monitors; hence, likelihood ratios for
a positive test result can be high enough with some
monitors to ‘‘rule in’’ sleep apnea as well. Not all
monitors record and analyze signals in the same way;
it is not possible to generalize results from one
monitor across all monitors of a particular type.
Limited evidence is available for many portable
monitors in the unattended setting, and further
research is required in this area.
Clinicians should identify how they plan to use a
portable monitor: as a mechanism to exclude disease
in asymptomatic snorers, to confirm disease in

Fig. 5. Severe sleep apnea. Cyclic oxygen desaturations are present, to as low as 74% (red tracing). The black vertical bars at the
nadir of the oxygen saturation indicate that the monitor scored this as a respiratory disturbance. There is intermittent cessation of
air flow (blue tracing) and tachycardia with termination of most apneas (green tracing). The patient is in the supine position
(magenta line), and intermittent snoring is also present (black vertical lines). (Time frame = 10 minutes.)
294 C.K. Li, W.W. Flemons / Clin Chest Med 24 (2003) 283–295
patients with a high clinical probability of disease, or
to risk stratify patients so that proper priority for
polysomnography can be determined. This deter-
mination allows them to select a portable monitor
with signals most appropriate to their needs. The
quality of the validation studies for each portable
monitor also should be evaluated carefully before
implementation in clinical practice. The ability for a
clinician to review raw data manually and consider
artifact is a necessary feature. Measurement of oxy-
gen saturation also is important to identify patients
with previously unsuspected serious desaturation that
would indicate the need for more urgent treatment.
In centers in which polysomnography is not
readily available, a clinical decision algorithm that
incorporates a clinical prediction rule with the use of
portable monitors can guide clinicians toward insti-
tution of therapy or further investigations. Intuitively,
this approach could reduce waiting times for poly-
somnography and delays in diagnosis, but additional
evidence for the validity and cost effectiveness of this
approach is required.
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 Clin Chest Med 24 (2003) 297 – 306

Monitoring respiration during sleep

Teofilo L. Lee-Chiong Jr, MD
Division of Pulmonary and Critical Care Medicine, University of Arkansas for Medical Sciences,
4301 West Markham, Slot 555, Little Rock, AR 72205, USA

Sleep-related breathing disorders accompanied by oxygen desaturation, arousals, and

The sleep-related breathing disorders have been
categorized in various ways. The most basic sche-
ma divides them into obstructive or central apneic
events. An American Academy of Sleep Medicine
(AASM) Task Force Report published in 1999 defined
four separate syndromes associated with abnormal
respiratory events during sleep among adults,
namely, obstructive sleep apnea-hypopnea syndrome
(OSAHS), central sleep apnea-hypopnea syndrome,
Cheyne-Stokes breathing syndrome, and sleep hypo-
ventilation syndrome [1]. In this classification, the
upper airway resistance syndrome was not regarded
as a distinct syndrome; instead, respiratory event-
related arousals (RERAs) were considered part of the
syndrome of OSAHS.
Obstructive sleep apnea-hypopnea syndrome
OSAHS is characterized by repetitive reduction
or cessation of airflow during sleep caused by partial
or complete upper airway occlusion in the presence
of respiratory efforts. Mixed apnea, in which an
initial period of apnea caused by an absence of res-
piratory efforts precedes upper airway obstruction, is
included in this syndrome. These events are typically
Portions of the text have appeared previously in Lee-
Chiong TL. Monitoring respiration during sleep. In: Lee-
Chiong TL, Sateia MJ, Carskadon MA, editors. Sleep
medicine. Philadelphia: Hanley and Belfus, Inc.; 2002.
E-mail address: leechiongteofilol@uams.edu
sleep disruption.
Apnea is characterized by the cessation of airflow
for 10 seconds or longer. Although there is almost
universal consensus regarding the definition of apnea
in adults, the presence of hypopnea continues to be
identified using various criteria, including (1) a 50%
reduction in airflow accompanied by a 4% fall in
oxygen saturation (SaO2) or an arousal, (2) a 50%
reduction in airflow accompanied by any fall in SaO2,
or (3) any reduction in airflow with or without
oxygen desaturation or arousal [2].
The criteria used for scoring hypopneas influence
the diagnosis of OSAHS and the rating of its
severity. Different scoring criteria for hypopneas
may result in varying apnea-hypopnea indices [3].
Interpretation of polysomnographic records ideally
should include a description of the scoring method
used to derive hypopneas.
The sum of apneas and hypopneas divided by the
total sleep time is commonly referred to as the apnea-
hypopnea index. The respiratory disturbance index
(RDI) is the sum of apneas, hypopneas, and RERAs
divided by the total sleep time.
Estimates of the severity of sleep-disordered
breathing depend on the approach to measuring
RDI. Redline et al examined the relationships among
RDIs defined by different definitions of apneas and
hypopneas in 5046 participants in the Sleep Heart
Health Study who underwent overnight unattended
12-channel polysomnography. The correlation bet-
ween RDIs based on various definitions ranged from
0.99 to 0.68, and the magnitude of the median RDI
varied from 29.3 when it was based on events iden-
tified on the basis of flow or volume amplitude criteria
alone to 2 for an RDI that required a 5% oxygen
desaturation with events [4].

0272-5231/03/$ – see front matter D 2003, Elsevier Inc. All rights reserved.
doi:10.1016/S0272-5231(03)00021-2
298 T.L. Lee-Chiong Jr / Clin Chest Med 24 (2003) 297–306
It is generally not necessary to distinguish apneas
from hypopneas in routine clinical care, and often the
two respiratory events are scored and reported togeth-
er. The diagnostic criteria for apneas and hypopneas
recommended by the AASM Task Force include a
reduction ( > 50%) in the amplitude of breathing from
baseline during sleep or a reduction ( < 50%) in the
amplitude of breathing from baseline during sleep
associated with either an oxygen desaturation (>3%)
or an arousal plus an event duration of at least
10 seconds [1]. RERAs, which do not fulfill the criteria
for either apnea or hypopnea, consist of increasing
respiratory efforts that last 10 seconds or longer and
culminate in an arousal or a progressively more
negative esophageal pressure preceding a change in
esophageal pressure to a less negative level.
The reference standard for measuring an obstruc-
tive apnea-hypopnea is a reduction in total oronasal
airflow detected by a pneumotachometer placed in a
well-fitted facemask [1]. Other methods used to
identify obstructive apnea-hypopneas include mea-
surement of nasal pressure, respiratory inductance
plethysmography (RIP), piezo sensors, strain gauges,
thoracic impedance, thermal sensors, and expired
carbon dioxide (CO2). Whereas measurement tech-
niques that identify apneas also are able to detect
hypopneas, methods that measure hypopneas may
not necessarily be adequate in identifying apneic
events. The reference standard for identifying a RERA
is the measurement of esophageal pressure [1]. RERAs
also can be detected using measurements of nasal
pressure and surface diaphragmatic electromyography.
The demonstration of five or more obstructive
apneas-hypopneas or RERAs per hour of sleep dur-
ing an overnight study, plus excessive daytime sleepi-
ness (that is not caused by other factors) or two or
more of the following manifestations, including
choking or gasping during sleep, recurrent awaken-
ings from sleep, unrefreshing sleep, daytime fatigue,
or impaired concentration, establishes the diagnosis
of OSAHS [1].
Central sleep apnea-hypopnea syndrome
This syndrome is characterized by repetitive epi-
sodes of sleep-related apnea unaccompanied by upper
airway obstruction. Each respiratory event consists of
reduced airflow, 10 seconds or longer in duration,
associated with a reduction in esophageal pressure
excursions from baseline levels and often with oxy-
gen desaturation and arousals.
The diagnostic criteria for central sleep apnea-
hypopnea syndrome consist of (1) excessive day-
time sleepiness or frequent arousals/awakenings,
and (2) at least five central apnea-hypopneas per hour
of sleep during an overnight study, and (3) awake
arterial carbon dioxide tension (PaCO2) of less than
45 mm Hg [1].
Esophageal pressure monitoring is the reference
standard measurement of central apnea-hypopneas
[1]. Other methods, such as RIP, surface diaphrag-
matic electromyography, thermal sensors, expired
CO2, piezo sensors and strain gauges, are relatively
insensitive in identifying these events.
Cheyne-Stokes breathing syndrome
In this syndrome, cyclical waxing and waning of
respiration develops, with central apnea or hypopnea
alternating with hyperpnea. Transient arousals that
occur at the crest of hyperpnea may lead to sleep
fragmentation and excessive somnolence.
The reference standards of measuring airflow and
respiratory effort are pneumotachometry and esopha-
geal pressure monitoring, respectively [1]. Other tech-
niques for detecting Cheyne-Stokes breathing include
RIP, surface diaphragmatic electromyography, oro-
nasal airflow monitoring, and oximetry. Cheyne-
Stokes breathing syndrome is diagnosed based on
the following criteria: (1) presence of congestive heart
failure or cerebral neurologic disorders, (2) three or
more consecutive cycles of respiratory irregularity
characterized by crescendo-decrescendo amplitude of
breathing lasting at least 10 consecutive minutes, and
(3) five or more central apnea-hypopneas per hour of
sleep [1].
Sleep hypoventilation syndrome
Persons with sleep hypoventilation syndrome may
have oxygen desaturation and hypercapnia during
sleep unrelated to distinct periods of apnea-hypopnea.
Periods of hypoventilation are more frequent and
severe during rapid eye movement sleep than in
non – rapid eye movement sleep. PaCO2 monitoring
is the reference standard measurement for identifying
sleep hypoventilation [1]. Continuous oximetry
(demonstrating a decline in SaO2 without accom-
panying respiratory events), transcutaneous carbon
dioxide (PtcCO2) monitoring, calibrated RIP (show-
ing reduced tidal volume and minute ventilation), and
end-tidal carbon dioxide (PetCO2) measurements also
have been used to monitor sleep hypoventilation. The
diagnosis of sleep hypoventilation syndrome is based
on the presence of cor pulmonale, pulmonary hyper-
 T.L. Lee-Chiong Jr / Clin Chest Med 24 (2003) 297–306
tension, excessive somnolence not secondary to other
factors, erythrocytosis or awake PaCO2 of more than
45 mm Hg, and an increase in PaCO2 during sleep by
more than 10 mm Hg compared with levels during
wakefulness or sleep-related oxygen desaturation not
caused by apnea-hypopnea [1].
Monitoring respiration during sleep
Accurate monitoring of respiration during sleep,
including measurements of airflow, respiratory effort,
oxygenation, and ventilation, is indispensable in
identifying sleep-disordered breathing.
Measurement of respiratory effort
Measurement of respiratory effort using either
esophageal pressure monitoring or surface diaphrag-
matic electromyography is vital in distinguishing
central from obstructive apneas.
Esophageal pressure
Changes in pleural pressure accompany respi-
ratory effort. Esophageal pressure monitoring during
polysomnography, using either esophageal balloons
or newer catheter transducers, is considered the
reference standard for detecting respiratory effort
during sleep and is a direct measure of respiratory
load [1]. This method requires a transnasal insertion
of an esophageal catheter with a pressure transducer
placed on its tip after topical anesthesia of the nares
and pharynx. During episodes of RERAs in patients
with upper airway resistance syndrome, esophageal
pressures become increasingly more negative imme-
diately preceding an arousal, followed by a rapid
return to baseline levels [1]. Virkkula et al reported
that esophageal pressure monitoring improved the
diagnostic value of limited polygraphic recording of
oxygen saturation, respiratory and leg movements,
airflow, body position, and snoring in detecting sleep-
disordered breathing [5].
Transnasal insertion of esophageal catheters in
sleep studies may increase ipsilateral nasal resistance,
as measured by anterior rhinomanometry, but does not
affect combined nasal resistance [6]. Changes in nasal
pressure and airflow during esophageal pressure moni-
toring may be particularly relevant in persons with
already compromised nasal airflow. The amount of
apneas and arousals has been shown to increase with
nasal airflow obstruction. The use of nasoesophageal
catheters is generally associated with only minimal
299
changes in sleep architecture [5]. Patient compliance
with esophageal catheter is generally good [5].
Surface diaphragmatic electromyography
Although the presence of respiratory efforts may
be inferred by analysis of signal tracings derived from
electrodes placed on the chest wall during poly-
somnography, surface diaphragmatic electromyogra-
phy by itself is seldom helpful in detecting RERAs or
central apnea-hypopneas [1].
Measurement of airflow
Airflow during sleep can be measured either
directly or indirectly. The only method that measures
airflow directly is pneumotachography. Thermal sen-
sors and PetCO2 monitors detect changes in the
thermal and chemical characteristics of inspired
ambient air and expired air originating from the
airways; both methods provide only an indirect
estimate of airflow [7].
Although indirect methods of measuring airflow
can detect episodes of apnea reliably, they are less
consistent in identifying hypopneas. Simultaneous
measurement of lung volume or effort and thermal
or PetCO2 sensors is required to distinguish among
central apneas, obstructive apneas, and a prolonged
inspiration [7].
Pneumotachometer
A pneumotachometer, attached to a well-fitted
facemask, can measure total oronasal airflow by
detecting changes in pressure between inspiration
and expiration and is the reference standard for
measuring airflow [1]. Patient discomfort from a
tightly fitting facemask may disturb sleep and limit
its use in clinical sleep studies.
Nasal pressure
Nasal airflow can be measured quantitatively and
directly with a pneumotachograph that detects
changes in nasal pressure during respiration. Nasal
airway pressure decreases during inspiration and
increases during expiration. The fluctuations pro-
duced on the transducer signals are proportional to
flow [8]. The device consists of a standard oxygen
nasal cannula connected to a pressure transducer and
placed in the nares.
The shape and amplitude of signals obtained from
a nasal cannula are comparable to those from a
300 T.L. Lee-Chiong Jr / Clin Chest Med 24 (2003) 297–306
facemask pneumotachograph [9]. A plateau on the
inspiratory flow signal is associated with increased
upper airway resistance and airflow limitation. In one
study, airway resistance was increased for breaths
with flattened or intermediate inspiratory flow signal
contours compared with breaths with normal flow
contours [8].
Measurement of pressure by nasal prongs is
superior to the use of thermistors in detecting respi-
ratory events during sleep studies [9]. Nasal cannula/
pressure sensors may recognize additional events
characterized by flow limitation that are missed by
thermistors [10]. Nasal pressure monitoring is not
recommended for persons who are predominantly
mouth breathers or who have nasal obstruction
[7,11]. In persons with narrow nares or a deviated
septum, nasal prongs used to assess nasal flow during
sleep can increase nasal airflow resistance—as esti-
mated by posterior rhinomanometry—and possibly
alter the diagnosis of OSAHS and its severity [12].
Nasal prongs that partly occlude the nasal passages
can cause sleep breathing disorders associated with
brief arousals. Thurnheer et al observed that com-
pared with facemask pneumotachography, nasal can-
nula pressure recordings provided accurate clinical
assessment of ventilation during sleep even in pa-
tients who reported nasal obstruction [13].
Thermal sensors
Thermal sensors (thermistors or thermocouples)
afford an indirect and semiquantitative measurement
of airflow. These devices are placed over the nose and
mouth and infer airflow by sensing differences in the
temperature of the warmer expired air and the cooler
inhaled ambient air. The flow signal generated is
related directly to the sensor temperature and indi-
rectly to airflow. Unfortunately, temperature changes
of respiratory air often bear little correlation to air-
flow. The flow signal also is influenced by the pattern
of airflow and the placement of the sensor in relation
to the nostril. Even minor displacements of the
thermal sensors or alternations in the proportion of
nasal and oral breathing relative to the sensor position
can lead to large changes in signal amplitude [14].
Although temperature-sensing receptors can de-
tect apneas reliably, they are less accurate in iden-
tifying hypopnea [10]. Farre et al noted that thermal
sensors were imprecise in monitoring airflow and,
when a reduction in thermal sensor signal is used
to quantify hypopneas, they tend to underestimate
hypopneic events [15]. Thermistors do not allow the
detection of inspiratory flow limitation, which is
suggestive of upper airway narrowing.
Oronasal thermistors are typically located at the
upper lip; in this location, thermistors may be unable
to differentiate between high and low rates of airflow
and detect hypopneas. Akre et al introduced the use
of internal thermistors to measure airflow in the
pharynx. They reported that this method was more
sensitive than external thermistors in detecting minor
changes in air flow and hypopneas [16,17]. In awake,
normal subjects, the reliability of internal thermistors
in diagnosing hypopneas is comparable to that of
pneumotachography [18].
In summary, signals obtained from thermocouples
and thermistors provide only qualitative data regard-
ing airflow, and as a rule, thermal sensors are unable
to identify reliably the presence of hypopnea and
cannot distinguish central from obstructive apnea-
hypopneas [1].
Expired carbon dioxide
Ambient air contains negligible amounts of CO2
compared with expired air from the lungs, which has
a higher concentration of CO2. A qualitative measure
of airflow can be obtained using infrared analyzers of
expired CO2 placed in front of the nose and mouth.
An advantage of PetCO2 monitoring over thermal
sensing techniques is its ability to infer the occur-
rence of hypoventilation by a rising PetCO2 level.
Minute fluctuations in lung volume that accom-
pany each heart beat also may be transmitted to the
sensor via a patent upper airway during central
apneas [7]. These fluctuations may appear as cardiac
oscillations in the CO2 tracings, further corroborating
the diagnosis of central apneas.
Tracheal sound recording
Tracheal sound recordings, made by using a
stethoscope head taped over the manubrium sternum
and air-coupled to a microphone, have been proposed
as a method of detecting and monitoring airflow. This
method is limited by interference from environmental
noise [19].
Strain gauges
Rib cage and abdominal excursions can be mea-
sured by placing length-sensitive strain gauges below
the axilla and at the level of the umbilicus, respec-
tively [20]. Respiratory movements can be detected
by a single uncalibrated abdominal or chest gauge.
Calibration of the rib cage and abdominal gauges
against another volume-measuring device is required
to measure volume changes quantitatively. The
 T.L. Lee-Chiong Jr / Clin Chest Med 24 (2003) 297–306
summed rib cage-abdominal volume signals do not
distinguish central events (no net volume change
caused by absence of respiratory effort) from ob-
structive sleep apnea (no net volume change caused
by rib cage-abdominal paradox). Loss of tone of the
diaphragm or the accessory respiratory muscles also
can lead to paradoxical motion of the rib cage and
abdomen [7]. Esophageal pressure monitoring may
be needed to verify respiratory efforts whenever most
apneas detected by strain gauges appear central in
origin [20].
Displacement of the strain gauges during the
monitoring period because of changes in sleep posi-
tion or body movements influences signal quality
[20]. Accuracy of measurements is affected by over-
stretching or understretching of the gauges and altera-
tions in muscle tone during sleep [7].
Respiratory inductance plethysmography
Respiratory inductance plethysmography (RIP)
can be used to measure changes semi-quantitatively
in chest and abdominal volume during respiration.
Transducers are placed around the chest and abdomen
to monitor changes in the cross-sectional area of
the respective body compartments as reflected by
changes in inductance (resistance to change in flow
of current) of the transducers [7]. RIP is based on the
principle of a two-compartment model of thoraco-
abdominal wall movement during respiration [21].
With a closed glottis, the sum of chest and abdominal
volume is fixed, and any increase or loss of volume
of the rib cage is accompanied by a simultaneous,
equal but opposite change in volume of the abdomen
[22]. The sum of the signals from calibrated chest and
abdominal sensors can estimate tidal volume and
respiratory pattern during sleep but cannot provide
data regarding airflow [11].
Thoracoabdominal asynchrony during breathing is
currently most commonly identified by visual analy-
sis of records. Brown et al described a novel auto-
mated analysis approach using a recursive linear
regression to identify synchrony or asynchrony
between ribcage and abdominal movements during
breathing in 15 infants [23]. Paradoxical ribcage
motion also can be assessed by measuring thoracic
delay based on the degree to which peaks in ribcage
and abdominal signals are synchronized in time [23].
Hypopneas could be scored reproducibly using
RIP to monitor thoracoabdominal movement with or
without a simultaneous flow sensor signal [24].
Hypopnea is scored if there is a at least a 50%
reduction of RIP sum from baseline of either cali-
brated or uncalibrated signals; at least a 50% reduc-
301
tion from baseline in chest and abdominal signals
(dual channel) in the absence of an RIP sum; or more
than a 50% reduction from baseline or less than a
50% reduction from baseline accompanied by either
an arousal or an oxygen desaturation (  3%) in either
chest or abdominal signal (single channel) [1].
The accuracy of RIP in monitoring the volume
and duration of respiration depends on its initial
calibration and the constancy of calibration with body
movements and changes in lung volumes [25]. Vari-
ous procedures, such as the simultaneous equation
method, isovolume maneuver method, and least
squares regression method, can be used to calibrate
RIP [25,26]. Displacements of the transducer bands
or alterations in posture during sleep can lead to
inaccuracies in measurements. Bands should be taped
firmly to the skin to avoid slippage during overnight
monitoring. Sleep-related thoracoabdominal distor-
tion or movement asynchrony also can affect accu-
racy of RIP measurements during sleep [26,27].
Thoracic impedance
Thoracic impedance can be used to measure
airflow qualitatively. Impedance varies with the
relative amount of conductive materials (body fluids
and tissue) and nonconductive air between a pair of
electrodes placed at opposite sides of the thoracic
cage. It decreases as the volume of conductive
material increases in proportion to air and vice
versa. The volume of air contained within the
thoracic cage during the different phases of respira-
tion can be estimated based on changes in recorded
impedance [7].
Measurement of snoring intensity
Another method that has been used to measure
airflow is measurement of snoring intensity. One
study demonstrated a linear correlation, albeit weak,
between snoring intensity and respiratory effort and
flow limitation during sleep [28].
Piezo sensors
Piezo sensors can monitor changes in airflow
qualitatively but cannot distinguish central apnea-
hypopneas from obstructive respiratory events [1].
Magnetometers
Respiratory magnetometer recordings of chest and
abdominal motion have been shown to be able to
distinguish between obstructive and central apneic
302 T.L. Lee-Chiong Jr / Clin Chest Med 24 (2003) 297–306
events by differences in patterns of motion (ie,
paradoxical motion of the rib cage and abdomen with
obstructive events) [29]. The recordings also can be
used to monitor changes in body position during the
sleep study.
Canopy with a neck seal
The use of a canopy ventilation monitor to
measure ventilation quantitatively during sleep has
been described [30]. The device directly measures
gas flow using a pneumotachograph and consists of a
rigid canopy fitted over the head. It is sealed at
the neck, which creates an airtight enclosure through
which a continuous flow of air or oxygen is pro-
vided. Inflow of gas is kept equal to outflow. Airflow
is measured as respiration alters the flow in and out
of the canopy. Canopy ventilation monitoring has a
reported accuracy of approximately 92% in mea-
suring tidal volume [30].
Flow-volume loop analysis
The presence of airway obstruction during wake-
fulness and sleep can be inferred by analyzing
abnormalities of the flow-volume loop. Flow limita-
tion and an elevated upper airway resistance are
suggested by the presence of a plateau (normally
rounded) on the contour of the inspiratory flow
tracing obtained during continuous positive pressure
(CPAP) therapy for OSAHS. In one study, breath-by-
breath analysis of the flow-volume curve of a tidal
breath was accurate in identifying inspiratory flow
limitation during sleep in persons with OSAHS on
CPAP therapy [31]. Inspiratory flow limitation was
defined by the presence of an inspiratory plateau or
reduction in inspiratory flow independent of any
increase in inspiratory efforts.
Cardiac oscillometry
Small oscillations at cardiac frequency may be
appreciated in the airflow signal tracing during epi-
sodes of central apnea. These cardiogenic oscillations
are believed to be related to persistence of airway
patency possibly coupled with relaxation of the
thoracic muscles during central apneas [32].
Air mattress
Chow et al described the use of an air mattress
system that consists of multiple air compartments to
monitor noninvasively thoracic and abdominal move-
ments separately. The sensitivity and accuracy rates
of the air mattress for detecting hypopnoeas were
above 90% compared with respiratory inductive
phlethysmography [33].
Measurement of oxygenation and ventilation
Oxygenation and ventilation change rapidly dur-
ing sleep in patients with sleep-disordered breathing.
To be accurate and reliable, methods to assess oxy-
genation and ventilation must be capable of rapid and
repetitive measurements. Direct measurements of
arterial oxygen tension (PaO2), arterial carbon diox-
ide tension (PaCO2), and SaO2 via arterial blood
sampling are more accurate than estimates derived
from noninvasive methods such as pulse oximetry,
transcutaneous oxygen tension (PtcO2) measurement,
transcutaneous carbon dioxide tension (PtcCO2)
measurement, or airway CO2 (PetCO2) monitoring.
Arterial blood gas sampling provides only a static
measure of oxygenation and ventilation rather than a
continuous monitoring, however. Repetitive sampling
of arterial blood during sleep studies is painful, time
consuming, inconvenient, expensive, and intrusive of
sleep and is associated with more complications than
noninvasive assessments.
Pulse oximetry
With pulse oximetry, a pulsating vascular bed
(eg, earlobe or fingertip) is placed between a two-
wavelength light source and a sensor. This arrange-
ment is designed to eliminate any artifact that might
originate from absorption of light by venous blood or
tissue [34].
Pulse oximeters are used routinely during over-
night polysomnography to monitor SaO2. They are
easy to use, portable, relatively inexpensive, readily
available, noninvasive, respond rapidly to changes in
SaO2, and allow continuous monitoring of SaO2 [7].
Several factors influence the accuracy and reli-
ability of pulse oximetry. Pulse oximetry response
time can be affected by changes in heart rate and
circulation time. Altering the pulse oximeter response
time influences the accuracy of pulse oximeters in
measuring changes in SaO2. For instance, SaO2
recordings may be inaccurate if the oximeter response
time approximates the duration of oxygen desatura-
tion events. In one study that involved subjects with
severe OSAHS, increasing the pulse oximeter aver-
aging time from 3 seconds to 12 and 21 seconds
resulted in significant differences in the measured
SaO2, with underestimation of oxygen desaturation
by up to 60% [35].
 T.L. Lee-Chiong Jr / Clin Chest Med 24 (2003) 297–306
SaO2 measurement and response characteristics
using pulse oximetry also vary with sensor location
(eg, earlobe or fingertip) and type [36]. Finally,
sensitivity of pulse oximetry is greater with shorter
sampling intervals, and the least filtering to achieve
the most rapid response is recommended [7,37].
Several factors limit the use of oximetry in the
evaluation of persons with sleep-disordered breath-
ing. Oximetry alone is inadequate in persons without
oxygen desaturation [37]. The presence of dyshemo-
globin species, such as carboxyhemoglobin or met-
hemoglobin, produces errors in measurement because
of its reliance on only two light wavelengths [7].
Reduced skin perfusion caused by hypothermia,
hypotension, or vasoconstriction and by poor sensor
attachment may alter signal amplitude [14]. Finally,
oximetry readings may overestimate low oxygen
saturation values [38].
As a screening test for OSAHS, nocturnal pulse
oximetry has a reported sensitivity rate of 69% and a
specificity rate of 97%. Accuracy was decreased in
persons who had higher awake baseline SaO2, were
less overweight, and had milder disease [39]. Yama-
shiro and Kryger noted that nocturnal oximetry may
not be able to detect breathing disorders during sleep
with sufficient sensitivity and specificity and is inef-
fective in identifying other disorders of sleep [40]. In
another study that compared clinical assessment,
unsupervised home oximetry, and formal poly-
somnography in the diagnosis of OSAHS, clinical
assessment was superior to home oximetry analyzed
by counting the number of recorded arterial oxygen
desaturations [41].
Epstein et al compared polysomnography to two
patterns of oxyhemoglobin desaturation used as a
method of screening for OSAHS: (1) a ‘‘deep’’
pattern that consisted of more than 4% fall in SaO2
to less than or equal to 90% and (2) a ‘‘fluctuating’’
pattern that consisted of repetitive, brief drops in
SaO2 [42]. As screening tools for sleep-disordered
breathing, the ‘‘deep’’ pattern had greater specificity
and positive predictive value and the ‘‘fluctuating’’
pattern had a greater sensitivity and negative predic-
tive value. For mild disease, screening nocturnal
oximetry using the ‘‘fluctuating’’ pattern is less
sensitive compared with polysomnography, with
61% of patients with abnormal polysomnographic
studies having normal oximetry results [42].
Transcutaneous oxygen monitoring
Oxygen tension at the skin surface (PtcO2), which
is measured using a modified Clark electrode, is
influenced by cutaneous perfusion, temperature, and
303
metabolism. The application of PtcO2 monitoring
during adult polysomnography is limited by the
variable relationship between PaO2 and PtcO2 and
its slow response time that fails to mirror rapid
changes in PaO2. It requires meticulous skin prepara-
tion. Blood flow to the skin can be increased by local
application of heat, with periodic site changes every
4 to 6 hours to prevent cutaneous thermal injury [37].
A delay in recording in the warm-up period after site
changes is expected [37].
Transcutaneous carbon dioxide
Transcutaneous carbon dioxide (PtcCO2) refers to
the CO2 tension at the epidermal surface. It can be
monitored noninvasively and continuously during
sleep using a silver chloride electrode or an infrared
capnometer. PtcCO2 monitoring may provide useful
information during pediatric polysomnography
because pediatric OSAHS is associated with partial
airway obstruction, alveolar hypoventilation, and
hypercarbia. PtcCO2 monitoring is most commonly
used in neonates. It requires meticulous skin pre-
paration and arterial blood gas sampling for cali-
bration [37].
Among adults, PtcCO2 often differs significantly
from a simultaneously obtained PaCO2 [1,43]. Rou-
tine PtcCO2 monitoring has minimal clinical use
during adult polysomnography. Its slow response time
makes it unsuitable for monitoring blood gas tensions
during sleep, in which rapid and short-lasting changes
can occur [7]. PtcCO2 monitoring may be of some
use in adults with waking hypercapnia or suspected
sleep-related alveolar hypoventilation.
Expired end tidal carbon dioxide
Airway carbon dioxide (PetCO2) measured at the
end of a complete expiration is related to PaCO2.
PetCO2 can be monitored continuously during poly-
somnography using infrared spectrophotometers or
respiratory mass spectrometers. PetCO2 measure-
ments are affected by conditions that alter the rela-
tionships among ventilation, perfusion, and PaCO2
[38]. PetCO2 may underestimate PaCO2 when dead
space to tidal volume ratio is increased during sleep
because of a reduction in tidal volume. PetCO2
measurements using facemasks or nasal cannula or
during nasal CPAP ventilation may not reflect PaCO2
reliably because of gas dilution with room air or
continuous gas leakage via the CPAP mask, respec-
tively. Hypoventilation, mouth breathing, or concom-
itant use of supplemental oxygen therapy also can
give rise to inaccuracies in measurement [37,43].
304 T.L. Lee-Chiong Jr / Clin Chest Med 24 (2003) 297–306
In one study, neither PetCO2 nor PtcCO2 accurately
or consistently reflected simultaneously recorded
PaCO2 values during polysomnography in persons
who were spontaneously breathing room air, re-
ceiving supplemental oxygen given via nasal cannula,
or receiving nocturnal positive pressure ventilatory
assistance [43].
Newer approaches
Pulse transit time analysis
Blood pressure fluctuates during sleep in persons
with OSA. Blood pressure transiently increases dur-
ing arousals from sleep and falls during inspiration.
Davies et al reported that the degree of inspiratory fall
in blood pressure progressively increased from nor-
mal sleep, through snoring, to obstructive respiratory
events. The frequency of arousal-related increases in
blood pressure also rose during obstructive apnea and
during snoring accompanied by arousals [44].
Pulse transit time (PTT) is the transmission time
for the arterial pulse pressure wave to travel from the
aortic valve to the periphery. It is measured using
electrocardiography as the interval between the
R-wave and the subsequent pulse shock wave
detected at the finger. PTT is typically approximately
250 milliseconds. The speed of the shock wave is
affected by the stiffness of the arterial walls and blood
pressure. PTT is inversely related to blood pressure: as
blood pressure rises, PTT falls because of increases in
arterial wall stiffness and pulse wave speed. PTT
increases during inspiratory falls in blood pressure
and decreases during arousal-induced increases in
blood pressure [45].
With esophageal pressure as a reference, PTT has
been reported to have high sensitivity and specificity
rates in distinguishing between central and obstruc-
tive apnea-hypopnea [46]. Among persons with
OSAHS, PTT studies also have been demonstrated
to differentiate reliably between persons who require
nasal CPAP and persons who do not [47].
Forced oscillation technique
Forced oscillation technique has been proposed as
a method for detecting upper airway obstruction
during sleep and titrating CPAP therapy [48 – 51].
This technique is a noninvasive measure of input
impedance of the respiratory system that uses high-
frequency pressure oscillation to the upper airway
[49]. Forced oscillation techniques are able to par-
tition reliably the airway component of respiratory
impedance from that of lung tissue [50]. This tech-
nique does not require patient cooperation and may
prove useful for assessing uncooperative patients.
Contrary to earlier concerns, Badia et al observed
that the use of forced oscillation technique does not
alter upper airway muscle tone or affect electroence-
phalographic variables [49]. This novel approach
requires further standardization before it can be used
in clinical sleep studies [50].
Steltner et al evaluated the performance of a new
algorithm for automated detection and classification
of apneas and hypopneas based on time series analy-
sis of nasal mask pressure and a forced oscillation
signal related to respiratory input impedance [52].
They noted no significant difference in the variability
and discrepancy between automated analysis and
visual analysis of standard polysomnographic signals.
Acknowledgment
The author wishes to thank Grace Zamudio for her
assistance in the preparation of the manuscript.
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 Clin Chest Med 24 (2003) 307 – 313

Indications for treatment of obstructive sleep apnea in adults

Patrick J. Strollo, Jr, MD, FCCP
Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine,
University of Pittsburgh Medical Center, Montefiore Hospital, Suite 628 West, 3459 Fifth Avenue, Pittsburgh,
PA 15213-2582, USA

Why treat obstructive sleep apnea (OSA)? OSA
is associated with significant daytime sleepiness,
reduced quality of life, insulin resistance, motor
vehicle crashes, and vascular morbidity and mortality
[1 – 3]. Current evidence supports the belief that all
these parameters can be impacted favorably by treat-
ment. Medical therapy with positive pressure elimi-
nates snoring and favorably affects daytime sleepiness,
driving risk, vascular function, vascular risk, and
quality of life [4 – 8]. The conundrum for the clinician
is that patients are variably affected by OSA of similar
severity (Fig. 1). Treatment may be difficult to accept
or adhere to, and some treatment options are not
uniformly effective. The long-term impact of treatment
is uncertain.
The current convention is to grade the severity of
OSA by the apnea-hypopnea index (AHI). The Amer-
ican Academy of Sleep Medicine recommends grad-
ing sleep apnea as mild (AHI 5 – 15), moderate (AHI
15 – 30), and severe (AHI > 30) [9]. This metric sta-
tistically correlates the presence of sleepiness, neuro-
cognitive impairment, and vascular risk [10 – 12]. It is
relatively easy to treat patients with severe, symp-
tomatic OSA. The difficulty with regard to treatment
frequently occurs when patients with severe OSA are
not symptomatic or when patients are profoundly
symptomatic with a low AHI.
Treatment of the minimally symptomatic patient
with severe OSA can be challenging. The medical
therapy of choice—positive pressure via a mask—is
unique and not discrete [13]. The treatment is
administered in one of the most intimate settings,
the bedroom.
E-mail address: strollopj@msx.upmc.edu
In the absence of definitive long-term outcome
data, there is uncertainty regarding how hard to push
therapy in patients with mild to moderate OSA with
minimal symptoms [14]. Patients who are profoundly
symptomatic with relatively mild OSA may not
accept positive pressure therapy. The long-term effect
of alternative treatments to positive pressure is un-
known but may be of value in select circumstances.
Patient assessment
Successful treatment cannot be accomplished with-
out proper patient assessment. It is helpful to under-
stand what a patient hopes to gain from the evaluation.
This expectation is best handled by seeing the patient
before polysomnography. The clinician can under-
stand what is driving the evaluation: the complaint of
snoring, the complaint of fatigue or daytime sleepi-
ness, or the concern of vascular risk. It is also helpful to
understand up front whether the patient, spouse, or
referring physician is most concerned about OSA.
If the patient is most concerned with the pos-
sibility of OSA and he or she is subjectively sleepy,
there is a good chance that medical therapy with
positive pressure will be accepted. These patients are
good candidates for split-night polysomnography
[15 – 17]. If the patient does not complain of daytime
fatigue or sleepiness or does not regard snoring as a
significant problem, acceptance and adherence to
positive pressure therapy may be difficult to estab-
lish, and split-night polysomnography may not be
the best approach [18,19]. In this circumstance, it is
generally best to obtain a full night of diagnostic
polysomnography data and review the findings
before a trial of positive pressure.

0272-5231/03/$ – see front matter D 2003, Elsevier Inc. All rights reserved.
doi:10.1016/S0272-5231(03)00025-X
308 P.J. Strollo, Jr / Clin Chest Med 24 (2003) 307–313
Fig. 1. The variable effect of OSA on physiologic outcomes.
The clinician must know if insufficient sleep or
depression contribute to the complaint of daytime
sleepiness or fatigue [20]. Does shift work or a
possible sleep phase shift contribute to daytime
impairment? Could concomitant narcolepsy without
cataplexy or idiopathic hypersomnolence be present?
Does the patient have difficulty with sleep mainte-
nance unrelated to OSA? If so, adequate therapy may
involve treatment of insomnia or restless leg syn-
drome. Can non – sleep-related pathology, such as
chronic pain, contribute to alterations in sleep archi-
tecture and continuity?
Before positive pressure therapy is attempted,
several issues that are likely to impact on acceptance
or adherence of positive pressure should be consid-
ered. Is the patient familiar with positive pressure
therapy? If not, an educational intervention is neces-
sary before the introduction of therapy [21,22]. Is
nasal obstruction present? If so, medical and possibly
mechanical treatment of the nose may be necessary for
effective treatment [23 – 25]. Is the patient claustro-
phobic? If this is the case, an attempt at desensitization
may be beneficial before instituting therapy [26].
Tailoring the treatment to a given patient
Once the decision has been made that a patient
potentially would benefit from a trial of therapy, the
first intervention in conjunction with lifestyle recom-
mendations (ie, avoiding alcohol and sedatives,
ensuring proper sleep hygiene, beginning smoking
cessation, and maintaining fitness) should be a trial of
positive pressure via a mask [13,27]. The trial is best
accomplished in the laboratory with a technician in
attendance. Attended positive pressure titrations
allow for further patient education and reassurance
by the technical staff and proper mask fit, optimal
modality (ie, continuous positive airway pressure
[CPAP] or bi-level pressure) and an accurate pressure
prescription [21]. Whether this is accomplished in the
context of a split- or full-night study depends on the
previously discussed considerations.
In-line heated humidification may be particularly
useful in elderly patients and patients with nasal
congestion or mouth leaks [28,29]. It should be
prescribed for patients who are treated with sys-
temic anticoagulation [30]. Chin straps and oronasal
masks may be tried for mouth leaks but are poorly
tolerated compared with nasal interfaces with
heated humidification.
Second-line therapy: alternatives to
positive pressure
Despite adequate preparation and an effective
attended titration, several patients with an elevated
AHI or daytime symptoms will not accept or adhere
to positive pressure therapy. This possibility high-
lights the need for follow-up with objective measure-
ment of adherence to positive pressure therapy. In
these patients, it is important to revisit the primary
complaint that drove the evaluation in the context of
the severity of OSA and underlying vascular risk
(Fig. 2).
Primary concern: snoring
In patients with mild OSA (AHI 5 – 15), minimal
symptoms of fatigue or daytime sleepiness, and the
primary complaint of snoring, trial of an oral appli-
ance or a palatal procedure is a reasonable option
[27]. Patients may prefer an oral appliance to positive
pressure [31]. The response to treatment is not
complete, which mandates follow-up [7]. Despite
expert adjustment, treatment with oral appliance
therapy may be limited by tooth movement and bite
discomfort [32,33]. The long-term outcomes with
oral appliance therapy are not well characterized.
 P.J. Strollo, Jr / Clin Chest Med 24 (2003) 307–313
Fig. 2. Focusing the treatment on the primary patient complaint.
Palatal procedures include conventional scalpel
technique uvulopalatopharyngoplasty, laser assisted
uvulopalatoplasty, and radiofrequency treatment of
the palate (somnoplasty) [34,35]. The pros and cons
of the palatal procedures are discussed in detail
elsewhere in this issue. Overall, palatal procedures
alone can be effective treatments of snoring. If a
tonsillectomy is included, mild OSA can be impacted
favorably, although as in the case of oral appliances,
the response to treatment may not be complete and
follow-up is mandatory [36].
Optimal treatment of nasal pathology can modify
snoring favorably and may be an important contri-
bution to the treatment plan. This treatment may
require medical interventions (ie, antihistamines,
nasal steroids, or leukotriene antagonists) [23,25].
Mechanical treatment of nasal obstruction may pro-
vide additional added value. Radiofrequency treat-
ment of the nasal turbinates can be effective and may
avoid an operating room procedure [24].
Primary concern: vascular risk
Patients with OSA are at risk for vascular
morbidity or mortality [37]. If vascular comorbidity
is present in the absence of significant daytime
impairment, treatment with positive pressure may
not be accepted [19]. Similar difficulty may be
encountered with oral appliance therapy. No defin-
itive data support surgery – other than tracheos-
tomy – as an effective treatment option to impact
vascular comorbidities related to OSA [38,39].
Burgeoning evidence supports the concept that
intermittent hypoxia may be the primary determi-
309
nant of vascular risk related to OSA [40]. This may
be mediated, in part, by reactive oxygen species
that are precipitated by an ischemia-reperfusion
insult related to the intermittent cell hypoxia [41].
In animal experiments, intermittent hypoxia has
been shown to upregulate sympathetic tone, which
results in catecholamine release and elevated blood
pressure [42].
Nocturnal oxygen may be accepted in patients
who do not tolerate positive pressure therapy [43].
Although definitive evidence is lacking, it is bio-
logically plausible that nocturnal oxygen would affect
vascular risk favorably. One current limitation to this
treatment option is the inconvenience of transporting
oxygen concentrators that are bulky and weigh on
average between 20 and 50 lbs [44].
Primary concern: daytime symptoms
It is always helpful to determine the response of
impaired daytime function (ie, fatigue and sleepi-
ness) to positive pressure therapy. It is a considerable
problem to sort out this effect when patients are
unwilling to accept treatment with positive pressure.
Chronic sleep deprivation (the most common cause
of daytime impairment) and depression as confound-
ers should be excluded [20]. An objective assess-
ment of daytime sleepiness, such as the multiple
sleep latency test, can be helpful in determining the
degree of daytime impairment and providing insight
into the possibility of a concomitant diagnosis of
narcolepsy without cataplexy or idiopathic hyper-
somnolence [45].
310 P.J. Strollo, Jr / Clin Chest Med 24 (2003) 307–313
A judicious trial of a daytime stimulant may
improve quality of life. This trial is best accom-
plished in conjunction with treatment with positive
pressure therapy. Certain patients may have contin-
ued daytime sleepiness despite treatment with CPAP
or bi-level pressure. Pack et al reported success with
modafinil as adjunctive therapy for daytime sleepi-
ness in OSA [46]. In their 4-week double blind
treatment trial (n = 157), inclusion criteria required
that patients adhere to CPAP (7.1 + 2.9 hours placebo
versus 7 + 1.2 modafinil). Modafinil at a dose of
400 mg/day resulted in a significant improvement in
subjective daytime sleepiness and objective daytime
sleepiness measured by the multiple sleep latency test.
There was no difference between the two treatment
groups in the percentage who normalized their mul-
tiple sleep latency test scores to more than 10 minutes
(25% placebo versus 29% modafinil, P = 0.613) [46].
Nonamphetamine daytime stimulants seem to be
reasonably safe as an adjunct to treatment with
positive pressure for daytime sleepiness [47]. Cur-
rently, stimulant therapy alone cannot be recom-
mended for patients with sleep apnea (AHI >5)
[46,48]. If the patient does not accept positive pressure
therapy, second-line therapy for OSA should be pur-
sued, whether medical, surgical, or dental, before
contemplating adjunctive stimulant treatment. It is
imperative that the potential impact on vascular risk
be examined carefully. Follow-up monitoring of blood
pressure is necessary.
Special circumstances
Upper airway resistance syndrome
There is uncertainty regarding the use of stimulant
therapy alone in patients with the upper airway
resistance syndrome [49 – 51]. Ideally, a trial of treat-
ment with positive pressure is advisable. Unfortu-
nately, a significant percentage of these patients may
not accept treatment with positive pressure. This
approach is frequently hampered by the fact that third
party payers will not reimburse homecare companies
for a positive pressure treatment trial of upper airway
resistance syndrome, and the patient may be unwill-
ing to bear the cost.
Down syndrome
Patients with Down syndrome have upper airway
abnormalities that place them at risk for sleep-disor-
dered breathing [52]. In the adult patient with Down
syndrome, the challenge is therapeutic, not diagnostic
[53]. Many of these patients have difficulty accepting
positive pressure therapy. Oxygen may be easier to
tolerate and worth trying if CPAP or bi-level pressure
is not an option [43]. It is essential that the caregiver
responsible for the patient be trained to help the
patient with the prescribed therapy.
Hospitalized patients
Obstructive sleep apnea can be found in medical
patients hospitalized with another primary diagnosis.
Clinical experience dictates that the prevalence is
increased compared with healthy outpatients. This
rate undoubtedly reflects the high incidence of obe-
sity, cardiovascular disease, cerebrovascular disease,
and diabetes in this patient population. These patients
present a challenge to diagnose and treat while
acutely hospitalized. The need for monitoring and
intravenous medications poses problems for the sleep
laboratory in which nursing personnel may not be
available to provide additional care. The patient may
be reluctant to pursue treatment with positive pres-
sure during the hospitalization. Sleep deprivation, the
use of sedatives and narcotics, and suboptimal volume
status also may tend to worsen the severity of the
underlying OSA. It may be important to identify OSA
acutely, but definitive treatment with CPAP or bi-level
pressure may be best reserved when the patient is
stabilized as an outpatient. Head of bed elevation and
supplemental oxygen may be better tolerated acutely
[43,54 – 56].
Elderly patients
Elderly patients (particularly older than 80 years),
much like hospitalized patients, are challenging to
treat. Major abnormalities of the sleep schedule are
frequently present. Concomitant insomnia and ad-
vanced phase disorders make it problematic to assess
a response to positive pressure if OSA is present [57].
Many of these patients have significant vascular risk,
and treatment makes good clinical sense. Second-line
therapy with oxygen or head of bed elevation is
frequently the best fit in these patients and may
provide significant benefit [43,54 – 56].
Hypoventilation syndromes
Hypercapnia is common in OSA but frequently
overlooked. One recent series found that 17% of
patients referred for polysomnography had evidence
of daytime hypercapnia [58]. There is uncertainty
whether CPAP is contraindicated. If a patient com-
plains of frequent morning headaches or has evidence
 P.J. Strollo, Jr / Clin Chest Med 24 (2003) 307–313
of persistent right heart failure or hypercapnia—or
both—at the time of follow-up, a bi-level pressure
titration should be considered [59].
Summary
The primary treatment modality for OSA remains
positive pressure therapy. Differential susceptibility
to daytime sleepiness and vascular risk exists. In
patients who do not accept positive pressure therapy
despite careful attempts to optimize the treatment,
second-line therapy should be explored.
A careful assessment of the primary treatment con-
cern should guide further intervention(s). Although pal-
atal surgery can treat snoring effectively, the effect on
the AHI and daytime sleepiness is less robust. Oral ap-
pliances may help some patients [31]. Recent data
suggest that the durability of the treatment over time is
uncertain and subject to frequent dental complications
[32,33].
Treatment with oxygen should be considered in
patients who do not accept positive pressure therapy
and are believed to be at increased risk for vascular
complications [43]. Current generation oxygen con-
centrators are difficult to transport and limit the use of
this treatment option in highly mobile patients [44].
Special populations, including patients with Down
syndrome, hospitalized patients, and elderly persons,
may be more accepting of treatment with oxygen via
nasal cannula alone. Although this approach makes
biologic sense, definitive outcome evidence is lacking.
Future expectations
Cumulative epidemiology data provide a con-
vincing argument that patients with OSA are at risk for
impaired daytime performance (sleepiness or fatigue),
insulin resistance, automobile crashes, and vascular
complications. It also has become evident that whereas
a dose-response relationship exists with regard to the
AHI and risk for the group as a whole, differential
susceptibility may exist for a given patient [10 – 12].
The challenge for the future is to define the risk in
a given patient. Physiologic tests that provide added
value to the current evaluation are welcome. Quan-
tifying daytime impairment with vigilance testing and
better assessing vascular risk with new technology
may prove to be useful [60 – 62]. On the horizon,
insights gained from functional genomics, proteo-
mics, and possibly metabonomics undoubtedly will
provide powerful data for future clinical decision
making in OSA [63].
311
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restricted to 4 – 5 hours per night. Sleep 1997;20:
267 – 77.
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effect of upper airway obstruction and arousal on pe-
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[62] Pitson DJ, Sandell A, van den Hout R, Stradling JR.
Use of pulse transit time as a measure of inspiratory
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[63] Brindle JT, Antti H, Holmes E, et al. Rapid and non-
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 Clin Chest Med 24 (2003) 315 – 342

Continuous positive airway pressure: new generations

Francoise J. Roux, MD, PhDa,b,*, Janet Hilbert, MDa,c
a
Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, 333 Cedar Street,
Post Office Box 208057, New Haven, CT 06520-8057, USA
b
West Haven VA Medical Center Sleep Laboratory, 950 Campbell Avenue, West Haven, CT 06516, USA
c
Yale Center for Sleep Medicine, 333 Cedar Street, Post Office Box 208057, New Haven, CT 06520-8057, USA

Continuous positive airway pressure (CPAP) ther-
apy for obstructive sleep apnea (OSA) was first
described in 1981 [1]. Since that time, CPAP has
become the mainstay of therapy for OSA [2]. CPAP
effectively prevents repetitive upper airway obstruc-
tion, most likely by acting as a pneumatic splint [3],
and is associated with improved respiratory [1,4] and
sleep parameters [5] and clinical outcomes [5 – 15].
CPAP therapy continues to evolve, and, since the last
review of positive airway pressure therapy in this
Clinics issue [16], further advancements have been
made in newer generations of CPAP. Automatic (also
known as automated, autotitrating, or autoadjusting)
positive airway pressure (APAP) devices detect and
respond to changes in upper airway resistance by
variably increasing or decreasing the pressure gener-
ated. As such, APAP potentially may be able to (1)
assist with the initial diagnosis of OSA, (2) act
therapeutically in patients with OSA instead of con-
ventional CPAP, and (3) assist with CPAP titration to
determine an effective conventional CPAP pressure in
patients with confirmed OSA. In this article, the
authors present an updated review of the technical
aspects of APAP and the diagnostic, therapeutic, and
titrating capabilities. They also discuss the current
clinical recommendations for use of these devices.
* Corresponding author. Section of Pulmonary and
Critical Care Medicine, Yale University School of Medi-
cine, 333 Cedar Street, PO Box 208057, New Haven, CT
06520-8057.
E-mail address: francoise.roux@yale.edu (F.J. Roux).
Technical aspects of automatic positive
airway pressure
Background
The original CPAP device described by Sullivan
et al in 1981 [1] (Fig. 1) consisted of a vacuum
cleaner blower motor with variable speed control
installed in a box lined with acoustic material. This
was connected to a wide bore tube, into which were
inserted soft plastic tubes to fit into the patient’s nares
and which then distally narrowed with mechanical
resistance. A range of pressures could be generated.
Although effective in maintaining the patency of the
upper airway in patients with OSA, the original
CPAP machines in the 1980s were heavy (approx-
imately 15 – 20 lbs), loud, and fairly simple, with
limited capabilities.
Over the past 20 years, machines have become
lighter (typically ranging from 3.5 – 6 lbs), quieter,
and more sophisticated. In some CPAP machines,
microprocessors allow compliance data (most cur-
rently using mask-on-time rather than the earlier
machine-on-time) to be stored for variable amounts
of time and downloaded. Various options, including
specialized filters, ramps, automatic altitude adjust-
ment, automatic leak compensation, internal power
adaptors, and internal humidification, have been
incorporated into various machines. Options for
CPAP accessories, including nasal and oronasal
masks, headgear, and humidification, also have
increased, seemingly exponentially.
Another level of sophistication has been added
with the development of APAP devices. APAP devices

0272-5231/03/$ – see front matter D 2003, Elsevier Inc. All rights reserved.
doi:10.1016/S0272-5231(03)00017-0
316 F.J. Roux, J. Hilbert / Clin Chest Med 24 (2003) 315–342

ers also are required downstream and upstream of the

Fig. 1. Diagram of apparatus used to provide CPAP from the
nares. In the experimental system, pressure (Pa) was measured
via a catheter in one nasal tube, and airway CO2 (CO2) was
sampled via a catheter in the other nasal tube. (From Sullivan
CE, Issa FG, Berthon-Jones M, Eves L. Reversal of
obstructive sleep apnoea by continuous positive airway
pressure applied through the nares. Lancet 1981;1:862;
with permission.)
central processing unit. Technology does not come
without a price; the cost of currently available APAP
devices can be 1.5 to 3 times that of conventional
CPAP machines, depending on incorporated features.
APAP devices can function exclusively in a diagnostic
mode and recognize and record abnormal respiratory
events without correcting them. APAP devices also
function in a therapeutic mode, responding to events
(or lack of them) by adjusting the positive airway
pressure accordingly.
Detection of upper airway obstruction by
automatic positive airway pressure

As shown in Table 1, current APAP devices detect

use noninvasive methods to detect evidence of upper
airway obstruction, including snoring, apneas, hypo-
pneas, or airflow limitation. As shown in Fig. 2, a
diagram of prototype device that detects and responds
to pharyngeal wall vibration [17], APAP devices
incorporate one or more sensors to detect a signal (in
this case, a pressure transducer to detect pharyngeal
wall vibration) and a central processing unit to inter-
pret the signal(s) (according to specific diagnostic
algorithms) and determine the resultant voltage for
the APAP blower in response to the signal(s) (accord-
ing to specific therapeutic algorithms). Additional
band filters and rectifiers are needed to process the
signal, and analog-digital and digital-analog convert-
multiple abnormalities, such as snoring, apneas, hypo-
pneas, or flow limitation, which are surrogates of
upper airway obstruction. Clinical studies have been
published in the peer-reviewed literature to date on
versions of the Autoset (ResMed, Sydney, Australia)
[18 – 32], Goodknight 418A (Puritan Benett/Malinck-
rodt, Les Ulis, France) [33] and its precursor, REM +
auto (SEFAM/Nellcor Puritan Benett, Nancy, France)
[34 – 37], Horizon AutoAdjust (DeVilbiss/Sunrise
Medical, Somerset, PA) [38 – 42], Morphee Plus/
Cloudnine (Pierre Medical/Nellcor Puritan Benett,
Verrieres-Le-Buisson, France, and Minneapolis, MN)
[41,43 – 46], REM + with MC + (SEFAM/Nellcor
Puritan Benett) [47], Somnosmart (Weimann, Ham-

Fig. 2. Diagram of prototype APAP system’s major components. LCD, liquid crystal display; CPU, central processing unit;
ROM, read only memory; RAM, random access memory. (From Behbehani K, Yen FC, Burk JR, Lucas EA, Axe JR. Automatic
control of airway pressure for treatment of obstructive sleep apnea. IEEE Trans Biomed Eng 1995;42:1007; with permission.)
 F.J. Roux, J. Hilbert / Clin Chest Med 24 (2003) 315–342 317

Table 1
Comparison of parameters detected by automatic positive airway devices
Parameters detected
Device Manufacturer Sn A/H (flow) A/H (FOT) FL
Autoset ResCare/ResMed, + + +
Autoset Clinical Sydney, Australia,
Autoset Portable San Diego, CA,
Autoset T Saint Priest,
Autoset Spirit France

Eclipse Auto Taema, Antony, France + +

Goodknight Puritan Benett, Pleasanton, + +

TM418A CA/Mallinckrodt, Les Ulis, France

Goodknight Puritan Benett, Pleasanton, + + +

TM418P CA/Mallincrodt, Les Ulis, France

Horizon DeVilbiss Healthcare,Inc./Sunrise Medical, + +

AutoAdjust Somerset, PA, Parcay Meslay, France

Morphee Plus Pierre Medical, Verrieres-Le-Buisson, +

Cloudnine France/Nellcor-Puritan Benett, Minneapolis, MN

REM + with MC + SEFAM/Nellcor-Puritan Benett, Nancy, France + +

REM + Auto

REMstar Auto Respironics Inc., Murrysville, PA + + +

Somnosmart Weiman, Hamburg,Germany +

Tranquility Auto Respironics Inc., Murrysville, PA + +

Virtuoso LX Respironics Inc., Murrysville,PA +

Abbreviations: Sn, snoring (detected by mask pressure vibration); A, apnea; H, hypopnea; flow, airflow detected by pneu-
motachograph, nasal pressure, or changes in compressor speed; FOT, forced oscillation technique; FL, flow limitation (detected
by flow versus time profile).

burg, Germany) [48 – 53], and Virtuoso (Respironics,
Murrysville, PA) [33,54 – 56]. Sensors used to detect
evidence of upper airway obstruction and diagnostic
algorithms vary among devices.
Most, but not all, APAP devices have the capabil-
ity of detecting snoring. Snoring is typically detected
by a high frequency response pressure transducer in
the presence of mask pressure vibration [17,25,
34,37,47,54,57]. The signal is then band-pass filtered
using high pass and low pass filters specific to the
device (eg, 30 Hz and 280 Hz in the REM + auto
[34,37] and the REM + with MC plus [47] devices
and 20 Hz and 120 Hz in another prototype [17]), and
the amplitude is then analyzed to detect amplitude
variations, such as snoring.
Many APAP devices also can identify apneas, as
indicated by absence of flow or pressure, and hypo-
pneas, as indicated by decrements of flow or pressure.
Early versions of the Autoset in diagnostic mode
detected apneas (and later, apneas and hypopneas) by
analyzing the pressure tracing from nasal prongs [19],
whereas later therapeutic models detected changes in
flow with a built-in pneumotachograph [30]. The
Horizon AutoAdjust [40] also uses a pneumotacho-
graph to detect apneas and hypopneas. The Morphee
Plus determines patency of the upper airway by
monitoring the breath-by-breath difference between
maximal inspiratory and expiratory flow based on
machine compressor speed [43]. The default defini-
tions of apneas or hypopneas used by the detection
software vary with the specific device and software
version, as does the ability for the clinician or
investigator to change the detection algorithm. For
example, on the Horizon Autoadjust, the criteria for
318 F.J. Roux, J. Hilbert / Clin Chest Med 24 (2003) 315–342

hypopnea (eg, percent flow decrement and duration)
can be programmed [39].
Forced oscillation technique (FOT), initially
described by DuBois et al in 1956 [58], is a unique
noninvasive method that detects changes in airway
resistance or impedance [59]. Since the initial
description, this technique has been validated in a
research model of airway obstruction [60] and in
patients with OSA [61,62]. A pump, connected to
the CPAP system, generates a sinusoidal pressure
signal at a constant frequency during spontaneous
breathing; respiratory impedance (Z) or respiratory
system resistance (Rrs) is derived from the oscillatory
pressure and flow signal at the nasal mask. In patients
with OSA, apneas are associated with sustained
increases in impedance throughout the respiratory
cycle, whereas hypopneas are associated with inter-
mittent increases in impedance (Fig. 3). With CPAP
treatment, as CPAP is progressively increased to the
effective range (Fig. 4), breathing flow normalizes,
esophageal pressure swings become less negative,
and respiratory resistance or impedance decreases to
normal. This technique has since been used to control
the pressure algorithm in several devices, including
the Somnosmart [48 – 53] and other prototypes
[60,63].
As shown in Table 1, few of the currently avail-
able devices can detect flow limitation. The char-
acteristic inspiratory airflow flattening seen with
increased upper airway resistance [64] may be the
most sensitive indicator of upper airway obstruction
[65,66]. In the Autoset, the flow-time profile (with
flow measured by pressure transducer or pneu-
motachograph) is expressed as a curvature index
(Fig. 5) [25]. A low curvature index suggests inspir-
atory airflow limitation, whereas a higher curvature
index suggests more normal airflow.
Adjustment of positive airway pressure by
automatic positive airway pressure
Once a respiratory event is detected, APAP devices
increase the pressure automatically in a progressive
fashion until an effective therapeutic pressure is
reached. Conversely, in the absence of respiratory
events, the pressure level decreases until evidence of
upper airway obstruction recurs. APAP devices are
inherently unstable [67]. The algorithms for pressure
adjustment vary among specific APAP devices. Even
within a specific device, the amount of pressure
increase and the time course of pressure change vary

Fig. 3. Representative compressed polysomnographic recording (6 epochs, 3 minute). Note that impedance (Z) increases during
apnea and is low during arousal. The pattern of Z shows a cyclic increase before apnea and during hypopnea (the last event in
this figure). EOG, electrooculogram; C4-A1 and C4-A2, electroencephalogram channels; EMG-GC, chin electromyogram; Flow,
flow by pneumotachograph; Effort, effort by thoraco-abdominal bands; Sum, thoraco-abdominal sum; SaO2, arterial oxygen
saturation; Gen DC Z, respiratory impedance. (From Badia JR, Farre R, Montserrat JM, Ballester E, Hernandez L, Rotger M,
et al. Forced oscillation technique for the evaluation of severe sleep apnoea/hypopnoea syndrome: a pilot study. Eur Respir J
1998;11:1128; with permission.)
 F.J. Roux, J. Hilbert / Clin Chest Med 24 (2003) 315–342 319

Fig. 4. Breathing flow (V), esophageal pressure (Pes), and respiratory resistance (Rrs) in a patient at different levels of CPAP.
Note that at low subtherapeutic CPAP levels (CPAP = 4 cm H20), obstructive apnea—characterized by minimal V, wide swings
in Pes, and high Rrs—occurs. With increasing, but still suboptimal CPAP (CPAP = 8 cm H20), hypopnea occurs, characterized by
variable Rrs. With therapeutic CPAP (CPAP = 12 cm H20) and return of normal V and Pes, Rrs decreases to normal. (From
Navajas D, Farre R, Rotger M, Badia R, Puig-de-Morales M, Montserrat JM. Assessment of airflow obstruction during CPAP
by means of forced oscillation in patients with sleep apnea. Am J Respir Crit Care Med 1998;157:1526; with permission.)

with the specific respiratory event detected, with
larger changes for apneas and smaller changes for
more subtle upper airway obstruction, such as snoring
or flow limitation. For example, in the Autoset
device, positive pressure increases in response to
snoring, apneas, and flow limitation [25]: snoring
(depending on the loudness of the snoring) results in
an increase in pressure by 1 cm H2O/breath; flow
limitation (depending on the curvature index) results
in an increase in pressure by 1.5 cm H2O/minute;
apneas (depending on calculated airway conductance)
result in an increase in pressure by 1 cm H2O/

Fig. 5. Schematic of Autoset software response to various flow versus time curves. The curvature index is a measure of the
deviation from unit scaled flow over the middle 50% of inspiratory time (indicated by shading). (Left) A severely flattened
curve with a low curvature index typical of inadequate CPAP pressure. The software responds by increasing CPAP pressure.
(Center) A breath showing slight flattening. The CPAP pressure remains unchanged. (Right) Rounded curve with high curvature
index; the software assumes that this breath represents hyperadequate CPAP pressure. The software reduces the CPAP pressure.
(From Teschler H, Berthon-Jones M, Thompson AB, Henkel A, Henry J, Konietzko N. Automated continuous positive airway
pressure titration for obstructive sleep apnea syndrome. Am J Respir Crit Care Med 1996;154:734; with permission.)
320 F.J. Roux, J. Hilbert / Clin Chest Med 24 (2003) 315–342
15 second of apnea. If no further abnormalities are
detected, pressure decreases with a time constant of
20 minutes for snoring and flow limitation and
40 minutes for apnea. In contrast, in the Morphee
Plus, if upper airway obstruction is detected (based
on changes in compressor speed), the pressure
increases between 1 and 3 cm H2O at a rate of 1 cm
H2O/second depending on the severity of the respir-
atory abnormality. In the absence of a respiratory
abnormality, pressure decreases at a rate of 1 cm
H2O / 30 seconds [43]. In some devices, the clinician
can change the default algorithms [39].
Most APAP devices operate in the range of 3 to 4
to 18 to 20 cm H2O pressure, and the upper and lower
limits of acceptable pressure usually can be set by the
clinician. Typically, the pressure starts low and auto
adjusts depending on the therapeutic algorithm. Some
devices, such as the Morphee Plus [43] and the REM
+ auto [35], operate around an acceptable range (such
as + 2 cm and
4 cm H2O) of a reference pressure
(with the reference pressure set by the clinician using
either a previous CPAP titration or a formula); the
clinician also can set the acceptable range or use the
default settings for range.
Special issues: detection of leaks, central apneas,
and hypoventilation
Mask and mouth leaks and mouth breathing are
not uncommon in conventional CPAP titrations, with
continuous leaks occurring in 7 of 14 patients in one
study [68] and lasting from 4% to 70% of total sleep
time. Mouth leaks limited APAP therapy in 2 of 15
patients with OSA using a device based on snoring
detection (REM + Control with MC +, with apnea/
hypopnea detection disabled) [47]. With the Autoset,
leaks in excess of 0.4 L/second occur for an average
of 10% of a supervised night and 15% of an unsu-
pervised night [27]. Leaks tend to be interpreted by
many APAP systems as apneas or hypopneas and
result in increases in pressure, which, in turn, increase
leak [69]. Examining the raw flow signal can allow
for the detection of leaks [42]. Some devices have
algorithms that limit pressure increases when mask
pressure goes to zero, which indicates that the mask is
off or when there are excessive leaks as detected by
mean mask flow [25]. Leak alarms have been incor-
porated into some units. Some devices, such as the
Autoset and the Goodknight 418P, can record leaks
during the night for later use in interpretation. In
devices that use FOT, mouth leaks can induce false
low impedance values and lead to an underestimate of
upper airway obstruction, whereas mouth expiration
or change in the route of breathing can lead to a false
increase in impedance and an overestimate of upper
airway obstruction. Incorporating a pneumotacho-
graph along with FOT can be helpful in avoiding
misinterpretation of the FOT signal [68].
Another problem for APAP devices is the distinc-
tion between central and obstructive apneas. The
Autoset software classifies apneas as having closed
and open airways through the calculation of airway
conductance by modulating the mask pressure during
apnea and measuring the resultant induced airflow.
The pressure increases for obstructive apneas and for
central apneas in which the airway is closed [25].
Using FOT, whereas obstructive apneas are associ-
ated with sustained increases in impedance, central
apneas can be associated with high or low impedance
values, which suggests that different mechanisms
may be involved [61]. Cardiac oscillations may be
visible in the FOT signal to help distinguish central
from obstructive apneas [70]. Many clinical trials of
APAP devices have excluded patients at risk for
central apnea, such as persons with congestive heart
failure [69].
Current APAP devices do not incorporate oxime-
try and cannot detect sustained oxygen desaturation
in the absence of upper airway obstruction. Many
clinical trials of APAP have excluded patients at risk
for hypoventilation, including persons with chronic
obstructive pulmonary disease or other respiratory
disease/respiratory failure [69].
Comparison of commercially available automatic
positive airway pressure devices
Few studies have been published that directly
compare the available APAP devices listed in
Table 1. Farre et al [71] used a bench model with a
waveform generator to simulate normal breathing,
apneas, hypopneas, and flow limitation, with or with-
out snoring, and tested the response of five different
APAP devices (AutoAdjust LT, Autoset Portable II
Plus, Autoset T, Virtuoso LX, and Goodknight 418P)
to different combinations of signals. All these devices
responded to snoring; however, they responded differ-
ently to various degrees of hypopneas, and some did
not even respond to repetitive apneas. The time course
of pressure adjustment after normalization of breathing
also varied with devices, as did the behavior after a
simulated leak. Lofaso et al [33] also used a bench
model to study the performance of six commercially
available devices (Horizon AutoAdjust, Goodknight
418A, Goodknight 418P, Autoset T, Virtuoso LX, and
Eclipse Auto), this time in response to simulated
 F.J. Roux, J. Hilbert / Clin Chest Med 24 (2003) 315–342
snoring at varying frequencies and at different CPAP
pressures. Threshold pressure-amplitude differences
of up to threefold were found across devices, and the
sensitivity of snoring detection decreased as CPAP
increased in all devices.
A follow-up study was performed in six patients
with OSA to test the clinical significance of these
findings. The percentage of snoring events followed
by a pressure increase was higher in the device that
was more sensitive in the bench study (Goodknight
418P) than in the less sensitive device (Virtuoso LX).
The only other comparative study in patients reported
to date [41] compared the response of two different
devices to nasal obstruction induced by local instilla-
tion of histamine. One device was regulated by
analysis of changes in compressor speed (Morphee
Plus), and the other device was regulated by analysis
of changes in flow determined with a pneumotacho-
graph (Horizon); neither device analyzed flow versus
time curves. The authors found that increases in nasal
resistance occurred with histamine and that flow
limitation and arousals generally accompanied the
increase in nasal resistance. The behavior of the
two devices differed and was sometimes paradoxical,
however. Mask pressure initially decreased as nasal
resistance increased in the Morphee Plus and some-
times subsequently increased, whereas mask pressure
did not change with the Horizon. Whether and to
what extent these differences between devices impact
long-term clinical outcomes is not known.
Role of automatic positive airway pressure in
diagnosis of obstructive sleep apnea
Rationale for use of automatic positive airway
pressure in diagnosis of obstructive sleep apnea
The diagnosis of OSA is conventionally made by
level 1 polysomnography (PSG) performed by a
trained technologist who attends the patient (usually
in a sleep laboratory), with recording or documenta-
tion of sleep and respiratory variables including
electroencephalogram, electrooculogram, chin elec-
tromyogram, airflow, respiratory effort, arterial oxy-
gen saturation (SaO2), and body position, with or
without leg movement recording [72,73]. In general,
the number of respiratory disturbances per hour of
sleep (RDI) or the sum of apneas and hypopneas per
hour of sleep (AHI) is used as the summary statistic
to diagnose OSA and determine the severity of sleep-
disordered breathing. It has become increasingly clear
that the RDI can vary as much as tenfold [74]
depending on the technique used to measure airflow
321
[75] and the definitions used to define specific
respiratory events (eg, percent flow change, degree
of oxygen desaturation, presence/absence of arousal
on encephalogram). The best metric to define OSA
and the cutoff between normal and abnormal is
controversial [76,77]. The RDI can have internight
and intranight variability, and it is possible for OSA
to be missed on one night of monitoring [78,79].
Despite these limitations, in the United States, level I
PSG is the gold standard for diagnosing OSA and
guiding treatment options, and it is against this
standard that other options must be compared.
In light of the growing clinical recognition of OSA
[80], there have been attempts in the United States and
elsewhere [81 – 83] to perform unattended home mon-
itoring for OSA to reduce the diagnostic waiting time.
Portable and generally unattended studies may range
from comprehensive portable PSG (level II) to modi-
fied portable sleep apnea testing (level III) to continu-
ous single or dual bioparameter recording (level IV).
The benefits and limitations of portable monitoring
have been reviewed elsewhere in this issue and are not
discussed herein. APAP devices have inherent di-
agnostic capability that is consistent with a level IV
recording (or even a level III recording if additional
monitoring such as respiratory effort, oximetry, and
electrocardiogram or heart rate, with or without body
position is added to assessment of airway patency by
APAP), and APAP theoretically could be helpful in
diagnosing OSA. The rationale for the use of APAP in
the diagnosis of OSA is that it might provide an
accurate enough diagnosis in some patient groups, it
might reduce diagnostic waiting time, and it might
reduce health care costs.
Studies that evaluate automatic positive airway
pressure for the diagnosis of obstructive
sleep apnea
A limited number of published studies have eval-
uated whether APAP is reliable enough in the diag-
nostic mode to recognize sleep-disordered breathing
(Table 2). All [19 – 23,28,29,70] except one [42] of
these studies were performed in a supervised envi-
ronment, with concurrent PSG, with airflow during
PSG usually [19,21 – 23,28,29,70] but not always
[20] monitored with thermistor. Sometimes these
studies were conducted with unselected consecutive
patients [19,21,23], but often they were conducted
in patients who were suspected of having OSA
[20,22,28,29,42,70]. Exclusions were not always
stated, but several groups excluded technically unsat-
isfactory recordings [20,22] or technically unsatisfac-
 322
F.J. Roux, J. Hilbert / Clin Chest Med 24 (2003) 315–342
Table 2
Summary of diagnostic studies of automatic positive airway pressure devices
Sensitivity at threshold Specificity at threshold
AHI(AI) >5 AHI(AI) >5
AHI(AI) >10 AHI(AI) >10
AHI Mean Correlation APAP:PSG Limits of agreement APAP-PSG AHI(AI) >15 AHI(AI) >15
Author Device n (SE or SD) (AI:AI) AHI:AHI (AI-AIdiff ) (95% CI) AHI-AHIdiff (95% CI) AHI(AI) >20 AHI(AI) >20
Gugger et al [19] Autoset — (r = 0.85) — — —
‘‘Autumn’’ — — — —
27 — —
82% 90%
Bradley et al [21] Autoset 25 — — — —
Version 2.0 (SE = 4) r = 0.85 + 3.1 (+ 8.4,
1.6) — —
37 100% 92%
— —
Kiely et al [22] Autoset 19.4 (r = 0.85)
(
15.5, + 10.5) — —
Version 3.03 (SD = 24.7) r = 0.92
(
15.5, + 13) 85% 87%
36 100% 92%
88% 93%
Fleury et al [20] Autoset — (r = 0.98) + 2.6 (
11.6, + 6.4) (100%) 76%
— — — (100%) 87%
44 (100%) —
(100%) 88%
Mayer et al [29] Autoset 43.3 (SD = 33.4) — — 97% 50%
— r = 0.87
9.6 (
2.2, + 23.7) 92% 79%
95 86% 86%
79% 93%
Gugger [23] Autoset 26.2 (SE = 2.9) (r = 0.95) (+ 2.5) (+ 15.6,
10.6) — —
Version 3.03 r = 0.95 + 4.2 (+ 18.7,10.3) — —
67 — —
97% 100%
Rees et al [28] Autoset 39 (SD = 26) — — — —
Version 3.03 r = 0.9a
3.1a (+ 11.2,
17.4)a — —
27 — —
— —
Fletcher et al [42] Horizon — — — — —
63 r = 0.85b — — —
— —

F.J. Roux, J. Hilbert / Clin Chest Med 24 (2003) 315–342

— —
Steltner et al [70] Prototype AHI1= 34.2 — Kw1 = 0.45 — —
(FOT) (SD = 17.4) — —
19 AHI2= 25.4 — Kw2 = 0.5 — —
(SD = 19.6) — —
Abbreviations: AHI, apneas plus hypopneas per hour (AHI determined by APAP per recording time and determined by PSG per hour of sleep except where noted); AHI-AHIdiff, mean
difference between AHI determined by APAP and AHI determined by PSG; AHI1 and AHI2, apneas plus hypopneas per hour of sleep for scorer 1 and scorer 2, respectively; AI, apneas per
hour; AI-AIdiff, mean difference between AI determined by APAP and AHI determined by PSG; APAP, automatic positive airway pressure; CI, confidence interval; FOT, forced oscillation
technique; Kw1 and Kw2, weighted kappa for apneas plus hypopneas per hour of sleep computed on second-by-second basis to evaluate agreement between APAP and scorer 1 and scorer 2,
respectively; PSG, polysomnography; r, correlation coefficient; SD, standard deviation; SE, standard error.
a
This study compared AHI as detected by APAP to AHI per time in bed on PSG.
b
This study compared AHI as detected by APAP to AHI determined from visual analysis of flow from APAP study.

323
324 F.J. Roux, J. Hilbert / Clin Chest Med 24 (2003) 315–342
tory portions of recordings [28] from analysis. Chronic
obstructive pulmonary disease [22], respiratory failure
[70], awake hypoxemia [22], complicating medical
illnesses [42], severe arrhythmia [70], or suspicion for
complicating sleep disorders [42] were exclusions in
several reports.
Most of the diagnostic studies of APAP have been
conducted with the Autoset device, with early studies
using devices that detected only apneas [19,20] and
later studies using devices that detected apneas and
hypopneas, with [20,22,28,29] or without [21] differ-
entiating different types of respiratory events. In
general, as noted in Table 2, the correlation between
respiratory events detected by APAP and those
detected by PSG was good, with correlation coeffi-
cients of 0.85 to 0.98. The limits of agreement
between APAP and PSG were wide, however, with
mean differences in AHI detected by APAP compared
with PSG ranging from
9.6 to + 4.2, with 95% of
the true values for the difference ranging from
15.5
to + 23.7. Often, APAP overscored respiratory events
compared with PSG [19 – 23], but two groups found
that APAP underscored events [28,29]. In part, this
may be related to different denominators for the AHI
determined from APAP (ie, time in bed) and AHI
determined from PSG (ie, total sleep time in usual
practice and in most of the noted comparative studies).
APAP devices cannot detect sleep. Irregular breathing
in wakefulness may be detected as respiratory distur-
bances and may increase artificially the AHI deter-
mined by APAP, whereas long periods of wakefulness
with regular breathing or time off the device artificially
may decrease the AHI.
The use of thermistors to monitor airflow in PSG
also may lead to a lower AHI than the nasal pressure
used by this APAP device [23]. Sensitivity and spec-
ificity varied with the AHI threshold used to define
disease, with increased specificity with increasing
severity of OSA. In one multicenter study [29], a high
pretest probability added—not unexpectedly—to the
diagnostic accuracy of APAP. In two studies, APAP
was found to be superior to oximetry alone in diagnos-
ing OSA [21,23]. In a study that used a different
prototype APAP device incorporating FOT to monitor
upper airway obstruction [70], Steltner et al found that
APAP yielded diagnostic results similar to visual
analysis of standard PSG performed by two scorers.
In the only unattended (home) study reported to
date [42], Fletcher et al studied 63 patients (screened
for the presence of symptoms of OSA and the
absence of complicating illnesses) using a device that
monitors airflow with a built in pneumotachograph
(Horizon). No gold standard PSG was performed,
although analog flow tracings were examined in an
unblinded fashion by the investigators. The RDIs
determined by APAP correlated with the RDIs deter-
mined by visual analysis (r = 0.85), although the
former were systematically lower than the latter, in
part because the APAP software did not correct for
time off the device. Nine patients could not complete
the study because of failure to tolerate the mask,
inability to hook up the equipment properly, or failure
to return for follow-up. Of the 53 remaining patients
with successful studies, 45 were diagnosed with OSA
by APAP, 35 of whom ultimately returned for APAP
titration studies. The authors reported an average of
1.4 diagnostic studies and 2.4 titration studies to
establish the diagnosis and reach satisfactory treat-
ment pressures. Cost analysis showed that in this
group of patients, the estimated cost for all in-home
APAP studies was less than one fourth the estimated
cost for in-laboratory PSG. There are no published
data on subsequent compliance with CPAP therapy
when the diagnosis of OSA is made using APAP in
an unattended setting. Kreiger et al reported a lower
subsequent objective compliance with CPAP in a
group of patients diagnosed in the ambulatory setting
with a MESAM IV ambulatory monitoring device,
however, as compared with patients diagnosed by
PSG [84].
Taken together, these studies suggest that APAP in
diagnostic mode, after examination of the raw data to
exclude technical problems [19,23], can diagnose
severe OSA effectively, particularly in the presence
of high clinical suspicion and in the absence of
complicating factors. Given the wide limits of agree-
ment between APAP and conventional PSG, the use
of APAP to diagnose less severe OSA is problematic
[21,22]. In the presence of a high clinical suspicion
for OSA and a negative result on APAP, conventional
PSG still plays a role [29]. Although APAP studies
are less expensive than conventional PSG studies
[21,42] and could potentially save costs in some
patients, the overall health care cost-benefit of this
approach on a large scale remains to be clarified.
Role of automatic positive airway pressure in
therapy for obstructive sleep apnea
Rationale for the use of automatic positive airway
pressure in therapy for obstructive sleep apnea
Conventional CPAP, used at an effective pressure
in patients with OSA, has been shown to reduce
nocturnal respiratory disturbances and improve noc-
turnal oxygenation [1,4] and sleep architecture [5].
Regarding longer term clinical outcomes, CPAP
 F.J. Roux, J. Hilbert / Clin Chest Med 24 (2003) 315–342
improves neurocognitive function, including daytime
sleepiness [5 – 8], cognitive performance [9], driving
performance [10,11], and perceived health status
[7,8,12]. Treatment with CPAP also may be associ-
ated with improvement in mortality [13] and cardio-
vascular endpoints, such as systemic hypertension
[14,15], cardiac arrhythmias [85], nocturnal ischemia
[86], and left ventricular function [87]. Finally,
patients with OSA who are treated with CPAP have
decreased health care use compared with untreated
patients [88].
Despite these benefits, conventional CPAP is not
accepted by all patients [89,90]. An early study using
covert monitoring demonstrated that 35 patients who
were followed over 3 months attempted to use CPAP
only 66% of the monitored days, with a median use
of 4.9 hours [89]. ‘‘Inconvenience’’ and ‘‘stuffy
nose’’ were frequently cited problems, but only a
complaint of ‘‘claustrophobia’’ distinguished regular
users from irregular users; CPAP pressure was similar
in the two groups. In a larger long-term study of
1211 patients in Edinburgh followed for a median of
22 months [90], 68% used CPAP at least 2 hours/
night, with a median use of 5.7 hours. Reasons for
discontinuing CPAP included lack of benefit and
discomfort (including noise and feeling of claustro-
phobia). In multivariate analysis, CPAP pressure was
not found to be a determinant of long-term CPAP use.
In another study of 193 patients with moderate to
severe OSA who were followed an average of
19 months [91], 88% used CPAP every night, with
a mean use of 6.5 hours, despite side effects related to
the mask in 50%, dry nose or mouth in 65%, sneezing
or nasal drip in 35%, and nasal congestion in 25%.
There was no correlation between side effects and
level of pressure. Only 1% reported lack of benefit
from CPAP. It is generally believed, although not
formally studied, that having an inadequate pressure,
(whether too high, perhaps causing increased side
effects, or too low, resulting decreased benefit), can
be associated with decreased CPAP compliance [18].
Intensive CPAP education and support by staff
has been shown to improve compliance [92,93],
whereas lack of technician interaction may decrease
compliance [84].
In conventional CPAP therapy, after the diagnosis
of OSA has been established, patients typically
undergo an attended level I PSG for CPAP titration
[72]. After appropriate patient education and mask
fitting, while sleep and respiratory parameters are
being monitored, CPAP is titrated up manually in a
progressive fashion in the laboratory until an effective
pressure (Peff) is reached. This single Peff then deter-
mines the level of fixed CPAP for long-term home
325
use. The goals of titration and definition of Peff have
not been formally established and vary in different
studies, however. It has been suggested that the
endpoint of titration should be the abolition of
apneas, hypopneas, snoring, and airflow limitation
[64] with a concomitant decrease in the number of
arousals. Higher pressures are needed to eliminate
respiratory effort related arousals with airflow limita-
tion [65]. CPAP requirements or the RDI within the
same patient may have intranight and internight
variability [94], depending on sleep stage [32,95],
body position [95 – 97], consumption of alcohol or
other sedatives [98 – 100], nasal resistance [41,101],
inspiratory airflow [102,103], airway humidification
[103], and body weight [104].
Peff may, although not universally [27], decrease
during the first 8 months of CPAP therapy [105],
perhaps secondary to resolution of upper airway
edema on therapy [106]. Peff cannot be assumed
to be constant. The proportion of patients with
OSA with variable CPAP requirements and the mag-
nitude of that variability have not been well studied.
Rather than the goal of eliminating all respiratory
disturbances and respiratory arousals under all con-
ditions, other clinicians or investigators have used as
an endpoint of CPAP titration elimination of most of
these abnormalities. Varying targets for an acceptable
RDI at Peff (eg, < 5/hour or 10/hour or 15/hour) have
been used. Methods to monitor airflow impact the
measured RDI and the resultant titration results. The
art of titration thus encompasses a fine line between
efficacy (however defined) and side effects. Titration
is time consuming, labor intensive, and expensive
and requires highly qualified technologists. Conven-
tional CPAP therapy, delivered at a fixed Peff deter-
mined by in-laboratory PSG, is the gold standard to
which APAP therapy must be compared.
The rationale for APAP in treatment of OSA is
that the variable pressure delivered by APAP in
response to dynamic changes in airway resistance
might result in improved clinical outcomes compared
with conventional CPAP at fixed Peff, with perhaps
more favorable airway pressures, fewer side effects,
and better compliance. Despite the increased cost of
APAP devices, if fewer therapeutic PSGs need to be
performed or if overall health outcomes improve,
health care costs might be reduced. Alternatively, if
there are adverse outcomes (such as if APAP results
in increased leaks and arousals with higher pressures,
if oxygenation remains suboptimal, or if lack of
technician interaction limits compliance) or if the
group of patients who are candidates for APAP is
small, overall long-term benefits of APAP would
be limited.
 326
Table 3
Summary of therapeutic studies of automatic positive airway pressure devices
Oxygenation: Sleep: Pressure:
AHIAPAP %TST < 90APAP Arousal-IAPAP Symptoms: Mean pAPAP ComplAPAP
Device n AHIdiag Mean No. < 5, 10, or 15 mean Sa02APAP DeltaAPAP ESSAPAP Peak pAPAP Pref APAP

F.J. Roux, J. Hilbert / Clin Chest Med 24 (2003) 315–342

Author study design (SD or SE) Mean nadir Sa02APAP REMAPAP Other test APAP %TST APAP < pConv Side effects
Berthon-Jones [18] Prototype — < 5 in 19/20 — — — 6/20 zc, 14/20 #c —
(A,Sn,FL) — — — — — —
20 — — — —
Clinical series
Behbehani Prototype 49.9 < 5 in 3/5, — — — 6.8 #c —
et al [17] (Sn) < 10 in 5/5 — — — 12.2 X c —
5 4.76 — — — —
Clinical series
Llorberes Autoset 59 — — 12 F 7 X m — — —
et al [24] 20 (subgroup 9) (SD = 21) 5.6 F 6 — 36 F 14 X m — — —
RCT-CO (subgroup) — 27 F 13 X m — —
(Clinical series)
Lofaso et al [33] REM + with MC + 51 < 10 in 12/15 39 F 101m #d 13 F 20 #d — 7.5 F 2.5 in 12 —
(only Sn enabled) (SD = 30) 12 F 21 #d — 102 F 149m zd — 9.9 F 2.8 in 12 —
15 89 F 3 zd 55 F 31m X d — —
Clinical series
Meurice Morphee Plus 43.6 — — 10.1 F 2.5 X c 5.6 F 3.7 #d, X c — 6.5 F 1.0
et al [43] 16 (8/8) (SD = 19.8) 1.7 F 1.2 X c 96.0 F 0.3
dz, X c MWT: zd, X c — (3wk)zc
RCT-parallel —
dz TMT-A: #d, X c 49.3 F 14.9 —
TMT-B: X d, X c —
Scharf et al [38] Horizon 57.3 — — 9.9 F 9.5 X c — — —
Autoadjust (SD = 30.8) 4.4 F 2.2 X c 82.6 F 3.4 zd, X c 8.6 F 7.5 zc — — —
12 — 23.5 F 6.0 X c 63.1 F 34.2 —
RCT-CO
Sharma Prototype 50.8 — 13.9 F 25.6 #d, X m 11.3 F 0.3 #d, X m — — —
et al [54] (Sn) (SD = 28.8) 6.1 F 5.3 #d, X m — 17.1 F 9.3 zd, X m — 10.1 F 3.8 #m 11/18
20 79.9 F 9.7 zd,#m 25.3 F 7.4 zd, X m — (61%) X m
RCT-CO —
Teschler et al [25] Autoset 60.3 Success 19/20 — 8.9 F 0.6 #m, X c — — —
20 (SE = 5.7) 2.8 F 0.9 #m, X c — 29.8 F 3.1 X m, X c — — —
RCT-CO 90.4 F 0.8 #m, X c 21 F 1.3 X m, X c — —
Series [44] Morphee Plus 46.8a < 15 in 12/12 6.5 F 6.8 #d, X c
#d, X c 7 F 3.7 #d
#c 6.5 F 0.9
36 (12/12/12) (SD = 22.3)
#d, X c —
zd, X c MWT: zd, X c — (3wk) X c
RCT-parallel —
Xc 51 F 7.9% —
—
61.5b < 15 in 11/12 11.8 F 12.5 #d, X c
#d, X c 7.9 F 4.0 #d
#c 6.4 F 1.1
(SD = 27.7)
#d, X c —
zd, X c MWT: zd, X c — (3wk) X c
—
Xc 51 F 7.9% —
—

F.J. Roux, J. Hilbert / Clin Chest Med 24 (2003) 315–342

Behbehani Prototype 55.2 — — — — 8.4 F SE 3.3 #c —
et al [57] (Sn) (SD = 33.7) 5.4 F 5.4 #d, X c —
zd, X c — 12.8 F SE 4.3 X c —
31 —
zd, X c — —
RCT-CO
Ficker et al [35] REM + Auto 54.1 < 10 in 14/16 — 7.4 F 4.1 X c 5.3 F 3.9 X c 8.1 F 2.1 mbar zc —
16 (SD = 24) 4.2 F 5.1 #d, X c — 20.7 F 11.9 X c VT: X c — 6/16
RCT-CO — 18.1 F 5.5 X c — (37.5%) X c

Xc
Konermann Horizon 35.5 — 0.1 #d, X c 2.3 F 7.4 #d, #c — 6.5 F 1.7 #c 5.9 F 1.6
et al [40] 50 (48 completed) (SD = 9.6) 2.4 F SE 1.6 #d, X c 94.7 F 1.4 zd, X c 27.2 F 16.5 zd, zc — — (3 – 6mo) X c
(23:25) 90.3 F 3.6 zd, X c 20.1 F 10 zd, X c — —
RCT-parallel —
Boudewyns REM + Auto (1.6) Median: 65.8 — — 8.4 (5.4,12.8) #d, X c 5 (3,11) X c 5.2 (4.9,6.8) X c 6.1(5.2,6.8)
et al [36] 15 (CI:48.6 – 80.3) 2.1 (0.9,3.2) #d, X c X c
zd, X c — — (2 mo)
non-RCT —
zd, X c — —

Xc
Gagnadoux Autoset 69.6 < 10 in 21/24 0.2 F 1 #d — — — —
et al [31] 24 (SD = 29.8) 5.7 F 4.6 — 39.5 F 15.9 zd — — —
Clinical series — 18.8 F 8.8 zd —
Miyazaki Virtuoso 68.3 — — — — — —
et al [56] 11 (SD = 20.2) 9.6 F 14.5 X m — — — 9.4 F 2.0 —
RCT 89 F 3.7 #m — — —
Randerath Somnosmart 31.6 — — 21.2 F 13.1 #d — 5.4 F 1.0 mbar #c —
et al [48] 11 (SD = 26.6) 3.4 F 4.5c #d 94.4 F 2.4 X d 12.3 F 8.8 X d — 12.3 F 3.2 mbar —
RCT-COc,d 85.6 F 7.4 zd 22 F 7.7 zd 91.7 F 9.3 —
(continued on next page)

327
 328
Table 3 (continued )
Oxygenation: Sleep: Pressure:
AHIAPAP %TST < 90APAP Arousal-IAPAP Symptoms: Mean pAPAP ComplAPAP
diag
Device n AHI Mean No. < 5, 10, or 15 mean Sa02APAP DeltaAPAP ESSAPAP Peak pAPAP PrefAPAP
Author study design (SD or SE) Mean nadir Sa02APAP REMAPAP Other testAPAP %TSTAPAP < pConv Side effects
— — 24.5 F 10.2 #d — 5.1 F 0.7 mbar #c —

F.J. Roux, J. Hilbert / Clin Chest Med 24 (2003) 315–342

5 F 7.2d #d 93.7 F 2.9 X d 12.3 F 7.6 X d — 11.8 F 2.1 mbar —
86.7 F 6.9 zd 23 F 7.9 zd 90.4 F 6.3 —
d’Ortho et al [37] REM + Auto(2.1) 57.8 < 10 in 16/25 8.8 F 20.5 m #d, X c 15.5 F 8.9 #d, X c 9.3 F 4.8 #d, X c 8.8 F 1.8 #c 4.1 F 1.8
25 (SD = 5.8) 10.6 F 9.3 #d, X c 95.6 F 1.6 zd, X c 87 F 40 mzd, X c SQ: 32 F 11 X c — (2 mo) X c
RCT-CO 85.2 F 9.0 zd, X c 21 F 8 m zd, X c — 15/25 (60%)

Xc
Ficker et al [49] Somnosmart 48.0 < 10 in 17/18 — 6.6 F 2.1 X c 5.6 F 1.8 X c 0.84 F 0.26 kPa #c —
18 (28.1) 3.4 F 3.4 X c — 19.3 F 6.6 X c — — 8/18
RCT-CO — 21.7 F 4.9 X c — (44%) X c

Xc
Fletcher et al [42] Horizon 34.1 — — — 10.5 F 0.9 #d 9.4 F 0.6 —
30 (SD = 4) 8.6 F 0.8 #d — — MSLT: 5.7 F 0.8zd 12.9 F 0.6 —
Clinical series — — — —
Hudgel [55] Virtuoso 30 — — — 9 F 1 #d, X c 6.4 F 0.4 #c 6 F 0.3
60(39 completed) (SE = 4) — — — — — (12 wk) zc
RCT-CO — — — —
—
Randerath Somnosmart 18.2 — — 22.2 F 9.7 X d — 5.6 + /12.1 mbar #c —
et al [50] 10 (SD = 13.3) 2.5 F 1.9e #d — 20.2 F 10.4 zd — 13.9 F 3.2 mbar —
RCT-COe,f — 19.6 F 2.3 X d 73.6 F 31.4 —
— — 22.9 F 8.1 X d — 7.3 F 1.6 mbar #c —
1.8 F 0.7f #d — 22.3 F 9.3 X d — 13.4 F 3.5 —
— 18.3 F 6.4 X d 48.6 F 45.1 —
Teschler Autoset 52.9 — — 7.7 F 2.4 #d — Median 7.6 F 0.4 #c 6.3 F 0.4
et al [30] 10 (SD = 8.1) 3.5 F 1.7 #d — 24.6 F 2.8 zd —
zc (2 mo) X c
RCT-CO — 25.9 F 1.4 zd —
—
Randerath Somnosmart 32.2 — — 16.5 F 9.4 #d, X c — 5.7 F 2.1 mbar #c —
et al [52] 25 (SD = 18.1) 5.5 F 3.8 #d, X c — 21.6 F 10.9 zd, X c SQ:6.8 F 2.6 zc 12.6 F 4.6 —
RCT-CO 87.0 F 4.2 zd 20.3 F 7.3 zd, X c
Xc
Randerath Somnosmart 35.1 — — 10.3 F 6.4 #d
7.8 F 4.7 #d 6.6 F 2.4 c# 5.3 F 1.6
et al [51] 52 (47 completed) (SD = 26) 5.3 F 5.6 #d — 18 F 12 X d — 14.3 F 4zc (6 wk) X c
RCT-CO 92 F 5 X d 57 F 19 zd 81.5 F 21 35/47
(75%) zc

Xc
Fuchs et al [53] Somnosmart 47.7 — — 14.5 F 6.6 — — —
30 (SD = 21.9) 4.7 F 4.7 — — — — —
Clinical series — — — —
Marrone et al [32] Autoset Clinical 64.8 — — 11.5 F 6.5 — — —
15 (SD = 25.4) 1.8 F 1.5 — 7 F 8.4%TIB — — —
Clinical series 91.6 F 3.5 14.2 F 8%TIB —

F.J. Roux, J. Hilbert / Clin Chest Med 24 (2003) 315–342

Data are presented as means F standard deviation or standard error, as appropriate to each study, unless noted as median and 95% confidence interval.
Abbreviations: A, apnea; AHIAPAP, number of apneas plus hypopneas per hour of sleep on APAP; AHIdiag, number of apneas plus hypopneas per hour of sleep on baseline diagnostic night;
APAP, automatic positive airway pressure; Arousal-IAPAP, number of arousals per hour of sleep on APAP; CI, 95% confidence interval; CO, cross-over; ComplAPAP, compliance with APAP
in h/day of use over defined follow-up period; CPAP, continuous positive airway pressure; DeltaAPAP, amount of delta (slow-wave, stage 3 + 4) sleep on APAP [in % total sleep time unless
stated as %time in bed (%TIB) or minutes(m)]; ESSAPAP, Epworth Sleepiness Scale on APAP; FL, flow limitation; mean Sa02APAP, mean nocturnal arterial oxygen saturation on APAP (%);
Mean pAPAP, mean positive airway pressure level on APAP (cm/H20 unless noted as mbar or kPa); MSLT, mean sleep latency test (minutes); MWT, maintenance of wakefulness test
(minutes); nadir Sa02APAP, nadir arterial oxygen saturation on APAP (%); Other test APAP, semiquantitative or objective test of symptoms (sleepiness or performance) on APAP; Peak pAPAP,
peak positive airway pressure level on APAP (cm/H20 unless noted as mbar or kPa); Pref APAP, proportion (percentage) preferring APAP to CPAP; RCT, randomized controlled trial; SD,
standard deviation; SE, standard error; Sn, snoring; SQ, sleep questionnaire (specific to study and not standardized); %TST < 90APAP, percent total sleep time with arterial oxygen saturation
less than 90% on APAP (in %, unless stated as minutes (m)); %TSTAPAP < pConv, percent total sleep time on APAP at positive pressure less than conventional fixed CPAP as determined by
manual titration; TMT-A, trail-making test A; TMT-B, trail-making test B; VT, vigilance test.
X d, #d, zd: no change from, lower than ( P < 0.05), or higher than ( P < 0.05) diagnostic night, respectively.
X m, #m, zm: no change from, lower than ( P < 0.05), or higher than ( P < 0.05) manual CPAP-titration night, respectively.
X c, #c, zc: no change compared with, lower than ( P < 0.05), or higher than ( P < 0.05) with conventional fixed CPAP as determined by manual titration.
a
APAP device reference pressure set at effective pressure determined by manual titration.
b
APAP device reference pressure set at effective pressure estimated by a formula.
c
APAP device pressure range set at widest possible range (4 – 15.5 mbar).
d
APAP device pressure range set with maximum acceptable pressure calculated from formula based on effective pressure determined by manual titration and lower limit set at 4 mbar.
e
APAP device pressure range set at widest possible range (4 – 15.5 mbar).
f
APAP device pressure range set with minimum acceptable pressure calculated from formula based on effective pressure determined by manual titration and upper limit set at
15.5 mbar.

329
330 F.J. Roux, J. Hilbert / Clin Chest Med 24 (2003) 315–342
Studies that evaluate automatic positive airway
pressure for the therapy for obstructive sleep apnea
Multiple studies that evaluated APAP devices for
the therapy of OSA have been published in the
English literature (Table 3). Most have been single-
night studies, although some have been performed for
3 weeks to 6 months to assess certain outcomes
[30,37,40,43,44,51,55]. APAP usually has been
studied in an attended setting, in which a technician
could assess for leaks or other problems and intervene
as necessary. Study designs, APAP devices, defini-
tions, monitoring techniques, and outcome measures
have varied across studies. Most of the patients
studied have had moderately severe or severe OSA,
as indicated by the mean baseline AHI for each study
typically being in the 30/hour to 50/hour range, with
a large standard deviation (see Table 3). Only one
study included a small group of four patients with
upper airway resistance syndrome [55]. All patients
were diagnosed by PSG, except in one study in which
patients were diagnosed at home with APAP and
subsequently treated at home with APAP [42]. Many
patients were exposed to CPAP before treatment
with APAP. Most studies also listed exclusions
[18,25,30,35,37,38,40,42,44,47,49,52,54,55,57].
Patients with nonobstructive sleep-related breathing
disorders (eg, hypoventilation syndromes, Cheyne-
Stokes respiration, central sleep apnea) or compli-
cating medical illnesses (eg, congestive heart failure,
chronic obstructive pulmonary disease, respiratory
failure, cerebrovascular disease) were frequently
excluded. Patients with other sleep disorders (eg,
narcolepsy, periodic limb movement disorder, restless
legs syndrome), previous velopharyngeal surgery, or
need for increased CPAP level on CPAP titration
night (eg, >14 – 15 cm H20) also were excluded in
some studies.
Indexes of upper airway obstruction
As noted in Table 3, the mean AHI was signifi-
cantly reduced with APAP as compared with the
baseline diagnostic night in every study to date. The
AHI was not always reduced to normal in all
patients, however. In some patients, therapy with
APAP was not possible or was problematic because
of inability of the device to detect evidence of upper
airway obstruction or because of significant leaks.
Lofaso et al, using a device that exclusively detects
snoring, reported that APAP was ineffective in 3 of
15 patients, one with non-heavy snoring and two
with mouth breathing/leak [47]. The device in-
creased its pressure in response to snoring in only
f
84% F 6% of snoring events. In that study and in
another report by Miyazaki et al using a similar
device [56], esophageal pressure swings were
reduced with APAP, which indicated improved upper
airway obstruction. Miyazaki et al found that the
improvement in esophageal pressure was less than
that with manually adjusted CPAP, however. Tesch-
ler et al, using a different device that detects apnea,
snoring, and flow limitation, also noted that high
leak precluded single-night APAP use in 1 of 21 pa-
tients [25]. There is also one case report of a patient
with moderately severe OSA (AHI: 35.3/hour) who
was stable on CPAP 8 cm H20 who subsequently
developed central apneas and arousals when treated
with APAP [107]. In general, in the studies that
compared APAP to conventional fixed CPAP, the
improvement in AHI was similar in the two groups,
with no advantage of one mode of therapy over
the other.
Nocturnal oxygenation
In all of the studies in which the effect of APAP
on nocturnal oxygenation was examined, some or all
measures of oxygenation (eg, time with Sa02 < 90%,
mean Sa02, and mean nadir Sa02) improved com-
pared with the baseline diagnostic night (see Table 3).
Oxygenation did not necessarily normalize in all
patients, however. The improvement in oxygenation
with APAP was generally similar to the improvement
with manually titrated or conventional fixed CPAP. In
three studies that used different devices, however, the
mean nadir Sa02 was less with APAP than with
manually titrated CPAP [25,54,56].
Sleep architecture
The varying pressure supplied by APAP might be
expected to result in disturbed sleep; however, most
studies have shown improvement in sleep architec-
ture with APAP compared with the baseline dia-
gnostic night (see Table 3). The amount of sleep
fragmentation improved with APAP, as indicated by a
decrease in the number of arousals per hour of sleep
(arousal index) in almost all studies. Similarly, most
studies showed an increase in delta or slow wave
(stage 3 + 4 non-rapid eye movement[REM]) sleep
on APAP, and some studies showed an increase in
REM sleep. Sleep architecture was usually similar
with APAP and with manually titrated or conven-
tional fixed CPAP. Teschler et al [25], however,
reported a lower arousal index with APAP compared
with manually titrated CPAP but not with conven-
tional fixed CPAP. Scharf et al [38] and Konermann
 F.J. Roux, J. Hilbert / Clin Chest Med 24 (2003) 315–342
et al [40], each using a device that monitors snoring
and respiratory events, reported more delta sleep with
APAP compared with conventional fixed CPAP.
Improvements in sleep architecture, along with
improvements in AHI and oxygenation, have been
shown to be maintained over 6 weeks [51] and up to
6 months [40]. A more detailed analysis of whether
changes in pressure with APAP could induce arousal
was performed by Fuchs et al [53]. Thirty patients
with OSA were studied with PSG during APAP
therapy using a device controlled by impedance. As
in other studies, the overall number of arousals during
sleep improved with APAP compared with baseline.
During periods of sleep time in which there was a
pressure variation by more than 0.5 mbar, however,
there was an increase in arousals as compared with pe-
riods of time in which pressure was constant. There al-
so was considerable interindividual variability among
patients, with some having relatively few pressure-
dependent arousals and others having up to 61% of
arousals being classified as pressure dependent.
Obstructive sleep apnea symptoms
Changes in nocturnal and daytime symptoms of
OSA have been assessed with subjective and objec-
tive tests (see Table 3). Randerath et al [52] used a
sleep questionnaire to evaluate the quality of sleep in
25 patients randomly assigned to conventional fixed
CPAP or impedance-controlled APAP in a single-
blind cross-over comparison. The 16 patients who
completed the questionnaire rated the quality of
their sleep higher with APAP than with CPAP. In con-
trast, d’Ortho et al [37], using a randomized cross-
over design with 2-month treatment periods to study a
different APAP device that senses snoring and respi-
ratory events, found similar OSA symptom scores on
their sleep questionnaire in the APAP and conven-
tional fixed CPAP groups. Daytime sleepiness has
been assessed most commonly with the Epworth
Sleepiness Scale (ESS) [108], which ranges from 0
(least sleepy) to 24 (most sleepy), depending on the
patient’s perception of level of sleepiness in eight
situations. In general, ESS has decreased (improved)
with APAP therapy, similar to conventional fixed
CPAP. Hudgel and Fung reported similar improve-
ments in ESS in a subgroup of four patients with upper
airway resistance syndrome treated with APAP or
conventional fixed CPAP over a 12-week period
[55]. In the only study that did not note improvement
in ESS with APAP, the baseline ESS was already in
the normal range [36]. Multiple Sleep Latency Test
[109,110] and Maintenance of Wakefulness Test [111]
results have confirmed objective improvements in the
331
latency to sleep in the daytime in patients treated with
APAP (two studies used devices that sense respiratory
events and one used a device that senses snoring and
respiratory events), again similar to conventional fixed
CPAP [42 – 44]. Meurice et al [43] used two trailmak-
ing tests (TMT-A and TMT-B) to assess alertness and
concentration after 3 weeks of APAP or 3 weeks of
conventional fixed CPAP. TMT-A score improved to a
similar degree with APAP and CPAP, whereas TMT-B
did not change. Finally, Ficker et al [35], using a device
that senses snoring and respiratory events, reported
that a standardized vigilance test normalized in all
patients after a single night of treatment with APAP or
conventional fixed CPAP.
Cardiovascular outcomes
There are no published reports to date on the acute
or chronic effects of APAP on blood pressure or other
cardiovascular outcomes.
Positive airway pressure levels
Almost all studies show a decrease in mean
treatment pressure with APAP compared with con-
ventional fixed CPAP (see Table 3). In some studies,
more than 50% of total sleep time on APAP was
spent at a pressure level less than Peff determined by
conventional manual CPAP titration (Peffconv) [45,48,
51]. The average mean APAP pressure was lower
than Peffconv by 0.9 cm H20 [37] to 3.1 cm H20 [57];
however, this was not true for all patients in each
study. The mean peak pressure delivered by APAP
was often higher than Peffconv, however (see Table 3).
In the original report of APAP therapy using a device
that responded to apnea, snoring, and flow limitation
[18], expiratory leak through the lips confused the
auto-setting algorithm in 6 of 20 patients, which led
to increased pressure in these patients. In another
report, Teschler et al noted that high leak caused
unnecessary increases in pressure in 3 of 21 patients
[25]. Randerath found that whereas the average of
mean APAP pressure was lower than Peffconv by 2.1 cm
H20, the range of differences was 6 cm H20 lower to
4 cm H20 higher than Peffconv [51]. The magnitude of
the difference between APAP mean pressure and
Peffconv has been shown to depend at least partially
on the algorithm used to select Peffconv and the
algorithm controlling the APAP device. Sleep stage
and body position are also important in some patients.
Mean positive airway pressure levels with APAP have
been shown to decrease during delta sleep compared
with stage I-II non-REM sleep and REM sleep [32,35,
43,44] and in the lateral position compared with the
332 F.J. Roux, J. Hilbert / Clin Chest Med 24 (2003) 315–342
supine position [44]. Many patients with body posi-
tion – dependent OSA also may have sleep stage –
dependent OSA [46]. In a randomized parallel group
study [46], the night-to-night variability of pressure
levels with APAP was higher in body position – and
sleep stage – dependent patients than independent
patients. Six patients with body position and sleep
stage dependence treated with 3 weeks of APAP had
less subjective and objective sleepiness than a similar
group of six patients treated with CPAP, which sug-
gests that there may be a treatment advantage for
APAP over CPAP in this group.
Side effects
Side effects with APAP as compared with con-
ventional fixed CPAP have been examined, either in
the form of questionnaires [35 – 37,49,51,52]or sur-
rogates, such as use of humidifiers to correct nasal
symptoms [44] (see Table 3). Patients were more
aware of pressure variations when treated with
APAP than CPAP in one report [51], felt the
pressure was lower on APAP than CPAP in another
report [35], and had a tendency to report breathing
against the machine more with APAP than CPAP in
yet another report [49], but no other differences have
been noted.
Compliance
Compliance with APAP therapy has been exam-
ined over 3-week to 3-to- 6-month time periods (see
Table 3). Some studies [40,43,55], but not all
[30,37,44,51], have found that some measures of
compliance improved with APAP compared with
conventional fixed CPAP. Meurice et al reported
f
7.1 F 1 hour nightly use in the APAP group com-
f
pared with 5.1 F 1.1 hours in a parallel CPAP group
[43]. In another randomized parallel group study,
Konermann et al reported similar compliance be-
tween APAP and CPAP in terms of hours per night
but increased compliance with APAP compared
f
with CPAP in terms of nights per week (6.5 F 0.4
f
and 5.7 F 0.7, respectively) [40]. Hudgel and Fung,
in a randomized cross-over study [55], found in-
creased nightly use of APAP compared with CPAP
f f
(6 F 0.3 hours and 5.5 F 0.3 hours, respectively) but
no difference in nights of use, cumulative hours of
use, or patterns of use. In a subgroup of four patients
with upper airway resistance syndrome, cumulative
hours of use and nights of use were higher with
APAP than CPAP.
Preference
Several single night and longer-term studies have
evaluated whether patients prefer APAP or conven-
tional fixed CPAP (see Table 3). In general, patient
preferences were not different between the two mo-
dalities, with the exception of one single blind study
in which 35 of 47 patients (75%) preferred APAP.
Health care costs
In a strategy that used APAP for in-home diagnosis
and therapy [42], Fletcher et al reported cost savings
with APAP compared with conventional therapy. No
other systematic comparisons have been published.
In summary, these studies suggest that APAP can
be an effective therapy for OSA in patients without
complicating sleep or medical diagnoses. APAP ther-
apy can result in a reduced AHI, although devices
that predominantly detect snoring as a measure of
upper airway obstruction may be less effective. Not
all patients can achieve equivalent results. Sleep and
oxygenation parameters improve, although there may
be a somewhat lower Sa02 nadir with APAP than
CPAP. OSA symptoms also improve. Mean airway
pressures tend to be lower with APAP, without
significant change in side effect profile. Compliance
and preference tend to be similar or somewhat better
with APAP. Patients with sleep-stage and body posi-
tion-dependent OSA may gain the most from APAP
therapy, but further work is needed to define the most
appropriate patients for this modality. The effects of
APAP on cardiovascular outcomes and health cares
costs and the differences between devices also require
further study.
Role of automatic positive airway pressure in the
titration of continuous positive airway pressure
for obstructive sleep apnea
Rationale for use of automatic positive airway
pressure to determine an effective continuous positive
airway pressure in patients with obstructive
sleep apnea
Traditionally, in patients with OSA who are
treated with conventional fixed CPAP, a full-night
attended PSG for manual CPAP titration to determine
Peff (as described earlier) follows the initial diagnostic
night, which requires two separate studies for diag-
nosis and therapy. ‘‘Split-night’’ PSG, with the first
half of the night to establish the diagnosis and the
second half of the night to titrate CPAP, is an
 F.J. Roux, J. Hilbert / Clin Chest Med 24 (2003) 315–342
accepted alternative used by many centers in patients
who meet certain criteria [72,73]. Although this
technique has demonstrated efficacy and saves the
cost of one PSG, not all patients ultimately found to
have OSA meet the diagnostic criteria early enough
in the night to initiate a CPAP titration on the same
night. Even in patients who do undergo a CPAP trial
in a split-night format, not all patients are titrated
successfully by the end of the night. A second study
may be required to titrate CPAP.
Rather than using full-night or split-night in-
laboratory PSG, some investigators have used pre-
diction formulae [112], patient and bedpartner
reports [113], and limited unattended or attended
respiratory F sleep portable monitoring [81] to help
determine Peff. Home titration to determine Peff in
patients with established OSA using a four channel
portable device in the home (EdenTech, Eden
Prairie, MN) guided by patient or bedpartner inter-
view [113] was found to be feasible and lead to
improvement in AHI on follow-up PSG at machine-
derived Peff (Peffdevice). In a study of 17 patients with
OSA attended by a registered nurse or polysomno-
graphic technician in the home using the same
device for titration [114], AHI was reduced on the
titration night at a lower cost than conventional PSG.
Compliance on CPAP determined by Peffdevice was
similar to historical controls at 18 and 13 months
follow-up in both studies, respectively. Using a
different device that records cardiorespiratory data,
airway pressure, and sleep (VITPAP, Vitalog HMS-
5000, Vitalog Monitoring Inc., Redwood City, CA),
unattended machine-controlled titration was per-
formed in 21 unselected patients with OSA [115].
In the 19 patients who completed the machine
titration, the Peff was determined after the recording
was reviewed visually and scored by the investiga-
tors. This Peffdevice was highly correlated (r = 0.90)
with Peff determined by conventional manual CPAP
titration (Peffconv), with a mean difference of 0.21 F
1.08 cm H 2 O. Cardiorespiratory complications
occurred in six patients, however, including mild
discomfort that required a resetting of CPAP pres-
sure, central apnea with oxygen desaturation of more
than 85%, and ventricular ectopy, with termination
of the procedure required in two patients.
Subsequently, unattended home CPAP titration
was studied in 30 patients with OSA using a portable
respiratory and sleep monitoring system with modem
technology that allowed transfer of data from home to
the laboratory (NightWatch, Healthdyne) [116] and
compared with in-laboratory titration in a parallel
group of 30 patients. In this study, patients were
excluded if they had severe cardiopulmonary or renal
333
disease or important arrhythmia or if they required
oxygen or nocturnal ventilation, and all patients in
both groups met with a respiratory therapist for a
pretitration education session. AHI and sleep stage
distribution at follow-up PSG at 6 to 8 weeks and
objective compliance were similar in the group using
fixed CPAP at Peffdevice and the group using fixed
CPAP at Peffconv.
Instead of using APAP with the goal of long-term
treatment, there have been attempts to use APAP in
the short term (one or several nights), similar to other
portable monitoring systems, to determine Peff after
an initial diagnostic PSG. This PeffAPAP then could be
administered long term at a fixed level at home using
a conventional CPAP device. The Peff conv is the gold
standard to which the PeffAPAP must be compared.
Titration with APAP can be done during an attended
study, in which the advantage over traditional CPAP
titration might be freeing up technician time. It also
could be done in the unattended home setting over 1
or more days as a way of determining a more
effective level of CPAP for the long term, given that
sleep might be expected to be more normal at home
than in the laboratory. Turnaround time between
diagnosis and therapy potentially could be improved.
By eliminating the need for a second study, cost
savings also could be realized, especially compared
with a traditional 2-night approach to diagnosis and
therapy. Because patient-technician interaction is lim-
ited with the use of home titration with APAP,
however, if the patient does not have a successful
autotitration, long-term adherence and compliance
might be adversely affected.
Studies that evaluated automatic positive airway
pressure for determining an effective continuous
positive airway pressure in patients with
obstructive sleep apnea
Studies that evaluated APAP in determining Peff
are summarized in Table 4. Patients included in
these studies were previously diagnosed with OSA
by laboratory-based or portable PSG and gener-
ally had a baseline mean AHI in the severe range
(Table 4). Usually patients were not previously
treated with CPAP [24,26,30,31,34,45,68], but this
was not always stated [25,39]. As in studies that
evaluated the role of APAP for diagnosis and
therapy, patients with complicating medical or sleep
disorders were often [25,26,30,34], but not always
[24,31,39,45,68], excluded. Studies often were per-
formed in an attended setting so that the technician
(or another health professional in the case of par-
 334
Table 4
Summary of titration studies using automatic positive airway pressure devices to determine an effective continuous positive airway pressure level for treatment of obstructive sleep apnea
Device

F.J. Roux, J. Hilbert / Clin Chest Med 24 (2003) 315–342

n
Study design AHIdiag Peffconv PeffAPAP (a) AHI-PeffAPAP
Author Setting of APAP titration Mean (SD or SE) Mean F SD or SE Mean F SD or SE Mean F SD or SE
Llorberes et al [24] Autoset 53.3 10.1 F 1.8 10.3 F 1.5 (A1) X m —
20 (SD = 19) 11.5 F 2.9 (B4) X m
RCT-CO 10.7 F 2.7 (B4) X m
Partially attended—hospital
Teschler et al [25] Autoset 60.3 8.6 F 0.4 9.9 F 0.4 (A4) zm 2.5 F 0.7
20 (SE = 5.7)
RCT-CO
Attended
Stradling et al [39] Horizon (H definition changed) — 8.7 F 2.5 8.2 F 2.1(A3) X m —
112 (52/61)
RCT-Parallel
Unattended—laboratory
Teschler et al [26] Autoset 60.3 11.0 F 0.5 (at 3 mo) 10.6 F 0.4 (A4) X m (at 3 mo) 4.3 F 0.6 # (at 3 mo)
20 (SE = 5.7) 10.4 F 0.4 (at 8 mo) 9.7 F 0.5 (A4) X m (at 8 mo) 3.6 F 0.5 # (at 8 mo)
RCT-CO
Attended (at 3 mo and 8 mo
follow-up of prior study
group from Teschler [25]
Berkani et al [34] REM + auto (Only Sn enabled) 55 — 10.5 F 2.2 (B1) 7F5 #
10 (SD = 16)
Clinical series
Unattended—hospital
Badia et al [68] Prototype (FOT) 63.7 F 3.1 10.6 F 0.6 11.1 F 0.6 (A2) X m —
28 (nap study, n = 14) 9.9 F 0.7 9.9 F 0.6 (A2) X m —
Simultaneous recording 67.3 F 2.89
Attended—laboratory (overnight study, n = 14)
Gagnadoux et al [31] Autoset 69.6 — 11.2 F 1.6 (A4) 4.1 F 3.2 # at 3 mo
24 (SD = 29.8) < 10 in 17/18
Clinical series
Attended—laboratory
Series [45] MorpheePlus 43.6 — 10 F 1.7 (B6) 4.8 F 6 at 2 wk
42 (SD = 19.8) (1 wk) < 10 in 38/40
Clinical series 9.7 F 1.1 (B6)
Unattended—home (2 wk)
(1- or 2-wk titration)
Teschler et al [30] Autoset 52.9 9.4 F 0.6 10.3 F 0.4 (A3)zm —
10 (SE = 8.1) (attended)

F.J. Roux, J. Hilbert / Clin Chest Med 24 (2003) 315–342

RCT-CO 10.1 F 0.5 (A3)zm
Attended—laboratory (unattended)
(3 d titration at d 0,60,120)
Unattended—home
(12 d titration over 2 mo)
Data are presented as means F standard deviation or standard error, as appropriate for each study.
Abbreviations: AHI-PeffAPAP, apneas plus hyponeas per hour of sleep on fixed CPAP at effective pressure as determined by APAP titration (AHI determined by conventional PSG unless #
to indicate portable home study); APAP, automatic positive airway pressure; FOT, forced oscillation technique; H, hypopnea; PeffAPAP, effective pressure (cm H20) as determined by APAP
titration; Peffconv, effective pressure (cm H20) as determined by conventional manual titration; SD, standard deviation; SE, standard error; Sn, snoring.
X m, #m, zm: no change from, lower than (P < 0.05), or higher than (P < 0.05) Peff from manual CPAP-titration night, respectively.
a
Method of determination of PeffAPAP: A, review of raw data to exclude periods of leak or poor recording prior to determining Peff; B, no mention of review of raw data prior to
determining Peff; 1, highest pressure; 2, pressure that eliminates upper airway obstruction events; 3, pressure that eliminates most upper airway obstruction events; 4, P95: pressure that is
exceeded only 5% of the time: 5, P90: pressure that is exceeded only 10% of the time; 6, pressure determined by percentage of time spent below reference pressure (in turn determined by a
formula incorporating body mass index, neck circumference, and AHI), constrained by a range + 3cm H20/
4cm H20.

335
336 F.J. Roux, J. Hilbert / Clin Chest Med 24 (2003) 315–342
tially attended studies) could monitor for leaks or
other technical problems (see Table 4). Only one
study, a clinical series with historical controls [45],
was performed in an unattended home setting in
CPAP-naı̈ve patients. The amount of time for APAP
titration varied from a single night in most studies,
to 1 or 2 weeks [45], to an average of 12 nights
over 2 months [30].
Studies differed in device used, study design,
setting, and outcomes assessed (see Table 4). The
primary outcome was usually PeffAPAP, which was
either compared directly with Peff conv or assessed for
effectiveness by follow-up conventional fixed CPAP
therapy at PeffAPAP. Methods of determining PeffAPAP
varied across studies (see Table 4). The raw data
usually were excluded to eliminate periods of high
leak or poor recording. In some reports, however,
data review was not specifically mentioned or was
not performed. Subsequently, PeffAPAP was deter-
mined by analysis of pressure during the APAP
titration night(s) and was variably defined as the
highest pressure of the recording, the pressure that
eliminated all or most upper airway obstruction
events, the pressure that was exceeded only 5% or
10% of the time (P95 or P90, respectively), or the
percent of time spent below a reference pressure as
determined by a formula (see Table 4). Methods to
determine Peff conv varied, and the goals of the
conventional manual titration were not necessarily
the same as the goals of the APAP titration [26].
As outlined in Table 4, most patients had a
successful APAP titration, and PeffAPAP and Peff conv
were similar in most studies. PeffAPAP also has been
shown to be stable over 8 months of follow-up [26].
Teschler et al, using a device that detects snoring,
apnea, hypopnea, and flow limitation, initially noted
that PeffAPAP was higher than Peff conv by an average
of 1.3 F 0.3 cm H20 [25], despite excluding periods
of leak. This difference subsequently decreased in a
follow-up study of this same group of patients after
changing the goals of the manual titration to be more
similar to those used by the device [26].
Not all patients were able to have PeffAPAP deter-
mined with APAP titration. Teschler reported that
high leak prevented autotitration in one patient and
caused unnecessary increases in pressure in 3 of 21
patients, although for most of the night, leak was low
(< 0.4 L/second) [25]. During the APAP titration
night, the technician reseated the mask an average
of 1.9 F 0.4 occasions per patient per night, a
frequency similar to the manual CPAP titration night.
Gagnadoux et al also reported leaks of more than 0.4
L/second in 3.1% F 4.8% of titration time (range 0%
to 15%), with the technician repositioning the mask
an average of 0.93 F 0.46 times per night [31].
Periods of continuous leak occurred in 7 of 14 pa-
tients and ranged from 4% to 70% of total sleep time
during a manual titration when impedance was simul-
taneously monitored with FOT and subsequently
interpreted in a blinded fashion by the investigators
[68]. As in the previous studies, these periods of leak
were excluded before determining PeffAPAP.
Llorbes et al found that PeffAPAP determined by
review of raw data to exclude mask leaks and atypical
pressure changes followed by visual inspection to
determine the highest level of pressure was similar to
PeffAPAP determined by P90 or P95. Berkani et al
reported that APAP titration, using a device adjusted
to detect only snoring, was unsuccessful in two of ten
patients, one of whom had a laryngectomy for laryn-
geal cancer and one of whom underwent uvulopalato-
pharyngoplasty [34]. These two patients ultimately
had successful titration when the APAP pressure
range was less constrained. Increased mouth leak,
even at low CPAP pressures, previously has been
reported in patients who have undergone uvulopalato-
pharyngoplasty [117]. Series reported that 2 of 42
patients were not successful with home APAP titra-
tion using a device that detects apneas and hypopneas
and operates within a set range of a reference pres-
sure, 1 because of central apnea and 1 because of
machine malfunction [45].
Gagnadoux et al, using a device that detects
snoring, apnea, hypopnea, and flow limitation, found
that APAP titration was unsuccessful (defined as an
AHI > 10/hours on subsequent PSG at fixed PeffAPAP)
in 3 of 24 patients, perhaps because of severity of
OSA [31]. All 3 patients had a high AHI at baseline
that ranged from 95/hour to 123/hour. Finally, the
variability of APAP pressure levels was studied in
relation to sleep architecture in 15 patients on home
therapy with APAP [32]. The highest pressures gen-
erally occurred during periods of drowsiness or
fragmented non-REM sleep, which suggested that
if APAP had been used for titration at home in
patients with poor sleep quality, PeffAPAP could have
been overestimated.
After successful determination of PeffAPAP, pa-
tients have been treated with CPAP at fixed PeffAPAP
and other outcomes have been assessed. Mean AHI
on repeat PSG or limited home monitoring with
CPAP at fixed PeffAPAP improved compared with
the baseline diagnostic night (see Table 4). Improve-
ments in sleep architecture [34,45], including a
decrease in arousal index and an increase in delta
sleep and REM sleep and improvements in nocturnal
oxygenation [34,45], also have been reported. ESS
also improved compared with baseline [31,45] and
 F.J. Roux, J. Hilbert / Clin Chest Med 24 (2003) 315–342 337

was similar for patients treated with CPAP at fixed
Peff conv [39].
Compliance with CPAP at fixed PeffAPAP has been
evaluated in several studies. Subjective compliance
was assessed 6 weeks after APAP titration in 52
patients and compared with a parallel group of 61
patients after manual CPAP titration. The proportion
of successful patients who were established on CPAP
in the APAP group was similar to the manual group
(73% and 64%, respectively; 25% and 23%, respec-
tively, were undecided about CPAP therapy). Fewer
patients in the APAP group (2%) had decided defi-
nitely against CPAP therapy compared with the
manual group, however (13%). In two other studies,
objective 3-month compliance by hour meter was
4.9 F 0.3 hours/night in 20 patients [25] and 5.25 F
1.82 hours/night in 18 of 22 patients [31], both
similar to historical controls. Finally, in a study in
which PeffAPAP was determined by home titration, 86%
of patients initially accepted CPAP for home therapy,
and objective compliance was 6.1 F 1.7 hours/night
in 36 of the 40 patients who were successful with
APAP titration [45].
Minimal data are available on the impact of
APAP titration on health care resources. In using
APAP for titration in the attended setting, Teschler et
al and Gagnadoux et al each reported an average of
one to two technician interactions per patient per
night—fewer than would be expected on a manual
titration night, thus potentially reducing technician
workload [25,31]. Berkani et al, using APAP in an
unattended setting, estimated that the cost of the 12
ambulatory studies required to determine PeffAPAP in
10 patients was less than that of conventional manual
titration [34].
Overall, these studies suggested that APAP can be
a useful modality in uncomplicated patients to deter-
mine Peff for long-term conventional CPAP therapy.
The best device and best method for determining Peff
are not known. Regardless of device, final PeffAPAP is
generally similar to Peff conv, but some patients do not
have an effective titration. Patients who do not snore
may not have an adequate APAP titration using a
device based on snoring detection. Supervised APAP
titration may be required because leaks and the need
for intervention occur. Unsupervised titration can be

Table 5
American Academy of Sleep Medicine practice parameters (2002) for the use of autotitrating positive airway pressure devices in
adult patients with obstructive sleep apnea
Recommendation Level of recommendation
1 A diagnosis of OSA must be established by an acceptable method. Standard
2 Patients with the following conditions are not candidates for APAP titration Standard
and APAP treatment:
congestive heart failure
significant lung disease (eg, chronic obstructive pulmonary disease),
daytime hypoxemia, or respiratory failure
prominent nocturnal desaturation other than that from OSA
(eg, obesity-hypoventilation syndrome).
Patients who do not snore should not be titrated with an APAP device that
relies on vibration or sound in the device’s algorithm.
3 APAP devices are not currently recommended for split-night studies. Standard
4 Certain APAP devices may be used during attended titration to identify, by Guideline
polysomnography, a single pressure for use with standard CPAP for treatment of OSA.
5 Once an initial successful attended CPAP or APAP titration has been determined by Guideline
polysomnography, certain APAP devices may be used in the self-adjusting mode for
unattended treatment of OSA.
6 Use of unattended APAP to either initially determine pressures for fixed CPAP or provide Option
for self-adjusting APAP treatment in CPAP naı̈ve patients is not currently established.
7 Patients being treated with fixed CPAP on the basis of APAP titration or being treated Standard
with APAP must be followed to determine treatment efficacy and safety.
8 A reevaluation and, if necessary, a standard attended CPAP titration should be Standard
performed if symptoms do not resolve or the CPAP or APAP treatment seems
to lack efficacy.
Modified from Berry RB, Parish JM, Hartse KM. The use of auto-titrating continuous positive airway pressure for treatment of
adult obstructive sleep apnea: an American Academy of Sleep Medicine review. Sleep 2002;25:148; with permission.
338 F.J. Roux, J. Hilbert / Clin Chest Med 24 (2003) 315–342
successful in some patients, however. Use of APAP
for titration does not seem to impact compliance
negatively. Data on the impact on health care resources
of a patient-care strategy that incorporates APAP
devices for titration are preliminary.
Recommendations for the clinical use of automatic
positive airway pressure
Several authors have presented algorithms for the
use of APAP in the unattended setting for diagnosis
and therapy [23,42]. In general, in the straightforward
patient with classic signs and symptoms of OSA
[118,119] without complicating disorders, such as
respiratory insufficiency or congestive heart failure
or reasons for mask/mouth leak, APAP could be used
for diagnosis. If the study is positive and of satisfac-
tory quality, APAP then could be used for therapy,
with close patient follow-up for resolution of symp-
toms and compliance. If the study is negative or of
poor quality or if the patient’s symptoms are persist-
ent, conventional in-laboratory attended PSG would
be recommended. Careful patient selection, patient
education and support, and close follow-up must be
incorporated into the algorithm to ensure the success
of such a strategy [27]. Although appealing in many
respects, the effect of this strategy on long-term
outcomes of OSA has yet to be tested formally in a
large series of patients.
Practice parameters for the use of APAP devices
for titrating pressures and treating patients with OSA
have been published recently by the American Acad-
emy of Sleep Medicine [120]. Available data on the
therapeutic and titrating but not diagnostic roles of
APAP were reviewed by the Standards of Practice
Committee of the American Academy of Sleep Medi-
cine [69], and studies were graded according to levels
of evidence [121]. Based on this review, the commit-
tee made recommendations for the clinical use of
APAP, which were approved by the Board of Direc-
tors of the American Academy of Sleep Medicine. As
noted in Table 5, practice parameters were divided
into standards (a generally accepted patient-care
strategy, which reflects a high degree of clinical
certainty), guidelines (a patient-care strategy which
reflects a moderate degree of clinical certainty), and
options (uncertain patient-care strategy) [122].
Summary
Automatic positive airway pressure devices are the
most technologically advanced positive airway pres-
sure devices available for use in OSA. Although
heterogeneous, they have in common the ability to
detect and respond to changes in upper airway resist-
ance. Data cannot necessarily be extrapolated from
one device to another, and the field is rapidly advan-
cing. Most studies of APAP have been performed in a
supervised setting, or patients have been carefully
selected to have a high likelihood of OSA uncompli-
cated by disorders such as alveolar hypoventilation or
central apnea or technical problems such as mask
leaks. Studies of APAP for the diagnosis of OSA have
shown that APAP can diagnose severe OSA effec-
tively, but the diagnosis of mild-moderate OSA is less
reliable. APAP devices also can be effective therapy
for selected patients with OSA, with overall similar
results to conventional fixed CPAP in terms of respi-
ratory disturbances, sleep quality, nocturnal oxygena-
tion, and daytime sleepiness and performance, with
less known or other long-term outcomes. In most
studies, mean treatment pressures are lower, without
change in side effect profile. Compliance and pref-
erence with APAP are similar to or somewhat better
than CPAP in most studies. APAP also can be used in
an attended setting to titrate an effective pressure for
use in long-term conventional CPAP therapy, also
with similar results to CPAP in many patients. APAP
devices are more expensive than CPAP devices, but
the cost may be outweighed if a group of patients who
can be diagnosed, treated, or titrated safely in the
unattended setting can be identified. Although diag-
nostic and therapeutic algorithms for APAP have been
proposed, the best candidates for this modality must
be defined better.
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 Clin Chest Med 24 (2003) 343 – 353

Behavioral and pharmacologic therapy of

obstructive sleep apnea
Ulysses J. Magalang, MDa,b,*, M. Jeffery Mador, MDa,c
a
Division of Pulmonary, Critical Care, and Sleep Medicine, University at Buffalo,
State University of New York, 3435 Main Street, Buffalo, NY 14214, USA
b
Associated Sleep Center, 1400 Sweet Home Road, Amherst, NY 14228, USA
c
Buffalo Veterans Affairs Medical Center Sleep Disorders Center, 3495 Bailey Avenue, Buffalo, NY 14215, USA

Behavioral therapy of obstructive sleep apnea
In this section, the authors discuss the role of
weight loss and modification of sleep posture in the
treatment of obstructive sleep apnea (OSA).
Weight loss
Obesity is strongly correlated with OSA in clinic
populations and population-based epidemiologic
studies [1,2]. In the Wisconsin Sleep Cohort Study,
a group of state employees were prospectively
studied [2]. In this study, 4% of men and 2% of
women had an apnea-hypopnea index (AHI) of more
than 5/hour and symptoms of daytime hypersomno-
lence, and 24% of men and 9% of women had an
AHI of more than 5/hour with or without symptoms.
In this study, an increase in body mass index (body
weight in kilograms divided by height2 in meters) of
one standard deviation was associated with a fourfold
increase in the risk of having an AHI of more than
5/hour. All measurements of body habitus, including
weight, significantly influenced the AHI.
Obesity can promote OSA by various mecha-
nisms. A detailed discussion of potential mechanisms
has been provided elsewhere [3]. It is believed that
* Corresponding author. Suite 162, Erie County Med-
ical Center, 462 Grider Street, Buffalo, NY 14215.
E-mail address: magalang@buffalo.edu
(U.J. Magalang).
obesity can reduce the size or change the shape of the
upper airway, which promotes airway occlusion.
Some CT scan studies of the upper airway have
shown a smaller and differently shaped retropalatal
airway in patients with OSA than control subjects
[4,5]. MRI studies, which are better at identifying fat,
also have shown increased fat deposits in the upper
airway in patients with OSA compared with weight-
matched controls [6]. All of these studies were
conducted while patients were awake. Obesity also
seems to alter upper airway function. Various indirect
measurements have suggested that the upper airway
is more collapsible in patients with sleep apnea [7,8].
Weight loss in overweight patients with sleep apnea
reduced the pharyngeal critical closing pressure dur-
ing sleep, which indicated a reduction in upper air-
way collapsibility [9].
One study has examined the effects of changes in
weight on the AHI in a longitudinal population study
[10]. In this study, a group of healthy volunteers
underwent repeat sleep studies 4 years after their
initial polysomnogram. The changes in AHI were
correlated to changes in weight after potential co-
variates were taken into account. For each percentage
change in weight, there was approximately a 3%
change in the AHI. For example, a 10% reduction
in weight was associated with a 26% reduction in the
AHI. For subjects with normal or mildly increased
AHI at baseline (AHI < 15/hour), a 10% increase in
weight was associated with a sixfold increase in the
chance of developing moderate to severe sleep-dis-
ordered breathing (AHI > 15/hour).

0272-5231/03/$ – see front matter D 2003, Elsevier Inc. All rights reserved.
doi:10.1016/S0272-5231(03)00022-4
344 U.J. Magalang, M.J. Mador / Clin Chest Med 24 (2003) 343–353

Table 1
Dietary weight loss: effect on sleep apnea
Length of
n follow-up Method of weight loss Weight change kg (%) AHI pre AHI post
Smith et al [11] 15 5.3 mo Dietary advice/follow-up 9.6 ( 9) 55 29.2
Schwartz et al [9] 13 17 mo Dietary advice/follow-up 11.8 ( 17.4) 83.3 32.5
Rubinstein et al [12] 12 8 – 18 mo Diet/gastroplasty 24 ( 20.5) 57 14
Kiselak et al [13] 19 18 – 20 wk Diet/exercise/behavioral therapy 27.2 ( 23.9) 17.6 ?
Suratt et al [14] 8 24 mo Very low calorie diet 21 ( 14) 90 62
Pasquali et al [18] 23 ? Diet or very low calorie diet/follow-up 18.5 ( 17.5) 66.5 33
Rajala et al [15] 8 ? Diet ? ( 13) 39.5 31.6
Lojander et al [16] 24 1y Very low calorie diet/diet/follow-up 11 ( 10) ? ?
Kansanen et al [17] 15 3 mo Very low calorie diet 9 ( 7.9) 31 19

Short-term effects of weight loss
Several small clinical studies have evaluated the
short-term effects of varying degrees of weight loss in
patients with OSA (Table 1) [9,11 – 18]. Most of these
studies were uncontrolled, and the severity of obesity
at baseline varied widely. Virtually all of these studies
showed that weight loss improved sleep apnea to
some extent, however, at least in some patients. In
one controlled study, 23 mild to moderately obese
patients were randomized to receive dietary counsel-
ing (15 patients) or no intervention (control group of
8 subjects) [11]. The sleep study was repeated when
they had lost at least 5% of their initial body weight
(intervention group) or when their weight had
remained stable (control group). The mean fall in
body weight was 9%. This modest reduction in
weight was associated with a significant reduction
in the apnea index, an improvement in nocturnal
oxygenation, improvements in sleep architecture,
and a borderline improvement in the multiple sleep
latency test. No changes were observed in the control
group. 4 patients had a reduction in the apnea index
to normal.
In a follow-up study, 23 additional patients re-
ceived dietary advice and follow-up [9]. 13 patients
lost at least 5% of their initial body weight (ie,
the therapy worked and the patients were restudied
and compared with 13 matched controls). The dietary
intervention group lost approximately 17% of their
body weight. The AHI decreased from 83.3/hour F
31/hour to 32.5/hour F 35.9/hour. In 7 of the patients
the AHI decreased to below 20/hour (close to 0 in
5 patients). The pharyngeal critical closing pressure
was reduced significantly after weight loss, which
indicated a reduction in upper airway collapsibility.
When the pharyngeal critical closing pressure was
below 4 cm H2O (ie, more negative), sleep apnea
was virtually abolished. These results provide an
attractive potential mechanism by which weight loss
influences the AHI. The extent to which the AHI is
improved by weight loss depends on how much weight
loss improves upper airway collapsibility.
Several case studies have examined the effects of
dramatic weight loss on sleep apnea in morbidly obese
persons. Weight loss has been achieved by surgical
procedures (Table 2) [19 – 24] or very low calorie diets
[14] (see Table 1). When significant weight loss has
been achieved, improvements in sleep apnea have
been observed, with total resolution of sleep apnea
in some patients. Similar to the small studies per-
formed in moderately obese sleep apnea patients, the
amount of weight loss achieved did not always
correlate with the extent of improvement, possibly
because a given degree of weight loss affects upper

Table 2
Surgical weight loss: effect on sleep apnea
Length of
n follow-up Surgical procedure Weight change kg (%) AHI pre AHI post
Harman et al [21] 4 24 mo Jejuno-ileal bypass 108 ( 47) 78 1.4
Peiser et al [19] 15 2 – 4 mo Gastric bypass 35.1 ( 25) 81.9 15
Scheuller et al [23] 15 1 – 12 y Gastric bypass/gastroplasty 54.7 ( 34) 96.9 11.3
Pillar et al [24] 14 4.5 mo Gastric bypass/gastroplasty 35.6 ( 27) 40 11
Pillar et al [24] 14 5 – 10 y Gastric bypass/gastroplasty 29.9 ( 23) 40 24
Sugerman et al [20] 40 ? Gastric bypass/gastroplasty 57 ( 32) 64 26
Charuzi et al [22] 13 6 mo Gastric bypass ?( 72.5) 88.8 8
 U.J. Magalang, M.J. Mador / Clin Chest Med 24 (2003) 343–353
airway collapsibility to different degrees in individual
patients. In contrast, in the large population study
described previously, changes in weight affected the
AHI in the expected dose-response manner (ie, the
more the weight loss, the greater the improvement in
the AHI). In this study, only changes in weight of less
than 20% of initial body weight were examined. In a
recent review, the average weight loss and average
reduction in AHI from the various clinical studies
were plotted [25]. A clear relationship between the
extent of weight loss and AHI could be appreciated.
In most published studies, many or all of the
patients studied had severe OSA defined arbitrarily
as an AHI of more than 30/hour [26]. In the clinical
arena, weight loss is often considered in patients with
mild to moderate disease who are reluctant to try or
are noncompliant with more definitive therapies for
sleep apnea, such as continuous positive airway
pressure (CPAP). Studies that particularly address
this patient population are largely lacking. The popu-
lation study [10] suggests that weight loss might be
efficacious, however, at least in the short term in this
patient group.
In a recent systematic review, the effects of weight
loss on sleep apnea were specifically assessed [27].
No study to date (last reviewed July 2, 2002) met the
entry criteria pointing out the limitations of the
existing database. Only the study by Smith et al
was randomized and included a control group [11].
The reason why this study was excluded was not
specifically reported but may have been because the
investigators were not blinded to treatment allocation.
Long-term effects of weight loss
Long-term data on the effects of weight loss are
sparse. Studies that involve obese patients without
sleep apnea indicate that whereas achieving weight
loss is difficult, maintaining weight loss is even
harder [28,29]. Unfortunately, most patients who lose
weight ultimately regain it. One recent study exam-
ined the long-term effects of weight loss in sleep
apnea patients [30]. Two hundred sixteen mildly
obese patients with sleep apnea were treated with a
weight reduction program that consisted of a hypo-
caloric diet, encouragement to increase physical
activity, and periodic appointments for reinforcement.
One hundred four patients lost at least 10% of their
initial weight. One hundred one patients underwent a
follow-up sleep study. Thirty-four patients had a
follow up AHI of less than 10 /hour with resolution
of daytime hypersomnolence and were considered
cured. Four patients also stopped excessive alcohol
or sedative usage. Six patients were lost to follow-up.
Twenty-four patients were followed for 5 to 11 years.
345
Over this time period, 11 of the patients regained a
significant amount of weight defined as at least 50%
of the initial weight loss. Not surprisingly, sleep
apnea recurred in 8 of these patients. Most impor-
tantly, in the 13 patients who maintained their weight
loss, sleep apnea recurred in 7.
Similarly, Pillar et al followed a group of morbidly
obese patients after bariatric surgery [24]. After
surgery, there was an impressive weight loss associ-
ated with a dramatic reduction in the apnea index
from 40/hour F 29/hour to 11/hour F 16/hour. Forty-
eight percent of patients had complete resolution of
apneas. 7.5 years later, the apnea index had increased
to 24/hour F 23/hour in these patients despite only a
modest increase in weight from their postoperative
minimum. 5 patients had an increase in their apnea
index despite absolutely no gain in weight. These
studies showed clearly that sleep apnea can recur in
overweight patients in the absence of weight gain.
Not all patients with obesity have sleep apnea.
Additional factors must be present—such as upper
airway size and function—that predispose some
obese patients to sleep apnea [18]. Presumably, these
factors can progress over time sufficiently to induce
sleep apnea at the reduced body weight.
Summary
Although data that address weight loss in patients
with sleep apnea are somewhat limited, the data
available suggest that weight loss can be a highly
effective treatment of sleep apnea in the short term.
Although long-term data are sparse, recurrence of
sleep apnea seems to be common either because of
failure to maintain weight loss or recurrence of sleep
apnea despite maintenance of weight loss. Because of
these factors, clinicians remain appropriately skepti-
cal of the overall efficacy of weight loss in patients
with OSA. Further study of weight loss in less
severely affected patients (AHI < 30/hour) in whom
acceptance of standard therapies for sleep apnea may
be difficult is warranted.
Positional therapy
In patients with OSA, the frequency of apnea and
hypopneas is influenced by body position in 50% to
60% of patients [31,32]. The AHI increases in the su-
pine position and is lower in the lateral position or with
the head of the bed elevated to 30° to 60° [31 – 33].
Even in patients in whom the AHI is not influenced by
body position, the duration of apnea/hypopnea and the
degree of associated desaturation are worse in the
supine position [34].
346 U.J. Magalang, M.J. Mador / Clin Chest Med 24 (2003) 343–353
This observation led early investigators to explore
methods to avoid sleep in the supine position. Ini-
tially, investigators considered patients eligible for
this therapy if the AHI in the supine position was at
least twice that in the lateral position [35,36]. If the
AHI is 80/hour in the supine position and 30/hour in
the lateral position, however, even if the therapy is
totally effective in eliminating supine sleep, the
patient still has an AHI likely to cause continued
symptoms. A better definition for eligible patients
would be an elevated AHI in the supine position and
an AHI in the lateral position less than a predefined
threshold value. In prior studies, an AHI of less than
15/hour has been used [37]. Depending on the
clinician’s threshold for distinguishing what is an
elevated AHI, a different threshold value of 5/hour
or 10/hour could be used. The prevalence of posi-
tional sleep apnea when this alternative definition is
used has not been determined.
In the United States, so-called split-night studies
(diagnostic and CPAP titration performed on the
same night) are becoming increasingly popular
because of pressures from commercial payors.
Whether positional sleep apnea can be diagnosed
accurately during a split-night study must be deter-
mined. Given the limited amount of time typically
available for the diagnostic portion of the study, it
seems doubtful that positional sleep apnea could be
assessed accurately during a split-night study. For-
tunately, positional sleep apnea seems to be more
common in patients with milder disease [31], whereas
split-night studies are generally reserved for patients
who display sleep study findings of severe disease.
Mechanisms for the effect of posture on sleep apnea
In awake, normal subjects [38] and patients with
sleep apnea, upper airway size increases in the seated
position compared with the supine position [7,39]. In
contrast, upper airway size does not seem to increase
when patients with sleep apnea move from the supine
to the lateral position [39]. Upper airway collapsibil-
ity is reduced in the seated position compared with
the supine position [40,41]. Conflicting results
between studies have been obtained in the lateral
position, but at least some measures in some studies
have shown a reduction in upper airway collapsibility
in the lateral position compared with the supine
position, which provides a potential explanation for
the improvement in the AHI [40,41].
Methods for avoiding supine sleep position
In the original studies of positional therapy, Cart-
wright et al used a posture alarm [35,36]. The patient
wore a positional monitor that triggered an alarm if
the patient remained in the supine position for more
than 15 seconds. The posture alarm was highly
effective in preventing supine sleep posture. In a
study of 15 patients, 1 slept in the supine position
for 35.5 minutes, 4 slept in the supine position for
less than 10 minutes, and supine sleep was com-
pletely eliminated in 10 patients [35]. Interestingly,
after 8 weeks of therapy, 8 of the patients slept
minimally in the supine posture during one night of
monitoring without the posture alarm [35]. In another
study, patients wore a backpack with a softball inside
positioned to prevent them from sleeping in the
supine position [42]. This modality also was highly
effective at preventing supine sleep posture. In a
study of 13 patients, 3 slept in the supine position
for 18 to 32 minutes, 1 slept in the supine position for
less than 10 minutes, and in 9 patients supine sleep
was totally prevented. Other methods to prevent
supine sleep position include pinning a tennis ball
to the patient’s pajama top or placing a wedge pillow
lengthwise in the bed.
Effectiveness of positional therapy
Surprisingly few studies have evaluated positional
therapy formally. In one study, 13 patients who were
studied during a single overnight sleep study spent
half the night in the supine position and half the
night in the semi-seated position with the bed inclined
at a 60° angle [33]. The AHI decreased significantly
from 68/hour F 12/hour in the supine position to
47/hour F 30/hour in the semi-seated position. Two
patients had an AHI of less than 10/hour in the semi-
seated position. This study showed that positional
therapy is not effective in unselected patients with
severe sleep apnea. Further studies are required to
evaluate the semi-seated position in patients with
positional sleep apnea identified on their initial sleep
study and in patients with milder disease.
In another study, 15 patients with an AHI in the
supine posture more than twice that in the lateral
posture were evaluated with the posture alarm [35].
The AHI was reduced from 33/hour F 21/hour to
21/hour F 29/hour with positional therapy. The
AHI was reduced to less than 10/hour in 10 of the
15 patients. Interestingly, equivalent results were
obtained in this study when subjects were just told to
learn to sleep on their side, lose weight, moderately
exercise, and avoid alcohol after 6 PM. In 15 patients
given these instructions, the AHI was reduced from
27/hour F 13/hour to 8/hour F 10/hour. The AHI was
reduced to less than 10/hour in 11 of the 15 patients.
Positional therapy has been compared with nasal
CPAP in a randomized cross-over study in 13 patients
who had an AHI in the supine posture more than twice
 U.J. Magalang, M.J. Mador / Clin Chest Med 24 (2003) 343–353
that in the lateral posture with an AHI of less than
15/hour in the lateral posture [42]. Each therapy was
delivered for 2 weeks, and the patient then switched to
the other therapy with no washout period between
therapies. Various outcome variables were evaluated.
The patients in this study had relatively mild disease,
with an AHI of 18/hour F 5/hour on the initial baseline
study. The AHI was reduced to 9.5/hour F 1.9/hour
with positional therapy and 3.4/hour F 0.5/hour with
nasal CPAP therapy. This difference was statistically
significant. The AHI during positional therapy corre-
lated with the severity of sleep apnea during the
baseline study (ie, the milder the disease the more
likely positional therapy was to be successful). The
subjective sensation of sleepiness as assessed by the
Epworth Sleepiness Scale improved significantly with
both therapies, and the degree of improvement was not
significantly different between therapies. Objective
alertness as assessed by the maintenance of wakeful-
ness test was not significantly different after the two
treatments. Tests of cognitive function improved
equally with both therapies. Four patients preferred
positional therapy, 7 preferred CPAP, and 2 had no
preference. In this group of patients with mild disease,
positional therapy seemed to be almost as effective as
nasal CPAP therapy. Although nasal CPAP improved
the AHI to a greater extent than positional therapy, it
did not result in greater improvements in subjective
and objective sleepiness or cognitive performance.
Positional therapy seems to be a reasonable alternative
to nasal CPAP in patients with mild disease with a
positional component. The long-term effects of posi-
tional therapy have not been evaluated.
A recent systematic review evaluated the effects
of positional therapy on sleep apnea [27]. No study
met the entry criteria. The study by Jokic et al [42]
came closest but was rejected because it compared
positional therapy to nasal CPAP rather than placebo.
This may not be fair because comparison to a therapy
that is known to be effective for sleep apnea (nasal
CPAP) is not an unreasonable approach and has been
used successfully to evaluate dental appliances. This
study only included 13 patients, which clearly poin-
ted out the need for additional studies to evaluate this
treatment modality.
Summary
Positional therapy can be considered in patients
with sleep apnea who have at least twice the number
of respiratory events in the supine position than in the
lateral position and have an AHI of less than 15/hour
and preferably less than 10/hour in the lateral posi-
tion. The number of such patients seen in a typical
347
sleep laboratory has not been determined adequately.
If a patient’s overall AHI is more than 15/hour (ie, the
patient’s sleep apnea is at least moderate [26]), a
follow-up sleep study that documents that the posi-
tional therapy chosen is effective at reducing the AHI
should be performed. In the authors’ sleep center, a
tennis ball attached to the pajamas or in a backpack or
wedge pillows are used to train patients to sleep in the
lateral position because these methods are much
simpler and less expensive than the posture alarm.
Pharmacologic therapy for obstructive
sleep apnea
An effective pharmacologic therapy for OSA is
desirable because all current forms of treatment have
significant limitations. Over the past several years,
much has been discovered about the pathogenesis of
OSA. Although ventilation may be normal during
wakefulness in patients with OSA, a sleep-induced
reduction in upper airway dilator muscle activity
results in collapse of an anatomically narrowed
upper airway [43]. Augmenting the activity of upper
airway dilator muscles during sleep by excitation of
motoneurons that innervate them is an attractive
approach in the development of an effective pharma-
cologic agent. Other approaches that have been used
include modifying sleep architecture (eg, reducing
rapid eye movement [REM] sleep because OSA
tends to be worse during this sleep stage) and using
respiratory stimulants. Several agents have been
tried, but none has been found to be consistently
efficacious to be recommended as standard therapy.
A detailed review of trials of medications in OSA
has been published [44].
Protriptyline
Two randomized, double-blind, placebo-con-
trolled, cross-over trials of protriptyline, a non-
sedating tricyclic antidepressant and REM sleep
suppressant, have been performed involving only a
total of 15 patients with OSA, with conflicting results.
Brownell et al [45] did not find a significant change in
the overall apnea index after 2 weeks of protriptyline
(20 mg/day) compared with placebo in 5 male patients
with OSA with relatively severe disease. The apnea
index during REM sleep (but not during non-REM
sleep) was reduced in association with a decrease in
REM apnea time, which is expressed as a proportion
of total sleep time and improvement in nocturnal
oxygenation. Subjective daytime sleepiness was
improved in 4 patients. The reduction in REM sleep
348 U.J. Magalang, M.J. Mador / Clin Chest Med 24 (2003) 343–353
seen during treatment accounted for the decrease in
REM apnea time. In 3 patients, follow-up sleep
studies after 6 months of protriptyline did show a
statistically significant reduction in the overall apnea
index, but the changes seen were modest (56/hour F
8.1/hour compared with 70.9/hour F 12.2/hour at
baseline). The REM apnea index was decreased from
15.7/hour F 4.2/hour during placebo to 3.7/hour F
0.7/hour during protriptyline, although this change
did not attain statistical significance.
Whyte et al [46], using a similar study design,
found that protriptyline (20 mg/day) for 2 weeks did
not have significant effects on symptoms, frequency
of apneas and hypopneas, oxyhemoglobin desatura-
tion, and arousals in 10 patients with OSA who also
had relatively severe disease. Surprisingly, protripty-
line did not reduce significantly the amount of REM
sleep in this study. In an unblinded, uncontrolled
study, Hanzel et al [47] reported that protriptyline
(10 mg/day) for 4 weeks reduced the AHI from
57/hour F 9/hour to 33/hour F 8/hour. The AHI dur-
ing REM sleep did not change significantly, but this
was difficult to interpret given the significant reduc-
tion of REM sleep with therapy. Protriptyline sig-
nificantly reduced the AHI during non-REM sleep,
however. Two other unblinded, uncontrolled studies
showed improvements in the AHI and nocturnal
oxygenation [48] and daytime hypersomnolence
[49] with protriptyline.
Summary
Protriptyline may reduce modestly (but not abol-
ish) the AHI in some patients with OSA that may be
associated with improvement in daytime sleepiness.
Aside from reducing REM sleep, other mechanisms,
such as stimulation of hypoglossal motoneurons, may
be responsible for the effects on sleep-disordered
breathing [50]. Given the small number of patients
involved in these trials, the occurrence of anticholi-
nergic side effects, including dry mouth, constipation,
and urinary retention, in a significant number of
patients, and modest reduction in the AHI in only
one controlled study, protriptyline cannot be recom-
mended currently as an effective pharmacologic agent
in the treatment of OSA. Further studies are required
to determine its efficacy in persons with mild to
moderate disease (AHI < 30/hour) or in patients with
only REM-related OSA.
Progesterone
Progesterone, a ventilatory stimulant, has been
tried in the treatment of OSA. An uncontrolled study
reported a possible role of medroxyprogesterone
acetate (MPA) in the treatment of OSA, especially
in hypercapnic patients [51]. Other uncontrolled
studies did not show any significant effects of
MPA, however [52,53]. Progesterone hormone
replacement in postmenopausal women with OSA
also has not been found to be effective [54]. Most
importantly, a randomized, double-blind, placebo-
controlled cross-over trial that involved ten male
patients with OSA also failed to show any effect of
MPA on sleep-disordered breathing [55]. This study
included four patients with daytime hypercapnea
(PaCO2>45 mm Hg).
Medroxyprogesterone acetate also has been tried
in the treatment of patients with obesity-hypoventila-
tion syndrome (in whom OSA is frequently present).
In an uncontrolled study of ten patients with the
obesity-hypoventilation syndrome (Pickwickian syn-
drome), MPA (20 mg every 8 hours) significantly
reduced the daytime pCO2 by 13 F 2.6 mm Hg (SEM)
and increased daytime pO2 by 12.6 F 2.7 mm Hg after
4 to 9 months of treatment [56]. There was no
significant change in body weight during treatment.
Withdrawal of MPA for 1 month in seven patients
resulted in deterioration to pretreatment levels, and
reinstitution of MPA resulted in improvement of
arterial blood gas values. Randomized, controlled
trials in a larger sample of patients are lacking,
however, and the role of progesterone in association
with nocturnal positive airway pressure therapy in
obesity-hypoventilation syndrome is unclear.
Currently, there is no good evidence that proges-
terone is a useful agent in the treatment of OSA. Its
role in the treatment of patients who develop obesity-
hypoventilation syndrome is also unclear, because no
long-term, controlled studies have been conducted
regarding its efficacy and safety in this condition.
Thyroid hormone replacement
Hypothyroidism has been associated with OSA.
In small case series, the presence of OSA was
reported in 25% to 82% of diagnosed hypothyroid
patients [57 – 60]. Not all of the patients in these
reports were obese, and other mechanisms aside from
obesity have been implicated, including hypotonia of
upper airway dilator muscles caused by myopathy
[58], narrowing of the upper airway by deposition of
mucopolysaccharides and protein extravasation into
the tissues of the oropharynx [61], and impaired
ventilatory control [62].
In a group of 200 patients referred for polysom-
nography for suspected OSA and screened for hypo-
thyroidism, Skjodt et al [63] reported on 3 patients
 U.J. Magalang, M.J. Mador / Clin Chest Med 24 (2003) 343–353
who were confirmed to have OSA and undiagnosed
hypothyroidism. These 3 patients were treated with
thyroxine alone without the use of CPAP or a dental
device. Subjective symptoms, oxyhemoglobin desa-
turations, and the AHI all improved with thyroid
replacement therapy. The AHI decreased from
30/hour, 14/hour, and 24/hour, respectively, before
treatment to 1.7/hour, 1/hour, 16 /hour, respectively,
after therapy. There was no significant change in the
body mass index. In an earlier study, nine patients
with hypothyroidism with OSA were treated with
thyroxine for 3 to 12 months [59]. The apnea index
decreased from 71.8/hour F 18/hour to 12.7/hour F
6.1/hour after treatment without any significant
change in body weight. The reason why thyroid
replacement improves OSA is unclear, but mecha-
nisms other than weight loss also seem to be important.
Not all patients have responded to thyroid replace-
ment therapy alone. In six of eight hypothyroid
patients with relatively severe OSA, Grunstein et al
reported that normalization of thyroid status with
thyroxine therapy did not improve the apnea index
[58]. The apnea index was 51/hour F 6/hour before
treatment and 45/hour F 8/hour after correction of the
hypothyroid state. CPAP therapy was required in
these patients.
It would be reasonable to start CPAP therapy in
patients with hypothyroidism with severe OSA and in
patients with an urgent reason to treat the sleep apnea,
in combination with thyroid replacement therapy. An
evaluation of whether CPAP therapy is still required
can be performed after euthyroid status has been
achieved. In persons with less severe sleep apnea,
treatment with thyroid replacement alone can be tried
and a follow-up study performed after achievement of
euthyroid state to ensure that OSA has been elimi-
nated. Whether it is cost effective to screen all
patients diagnosed with OSA for hypothyroidism is
controversial [63], but it seems to be unwarranted
[64,65] unless clinical symptoms suggest the pres-
ence of hypothyroidism.
Serotonergic agents
Obstructive sleep apnea is characterized by repet-
itive episodes of upper airway obstruction during
sleep. Airway obstructions are associated with a
decrease in the activity of upper airway dilator
muscles, such as the genioglossus (which controls
tongue movements) [43]. If upper airway dilator
muscle activity can be maintained or augmented dur-
ing sleep, then pharyngeal collapse may be prevented.
Several animal studies have suggested that serotonin is
important in the maintenance of upper airway patency.
349
Serotonergic neurons exert an excitatory effect on
upper airway dilator motoneurons [66,67]. In the
English bulldog, a natural animal model of OSA, the
systemic administration of serotonin antagonists
resulted in suppression of upper airway dilator muscle
activity, which led to a reduction in upper airway cross-
sectional area and oxyhemoglobin desaturations [68].
On the other hand, administration of the serotonergic
agents, trazodone and L-tryptophan, was effective in
treating sleep-disordered breathing in the English
bulldog, and the effectiveness of this therapy was
related to increased upper airway dilator muscle activi-
ty during sleep [69].
In humans, administration of a selective serotonin
reuptake inhibitor (SSRI) increased activity of upper
airway dilator muscle muscles during wakefulness in
normal subjects [70] and during non-REM sleep in
patients with OSA [71], which suggested that these
agents may be effective in treating OSA. Adminis-
tration of the serotonin precursor, L-tryptophan, was
reported to be effective in decreasing obstructive
apneas in non-REM sleep in an uncontrolled study
of 12 patients with OSA [72].
At least three published studies have used SSRI as
treatment for OSA. In an unblinded, uncontrolled
study, Hanzel et al [47] found that fluoxetine
(20 mg/day) reduced the AHI from 57/hour F 9/hour
to 34/hour F 6/hour after 4 weeks of treatment. The
AHI and the number of desaturation events per hour
of sleep were reduced by at least 50% in 4 of
12 patients. The reduction in AHI was seen only
during non-REM sleep and not during REM sleep.
Berry et al [71] studied the effects of a single 40-mg
dose of paroxetine in a group of eight adult men with
severe OSA in a double-blind cross-over manner.
Paroxetine did not decrease the AHI, although it
did increase genioglossus muscle activity. It would
be hard to assess the efficacy of a medication after a
single dose, however. Kraiczi et al conducted a
double-blind, randomized, placebo-controlled trial
[73] and determined the effects of a relatively low
dose of paroxetine (20 mg/day) for 6 weeks in
patients with OSA without known psychiatric disease.
The AHI was 36.3/hour F 24.7/hour ( F standard
deviation) during placebo and was 30.2/hour F
18.5/hour during treatment. The reduction was statis-
tically significant, albeit small, and was not attrib-
uted to changes in total sleep time or sleep
architecture. The mild reduction in AHI was mainly
caused by a decrease in the frequency of obstructive
apneas rather than hypopneas, and again this occurred
only during non-REM sleep. The number of apneas
and hypopneas during REM sleep was unchanged.
Overall, there was no change in psychopathologic
350 U.J. Magalang, M.J. Mador / Clin Chest Med 24 (2003) 343–353
symptoms (assessed by the Comprehensive Psycho-
pathological Rating Scale) and OSA-related daytime
complaints, including sleepiness, morning headache,
difficulties in concentration, memory complaints, and
low mood. Some patients did report improvements in
their well-being during paroxetine therapy compared
with placebo.
Summary
There is a growing body of evidence that sero-
tonin is important in the maintenance of upper airway
patency. SSRI therapy evaluated in a single random-
ized, controlled trial for several weeks resulted only
in a small reduction in the number of obstructive
apneas during non-REM sleep that was not accom-
panied by improvement in daytime symptoms.
Whether higher doses of SSRI will be more effective
is unknown. SSRI currently cannot be recommended
as an effective treatment for OSA. Further studies that
examine the effects of SSRI in persons with milder
disease are needed.
Fourteen different serotonin receptor subtypes
have been identified so far [74,75]. The specific type
of serotonin receptor that mediates the excitatory
effects of serotonin in upper airway motoneurons is
unclear and must be determined. Of interest is that in
trials of SSRIs in OSA, no effect on the AHI during
REM sleep has been found. The effect of SSRI
depends on remaining serotonin release [76]. In ani-
mal studies, activity of nerve cells that contain sero-
tonin that innervates upper airway motoneurons is
profoundly suppressed during REM sleep [77,78].
One can speculate that the absence of an effect of
SSRI during REM sleep may be caused partially by
the lack of available extracellular serotonin, and
reuptake inhibition cannot prevent the suppression
of upper airway motoneuron activity. To be effective
for OSA, it appears that a drug also should have direct
serotonin receptor agonist activity aside from inhibi-
ting serotonin reuptake. Although serotonin seems to
be important in maintaining upper airway patency
during sleep, other neurotransmitters also may play
a role in modulating the activity of motoneurons,
which innervate the muscles of the upper airway [79].
Other agents
Acetazolamide was found to decrease the AHI
from 50/hour to 26/hour in ten patients with OSA in a
randomized, double-blind, cross-over trial [46]. The
decrease in AHI was not accompanied by improve-
ment in symptoms, however, and paresthesias were
common. Theophylline [80,81] and transdermal nic-
otine [82] also do not seem to be helpful in OSA and
frequently cause sleep disruption. It is doubtful that
future studies in the treatment of OSA will involve
these medications.
Adjunctive therapy
Some patients with OSA continue to have residual
daytime sleepiness despite good compliance with
nasal CPAP. Two randomized, double-blind, pla-
cebo-controlled trials have been performed involving
this type of patients with OSA using modafinil, a
nonamphetamine wake-promoting medication with
unknown mechanism of action [83,84]. Modafinil
initially was investigated in the treatment of excessive
daytime sleepiness in narcolepsy. It has a favorable
side-effect profile [85] and lacks abuse potential [86].
In view of its efficacy in vigilance promotion with
minor side effects, it was believed to have a potential
role in the management of patients with OSA with
residual daytime sleepiness despite regular use of
CPAP. In a multicenter trial, Pack et al studied
157 patients with OSA (80 treated with placebo and
77 treated with modafinil) who were compliant with
CPAP therapy [83]. Treatment with CPAP and mod-
afinil (400 mg daily) significantly improved both
subjective (Epworth Sleepiness Scale) and objective
(multiple sleep latency test) measures of daytime
sleepiness compared with CPAP and placebo at 4
weeks. The percentage of patients with normalized
daytime sleepiness, defined as an Epworth Sleepiness
Scale score of less than 10, was significantly higher
with modafinil (51%) compared with placebo (27%).
The AHI and mean duration of CPAP usage (6.2 hours/
night) were the same in both groups.
In another study that involved 30 patients with
OSA, Kingshott et al found significant improvements
in alertness as measured by the maintenance of wake-
fulness test after 2 weeks of CPAP and modafinil but
found no effects on subjective and objective measure-
ments of daytime sleepiness. Based on the results of
these two well-designed trials, modafinil may be
considered as an adjunctive therapy in patients with
OSA who complain of persistent daytime sleepiness
and in whom good compliance with optimal levels of
CPAP has been checked objectively [87]. Before
committing to long-term treatment with modafinil,
one is advised first to embark on a thorough investiga-
tion of the cause of persistent daytime sleepiness that
can be specifically addressed, such as inappropriate
CPAP pressure, insufficient sleep, presence of another
sleep disorder (eg, narcolepsy), or drug effects.
Modafinil does not seem to affect sleep-disor-
dered breathing. In studies that involved untreated
 U.J. Magalang, M.J. Mador / Clin Chest Med 24 (2003) 343–353
patients with OSA [88,89] modafinil did not change
the AHI but improved objective measures of sleepi-
ness compared with placebo. One major concern for
using modafinil to treat the symptom of daytime
sleepiness in OSA patients who are not on definitive
or are intolerant of treatment (CPAP or oral appli-
ance) is that it does not prevent the cardiovascular
consequences associated with OSA because it does
not eliminate upper airway obstruction during sleep
[90]. Currently, there have been no published con-
trolled, long-term studies of modafinil in patients who
are not on definitive treatment for their sleep apnea,
and its use cannot be recommended for these patients.
Summary
Previous attempts at using pharmacologic agents
in the treatment of OSA have been disappointing.
Medroxyprogesterone has not been found to be useful
in the treatment of OSA. Use of protriptyline is
limited by frequent side effects, but its role in mild
and REM-related OSA must be clarified. SSRIs seem
to be ineffective in treatment of severe OSA. Further
studies are needed to determine their effect in persons
with mild disease. This is important because patients
with mild OSA (AHI < 15 hours) are most likely to
be noncompliant with CPAP therapy [91].
A recent systematic review of drug treatments for
OSA concluded that the current data do not support
the use of any drug as an alternative to CPAP [92]. Of
56 studies identified, only 9 studies met methodo-
logic criteria. Clearly, basic research and adequately
powered clinical trials are needed to identify an
effective medication for OSA.
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 Clin Chest Med 24 (2003) 355 – 364
The role of oral appliance therapy in the treatment of
obstructive sleep apnea
Kathleen A. Ferguson, MD, FRCPC, FCCP
Division of Respirology, London Health Sciences Centre, University of Western Ontario, 375 South Street, London,
Ontario, N6A 4G5, Canada
Oral appliances are an established treatment op-
tion for simple snoring and obstructive sleep apnea
(OSA). Early evidence led to the recommendation
that they be used for the treatment of mild OSA or
simple snoring [1,2]. Recently published, randomized
controlled clinical trials have shown them to be an
effective treatment option in many patients, and some
studies have suggested a reasonable level of effec-
tiveness in more severe OSA. Oral appliances are
appealing because they are simple to use, reversible,
and portable and generally have a low complication
rate. This article reviews available types of oral ap-
pliances, their mechanism of action, and the evidence
for using oral appliance therapy. The role of the phy-
sician and dentist is discussed. The article also re-
views the side effects and complications of appliance
therapy and the evidence about predictors of outcome
of treatment.
Appliance types and mechanisms of action
There are two main appliance groups in common
clinical use: tongue repositioning devices and man-
dibular repositioning appliances (MRAs) (Figs. 1 – 3).
An infrequently used design is a palatal lifting device,
which contacts the soft palate directly. Because of the
limited effectiveness of this device in the treatment of
snoring [3] and obstructive sleep apnea (OSA) [4], it
is not discussed in this article.
E-mail address: kafergus@uwo.ca
0272-5231/03/$ – see front matter D 2003, Elsevier Inc. All rights reserved.
doi:10.1016/S0272-5231(03)00015-7
Effects of mandibular and tongue advancement on
upper airway patency
The effects of oral appliances on upper airway size
are variable and depend on the method of imaging the
airway, when the studies are performed (ie, wakeful-
ness versus sleep), the subject’s body position (ie,
supine versus upright), the type of appliance, and the
amount of mandibular protrusion. Oral appliances may
improve upper airway patency by enlarging the upper
airway or by decreasing upper airway collapsibility
(eg, improving upper airway muscle tone). Simple
active anterior movement of the tongue or mandible
can increase cross-sectional airway size in subjects
with and without OSA [5]. Passive mandibular ad-
vancement during general anesthesia stabilized the
upper airway by increasing airway size in the retro-
palatal and retroglossal area and reducing closing
pressure [6]. The effect of passive pharyngeal advance-
ment during anesthesia in the retropalatal area is great-
er in nonobese subjects [7].
Several studies have evaluated the effects of MRAs
on upper airway size using upright lateral cephalom-
etry (during wakefulness) (Fig. 4). These results are
sometimes conflicting. In two studies, an MRA in-
creased the posterior airway space in most subjects
[8,9]. In another study in which the amount of protru-
sion was individualized in each patient, there was no
change in the size of the posterior airway space with
the appliance on a cephalogram [10]. Other studies that
used upright lateral cephalometry have shown that
MRAs lower the tongue position, reduce the mandib-
ular-plane-to-hyoid distance, advance the mandible,
and widen the upper oropharynx (retropalatal and ret-
356 K.A. Ferguson / Clin Chest Med 24 (2003) 355–364
Fig. 1. The Klearway adjustable oral appliance. (Courtesy of
Great Lakes Orthodontics, Ltd., Tonawanda, NY.)
roglossal) in some subjects [9,11 – 13]. Similar reduc-
tions in mandibular-plane-to-hyoid distance [14],
increases in oropharyngeal airway size [14,15], and
velopharyngeal airway size [16] have been seen using
supine cephalograms.
Other imaging modalities (eg, CT, MRI) also have
demonstrated increases in pharyngeal airway size
[9,17] and volume [18]. Direct imaging of the awake
supine airway with videoendoscopy confirms that an
Fig. 2. An adjustable Herbst appliance. (Courtesy of Great
Lakes Orthodontics, Ltd., Tonawanda, NY.)
Fig. 3. A Monobloc appliance. (Courtesy of Dr. Konrad
Bloch, University of Zurich.)
MRA increases the cross-sectional area of the airway,
particularly in the velopharynx [19].
The presence of an intraoral device affects upper
airway muscle tone. Tongue retaining devices (TRDs)
affect genioglossus muscle activity in patients with
OSA (awake or asleep), but effects of a TRD on other
upper airway muscles have not been evaluated [20,21].
A TRD worn during sleep reduced the AHI and
decreased genioglossus electromyogram (EMG) activ-
ity [21]. The modified TRD (no bulb) also reduced the
apnea-hypopnea index (AHI) and increased the peak
genioglossus activity measured just before airway
reopening. The presence of the device without tongue
advancement did have an impact on genioglossus
activity and on apnea severity. The mechanism for this
effect is not certain. A study using an MRA found that
upper airway muscle tone increased with an MRA
except in the postapnea period in the genioglossus,
where tone was lower [22]. This study suggested that
activation of the upper airway muscles may contribute
to upper airway patency during sleep. In a more recent
placebo-controlled trial, the simple presence of an
intraoral appliance had no impact on the AHI or
oxygen saturation [23]. The study suggested that
mandibular advancement is required for the appliance
to improve OSA because the presence of an intraoral
device without advancement showed no clinical effect.
Effectiveness of oral appliance therapy
Mandibular repositioning appliances
Several studies have evaluated the efficacy of
mandibular advancers. A detailed review of oral
 K.A. Ferguson / Clin Chest Med 24 (2003) 355–364 357

Fig. 4. Diagrammatic representation of the anatomic points and planes used to identify craniofacial and soft tissue parameters and
areas on lateral cephalometric radiographs. S, center of the sella turcica; N, nasion; PNS, posterior nasal spine tip; ANS, anterior
nasal spine tip; Gn, gnathion; RGN, retrognathion; Me, menton; Go, gonion; H, anterior superior tip of hyoid bone; TT, tongue
tip; Eb, base of epiglottis; P, inferior tip of palate; SN-MP angle, angle between the cranial base (line between S and N) and the
mandibular plane. Linear measurements: 1. TGH, tongue height; 2. PNSP, soft palate length; 3. boundary between velopharynx
and nasopharynx; 4. RPAS, retropalatal airway space; 5. superior margin oropharyngeal airway space; 6. PAS, posterior airway
space; 7. inferior margin oropharyngeal airway space (upper boundary hypopharynx); 8. OB, overbite; 9. OJ, overjet; 10. MP,
mandibular plane, line between Me and Go; 11. MPH, mandibular plane to hyoid. Areas: Tongue area, area outlined by the dorsal
configuration of the tongue surface and lines which connect TT, RGN, H and Eb; Soft Palate Area, area confined by the outline
of the soft palate which starts and ends at PNS through P.

appliance therapy was published in 1995 [1]. The
literature at that time consisted of case reports and
retrospective and prospective case series (before and
after design), and most, but not all, were peer
reviewed. The authors pooled the results for the
TRD and MRA of different designs. Seventy percent
of the 304 subjects had a reduction in AHI by 50%,
51% had a posttreatment AHI of less than 10 per
hour, but as many as 40% had a posttreatment AHI of
more than 20 per hour. Snoring was reported to be
improved in most patients. Since 1995, several pro-
spective studies have been published, including
randomized and controlled trials. In the more recent
prospective case series of oral appliance therapy, 54%
to 81% of patients had a reduction in AHI by 50%
[24 – 27], and 51% to 64% of patients had a posttreat-
ment AHI of less than 10 per hour [24 – 26,28,29].
Ten prospective controlled clinical studies have
been published: five cross-over studies that compared
oral appliances to continuous positive airway pressure
(CPAP) (four randomized [30 – 33] and one non-
randomized [34]), three randomized studies that com-
pared two different appliance designs [35 – 37], and
two randomized, placebo-controlled trials [23,38].
Three of the cross-over studies that compared oral ap-
pliances to CPAP have been described in detail else-
where [39].
Clark et al published a cross-over study of the
Herbst appliance compared with CPAP therapy in
23 men with OSA [34]. The choice of initial therapy
was not randomized, and most patients used CPAP
before they used the MRA. Although not reported
directly, from the figure provided it seems that 4 pa-
tients (19%) had an AHI of less than 10 per hour with
the MRA set at roughly two thirds of maximal pro-
trusion. The mean decrease in AHI was 39%. Sleep
quality was improved more by CPAP than by the
MRA, and CPAP was more effective at reducing
the AHI. Symptoms of excessive daytime sleepiness
were equally improved by the two treatments. The
first cross-over study by Ferguson et al assessed a
fixed position, boil and bite MRA [30], and the sec-
ond study assessed a partly adjustable custom ap-
pliance [31]. Patients were randomly assigned to
4 months of treatment first with the MRA or with
CPAP and then they crossed over to the other treat-
358 K.A. Ferguson / Clin Chest Med 24 (2003) 355–364
ment for 4 months. Treatment success for the fixed
position MRA was 48% (reduction in AHI to
V 10 per hour with relief of symptoms). The appliance
was well tolerated and had fewer side effects than
CPAP, but some patients (24%) were unable or un-
willing to use the fixed position MRA because of
poor overnight retention or discomfort. The MRA was
effective in reducing snoring in most patients and re-
ducing excessive daytime sleepiness. The partly ad-
justable custom MRA was successful in treating 55%
of patients (AHI V10 per hour and relief of symp-
toms). In these three published prospective cross-over
studies of MRA therapy versus CPAP in the treatment
of mild to moderate OSA, CPAP was more effective
in reducing snoring, improving oxygenation, and de-
creasing the AHI. In two of the three studies they
were equally effective in relieving excessive daytime
sleepiness. The MRA had a lower side effect rate (in
one study) and was the form of therapy preferred by
patients in all three studies.
Randerath et al conducted a randomized cross-
over study of an intraoral sleep apnea device (ISAD)
versus CPAP in patients with mild to moderate OSA
(AHI between 5 and 30 per hour) [32]. The appliance
was arbitrarily set at two thirds of maximum man-
dibular protrusion and was not further adjusted during
the study. CPAP was titrated to an effective pressure
in the laboratory. After 6 weeks of therapy, CPAP was
more effective at improving snoring, AHI, and oxy-
genation. The ISAD was not particularly effective at
reducing the AHI (baseline AHI 17.5 F 7.7 to 13.8 F
hsp sp="0.17">11.1 at 6 weeks; P = NS), although
patients reported greater ease of use and higher
compliance with the ISAD. Overall only 30% of
patients (6/20) had an AHI of less than 10 per hour
with the ISAD. The relatively low level of efficacy of
the ISAD may be related to the lack of titration of the
appliance during the 6-week period of therapy.
Engleman et al published a randomized cross-over
study of CPAP and an oral appliance in patients with a
range of severity of OSA (AHI 11 – 43 per hour) and at
least two symptoms of OSA [33]. The patients were
selected for the presence of reported sleepiness. In
addition to the usual outcomes, the study included a
maintenance of wakefulness test, the functional out-
comes of sleep questionnaire, the Short Form 36 health
survey (SF-36), and an assessment of cognitive per-
formance. The appliance was set at roughly 80% of
maximum mandibular protrusion. CPAP was more
effective than the oral device for improving AHI and
subjective ratings of daytime function, even in the
patients with milder OSA (AHI between 5 and 15).
There were no differences between the treatments in
the effect on objective measures of sleepiness or
cognition or patient preference. Preference for CPAP
therapy over the oral appliance was related to a higher
body mass index and greater daytime impairment. The
authors concluded that CPAP would be the preferred
first-line therapy in patients with OSA who have
significant functional impairment and sleepiness over
an oral appliance, even in patients with mild OSA
(defined by a lower AHI).
Three studies have compared different oral appli-
ances or designs. Hans et al evaluated a fixed position
appliance (SnoreGuard) and a modified device in
24 patients with mild OSA [35]. The device that pro-
truded the mandible (Device A) was more effective in
reducing the AHI than the device that minimally
opened the vertical dimension but did not protrude
the mandible (Device B). Three out of 10 patients with
Device A (30%) had an AHI of less than 10 per hour
with the appliance. Four of the 7 subjects who
switched to Device A after failing on Device B had
an improvement in AHI. Some patients had an increase
in AHI using Device A or Device B. Bloch et al con-
ducted a randomized, 21 February 2003controlled,
cross-over study of the Herbst (Fig. 2) and Monobloc
(Fig. 3) appliances, both of which set approximately
75% of maximum protrusion [36]. The AHI was less
than 10 in 75% of patients with the Monobloc ap-
pliance and in 67% of patients with the Herbst ap-
pliance. Both devices reduced sleepiness and snoring,
but patients felt that the Monobloc device was more
effective in reducing symptoms and preferred it for
long-term therapy.
A recent randomized, cross-over study evaluated
the effect of vertical dimension opening on the effica-
cy of an oral appliance [37]. The splint was construct-
ed with 4 mm of interincisal opening (MAS-1) or
14 mm of opening (MAS-2). Twenty-three patients
wore each appliance for 2 weeks in a random order.
Both appliances had similar efficacy in reducing the
AHI (complete and partial response 74% with MAS-1
and 61% with MAS-2). Both appliances improved
snoring and sleepiness, but there was a trend to more
jaw discomfort with MAS-2. Overall, the patients pre-
ferred the MAS-1 for long-term therapy. In this short-
term study, increasing the vertical opening did not
have an impact on appliance efficacy, but there is con-
cern that with long-term use this could have an impact
on side effects and complications.
Mehta et al published the first prospective, ran-
domized, placebo-controlled cross-over trial of an
MRA for the treatment of OSA [23]. Twenty-eight
patients had an acclimatization period during which
the mandible was incrementally advanced until symp-
toms resolved or maximum tolerated protrusion was
obtained. Patients were then randomly assigned to
 K.A. Ferguson / Clin Chest Med 24 (2003) 355–364
treatment with the placebo followed by the active
device or treatment with the active device followed by
the placebo (lower plate of the appliance only). A
partial response was defined as symptomatic improve-
ment with an AHI reduced by 50% or more, but more
than 5 per hour and a complete response was defined
as a resolution of symptoms along with an AHI of less
than 5 per hour. The active appliance resulted in a
partial or complete response in 15 patients or 62.5%
(complete response in 9% – 37.5%). Seventy-one per-
cent of patients had an AHI of less than 10 per hour
with the active appliance. The placebo device had no
impact on the AHI or oxygen saturation. The active
appliance improved snoring, sleep structure, oxygena-
tion, and daytime symptoms. There were few impor-
tant side effects and no complications.
A recent study has evaluated the effect of oral
appliance therapy on symptoms of OSA in a random-
ized, cross-over design that compared a mandibular
advancement splint to a placebo device [38]. In con-
trast to most other trials, the study included a multiple
sleep latency test to assess the impact of oral appliance
therapy on an objective measure of sleepiness. Most
of the patients (62 of 73; 85%) had moderate to severe
OSA (AHI  15 per hour). 38 patients (52%) reported
subjective sleepiness (defined as an Epworth Sleepi-
ness Scale score > 10). On average the appliance was
set at 80% of maximum mandibular protrusion. The
active splint improved symptoms such as snoring and
reduced the AHI by 52% overall, with 63% of patients
having a complete or partial response. The active
splint reduced the Epworth Sleepiness Scale score
and increased the mean sleep latency significantly
when compared with the placebo device.
In summary, MRAs are an effective treatment
option for many patients with OSA, including some
patients with more severe OSA (higher AHI). They
improve snoring and daytime symptoms and reduce
the AHI and improve oxygenation during sleep. They
are not as effective as CPAP in reducing the AHI or
snoring. In some studies they were not as effective in
reducing symptoms of sleepiness as CPAP but in
other studies they were. Overall, CPAP is a more
effective treatment than an MRA and should be
considered first-line therapy in patients with more
severe symptoms and perhaps in patients with more
severe OSA, particularly if there is significant impair-
ment of oxygenation.
Tongue repositioners
Tongue repositioning devices include the TRD,
which is the best studied of these devices. The TRD is
a custom-made soft acrylic appliance that covers the
359
upper and lower teeth and has an anterior plastic bulb.
It uses negative suction pressure to hold the tongue in
a forward position inside the bulb. In 1982, Cartwright
and Samelson reported their initial experience with the
TRD in 20 patients [40]. Fourteen of the 20 patients
had undergone polysomnography before and with the
TRD. There was a reduction in AHI of approximately
50%, although patients only wore the TRD half the
night. Cartwright reported a second uncontrolled
study of the TRD in 16 patients [41]. Treatment
success in this study was defined as a reduction in
apnea index to the normal range (0 – 6 per hour) or a
50% reduction in apnea index. 69% were successfully
treated by the TRD by these criteria. In another case
series that evaluated the TRD in 15 patients, the
success rate was reported as 73% for the reduction
of the AHI to less than 10 per hour [42].
Side effects and complications
In a review published in 1995, the authors found
nine studies that reported side effects and complica-
tions [1]. Excessive salivation and temporary discom-
fort after awakening were commonly reported. In one
long-term study, 3 out of 20 patients stopped the
device because of temporomandibular joint pain, but
the pain ceased when they stopped treatment [43]. In
another study, 3 out of 14 patients reported a sense of
altered occlusion, but it was not systematically
studied [44]. In most short-term studies of oral
appliance therapy published since the 1995 review
article, side effects were common but generally minor
and no serious complications were generally observ-
ed. Several long-term studies have been published
that systematically have evaluated side effects and
complications from oral appliance therapy.
Pantin et al assessed 132 of 191 (69%) patients
consecutively treated with a mandibular advance-
ment splint over a 5-year period and performed a
dental examination on 106 of them [45]. Ten patients
had discontinued using the appliance because of
minor dental side effects. They documented occlusal
changes in 14% cases, and in two cases the changes
were great enough to recommend that the patient
stop treatment. Marklund et al investigated orthodon-
tic side effects of a soft and a hard acrylic MRA in
75 patients who reported using the device more than
50% of nights for approximately 2.5 years [46].
Overbite and overjet decreased, and 3 patients re-
ported a permanent change in occlusion. Hard acrylic
appliances and larger amounts of protrusion were
associated with more occlusal changes.
360 K.A. Ferguson / Clin Chest Med 24 (2003) 355–364
Fritsch et al evaluated 22 patients who had used
either a Monobloc or a Herbst oral appliance for the
treatment of OSA [47]. Common side effects included
mucosal dryness (86%), tooth discomfort (59%), ex-
cessive salivation (55%), jaw pain (41%), and occlu-
sal changes (32%), but they were described as minor
side effects. Long-term appliance use was associated
with small orthodontic changes: decreased overjet and
overbite, retroclined maxillary incisors, and slight
anterior movement of the first mandibular molars.
Patients reported that symptoms caused by these
changes generally resolved after a few minutes in
the morning. A detailed study of skeletal and dental
changes with mandibular advancers in 100 patients
found similar results [48]. At 6 months of follow-up,
a vertical change in condylar position was noted,
the total anterior and posterior facial height was in-
creased, and overbite and overjet were decreased.
After 24 months of treatment, similar changes were
noted but the decrease in overbite and overjet was
more marked related to proclination of the mandibular
incisors. By 30 months of reported regular MRA use,
the proclination of the mandibular incisors was more
pronounced. The author did not comment on whether
these changes led to any clinical problems for the
patients who used the oral device. Overall, there is a
degree of occlusal change in patients with long-term
MRA use, and these changes must be monitored and
dealt with when they arise. Patients must be informed
of the potential for occlusal change when they embark
on oral appliance therapy.
Worsening of sleep apnea
Occasionally, an oral appliance can worsen apnea
severity [8,27,31,35,41]. In one of the more recent tri-
als, 4 of 28 subjects (14%) had an increase in AHI with
the appliance. The reason for this increase could not be
determined from a review of the patient data [27].
Treatment compliance
Some studies in the 1995 review reported the
long-term compliance of patients using an oral appli-
ance. Reported regular appliance use was in the range
of 75% to 100% for most of the studies, with one
study having a low compliance rate of only 50%.
More recent studies have had 76% to 90% of patients
reporting regular use [14,26]. In two of the cross-over
studies that compared oral appliances to CPAP, com-
pliance was measured by patient reports [30,31].
There was no difference in reported nightly use of
approximately 60% for all treatment arms. Until
objective compliance monitors are available, the
actual long-term compliance rates will be uncertain
given the unreliability of patient self-report for treat-
ment usage.
Titration of oral appliance therapy
Relative medical contraindications to first-line
therapy with an oral appliance include severe OSA,
severe excessive daytime sleepiness, and marked
arterial oxygen desaturations during sleep (eg, obe-
sity-hypoventilation). It may take time to optimize the
anterior position of the appliance and optimize treat-
ment success. Two studies have assessed overnight
titration of an oral appliance to determine the effective
therapeutic position [49,50]. This is a promising ap-
proach that may allow better identification of patients
in whom an oral device might be effective. CPAP ther-
apy can be titrated to the optimal pressure in a single
night and overall is more effective than oral appliance
therapy at reducing the AHI and correcting abnormal-
ities of oxygenation [30,31,34]. If an appliance could
be titrated more rapidly, then patients with more se-
vere OSA could be treated without delay.
Predictors of treatment outcome
Clinical predictors
Many studies have evaluated variables that may
be associated with treatment outcome (Box 1). Most
studies have been underpowered to find a signifi-
cant relationship between treatment outcome and
these variables. A younger age [32,51], lower body
mass index [41,51], lower neck size [23], position-
al OSA [41,52,53], and lower AHI [8,23,34,51,54]
and further amounts of mandibular protrusion [55]
have been related to improved treatment response.
Some studies, however, have demonstrated reasonably
good success rates in patients with more severe OSA
[4,23,25,27,50,56].
Craniofacial and dental predictors
Published studies have used various imaging
techniques to assess the upper airway and the factors
associated with treatment response. Several features
from cephalometry, including a smaller or narrow
oropharynx [11,51], smaller overjet [51], normal
mandible length [57], shorter mandibular plane to
hyoid distance [10], shorter soft palate length [10],
smaller upper to lower facial height ratios [58],
 K.A. Ferguson / Clin Chest Med 24 (2003) 355–364
Box 1. Predictors of oral appliance efficacy
Clinical predictors
Younger age
Lower body mass index
Lower neck circumference
Positional OSA (worse supine)
Lower AHI (not a consistent predictor)
Increased protrusion of appliance
Dental and craniofacial variables
Smaller and/or narrow oropharynx
Smaller overjet
Normal mandible length
Shorter mandibular plane to hypoid
distance
Shorter soft palate length
Smaller upper to lower facial height
ratios
Normal or reduced lower facial height
Small soft palate and tongue
Increased retropalatal airway space
Larger angle cranial base to mandibu-
lar plane
normal or reduced lower facial height [57], small soft
palate and tongue [57], increased retropalatal airway
space [23], and larger angle between the anterior
cranial base and mandibular plane [23] are associated
with improved outcome. Some authors have sug-
gested that a more micrognathic or retrognathic
mandible is associated with improved treatment
response [59]. Finally, hypopharyngeal closure that
causes OSA may be associated with improved treat-
ment outcome, but many patients with velopha-
ryngeal closure still get a good result [27].
Indications for oral appliance therapy
The American Academy of Sleep Medicine has
published guidelines about the use of oral appliance
therapy in the treatment of OSA [2]. These guidelines
stated that oral appliances are indicated as first-line
therapy in patients with simple snoring and mild OSA
and as second-line therapy for patients with moderate
to severe OSA when other therapies have failed. At
the time the guidelines were published the available
studies of oral appliance therapy were only uncon-
trolled, largely retrospective case series. Since then,
361
many prospective studies have been published,
including controlled clinical trials with comparisons
to CPAP, other appliances, and placebo [23,30,31,
34 – 36]. With evidence of effectiveness from ran-
domized controlled trials it is reasonable to expand
the indications for first-line therapy with an oral appli-
ance to the treatment of patients with moderate OSA.
The guidelines defined the roles of the physician
and dentist in the provision of oral appliance therapy
[2]. Physicians, preferably trained in sleep disorders,
perform the initial assessment and determine whether
the patient is ‘‘medically’’ suitable for oral appliance
therapy. A dentist skilled in this type of treatment
determines the patients’ ‘‘dental’’ suitability for oral
appliance treatment from a full assessment of oral and
dental health.
Treatment must be individualized to each patient,
with the dentist choosing the most appropriate oral
appliance. Tongue repositioning devices, such as the
TRD, are used particularly in patients with large
tongues or inadequate healthy teeth to use an MRA.
In general, MRAs require an adequate number of
healthy teeth for good retention. Severe temporoman-
dibular joint problems, inadequate protrusive ability,
and advanced periodontal disease are relative contra-
indications to the use of an MRA. In a study of 100
patients consecutively assessed by oral and maxillo-
facial surgeons, 34% of patients had primary contra-
indications to therapy and 16% had dental problems
or concerns about temporomandibular joint function
that would require careful dental follow-up [60].
Although many patients may be medically suitable
for oral appliance therapy, they require a careful
assessment by a qualified dental practitioner to deter-
mine if dental contraindications are present.
Long-term dental follow-up includes optimizing
the appliance, monitoring retention, and assessing
effectiveness. Periodic adjustments and repairs may
be required. Monitoring dental health, side effects,
and complications of therapy is also important. Med-
ical follow-up is necessary to evaluate treatment
response and assess for recurrence of OSA. It is
recommended that follow-up sleep studies be per-
formed to verify the improvement in apnea, oxygena-
tion, and sleep fragmentation by the oral appliance
[2]. This recommendation is supported by the evi-
dence that some patients have an increase in AHI with
oral appliance treatment [8,27,31,35,41].
Future directions
Future randomized controlled trials are needed to
compare the effectiveness of different types of appli-
362 K.A. Ferguson / Clin Chest Med 24 (2003) 355–364
ances and different design features (eg, the amount of
vertical opening). The effect of oral appliances on
excessive daytime sleepiness and performance must
be determined with objective and validated tools. The
precise indications, complication rates, and reasons
for treatment failure must be determined for each oral
appliance if it is going to be used in clinical practice.
Ongoing refinements of appliance design eventually
may lead to improved treatment outcomes. Only
when the mechanisms of action of oral appliance
therapy are fully understood can more effective
appliances be developed. On the horizon for the field
of oral appliance therapy is the introduction of a
compliance monitor that will allow an objective
determination of appliance usage. Several investiga-
tors also are developing systems that would allow
overnight titration of oral appliances in the sleep
laboratory. This might ultimately shorten the time
from initiation of oral appliance therapy to optimiza-
tion of the appliance.
Summary
The development of oral appliance treatment for
OSA represents an important step in the management
of this disease. Randomized, controlled clinical trials
have shown them to be an effective treatment option
for snoring and OSA in some patients, particularly
patients with less severe OSA or simple snoring and
patients who have failed other treatment modalities.
Although oral appliances are not as effective as CPAP
therapy, they work in most patients to relieve symp-
toms and apnea and are well tolerated by patients.
Most patients report improvements in sleep quality
and excessive daytime sleepiness. Short-term side
effects are generally minor and are related to excessive
salivation, jaw and tooth discomfort, and occasional
joint discomfort. These symptoms may lead to dis-
continuation of appliance therapy but usually improve
in most patients over time. Serious complications are
not common, but occlusal changes are more common
than previously believed.
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 Clin Chest Med 24 (2003) 365 – 370
Surgical management of obstructive sleep apnea
Kasey K. Li, MD, DDS*
Stanford University Sleep Disorders and Research Center, 401 Quarry Road, Stanford, CA 94305, USA
Despite the effectiveness of nasal continuous pos-
itive airway pressure (CPAP) in the management of
obstructive sleep apnea (OSA), patient acceptance and
tolerance remain a significant problem. Consequently,
surgery remains a highly desirable option for many
patients and should be considered. Several major
surgical advances have improved significantly the
understanding and treatment of OSA since the first
tracheotomy performed by Kuhlo [1] for the treatment
of upper airway obstruction in ‘‘Pickwickian’’ subject.
Uvulopalatopharyngoplasty (UPPP) was initially
described by Ikematsu [2] and later popularized by
Fujita [3]. UPPP improves oropharyngeal obstruction
and is the most commonly performed procedure for the
treatment of OSA. With the increased recognition of
hypopharyngeal airway obstruction as a major con-
tributing factor of OSA, genioglossus and hyoid
advancement were later developed [4,5] to improve
surgical treatment outcomes. In the early 1980s,
numerous investigators reported that surgical advance-
ment of the mandible can improve OSA [6 – 8]. To
maximize the extent of mandibular advancement,
concurrent maxillary advancement was subsequently
advocated [9]. Maxillomandibular advancement also
has been noted to widen the retropalatal airway, which
further improves the outcomes. Currently, UPPP, ge-
nioglossus and hyoid advancement, and maxilloman-
dibular advancement (MMA) are used widely to
improve upper airway obstruction in OSA. Of the
available surgical interventions, MMA has been
shown to have the highest success rate [9 – 11]. Several
years ago, radiofrequency (RF) energy was investi-
* 750 Welch Road, Suite 317, Palo Alto, CA 94304.
E-mail address: kaseyli@hotmail.com
0272-5231/03/$ – see front matter D 2003, Elsevier Inc. All rights reserved.
doi:10.1016/S0272-5231(03)00016-9
gated as a potential treatment of OSA by ablation of the
excessive upper airway tissues [12 – 15]. Based on the
initial animal study and subsequent human clinical
trials, RF has been shown to improve OSA [15,16].
Clinical evaluation
Before embarking on any surgical procedure, a
thorough head and neck evaluation combined with
fiberoptic pharyngolaryngoscopy is performed to iso-
late and direct treatment at the region or regions of
obstruction. A lateral cephalometric radiograph also is
used to assist in treatment planning. Although ceph-
alometric radiography is only a static two-dimensional
method of evaluating a dynamic three-dimensional
area, it does provide useful information on the pos-
terior airway space. The posterior airway space mea-
surement on lateral cephalometric radiography has
been shown to correlate with the volume of hypo-
pharyngeal airway on three-dimensional CT scans
[17]. It also is a valuable study for assessing the
relation of the maxillofacial skeleton and the hyoid
bone to the airway. Based on the evaluations, the sites
of airway obstruction are identified and a surgical plan
is formulated based on the severity of the anatomic
obstruction, the severity of sleep apnea, and—more
importantly—the patient’s desire and health status.
Oropharyngeal surgery
Uvulopalatopharyngoplasty is an effective sur-
gical procedure to improve airway obstruction in
the oropharynx. UPPP consists of the removal of a
portion of the soft palate and uvula and a limited
amount of the lateral pharyngeal wall and tonsillar
366 K.K. Li / Clin Chest Med 24 (2003) 365–370

muscle and decreases its collapsibility during sleep,

which alleviates airway obstruction. Obstruction at
the hypopharyngeal level can be improved further by
anterior movement of the hyoid bone, and numerous
reports have supported the concept that surgical
intervention at the hyoid level improves the hypo-
pharyngeal airway [22,23].
Initially, advancement of the genioglossus muscle
and the hyoid bone was performed simultaneously to
improve the hypopharyngeal airway [4]. The tech-
nique has evolved over the years to improve outcome
and minimize morbidity. The current technique of
advancement of genioglossus muscle involves a lim-
ited osteotomy intraorally to isolate and advance the
genial tubercle [24]. We have not performed both
operations simultaneously on a routine basis, how-
ever, because most patients with OSA have diffused
airway obstruction, and genioglossus muscle
advancement is generally combined with UPPP. The
added insult to the infrahyoid region by combining the
genioglossus muscle and hyoid bone advancement
results in increased edema and was believed to be
inappropriate in some patients. The authors also have

Fig. 1. Lateral cephalometric radiograph before maxillo-

mandibular advancement.

tissues (if present). The most crucial aspect of the

operation lies not in the amount of the tissue removal
but rather in the way the wound is sutured to widen
the airway aperture. The temptation to remove an
excessive amount of the tissues should be resisted
because the risk of complications dramatically
increases. At the authors’ center, the uvulopalatal flap
[18] is the preferred procedure as opposed to the
conventional UPPP. The uvulopalatal flap achieves
similar result as UPPP but removes less tissue, which
potentially reduces the risk of complications. In
general, the success rate of UPPP as the sole treat-
ment of OSA is only approximately 40% [19]
because many patients have hypopharyngeal and
oropharyngeal obstruction. Improvement of the oro-
pharyngeal airway alone is thus insufficient.

Hypopharyngeal surgery

The hypopharyngeal airway is intimately related

to the mandible, tongue, and hyoid complex [20,21].
It has been shown that advancing the genioglossus Fig. 2. Lateral cephalometric radiograph after maxilloman-
muscle improves the tension of the genioglossus dibular advancement.
 K.K. Li / Clin Chest Med 24 (2003) 365–370
Fig. 3. Fiberoptic laryngoscopy demonstrating tongue base
obstruction before maxillomandibular advancement.
found that the hypopharyngeal airway obstruction is
resolved with only genioglossus muscle advancement
in some patients; thus hyoid bone may not always be
necessary. In some elderly patients ( > 60 years old),
airway edema after simultaneous genioglossus muscle
and hyoid bone can result in prolonged dysphagia that
may require days to recover. For these reasons the
authors perform hyoid bone advancement only in
some patients as a separate surgical step.
Maxillomandibular advancement has been shown
to be the most effective surgical option in the treat-
ment of OSA [9 – 11]. MMA achieves enlargement of
the pharyngeal and hypopharyngeal airway by phys-
ically expanding the skeletal framework. The forward
movement of the maxillomandibular complex also
improves the tension and collapsibility of the supra-
hyoid and velopharyngeal musculature. When MMA
is performed in patients with persistent OSA after
UPPP with genioglossus muscle and hyoid bone
advancement, MMA creates further tension and phys-
Fig. 4. Fiberoptic laryngoscopy demonstrating significant
lateral wall collapse during Mueller’s maneuver before maxil-
lomandibular advancement.
367
Fig. 5. Fiberoptic laryngoscopy demonstrating im-
proved tongue base obstruction after maxillomandibular
advancement.
ical room in the upper airway, which relieves residual
obstructions. To maximize airway expansion, a major
advancement of the maxillomandibular complex is
required to facilitate a successful result (Figs. 1 – 6). It
is important, however, to achieve maximal advance-
ment while maintaining a stable dental occlusion and
a balanced esthetic appearance. Over the past
17 years, patients with and without ‘‘disproportion-
ate’’ craniomaxillofacial features have undergone
MMA for persistent severe OSA caused by incom-
plete response to other procedures. Although patients
with craniomaxillofacial abnormality, such as max-
illary or mandibular deficiencies, usually have
improved facial esthetics after surgery, the authors
found that many patients with normal cephalometric
measurements preoperatively also have an improved
facial appearance after MMA, because many patients
are middle-age adults who are already showing signs
of facial aging caused by soft tissue sagging. Skeletal
Fig. 6. Fiberoptic laryngoscopy demonstrating improved
lateral wall collapse during Mueller’s maneuver after
maxillomandibular advancement.
368 K.K. Li / Clin Chest Med 24 (2003) 365–370
expansion of the maxilla and mandible enhances
appearance by improving soft tissue support.
Radiofrequency tissue reduction
Using temperature-controlled RF to reduce soft
tissue volume in the upper airway was first inves-
tigated in the animal tongue model [12]. After RF
treatment, tissue volume reduction results in a pre-
dictable pattern of wound healing, which consists of
coagulation necrosis that leads to fibrosis and tissue
contraction. The relationship of lesion size to total
RF energy delivery and the resultant volume reduc-
tion have been shown to be closely correlated, and
the application of RF to the human tongue in a serial
fashion was demonstrated to be the most effective
use of this technology in improving sleep-disordered
breathing (SDB) [15]. More importantly, the safety
parameters for temperature-controlled RF in the
human tongue were established in that speech and
swallowing were not affected based on barium
swallow, speech evaluation, and subjective question-
naires [15].
Oropharyngeal and hypopharyngeal
surgical outcomes
The authors’ surgical results were reported in
1992 [9]. Two hundred thirty-nine patients underwent
surgery, with most of the patients requiring interven-
tion at the pharyngeal and hypopharyngeal levels.
The overall cure rate was 61% (145/239 patients).
The surgical results were comparable to nasal CPAP
results. The mean preoperative respiratory distur-
bance index (RDI) was 48.3, with the postoperative
mean RDI of 9.5 (nasal CPAP RDI 7.2, P = NS). The
lowest oxygenation saturation (LSAT) improved from
75% to 86.6% (nasal CPAP LSAT 86.4%, P = NS).
There was a higher cure rate with mild to moderately
Table 1
Polysomnography results
Parameter Baseline
RDI 39.5 F 32.7
Apnea index 22.1 F 33
Hypopnea index 17.4 F 11.9
Total sleep time (min) 337 F 89
Sleep efficiency index (%) 80 F 10
Oxygen saturation nadir (%) 81.9 F 11.6
REM sleep (%) 11.4 F 7.5
a
Paired student’s t tests were performed on the change scores between posttreatment and follow-up.
severe disease (approximately 70%) as compared
with severe disease (42%). Most of the nonrespond-
ers had severe OSA (mean RDI 61.9) and morbid
obesity (mean body mass index [BMI] 32.3 kg/m2).
The postoperative morbidity rate was low. The
mean hospital stay was 2.1 days. The complications
associated with genioglossus muscle and hyoid bone
advancement were infection ( < 2%), injury of tooth
roots that required root canal therapy ( < 1%), per-
manent paresthesia and anesthesia of the mandib-
ular incisors ( < 6%), and seroma ( < 2%). Major
complications, such as mandibular fracture, alteration
of speech, alteration of swallow, or aspiration, were
not encountered.
More than 350 patients underwent MMA with a
success rate of approximately 90%. An analysis of
175 patients who underwent MMA between 1988
and 1995 demonstrated that 166 patients had a
successful outcome, with a cure rate of 95%. The
mean preoperative RDI was 72.3. The mean post-
operative RDI was 7.2. The surgical results were
comparable to nasal CPAP results (nasal CPAP RDI
8.2, P = NS). The mean LSAT improved from 64%
to 86.7% (nasal CPAP LSAT 87.5%, P = NS).
86 patients who failed UPPP and genioglossus
muscle/hyoid bone advancement underwent MMA.
The mean age of patients was 43.5 years. The cure
rate in this group was 97% (83/86 patients). The
mean hospital stay for MMA was 2.4 days. The
surgical morbidity included transient anesthesia of
the lower lip, chin, and cheek in all of the patients.
There was an 87% resolution rate between 6 and
12 months. There was no postoperative bleeding or
infection. Mild malocclusion encountered in some
patients was treated satisfactorily with dental occlusal
adjustment. No major skeletal relapse occurred.
To date, 59 patients (49 men) have had long-term
follow-up results [25]. The mean age was 47.1 years.
The mean BMI was 31.1 kg/m2. 19 patients had only
subjective (quality of life) results. These patients
refused long-term polysomnography for various reas-
Posttreatment Follow-up P valuea
17.8 F 15.6 28.7 F 29.4 0.29
4.1 F 6.2 5.4 F 10.3 0.88
13.6 F 11.5 22.9 F 23.1 0.20
346 F 75 337 F 97 0.66
80 F 10 80 F 10 0.80
88.1 F 5.3 85.8 F 6.6 0.18
17.6 F 8.9 14.5 F 7.8 0.16
 K.K. Li / Clin Chest Med 24 (2003) 365–370 369

Table 2
Short Form 36 scores
Domain Posttreatment Follow-up Mean change P valuea
Physical functioning 91 F 13.08 92 F 15.67 1 F 20.79 0.44
Role-physical 95 F 10.54 92.5 F 23.72 2.5 F 27.51 0.61
Bodily pain 87.3 F 18.37 80.7 F 19.31 6.60 F 27.58 0.77
General health 74.6 F 16.53 79.1 F 11.59 4.5 F 13.01 0.15
Vitality 60 F 23.57 71 F 13.5 11 F 17.76 0.05
Social functioning 81.3 F 20.58 92.5 F 16.87 11.2 F 15.91 0.03
Role emotional 86.6 F 28.25 96.7 F 10.44 10.1 F 31.71 0.17
Mental health 76 F 13.73 82 F 7.83 6 F 15 0.12
Physical component 54 F 4.08 52.39 F 7.89 1.61 F 9.5 0.69
Mental component 48.99 F 8.34 54.73 F 4.06 5.74 F 8.14 0.03
a
Paired student’s t tests were performed on the change scores.

ons, including inconvenience, time, and cost. Sixteen
of the 19 patients continued to report subjective
success with minimal to no snoring, no observed
apnea, and no recurrence of excessive daytime
sleepiness. All patients reported stable (unchanged)
weight to mild weight gain ( < 5 kg). Three patients
reported recurrence of snoring and excessive daytime
sleepiness. Long-term polysomnography data were
available in 40 patients (33 men). The mean age was
45.6 years. The mean BMI was 31.4 kg/m2. The
preoperative RDI and LSAT were 71.2 and 67.5,
respectively. The 6-month postoperative RDI was
9.3, and the LSAT was 85.6. The mean follow-up
period was 50.7 months, and long-term RDI and LSAT
were 7.6 and 86.3, respectively. The mean weight at
the long-term follow-up was 32.2 kg/m2 ( P = 0.002).
4 patients had recurrent OSA. The 6-month postoper-
ative RDI in these 4 patients was 10.5, but the long-
term RDI (61 F 24.7 months) was 43. The LSAT
decreased from 87.5% to 81.8%.
Radiofrequency treatment outcomes
The initial RF tongue base reduction study con-
sisted of 18 patients (17 men). All had the diagnosis
of SDB and reported symptoms of daytime sleepi-
ness. The mean age was 44.9 F 8.7 years. The mean
pretreatment BMI was 30.2 F 5.5 kg/m2, and the
mean posttreatment BMI was unchanged at 30.2 F
5.8 kg/m2 [15].
All of the patients had serial RF tongue base
reduction under local anesthesia to minimize risks.
The mean number of treatment sessions was 5.5 per
patient. The mean overall total number of joules
administered per patient was 8490 F 2687 J with
1543 J per treatment session. The mean duration from
the completion of treatment to the final PSG was 2.6 F
0.7 months. The mean RDI improved from 39.5 F
32.7 to 17.8 F 15.6 ( P = 0.003). The mean apnea
index improved from 22.1 F 33.0 to 4.1 F 6.2
( P = 0.023), and the mean hypopnea index improved
from 17.4 F 11.9 to 13.6 F 11.5 ( P = 0.326). The
mean LSAT improved from 81.9 F 11.6 to 88.1 F 5.3
( P = 0.03). The mean Epworth Sleepiness Scale
improved from 10.4 F 5.6 to 4.1 F 3.2 ( P = 0.0001),
and the speech and swallowing visual analog scale did
not change from baseline.
Sixteen of the original 18 patients completed a
long-term follow-up study [16]. 2 patients (both
men) were lost to follow-up. The mean follow-up
period was 28 F 4 months. There was a mean
weight increase of 3.1 F 7.9 kg. The follow-up PSG
data showed a persistent improvement of the mean
apnea index; however, there was a trend of worsen-
ing hypopnea index, which resulted in a trend of
worsening RDI (Table 1). There was also a trend of
worsening LSAT.

Table 3
Questionnaire visual analog scale results
Parameter Baseline Posttreatment Follow-up P valuea
Epworth Sleepiness Scale 10.4 F 5.7 4.1 F 3.2 4.5 F 3.4 1
Snoring 4.7 F 3.5 2 F 1.4 3.5 F 2.7 0.01
Speech 1.2 F 1.9 0.6 F 1.1 2.5 F 2.9 0.02
Swallowing 1.1 F 1.9 0.3 F 0.5 1.3 F 2.2 0.09
a
Paired student’s t tests were performed on the change scores between posttreatment and follow-up.
370 K.K. Li / Clin Chest Med 24 (2003) 365–370
The quality-of-life measurements by Short Form
36 (Table 2) and excessive daytime sleepiness by the
Epworth Sleepiness Scale (Table 3) demonstrated
persistent improvement compared with baseline, and
no differences were found compared with posttreat-
ment results. Although no changes in swallowing or
speech were reported, the visual analog scale mea-
surement did increase significantly (see Table 3).
Summary
Nasal CPAP is and should be the first-line treat-
ment for OSA. Any physician who uses nasal CPAP
undoubtedly recognizes that this treatment modality
has limitations, however. The authors believe that
surgery offers a viable alternative to nasal CPAP in
patients who are intolerant of nasal CPAP. Potential
risks and complications must be explained fully to any
potential surgical candidate. The selection of surgical
procedure(s) should be determined based on a
patient’s airway anatomy, medical status, severity of
sleep apnea, and his or her desire and preference.
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